Synthesis of Novel Substituted N-heterocycles and Their Use of Selective Poly(ADP-ribose) Polymerase 1 (PARP1) Inhibitors

Abstract

Poly(ADP-ribose) polymerase 1 (PARP1) is the most abundant and well-characterized member of the PARP family and plays a crucial role in gene expression, transcription, DNA damage response, and repair. This patent introduces the synthesis of substituted N-heterocycles and their applications in the treatment of PARP1-related diseases, such as cancer.

Graphical Abstract

Important Compound Classes:

Title:

Substituted nitrogen-containing tricyclic compounds as PARP inhibitors and the use thereof

Patent Publication Number:

WO2024/179547 A1, URL: https://patents.google.com/patent/WO2024179547A1/en

Publication Date:

September 6, 2024

Priority Application:

CN 202310188881.3, CN 202311280259.1

Priority Date:

March 1, 2023, September 28, 2023

Inventors:

Cai S. X.; Tian Y. E.; Wang X.;

Assignee Company:

Impact therapeutics (Shanghai), Inc. Room 603, NO. 3 Building, 111 Xiangke Road, China (Shanghai) Pilot Free Trade Zone, Pudong New Area, Shanghai, 201210, China.

Disease Area:

PARP1-related disease, such as cancer

Biological Target:

PARP1

Summary:

Poly(ADP-ribose) polymerases (PARPs) are a family of 17 enzymes that transfer negatively charged ADP-ribose groups from NAD+ onto target proteins. Among them, PARP1 is the most well-characterized member, exhibiting the highest intracellular abundance, and accounts for the majority of poly(ADP-ribose) (PAR) synthesis. PARP1 is rapidly activated upon DNA damage and is mostly involved in base excision repair (BER), a key mechanism for repairing single-strand DNA breaks (SSBs). Beyond BER, cells employ two additional major double-strand breaks (DSBs) repair mechanisms: homologous recombination (HR) and non-homologous end joining (NHEJ). Tumors with homologous recombination (HR) deficiency demonstrate particular sensitivity to PARP inhibitors. This synthetic lethality occurs because PARP inhibition disrupts BER, while the pre-existing HR defect prevents repair of resulting DNA damage, leading to cell death. Currently, several PARP inhibitors have been approved for treating breast, ovarian, pancreatic, and prostate cancers associated with DNA repair deficiencies, such as BRCA1/2 mutations. Beyond oncology, PARP1 inhibitors also hold potential for treating non-oncologic diseases linked to excessive cell death, including central nervous system (CNS) disorders such as stroke and neurodegenerative diseases. There is an increasing demand for selective PARP1 inhibitors with improved bioavailability and clinical efficacy. This patent discloses novel substituted N-heterocyclic compounds and their application as selective PARP1 inhibitors.

Definitions:

Ring Z = substituted 5-membered heteroaryl group,

Z₁, Z₂ and Z₃ = CR₁, NR₂, O, N or S,

Z₄ and Z₅ = C or N, and Z₄ and Z₅ are not N at the same time;

A₁, A₂ and A₃ = N and CR₃;

L = alkyl or alkylene optionally substituted by R₄ and/or R₅;

B ring = substituted heteroaryl or an optionally substituted heterocyclic group;

Cy = an optionally substituted aryl and heteroaryl;

R₁ = H, halogen, -OH, -CN, an optionally substituted alkyl, alkoxy and carbocyclic group;

R₂ = H, an optionally substituted alkyl, alkoxy, cycloalkyl, alkenyl and alkynyl;

R₃ = H, halogen, alkyl, alkoxy and carbocyclic group;

R₄ and R₅ = H, -CN, an optionally substituted alkyl, alkoxy, cycloalkyl, alkenyl, alkynyl; or R₄ and R₅ together with the attached C form a ring;

m and n = 1 or 2.

Key Structures:

Biological Assay:

The inhibition of selected compounds was evaluated by PARP1 and PARP2 chemiluminescent assay and proliferation of human breast cancer cells MDA-MB-436.

Biological Data:

Summary of inhibitory effect data (IC₅₀) of representative compounds:

Example	Enzyme activity IC50 (nM)		IC50 (nM) in human breast cancer cells MDA-MB-436
	PARP1	PAPR2
1-1	0.47	>10000	2.13
6	0.38	>10000	2.07
8	0.94	>10000	4.11
19	0.22	>10000	1.57
21	0.32	>10000	2.14
29	0.29	>10000	1.57

Claims:

Total claims: 12

Compound claims: 10

Composition claims: 2

Recent Review Articles

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