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NZ736222B2 - Benzoxazepin oxazolidinone compounds and methods of use - Google Patents

Benzoxazepin oxazolidinone compounds and methods of use Download PDF

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Publication number
NZ736222B2
NZ736222B2 NZ736222A NZ73622216A NZ736222B2 NZ 736222 B2 NZ736222 B2 NZ 736222B2 NZ 736222 A NZ736222 A NZ 736222A NZ 73622216 A NZ73622216 A NZ 73622216A NZ 736222 B2 NZ736222 B2 NZ 736222B2
Authority
NZ
New Zealand
Prior art keywords
cancer
compound
carcinoma
formula
oxazepinyl
Prior art date
Application number
NZ736222A
Other versions
NZ736222A (en
Inventor
Marie Gabrielle Braun
Richard Elliott
Emily Hanan
Robert Andrew Heald
Calum Macleod
Steven T Staben
Original Assignee
F Hoffmann La Roche Ag
Filing date
Publication date
Application filed by F Hoffmann La Roche Ag filed Critical F Hoffmann La Roche Ag
Priority to NZ775526A priority Critical patent/NZ775526B2/en
Priority claimed from PCT/EP2016/065455 external-priority patent/WO2017001645A1/en
Publication of NZ736222A publication Critical patent/NZ736222A/en
Publication of NZ736222B2 publication Critical patent/NZ736222B2/en

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/553—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B43/00—Formation or introduction of functional groups containing nitrogen
    • C07B43/06—Formation or introduction of functional groups containing nitrogen of amide groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D267/00—Heterocyclic compounds containing rings of more than six members having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D267/02—Seven-membered rings
    • C07D267/08—Seven-membered rings having the hetero atoms in positions 1 and 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems

Abstract

Described herein are benzoxazepin oxazolidinone compounds with phosphoinositide- 3 kinase (PI3K) modulation activity or function having the Formula (I) structure: or stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, and with the substituents and structural features described herein. Also described are pharmaceutical compositions and medicaments that include the Formula I compounds, as well as methods of using such PI3K modulators, alone and in combination with other therapeutic agents, for treating diseases or conditions that are mediated or dependent upon PI3K dysregulation.

Claims (29)

