WO2022036067A4 - Combination therapies for use in treating cancer - Google Patents

Combination therapies for use in treating cancer Download PDF

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WO2022036067A4
WO2022036067A4 PCT/US2021/045702 US2021045702W WO2022036067A4 WO 2022036067 A4 WO2022036067 A4 WO 2022036067A4 US 2021045702 W US2021045702 W US 2021045702W WO 2022036067 A4 WO2022036067 A4 WO 2022036067A4
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inhibitor
pharmaceutically acceptable
acceptable salt
cancer
abt
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PCT/US2021/045702
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WO2022036067A1 (en
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Fu LI
Kevin Marks
Katya MARJON
Petar KALEV
Marc Lee HYER
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Servier Pharmaceuticals, Llc
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    • A61K31/436—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
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    • A61K31/50—Pyridazines; Hydrogenated pyridazines
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    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
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    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/555—Heterocyclic compounds containing heavy metals, e.g. hemin, hematin, melarsoprol
    • A—HUMAN NECESSITIES
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    • A61K31/63—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide
    • A61K31/635—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide having a heterocyclic ring, e.g. sulfadiazine
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    • A61K31/00—Medicinal preparations containing organic active ingredients
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    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
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    • 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

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The compound of Formula (I), or pharmaceutically acceptable salts thereof, is useful in, among other things, the treatment of cancer and provides a therapeutic advantage when used in combination with other agents as herein described compared to treatment with each agent when administered alone.

Claims

AMENDED CLAIMS received by the International Bureau on 04 February 2022 (04.02.2022)
1. A method for the treatment of cancer in a patient in need thereof, comprising administering to said patient:
(a) a therapeutically effective amount of a compound of Formula (I):
Figure imgf000002_0001
or a pharmaceutically acceptable salt thereof; and
(b) a therapeutically effective amount of a therapeutic agent, wherein said therapeutic agent is a PARP inhibitor that is Olaparib (AZD2281), Veliparib (ABT-888), Rucaparib (AG- 014699) phosphate, Talazoparib (BMN 673), AG-14361, INO-1001 (3 -Aminobenzamide), A-966492, PJ34 HC1, Niraparib (MK-4827), UPF 1069, ME0328, RK-287107, Pamiparib (BGB-290), NMS-P118, E7449, Picolinamide, Benzamide, Niraparib (MK-4827) tosylate, NU1025, Iniparib (BSI-201), AZD2461, BGP-15 2HC1, XAV-939, 4-Hydroxyquinazoline, NVP-TNKS656, MN 64, or G007-LK; or a pharmaceutically acceptable salt thereof;[[,]] or a Chkl inhibitor that is AZD7762, Rabusertib (LY2603618), MK-8776 (SCH 900776), CHIR-124, PF-477736, VX-803 (M4344), GDC-0575 (ARRY-575), SAR-020106, CCT245737, PD0166285, or Prexasertib HC1 (LY2606368); or a pharmaceutically