Search

US-20260124214-A1 - HETEROCYCLIC COMPOUNDS FOR USE IN THE TREATMENT OF CANCER

US20260124214A1US 20260124214 A1US20260124214 A1US 20260124214A1US-20260124214-A1

Abstract

The invention relates to heterocyclic derivatives and their use in the treatment and prophylaxis of cancer, and to compositions containing said derivatives and processes for their preparation.

Inventors

  • Owen Davis
  • Robert Heald
  • Martin STOCKLEY
  • Harry Finch
  • Sam MANN

Assignees

  • ARTIOS PHARMA LIMITED

Dates

Publication Date
20260507
Application Date
20221021
Priority Date
20211021

Claims (19)

  1. 1 . A compound of formula (I): or a tautomeric or a stereochemically isomeric form, a pharmaceutically acceptable salt or a solvate thereof, wherein: n represents an integer selected from 0, 1, 2, 3 or 4; R 1 represents C 1-6 alkyl, C 2-6 alkenyl, C 1-6 alkoxy, hydroxy, halogen, haloC 1-6 alkyl, haloC 1-6 alkoxy, C 3-8 cycloalkyl, cyano or —NR x R y ; R 2 represents hydrogen, C 1-6 alkyl optionally substituted by one or more amino and/or hydroxy groups, C 2-6 alkenyl, C 1-6 alkoxy optionally substituted by one or more —NR x R y groups, C 1-6 alkanol optionally substituted by one or more —NR x R y groups, C 1-6 alkyl-NR x R y optionally substituted by one or more hydroxy groups, —X-aryl, —X-heterocyclyl, or —X-heteroaryl, wherein said aryl, heterocyclyl or heteroaryl groups may be optionally substituted with one or more halogen, hydroxy, oxo, cyano, —NR x R y , C 1-6 alkyl, haloC 1-6 alkyl, C 1-6 alkanol, C 1-6 alkoxy, C 1-6 alkyl-NR x R y , —CO—C 1-6 alkyl, —CO—C 1-6 alkanol, —CO—C 1-6 alkyl-NR x R y , —CONR x R y , —SO 2 —C 1-6 alkyl or a heterocyclyl group optionally substituted by a C 1-6 alkyl group, X represents a bond or a linker selected from —C(═O)— or a C 1 -C 4 alkylene group optionally substituted by one or more O, OH, C 3-8 cycloalkyl or CO groups; R 3 represents hydrogen or C 1-6 alkyl; R 4 , R 5 , R 6 and R 7 independently represent hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 1-6 alkoxy, halogen, haloC 1-6 alkyl, haloC 1-6 alkoxy, C 3-8 cycloalkyl, cyano or —NR x R y ; and R x and R y independently represent hydrogen or C 1-6 alkyl.
  2. 2 . The compound as defined in claim 1 , wherein n represents 0, 1, 2 or 3, such as 1.
  3. 3 . The compound as defined in claim 1 or claim 2 , wherein R 1 represents C 1-6 alkyl (such as methyl) or halogen (such as fluorine or chlorine), such as C 1-6 alkyl (in particular methyl).
  4. 4 . The compound as defined in any one of claims 1 to 3 , wherein: n represents 1 and R 1 represents C 1-6 alkyl (such as methyl) or halogen (such as fluorine or chlorine), such as wherein n represents 1 and R 1 represents C 1-6 alkyl (in particular methyl); or n represents 2 and R 1 represents halogen (such as fluorine or chlorine); or n represents 3 and R 1 represents halogen (such as fluorine or chlorine).
