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CN-121974888-A - Piperidin-1-yl-N-pyridin-3-yl-2-oxoacetamide derivatives useful for the treatment of MTAP deficiency and/or MTA accumulating cancers

CN121974888ACN 121974888 ACN121974888 ACN 121974888ACN-121974888-A

Abstract

Compounds according to formula (I) and pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof, are provided, wherein R 1 、R 2 、R 3 、R 4 、R 6 、R 7 、R 8 and n are as defined herein. The compounds of the invention are expected to be useful in the prevention and treatment of a variety of conditions. Formula (I)

Inventors

  • K.M. Cottrell
  • J.P. Maxwell

Assignees

  • 探戈医药股份有限公司

Dates

Publication Date
20260505
Application Date
20210730
Priority Date
20200731

Claims (10)

  1. 1. A compound of formula (I) or a pharmaceutically acceptable salt thereof; Wherein: The compound of formula (I), Each R 1 is independently selected from H, -C 1 –C 6 alkyl, -C 1 –C 6 haloalkyl, -OH, -O- (C 1 –C 6 alkyl), -O- (C 1 –C 6 haloalkyl), -NH 2 、–NH–(C 1 –C 6 alkyl), and-N- (C 1 –C 6 alkyl) 2 ; Each R 2 is independently selected from halo, -C 1 –C 6 alkyl, -C 1 –C 6 haloalkyl, -C 1 –C 6 haloalkoxy, -C 3 –C 9 cycloalkyl, 3-6 membered heterocyclyl, -C 1 –C 6 haloalkoxy, -OMe, -C (=o) H, -C (=o) NHOH, and-C (=o) NH 2 ; Each R 3 is independently selected from H, halo, -CN, -C 1 –C 6 alkyl, -C 1 –C 6 haloalkyl, and-N (R a3 ) 2 ; Each R 4 is independently selected from H, halo, -CN, -C 1 –C 6 alkyl, -C 1 –C 6 haloalkyl, and-N (R a4 ) 2 ; Each R 6 is independently selected from H, -C 1 -C 6 alkyl, -C 3 -C 10 monocyclic or bicyclic carbocyclyl, 3-10 membered monocyclic or bicyclic heterocyclyl, C 6 -C 10 monocyclic or bicyclic aryl, 5-6 membered monocyclic heteroaryl selected from thienyl, thiazolyl, pyrazolyl, imidazolyl, oxazolyl, pyridyl, pyrimidinyl, 8-10 membered bicyclic heteroaryl, wherein each alkyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is substituted with 0,1, 2, or 3 instances of R 10 ; Each R 7 is independently selected from H, -F, -Cl, -CN, -Me, -Et, -Pr, -iso-Pr, -sec-Bu, -tert-Bu, pyrazolyl, -CF 3 、–CHF 2 、–CH 2 CF 3 、–CH 2 OH, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -OH, -OMe, -OCHF 2 、–C(=O)NH 2 , and-C (=O) NHMe); Each R 8 is independently selected from H, -D, -F, -Me, -Et, -sec-Bu, -CN, -OMe, -O-iso-Pr, -OCF 3 , benzyl, -NHC (=O) Me, -NMe 2 、–CH 2 C(=O)NH 2 , -C (=O) -iso-Pr, and-OH; Each R 10 is independently selected from-D, =o, halo, -CN, -C 1 -C 6 alkyl, -C 1 -C 6 heteroalkyl 、-CH 2 CH(CH 3 )(NMe 2 )、-CH 2 OH、-CH(OH)(CH 3 ) 、 -C(OH)(CH 3 ) 2 、-CH 2 NH 2 )、-C 1 -C 6 haloalkyl, -C 3 -C 9 cycloalkyl, 3-10 membered heterocyclyl, 5-10 membered