acceptable salt thereof; or a MDM2 inhibitor that is Nutlin-3, NSC 207895, Nutlin-3a, Nutlin-3b, MX69, NVP- CGM097, MI-773 (SAR405838), Idasanutlin (RG-7388), RG-7112, HDM201 (Siremadlin), YH239-EE, (-)-Parthenolide, or Serdemetan (JNJ-26854165); or a pharmaceutically acceptable salt thereof; or a hypomethylating agent that is Decitabine, Azacitidine (5 -Azacytidine), RG108, Thioguanine, Zebularine, SGI-1027, CM272, 2'-Deoxy-5 -Fluorocytidine, Procainamide HC1, Bobcat339 hydrochloride, Gamma-Oryzanol, P-thujaplicin, or (-)-Epigallocatechin Gallate; or a pharmaceutically acceptable salt thereof; or a mTOR inhibitor that is Dactolisib (BEZ235), Rapamycin (Sirolimus), Everolimus (RAD001), AZD8055, Temsirolimus (CCI-779), PI-103, KU-0063794, Torkinib (PP242), Ridaforolimus (Deforolimus, MK-8669), Sapanisertib (MLN0128), Voxtalisib (XL765) Analogue, Torin 1, Omipalisib (GSK2126458), OSI-027, PF-04691502, Apitolisib (GDC-
64
AMENDED SHEET (ARTICLE 19) 0980), GSK1059615, Gedatolisib (PKI-587), WYE-354, Vistusertib (AZD2014), Torin 2, WYE-125132 (WYE-132), PP121, WYE-687, WAY-600, ETP-46464, GDC-0349, XL388, GNE-477, Bimiralisib (PQR309), SF2523, CZ415, Paxalisib (GDC-0084), CC-115, Onatasertib(CC 223), Voxtalisib (XL765), Zotarolimus(ABT-578), Tacrolimus (FK506), BGT226 maleate (NVP-BGT226 maleate), Palomid 529 (P529), LY3023414(Samotolisib), or Chrysophanic Acid; or a pharmaceutically acceptable salt thereof; or an ATM inhibitor that is KU-55933, KU-60019, Wortmannin, Torin 2, CP-466722, ETP-46464, CGK 733, AZ32, AZD1390, AZ31, or AZD0156; or a pharmaceutically acceptable salt thereof; or a CDK 4/6 inhibitor that is Palbociclib (PD-0332991), Palbociclib (PD-0332991) HC1, AT7519, JNJ-7706621, PHA-793887, Palbociclib (PD0332991) Isethionate, abemaciclib mesylate (LY2835219), BMS-265246, Milciclib (PHA-848125), R547, Riviciclib hydrochloride (P276-00), MC180295, G1T38, Abemaciclib, ON123300, AT7519 HC1, Purvalanol A, SU9516, Ribociclib (LEE011), or BSJ-03-123; or a pharmaceutically acceptable salt thereof; or a BCL-2 inhibitor that is ABT-737, Navitoclax (ABT-263), Obatoclax Mesylate (GX15-070), TW-37, Venetoclax (ABT-199), AT101, HA14-1, Sabutoclax, S55746, or Gambogic Acid; or a pharmaceutically acceptable salt thereof; or a PRMT5 inhibitorthat is JNJ-64619178 (AGI-931), HLCL-61, GSK591, EPZ015666(GSK3235025), GSK3326595 (EPZ015938; AGI-219); or a pharmaceutically acceptable salt thereof; or a PRMTl inhibitor that is GSK3368715 (EPZ019997), C7280948, EPZ020411 2HC1, MS023, or AMI-1; or a pharmaceutically acceptable salt thereof.
2.
3.
4. The method of claim 1, wherein said PARP inhibitor is Olaparib (AZD2281), or Talazoparib (BMN 673); or a pharmaceutically acceptable salt thereof.
5. The method of claim 4, wherein said PARP inhibitor is Olaparib (AZD2281), or a pharmaceutically acceptable salt thereof.
6. The method of claim 4, wherein said PARP inhibitor is Talazoparib (BMN 673); or a pharmaceutically acceptable salt thereof.
7.
8.
65
AMENDED SHEET (ARTICLE 19)
9. The method of claim 1, wherein said Chkl inhibitor is AZD7762 or Rabusertib (LY2603618), or a pharmaceutically acceptable salt thereof.
10. The method of claim 9, wherein said Chkl inhibitor is AZD7762 or a pharmaceutically acceptable salt thereof.
11. The method of claim 9, wherein said Chkl inhibitor is Rabusertib (LY2603618) or a pharmaceutically acceptable salt thereof.
12.
13.
14. The method of claim 1, wherein said MDM2 inhibitor is Nutlin-3 or Serdemetan (JNJ-26854165), or a pharmaceutically acceptable salt thereof.