  5. 5 . The compound as defined in any one of claims 1 to 4 , wherein R 2 represents: hydrogen; C 1-6 alkyl optionally substituted by one or more amino and/or hydroxy groups (such as —CH 2 —CH 2 —N(Et) 2 , —CH 2 —CH 2 —CH 2 —N(Me) 2 , —CH 2 —CH 2 —NH—CH 2 —CH 2 —NH-Me, or —CH 2 —CH 2 —N(Me)-CH 2 —CH 2 —OH); C 2-6 alkenyl (such as (—CH 2 ═CH 2 ); C 1-6 alkoxy optionally substituted by one or more —NR x R y groups (such as —CH 2 —CH 2 —O—CH 2 —CH 2 —N(Me) 2 ); C 1-6 alkanol optionally substituted by one or more —NR x R y groups (such as —CH 2 —CH 2 —OH, —CH 2 —CH 2 —CH 2 —OH, —CH 2 —CH(Me)-OH, —CH 2 —CH(OH)-Me, or —CH 2 —CH(OH)—CH 2 —N(Me) 2 ); —X-aryl (such as -phenyl, —CH 2 -phenyl, or -cyclobutyl-OCH 2 -phenyl); —X-heterocyclyl (such as —CH 2 -pyrrolidinyl, —CH 2 -piperidinyl, —CH 2 -morpholinyl, —CO-piperazinyl, —CH 2 —CH 2 -pyrrolidinyl, —CH 2 —CH 2 -piperidinyl, —CH 2 —CH 2 -piperazinyl, —CH 2 —CH 2 -morpholinyl, —CH 2 —CH 2 -thiomorpholinyl, —CH 2 —CH 2 -1-oxa-6-azaspiro[3.3]heptan-6-yl, —CH 2 —CH 2 -2-oxa-6-azaspiro[3.3]heptan-6-yl, —CH 2 —CH 2 -hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl, —CH 2 —CH 2 -2,5-diazabicyclo[2.2.1]heptan-2-yl, —CH 2 —CH 2 -3,8-diazabicyclo[3.2.1]octan-3-yl, —CH 2 —CH 2 —CH 2 -piperazinyl, —CH 2 —CH 2 —CH 2 -morpholinyl, or —CH 2 —CH(OH)—CH 2 -morpholinyl); and —X-heteroaryl (such as -pyridinyl, -pyrrolo[2,3-b]pyridin-6-yl, benzo[d]imidazol-6-yl, —CH 2 -pyridinyl, —CH 2 -tetrahydropyrazolo[1,5-a]pyrazin-2-yl, —CH 2 -tetrahydroimidazo[1,2-a]pyrazin-2-yl, —CH 2 -tetrahydro-[1,2,4]triazolo[1,5-a]pyrazin-2-yl, —CH 2 -tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl, —CH 2 -tetrahydroisoquinolin-6-yl, or —CH 2 -isoindolin-5-yl); wherein said aryl, heterocyclyl or heteroaryl groups may be optionally substituted with one or more halogen (such as fluorine), hydroxy, oxo, cyano, —NR x R y (such as —N(Me) 2 ), C 1-6 alkyl (such as methyl), haloC 1-6 alkyl (such as —CH 2 —CH 2 —F), —CO—C 1-6 alkyl (such as —CO-methyl), —CO—C 1-6 alkanol (such as —CO—CH(OH)-Me), C 1-6 alkanol (such as —CH 2 OH, or —CH 2 —CH 2 —OH), C 1-6 alkoxy (such as —OMe, or —CH 2 —CH 2 —OMe), —CONR x R y (such as —CON(Me) 2 ), —SO 2 —C 1-6 alkyl (such as —SO 2 Me) or a heterocyclyl (such as oxetanyl, azetidinyl, pyrrolidinyl) group optionally substituted by a C 1-6 alkyl (such as methyl) group, such as wherein R 2 represents: —X-heterocyclyl (such as —CH 2 -pyrrolidinyl, —CH 2 -piperidinyl, —CH 2 -morpholinyl, —CO-piperazinyl, —CH 2 —CH 2 -pyrrolidinyl, —CH 2 —CH 2 -piperidinyl, —CH 2 —CH 2 -piperazinyl, —CH 2 —CH 2 -morpholinyl, —CH 2 —CH 2 -thiomorpholinyl, —CH 2 —CH 2 -1-oxa-6-azaspiro[3.3]heptan-6-yl, —CH 2 —CH 2 -2-oxa-6-azaspiro[3.3]heptan-6-yl, —CH 2 —CH 2 -hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl, —CH 2 —CH 2 -2,5-diazabicyclo[2.2.1]heptan-2-yl, —CH 2 —CH 2 -3,8-diazabicyclo[3.2.1]octan-3-yl, —CH 2 —CH 2 —CH 2 -piperazinyl, —CH 2 —CH 2 —CH 2 -morpholinyl, or —CH 2 —CH(OH)—CH 2 -morpholinyl); wherein said heterocyclyl group may be optionally substituted with one or more halogen (such as fluorine), hydroxy, oxo, cyano, —NR x R y (such as —N(Me) 2 ), C 1-6 alkyl (such as methyl), haloC 1-6 alkyl (such as —CH 2 —CH 2 —F), —CO—C 1-6 alkyl (such as —CO-methyl), —CO—C 1-6 alkanol (such as —CO—CH(OH)-Me), C 1-6 alkanol (such as —CH 2 OH, or —CH 2 —CH 2 —OH), C 1-6 alkoxy (such as —OMe, or —CH 2 —CH 2 —OMe), —CONR x R y (such as —CON(Me) 2 ), —SO 2 —C 1-6 alkyl (such as —SO 2 Me) or a heterocyclyl (such as oxetanyl, azetidinyl, pyrrolidinyl) group optionally substituted by a C 1-6 alkyl (such as methyl) group, in particular wherein R 2 represents-CH 2 —CH 2 -piperazinyl wherein said piperazinyl group may be optionally substituted with one or more C 1-6 alkyl (such as methyl) group.