1. A compound selected from Formula I: H N O 5 and stereoisomers, geometric isomers, tautomers, and pharmaceutically acceptable salts thereof, wherein: R is selected from -CH , -CH CH , cyclopropyl, and cyclobutyl; 3 2 3 R is selected from -CH , -CHF , -CH F, and -CF . 3 2 2 3
2. The compound of claim 1 wherein R is CH or cyclopropyl. 10
3. The compound of claim 1 or 2, wherein R is -CHF .
4. The compound of any one of claims 1-3 wherein Formula I is: (S)((2-((S)(difluoromethyl)oxooxazolidinyl)-5,6- dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepinyl)amino)propanamide.
5. The compound of any one of claims 1-3 wherein Formula I is: 15 (S)cyclobutyl((2-((R)methyloxooxazolidinyl)-5,6- dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepinyl)amino)acetamide.
6. The compound of any one of claims 1-3 wherein Formula I is: (S)cyclopropyl((2-((S)(difluoromethyl)oxooxazolidinyl)-5,6- dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepinyl)amino)acetamide.
7. The compound of any one of claims 1-3 wherein Formula I is: 5 (S)cyclopropyl((2-((R)methyloxooxazolidinyl)-5,6- dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepinyl)amino)acetamide.
8. The compound of any one of claims 1-3 wherein Formula I is: (S)cyclopropyl((2-((S)(fluoromethyl)oxooxazolidinyl)-5,6- dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepinyl)amino)acetamide. 10
9. The compound of any one claims 1-3 wherein Formula I is: (S)((2-((S)(fluoromethyl)oxooxazolidinyl)-5,6- dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepinyl)amino)propanamide.
10. The compound of any one of claims 1-3 wherein Formula I is: (S)((2-((S)(difluoromethyl)oxooxazolidinyl)-5,6- 15 dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepinyl)amino)butanamide.
11. A compound of: or a pharmaceutically acceptable salt thereof.
12. A pharmaceutical composition comprised of a compound of any one of claims 1-11 and a pharmaceutically acceptable carrier, glidant, diluent, or excipient.
13. The pharmaceutical composition of claim 12 wherein the pharmaceutically acceptable carrier, glidant, diluent, or excipient is selected from silicon dioxide, powdered 5 cellulose, microcrystalline cellulose, metallic stearates, sodium aluminosilicate, sodium benzoate, calcium carbonate, calcium silicate, corn starch, magnesium carbonate, asbestos free talc, stearowet C, starch, starch 1500, magnesium lauryl sulfate, magnesium oxide, and combinations thereof.
14. The compound of any one of claims 1-11, or a pharmaceutically acceptable 10 salt thereof, for use as a medicament.
15. Use of a compound of any one of claims 1-11, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of cancer.
16. The use of claim 15, wherein the cancer is selected from the group consisting of breast cancer, ovary cancer, cervix cancer, prostate cancer, testis cancer, genitourinary 15 tract cancer, esophagus cancer, larynx cancer, glioblastoma, neuroblastoma, stomach cancer, skin cancer, keratoacanthoma, lung cancer, epidermoid carcinoma, large cell carcinoma, non- small cell lung carcinoma (NSCLC), small cell carcinoma, lung adenocarcinoma, bone cancer, colon cancer, adenoma, adenocarcinoma, thyroid cancer, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, sarcoma, bladder 20 carcinoma, liver carcinoma, kidney carcinoma, pancreatic cancer, lymphoma, hairy cell leukemia, buccal cavity cancer, naso-pharyngeal cancer, pharynx cancer, lip cancer, tongue cancer, mouth cancer, small intestine cancer, colorectal cancer, large intestine cancer, rectal cancer, brain cancer, central nervous system cancer, Hodgkin’s lymphoma, leukemia, bronchus cancer, thyroid cancer, liver cancer, intrahepatic bile duct cancer, hepatocellular 25 cancer, gastric cancer, glioma, glioblastoma, endometrial cancer, kidney cancer, renal cancer, pelvis cancer, urinary bladder cancer, uterine corpus cancer, uterine cervix cancer, multiple myeloma, acute myelogenous leukemia, chronic myelogenous leukemia, lymphocytic leukemia, chronic lymphoid leukemia (CLL), myeloid leukemia, oral cavity cancer, non- Hodgkin lymphoma, melanoma, and villous colon adenoma.
17. The use of claim 15 or 16, wherein the cancer is selected from the group consisting of colon cancer, breast cancer, cervix cancer, stomach cancer, lung cancer, and multiple myeloma.
18. The use of claim 15 or 16, wherein the cancer is selected from breast cancer 5 and non-small cell lung cancer.
19. The use of claim 18, wherein the medicament is to be administered with an additional therapeutic agent selected from 5-FU, docetaxel, eribulin, gemcitabine, cobimetinib, ipatasertib, paclitaxel, tamoxifen, fulvestrant, GDC-0810, dexamethasone, palbociclib, bevacizumab, pertuzumab, trastuzumab emtansine, trastuzumab and letrozole. 10
20. The use of any one of claims 15-19,wherein the cancer is breast cancer.
21. The use of claim 20, wherein the breast cancer is estrogen receptor positive (ER+) breast cancer.
22. The use of claim 20, wherein the breast cancer subtype is Basal or Luminal.
23. The use of any one of claims 15-20, wherein the cancer expresses a PIK3CA 15 mutant.
24. The use of claim 23, wherein the cancer expresses a PIK3CA mutant selected from E542K, E545K, Q546R, H1047L and H1047R.
25. The use of any one of claims 15-20, wherein the cancer expresses a PTEN mutant. 20
26. The use of any one of claims 15-20, wherein the cancer is HER2 positive.
27. The use of claim 20, wherein the breast cancer is HER2 negative, ER (estrogen receptor) negative, and PR (progesterone receptor) negative.
28. A kit for the therapeutic treatment of breast cancer, comprising: a) the pharmaceutical composition of claims 12 or 13; and b) instructions for use in the therapeutic treatment of breast cancer.
29. The compound of any one of claims 1-11 and 14, the pharmaceutical composition of claim 12 or 13, the use of any one of claims 15 to 27, or the kit of claim 28, 5 substantially as herein described with reference to any example thereof and with or without reference to the accompanying drawings. 2.70 A 2.43 A 2.61 A Ser8S4 Gln859
NZ736222A 2016-07-01 Benzoxazepin oxazolidinone compounds and methods of use NZ736222B2 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
NZ775526A NZ775526B2 (en) 2016-07-01 Benzoxazepin oxazolidinone compounds and methods of use

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US201562188029P 2015-07-02 2015-07-02
PCT/EP2016/065455 WO2017001645A1 (en) 2015-07-02 2016-07-01 Benzoxazepin oxazolidinone compounds and methods of use

Publications (2)

Publication Number Publication Date
NZ736222A NZ736222A (en) 2024-05-31
NZ736222B2 true NZ736222B2 (en) 2024-09-03

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