15. The method of claim 14, wherein said MDM2 inhibitor is Nutlin-3 or a pharmaceutically acceptable salt thereof.
16. The method of claim 14, wherein said MDM2 inhibitor is Serdemetan (JNJ- 26854165) or a pharmaceutically acceptable salt thereof.
17.
18.
19. The method of claim 1, wherein said a hypomethylating agent is Decitabine or Azacitidine (5 -Azacytidine), or a pharmaceutically acceptable salt thereof.
20. The method of claim 19, wherein said a hypomethylating agent is Decitabine or a pharmaceutically acceptable salt thereof.
21. The method of claim 19, wherein said a hypomethylating agent is Azacitidine (5 -Azacytidine) or a pharmaceutically acceptable salt thereof.
22.
23.
24. The method of claim 1, wherein said mTOR inhibitor is Everolimus (RAD001) or a pharmaceutically acceptable salt thereof.
25.
26.
27. The method of claim 1, wherein said ATM inhibitor is KU-60019 or a pharmaceutically acceptable salt thereof.
28.
29.
30. The method of claim 1, wherein said CDK 4/6 inhibitor is Palbociclib (PD- 0332991) or a pharmaceutically acceptable salt thereof.
66
AMENDED SHEET (ARTICLE 19)
32.
33. The method of claim 1, wherein said BCL-2 inhibitor is Venetoclax (ABT- 199), or a pharmaceutically acceptable salt thereof.
34.
35.
36. The method of claim 1, wherein said PRMT5 inhibitor is GSK3326595 (EPZ015938; AGI-219) or JNJ-64619178 (AGI-931); or a pharmaceutically acceptable salt thereof.
37. The method of claim 36, wherein said PRMT5 inhibitor is GSK3326595 (EPZ015938; AGI-219) or a pharmaceutically acceptable salt thereof.
38. The method of claim 36, wherein said PRMT5 inhibitor is JNJ-64619178 (AGI-931), or a pharmaceutically acceptable salt thereof.
39.
40.
41. The method of claim 1, wherein said PRMT1 inhibitor is GSK3368715 (EPZO 19997), or a pharmaceutically acceptable salt thereof.
42. The method of any one of claims 1, 4-6, 9-11, 14-16, 19-21, 24, 27, 30, 33, 36-38, and 41, further comprising administering to said patient a further therapeutic agent.
43. The method of claim 42, wherein said further therapeutic agent is a PARP inhibitor, a Chkl inhibitor, a MDM2 inhibitor, a hypomethylating agent, a mTOR inhibitor, an ATM inhibitor, a CDK 4/6 inhibitor, a PRMT5 inhibitor, a PRMT1 inhibitor, an antimetabolite, an Aurora inhibitor, a microtubule stabilizer, a DNA cross-linker, or a BCL-2 inhibitor.
44. The method of any one of claims 1, 4-6, 9-11, 14-16, 19-21, 24, 27, 30, 33, 36-38, and 41-43, wherein the cancer is an MTAP -deficient cancer.
45. The method of any one of claims 1, 4-6, 9-11, 14-16, 19-21, 24, 27, 30, 33, 36-38, and 41-43, wherein the cancer is an MTAP wild type cancer.
46. The method of any one of claims 1, 4-6, 9-11, 14-16, 19-21, 24, 27, 30, 33, 36-38, and 41-45, wherein the cancer is a cancer that responds to a reduction in SAM as a result of administering an MAT2A inhibitor.
47. The method of any one of claims 1, 4-6, 9-11, 14-16, 19-21, 24, 27, 30, 33, 36-38, and 41-46, wherein said cancer is a primary leukemia, hematological malignancies,
67
AMENDED SHEET (ARTICLE 19) acute myeloid leukemia (AML), glioma, melanoma, pancreatic cancer, non-small cell lung cancer (NSCLC), bladder cancer, kidney cancer, colorectal cancer, esophageal cancer, astrocytoma, osteosarcoma, head and neck cancer, myxoid chondrosarcoma, ovarian cancer, endometrial cancer, breast cancer, soft tissue sarcoma, non-Hodgkin lymphoma, or mesothelioma.