  6. 6 . The compound as defined in any one of claims 1 to 5 , wherein R 3 represents hydrogen or C 1-6 alkyl (such as methyl or ethyl), such as wherein R 3 represents C 1-6 alkyl (in particular methyl).
  7. 7 . The compound as defined in any one of claims 1 to 6 , wherein X represents a bond or a linker selected from —C(═O)— or a C 1 -C 3 alkylene group optionally substituted by one or more O, OH, C 3-8 cycloalkyl or CO groups (such as —CH 2 —, -cyclobutyl-OCH 2 —, —CH 2 —CH 2 —, —CH 2 —CH 2 —CH 2 —, or —CH 2 —CH(OH)—CH 2 —).
  8. 8 . The compound as defined in any one of claims 1 to 7 , wherein R x and R y independently represent hydrogen and C 1-6 alkyl (such as methyl or ethyl), such as both of R x and R y represent C 1-6 alkyl (such as methyl or ethyl).
  9. 9 . The compound as defined in any one of claims 1 to 8 , wherein R 4 represents: hydrogen; C 1-6 alkyl (such as methyl or ethyl); C 2-6 alkenyl (such as ethenyl); C 1-6 alkoxy (such as methoxy); halogen (such as chlorine); or —NR x R y (such as —N(Me) 2 or —N(Me)(Et)), such as wherein R 4 represents C 1-6 alkyl (in particular methyl).
  10. 10 . The compound as defined in any one of claims 1 to 9 , wherein R 5 represents: hydrogen; halogen (such as chlorine); or C 1-6 alkyl (such as methyl), such as wherein R 5 represents hydrogen.
  11. 11 . The compound as defined in any one of claims 1 to 10 , wherein R 6 represents: C 1-6 alkyl (such as methyl, ethyl or isopropyl); C 2-6 alkenyl (such as —C(═CH 2 )(Me)); halogen (such as bromine); haloC 1-6 alkyl (such as trifluoromethyl or —C(H)(Me)-CF 3 ); or haloC 1-6 alkoxy (such as difluoromethoxy), such as wherein R 6 represents haloC 1-6 alkyl (such as trifluoromethyl).
  12. 12 . The compound as defined in any one of claims 1 to 11 , wherein R 7 represents hydrogen or cyano, such as hydrogen.
  13. 13 . The compound as defined in claim 1 which is a compound of formula (I) a: or a tautomeric or a stereochemically isomeric form, a pharmaceutically acceptable salt or a solvate thereof, wherein n, R 1 , R 2 and R 3 are as defined in any of claims 1 to 6 .
  14. 14 . The compound as defined in claim 1 , wherein the compound is the free base of a compound of Examples 1-149 or a pharmaceutically acceptable salt or solvate thereof.
  15. 15 . A pharmaceutical composition comprising a compound of formula (I) as defined in any of claims 1 to 14 .
  16. 16 . A pharmaceutical composition comprising a compound of formula (I) as defined in any of claims 1 to 14 , in combination with one or more therapeutic agents.
  17. 17 . A compound as defined in any of claims 1 to 14 for use in therapy.
  18. 18 . A compound as defined in any of claims 1 to 14 for use in the prophylaxis or treatment of cancer.
  19. 19 . A process for preparing a compound of formula (I) as defined in claim 1 which comprises: (a) preparing a compound of formula (I) wherein R 2 represents hydrogen which comprises deprotection of a compound of formula (II); wherein n, R 1 , R 3 , R 4 , R 5 , R 6 and R 7 are as defined herein before and P 1 represents a suitable protecting group, such as Boc; (b) interconversion of a compound of formula (I) or protected derivative thereof to a further compound of formula (I) or protected derivative thereof, (c) deprotection of a protected derivative of a compound of formula (I); (e) optional formation of a pharmaceutically acceptable salt of a compound of formula (I).

Description

FIELD OF THE INVENTION The invention relates to heterocyclic derivatives and their use in the treatment and prophylaxis of cancer, and to compositions containing said derivatives and processes for their preparation. BACKGROUND OF THE INVENTION Robust repair of DNA double-strand breaks (DSBs) is essential for the maintenance of genome stability and cell viability. DSBs can be repaired by one of three main pathways: homologous recombination (HR), non-homologous end-joining (NHEJ) and alternative NHEJ (alt-NHEJ). Microhomology-mediated end-joining (MMEJ) is the most well characterised alt-NHEJ mechanism. HR-mediated repair is a high-fidelity mechanism essential for accurate error-free repair, preventing cancer-predisposing genomic stability. Conversely, NHEJ and MMEJ are error-prone pathways that can leave mutational scars at the site of repair. MMEJ can function parallel to both HR and NHEJ pathways (Truong et al. PNAS 2013, 110(19), 7720-7725). The survival of cancer cells, unlike normal cells, is often dependent on the mis-regulation of DNA damage response (DDR) pathways. For example, an increased dependency on one pathway (often mutagenic) to cope with either the inactivation of another one, or the enhanced replication stress resulting from increased proliferation. An aberrant DDR can also sensitise cancer cells to specific types of DNA damage, thus, defective DDR can be exploited to develop targeted cancer therapies. Crucially, cancer cells with impairment or inactivation of HR and NHEJ become hyper-dependent on MMEJ-mediated DNA repair. Genetic, cell biological and biochemical data have identified Polθ (UniProtKB—O75417 (DPOLQ_HUMAN) as the key protein in MMEJ (Kent et al. Nature Structural & Molecular Biology (2015), 22(3), 230-237, Mateos-Gomez et al. Nature (2015), 518(7538), 254-257). Polθ is multifunctional enzyme, which comprises an N-terminal helicase domain (SF2 HEL308-type) and a C-terminal low-fidelity DNA polymerase domain (A-type)(Wood & Doublié DNA Repair (2016), 44, 22-32). Both domains have been shown to have concerted mechanistic functions in MMEJ. The helicase domain mediates the removal of RPA protein from ssDNA ends and stimulates annealing. The polymerase domain extends the ssDNA ends and fills the remaining gaps. Therapeutic inactivation of Polθ would thus disable the ability of cells to perform MMEJ and provide a novel targeted strategy in an array of defined tumour contexts. Firstly, Polθ has been shown to be essential for the survival of HR-defective (HRD) cells (e.g. synthetic lethal with FA/BRCA-deficiency) and is up-regulated in HRD tumour cell lines (Ceccaldi et al. Nature (2015), 518(7538), 258-262). In vivo studies also show that Polθ is significantly over-expressed in subsets of HRD ovarian, uterine and breast cancers with associated poor prognosis (Higgins et al. Oncotarget (2010), 1, 175-184, Lemée et al. PNAS (2010), 107(30), 13390-13395, Ceccaldi et al. (2015), supra). Importantly, Polθ is largely repressed in normal tissues but has been shown to be upregulated in matched cancer samples thus correlating elevated expression with disease (Kawamura et al. International Journal of Cancer (2004), 109(1), 9-16). Secondly, its suppression or inhibition confers radio-sensitivity in tumour cells. