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NZ738832B2 - Chiral diaryl macrocycles and uses thereof - Google Patents

Chiral diaryl macrocycles and uses thereof Download PDF

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Publication number
NZ738832B2
NZ738832B2 NZ738832A NZ73883216A NZ738832B2 NZ 738832 B2 NZ738832 B2 NZ 738832B2 NZ 738832 A NZ738832 A NZ 738832A NZ 73883216 A NZ73883216 A NZ 73883216A NZ 738832 B2 NZ738832 B2 NZ 738832B2
Authority
NZ
New Zealand
Prior art keywords
fusion protein
cancer
clndw
alk
group
Prior art date
Application number
NZ738832A
Other versions
NZ738832A (en
Inventor
Jingrong Jean Cui
Wei Deng
Zhongdong Huang
Yishan Li
Evan W Rogers
Dayong Zhai
Original Assignee
Turning Point Therapeutics Inc
Filing date
Publication date
Application filed by Turning Point Therapeutics Inc filed Critical Turning Point Therapeutics Inc
Priority claimed from PCT/US2016/043132 external-priority patent/WO2017015367A1/en
Publication of NZ738832A publication Critical patent/NZ738832A/en
Publication of NZ738832B2 publication Critical patent/NZ738832B2/en

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    • 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
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
    • C07D491/16—Peri-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
    • C07D491/18—Bridged systems
    • 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
    • C07D498/12—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 three hetero rings
    • C07D498/18—Bridged systems

Abstract

This disclosure relates to the use of certain diaryl macrocycle compounds, specifically (7S,13R)-11-fluoro-7,13-dimethyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one in the treatment of disease in mammals. In an embodiment the disease is cancer mediated by (i) a fusion protein comprising a fragment of a protein encoded by a ROS1 gene and a fragment of a protein encoded by a gene selected from the group consisting of FIG, TPM3, SDC4, SLC34A2, CD74, EZR, and LRIG3; (ii) a genetically altered ALK that is an EML4-ALK fusion protein having at least one mutation selected from the group consisting of L1196M, G1202R, D1203R, L1152P/R, F1174C/L/V, C1156Y, I1171N, G1123S, S1206Y, G1269S/A, and 1151T insertion; (iii) a genetically altered ALK that is a TPR-ALK fusion protein having a L1196M point mutation; (iv) a genetically altered ALK having one or more point mutations selected from the group consisting of R1050H, F1174C/I/L/S/V, F1245C/I/L/V, R1275L/Q, T1151M, M1166R, I1170N, I1170S, I1171N, I1183T, L1196M, A1200V, L1204F, L1240V, D1270G, Y1278S, R1192P, G1128A, G1286R, and T1343I; (v) a QKI-TRKB fusion protein; or (vi) an ETV6-TRKC fusion protein. This disclosure also relates to compositions including such compounds, and to methods of using such compositions in the treatment of diseases in mammals, especially in humans.

Claims (19)