heteroaryl, cycloalkylalkyl, heterocyclylalkyl, heterocyclylalkoxy, heteroarylalkyl 、-OR b10 、-N(R b10 ) 2 、-NR b10 C(=O)R b10 、-C(=O)N(R b10 ) 2 、-OC(=O)R b10 、-S(=O)R b10 、-NR b10 S(=O) 2 R b10 , and-S (=o) 2 N(R b10 ) 2 , wherein each alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl, and heteroarylalkyl is substituted with 0,1, 2,3, 4, or 5 instances of-Me, -Et, - i Pr, cyclopropyl, oxetan-3-yl 、-OH、=O、-F、-OMe、-CH 2 CH 2 F、-CH 2 CHF 2 、-CH 2 CH 2 CF 3 、-C(=O)Me、-N(Me) 2 、-CH 2 N(CH 3 ) 2 、-CH 2 N(CH 3 )CH 2 CH 3 、-N( i Pr)(Et)、-N( i Pr)(Me)、-N(Et) 2 、-N(CH 3 )(Et)、-NHC(=O)Me, or a combination thereof Each R b10 is independently selected from H、-Me、-Et、-Pr、- i Pr、-sec-Bu、- t Bu、-CF 3 、-CHF 2 、-CH 2 CF 3 、-CH 2 CH 2 NMe 2 、-CH 2 C(=O)NMe 2 、-CH(CH 3 )CH 2 NMe 2 、-CH(CH 3 )C(=O)NMe 2 )、 tetrahydrofuran-3-yl, tetrahydropyran-4-yl, oxetan-4-yl, N-Me-2-oxopyrrolidin-3-yl and piperidin-4-yl; each R a3 、R a4 is independently selected from H and C 1 -C 6 alkyl, and N is 0, 1, 2 or 3 The preconditions are that: (i) When R 1 is H, R 2 is not halo or-CF 3 ; (ii) When R 1 is-OH, -O- (C 1 –C 6 alkyl), -O- (C 1 –C 6 haloalkyl), R 2 is not-C 1 -C 6 haloalkoxy or-OMe; (iii) When R 1 is H and R 2 is-CH 3 , R 6 is not H and is not thiazolyl; (iv) The compounds are not: A. 5- (2- (5-methyl-2- (p-tolyl) piperidin-1-yl) -2-oxoacetamido) nicotinamide or any one of its enantiomers or diastereomers; B. 2- (2- (4- (2H-tetrazol-5-yl) phenyl) -5-methylpiperidin-1-yl) -N- (5, 6-dimethylpyridin-3-yl) -2-oxoacetamide or any one of its enantiomers or diastereomers.
  2. 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R 6 and R 7 are not H and are in the trans-opposite configuration.
  3. 3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R 6 and R 7 are not H and are in the cis-opposite configuration.
  4. 4. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein is represented by Is selected from the group consisting of: , , , 。
  5. 5. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein is represented by Is selected from the group consisting of: And 。
  6. 6. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein is represented by Is selected from the group consisting of: And 。
  7. 7. The compound of claim 5, or a pharmaceutically acceptable salt thereof, wherein the compound has formula (Ia) Formula (Ia).
  8. 8. The compound of claim 5, or a pharmaceutically acceptable salt thereof, wherein the compound has formula (Ib) Formula (Ib).
  9. 9. The compound of claim 6, or a pharmaceutically acceptable salt thereof, wherein the compound is of formula (Ic) Formula (Ic).
  10. 10. The compound of claim 6, or a pharmaceutically acceptable salt thereof, wherein the compound has formula (Id) Formula (Id).

Description

Piperidin-1-yl-N-pyridin-3-yl-2-oxoacetamide derivatives useful for the treatment of MTAP deficiency and/or MTA accumulating cancers The present application is a divisional application of patent application with application number 202180067678.X, application number 2021, month 07, application number 202180067678.X, entitled "piperidin-1-yl-N-pyridin-3-yl-2-oxoacetamide derivatives useful for the treatment of MTAP deficiency and/or MTA accumulation cancers". Technical Field The application relates to the field of medicine. Background Cancer therapeutic agents can be broadly divided into two categories, cytotoxic therapies and targeted therapies. Although cytotoxic therapies are associated with broad toxicity, targeted therapies have the advantage of selectively targeting tumor cells depending on their stromal activity. The clinical efficacy of targeted therapies has been demonstrated for CML and non-small cell lung cancer with BCR/ABL and EGFR inhibitors, respectively. The success of these programs has prompted the development of other therapies that specifically target amplified or mutationally activated oncogenes. A further challenge is to develop selective therapies that target those tumors that have loss of function mutations or deletions of tumor suppressor genes, the loss of which precludes traditional strategies for molecular targeting of therapeutic agents. The work directed by groups such as cancer genome maps (Cancer Genome Atlas, TCGA) to characterize cancer genomes has made great progress in elucidating the size and frequency of deletion events that promote tumor growth by causing loss of tumor suppressor genes. However, these events are often regional and cause co-deletions of genes near their intended target. While it is not known whether these accidents (PASSENGER EVENT) cause accommodation advantages, they can cause collateral defects that can be balanced therapeutically. One example is the attendant disadvantage of PRMT5 inhibition conferred by the loss of methylthioadenosine phosphorylase (MTAP), which is frequently co-deleted with the well-described tumor suppressor CDKN2A (Kruykov et al, 2016; marjon et al, 2016 and Markarov et al, 2016). CDKN2A loss occurs in about 10-15% of all human cancers and is very frequent in histology, such as malignant peripheral schwannoma, glioblastoma, mesothelioma, bladder urothelial carcinoma, esophageal squamous Cell carcinoma, pancreatic adenocarcinoma, melanoma, non-small Cell lung carcinoma, head and neck Cancer, and cholangiosarcoma (cholangiosarcoma) (Gao et al Sci. Signal.2013; cerami et al Cancer discover.2012; and Marjon et al Cell Reports 2016). MTAP is frequently included in deletions due to proximity to CDKN2A on chromosome 9p 21. MTAP is a key enzyme in the methionine recycling pathway, which is a six-step process for recycling methionine from polyamine synthesis product methyl sulfanyl adenosine (MTA). The loss of MTAP causes its matrix MTA to accumulate, which has been demonstrated by multiple groups to act as a SAM-competitive PRMT5 inhibitor (Kruykov et al, 2016; marjon et al, 2016; and Markarov et al, 2016). PRMT5 is a type II arginine methyltransferase that regulates essential cellular functions, including regulation of cell cycle progression, apoptosis and DNA damage response, by symmetrically dimethyl proteins involved in transcription and signaling (Koh, bezzi and Guccione Curr Mol Bio Rep 2015 and Wu et al Nat Rev Drug Discovery 2021). However, data obtained from genome-wide genetic perturbation screening using shRNA revealed selective requirements for PRMT5 activity in MTAP deleted cancer cell lines (Kruykov et al, 2016; marjon et al, 2016; and Markarov et al, 2016). The accumulation of MTA in these cell lines caused by MTAP deletions partially inhibited PRMT5, thereby rendering those cells selectively sensitive to additional PRMT5 inhibition. PRMT5 inhibitors have been developed, but they have not demonstrated selectivity for MTAP-deficient cancer cell lines. This lack of selectivity can be explained by the mechanism of action of the inhibitors, as they are SAM non-competitive or SAM competitive inhibitors and are therefore MTAP-agnostic (Kruykov et al, 2016; marjon et al, 2016 and Markarov et al, 2016). However, if PRMT5 inhibitors were developed that leverage MTA accumulation by binding in a non-competitive, or mixed mode of MTA or in a cooperative binding of MTA, they could confirm selectivity for MTAP-deficient tumor cells. Disclosure of Invention In one aspect of the present invention, there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof; Wherein: , Each R 1 is independently selected from H, -D, halo, -CN, -C 1-C6 alkyl, -C 1-C6 heteroalkyl, -C 1-C6 haloalkyl, -C 3-C9 cycloalkyl, 3-10 membered heterocyclyl, heterocyclylalkyl, heteroarylalkyl, arylalkyl, cycloalkylalkyl 、-ORa1、-N(Ra1)2、-C(=O)Ra1、-C(=O)ORa1、-NRa1C(=O)Ra1、-NRa1C(=O)ORa1、-C(=O)N(Ra1)2、-OC(=O)N(Ra1)2、-S(=O)Ra1、-S(=O)2Ra1、-SRa1、-S