48. A method for the treatment of a cancer in a patient in need thereof, comprising administering to said patient:
(a) a therapeutically effective amount of a compound of Formula (I):
Figure imgf000006_0001
Formula (I) or a pharmaceutically acceptable salt thereof; and
(b) a therapeutically effective amount of a therapeutic agent, wherein said therapeutic agent is an antimetabolite, an Aurora inhibitor, a DNA-crosslinker, or a microtubule stabilizer; wherein said cancer is a MTAP wild type cancer.
49. The method of claim 48, wherein said cancer is a primary leukemia, hematological malignancies, acute myeloid leukemia (AML), glioma, melanoma, pancreatic cancer, non-small cell lung cancer (NSCLC), bladder cancer, kidney cancer, colorectal cancer, esophageal cancer, astrocytoma, osteosarcoma, head and neck cancer, myxoid chondrosarcoma, ovarian cancer, endometrial cancer, breast cancer, soft tissue sarcoma, nonHodgkin lymphoma, or mesothelioma.
50. The method of claim 48 or claim 49, wherein said therapeutic agent is an antimetabolite.
51. The method of claim 50, wherein said antimetabolite is pemetrexed.
52. The method of claim 50, wherein said antimetabolite is gemcitabine, or a pharmaceutically acceptable salt thereof.
53. The method of claim 48 or claim 49, wherein said therapeutic agent is an Aurora inhibitor.
54. The method of claim 48 or claim 49, wherein said therapeutic agent is a microtubule stabilizer.
68
AMENDED SHEET (ARTICLE 19)
55. The method of claim 48 or claim 49, wherein said therapeutic agent is a DNA cross-linker.
56. A method for the treatment of cancer in a patient in need thereof, comprising administering to said patient: a therapeutically effective amount of a compound of Formula (I):
Figure imgf000007_0001
Formula (I) or a pharmaceutically acceptable salt thereof; wherein said cancer is MTAP-deficient or MTAP wild type acute myeloid leukemia (AML).
57. The method of claim 56, wherein the AML is MTAP-deficient.
58. The method of claim 56, wherein the AML is MTAP wild type.
59. The method of any one of claims 56 to 58, wherein the AML responds to a reduction in SAM as a result of administering an MAT2A inhibitor.
60. The method of any one of claims 56 to 59, further comprising administering to said patient a therapeutically effective amount of a BCL-2 inhibitor.
61. The method of claim 60, wherein said BCL-2 inhibitor is ABT-737,
Navitoclax (ABT-263), Obatoclax Mesylate (GX15-070), TW-37, Venetoclax (ABT-199), AT101, HA14-1, Sabutoclax, S55746, or Gambogic Acid; or a pharmaceutically acceptable salt thereof.
62. The method of claim 61, wherein said BCL-2 inhibitor is venetoclax, or a pharmaceutically acceptable salt thereof.
63. The method of any one of claims 60 to 62, further comprising administering to said patient a therapeutically effective amount of a hypomethylating agent.
64. The method of claim 63, wherein said a hypomethylating agent is Decitabine, Azacitidine (5 -Azacytidine), RG108, Thioguanine, Zebularine, SGI-1027, CM272, 2'-Deoxy- 5 -Fluorocytidine, Procainamide HC1, Bobcat339 hydrochloride, Gamma-Oryzanol, - thujaplicin, or (-)-Epigallocatechin Gallate; or a pharmaceutically acceptable salt thereof.
65. The method of claim 64, wherein said hypomethylating agent is Azacitidine (5 -Azacytidine), or a pharmaceutically acceptable salt thereof.
AMENDED SHEET (ARTICLE 19)
PCT/US2021/045702 2020-08-12 2021-08-12 Combination therapies for use in treating cancer WO2022036067A1 (en)

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