CLAIMS :
1. Use of a therapeutically effective amount of (7S,13R)fluoro-7,13-dimethyl-6,7,13,14- tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one, or a pharmaceutically acceptable salt thereof, for preparation of a medicament for treating cancer in a patient, wherein the cancer is mediated by: (i) a fusion protein comprising a fragment of a protein encoded by a ROS1 gene and a fragment of a protein encoded by a gene selected from the group consisting of FIG, TPM3, SDC4, SLC34A2, CD74, EZR, and LRIG3; (ii) a genetically altered ALK that is an EML4-ALK fusion protein having at least one mutation selected from the group consisting of , G1202R, D1203R, L1152P/R, F1174C/L/V, C1156Y, I1171N, G1123S, S1206Y, G1269S/A, and 1151T insertion; (iii) a genetically altered ALK that is a TPR-ALK fusion protein having a L1196M point mutation; (iv) a genetically altered ALK having one or more point mutations selected from the group consisting of R1050H, F1174C/I/L/S/V, F1245C/I/L/V, R1275L/Q, T1151M, M1166R, , I1170S, I1171N, I1183T, , A1200V, L1204F, L1240V, D1270G, Y1278S, R1192P, G1128A, , and T1343I; (v) a QKI-TRKB fusion protein; or (vi) an ETV6-TRKC fusion protein.
2. The use of claim 1, wherein the therapeutically effective amount of (7S,13R)fluoro-7,13- dimethyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin- 4(5H)-one, or a ceutically acceptable salt thereof, is a therapeutically ive amount of R)fluoro-7,13-dimethyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3- f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one.
3. The use of claim 1 or 2, wherein the genetically altered ALK is an EML4-ALK fusion protein that ses at least one mutation selected from the group consisting of L1196M, G1202R, D1203R, /R, /L/V, , I1171N, G1123S, S1206Y, G1269S/A, and 1151T insertion.
4. The use of claim 1 or 2, wherein the genetically altered ALK is an TPR-ALK fusion protein that comprises a L1196M point mutation.
5. The use of claim 1 or 2, wherein the genetically d ALK has one or more point mutations selected from the group consisting of R1050H, F1174C/I/L/S/V, F1245C/I/L/V, R1275L/Q, T1151M, M1166R, I1170N, I1170S, I1171N, I1183T, L1196M, A1200V, L1204F, L1240V, , Y1278S, R1192P, G1128A, G1286R, and T1343I.
6. The use of claim 1 or 2, wherein the cancer is mediated by a fusion protein comprising a fragment of a protein encoded by an ROS1 gene and a fragment of a protein encoded by a gene selected from the group consisting of FIG, TPM3, SDC4, SLC34A2, CD74, EZR, and LRIG3.
7. The use of claim 6, wherein the fusion protein is a CD74-ROS1 fusion protein, SDC4-ROS1 fusion protein, or a SLC34A2-ROS1 fusion protein.
8. The use of claim 7, wherein the OS1 fusion protein comprises a G2032R point mutation.
9. The use of claim 7, n the SDC4-ROS1 fusion protein comprises a G2032R point mutation.
10. The use of claim 7, wherein the SLC34A2-ROS1 fusion protein ses a G2032R point mutation.
11. The use of claim 1, wherein the cancer is mediated by a QKI-TRKB fusion protein.
12. The use of claim 1, wherein the cancer is mediated by is a ETV6-TRKC fusion protein.
13. The use of claim 1, wherein the cancer in the patient is to be identified, and a eutically effective amount of the medicament is to be administered if the cancer in the patient is identified by subjecting a patient sample to a test selected from the group consisting of FISH, IHC, PCR and gene sequencing.
14. The use of claim 2, wherein the cancer in the patient is to be identified, and a therapeutically effective amount of the medicament is to be administered if the cancer in the patient is identified by subjecting a patient sample to a test ed from the group consisting of FISH, IHC, PCR and gene sequencing.
15. The use of any one of claims 1 to 14, n the patient has been usly treated with a cancer therapeutic.
16. The use of any one of claims 1 to 14, wherein the patient has been previously treated with a cancer therapeutic, and the cancer has developed resistance to the cancer eutic.
17. The use of claim 16, wherein the resistance is an acquired resistance or a bypass resistance.
18. The use of any one of claims 1 to 17, wherein the cancer is selected from the group consisting of glioblastoma, glioblastoma multiforme, non small cell lung cancer (NSCLC), cholangiocarcinoma, intrahepatic cholangiocarcinoma, colorectal cancer, thyroid papillary cancer, spitzoid neoplasms, a, astrocytoma, brain lower grade glioma, secretory breast carcinoma, mammary analogue carcinoma, breast cancer, acute myeloid leukemia, congenital mesoblastic nephroma, ital arcomas, Ph-like acute lymphoblastic leukemia, colon adenocarcinoma, thyroid carcinoma, skin cutaneous melanoma, head and neck squamous cell carcinoma and pediatric glioma.
19. The use of claim 18, wherein the cancer is non small cell lung cancer ). Turning Point Therapeutics, Inc. By the Attorneys for the Applicant SPRUSON & FERGUSON None set by CLNDW ionNone set by CLNDW Unmarked set by CLNDW None set by CLNDW MigrationNone set by CLNDW Unmarked set by CLNDW mwbm?w am?m “www?w §m§§§w @me \\\\\\\\\~ \\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\. None set by CLNDW MigrationNone set by CLNDW Unmarked set by CLNDW None set by CLNDW ionNone set by CLNDW Unmarked set by CLNDW 336 22m. m; amt We: a??? Mafiing imi?i‘t? 11118 mum Mum! '\.>. ‘ “\‘mx.
NZ738832A 2016-07-20 Chiral diaryl macrocycles and uses thereof NZ738832B2 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US201562195081P 2015-07-21 2015-07-21
US201662302231P 2016-03-02 2016-03-02
PCT/US2016/043132 WO2017015367A1 (en) 2015-07-21 2016-07-20 Chiral diaryl macrocycles and uses thereof

Publications (2)

Publication Number Publication Date
NZ738832A NZ738832A (en) 2024-08-30
NZ738832B2 true NZ738832B2 (en) 2024-12-03

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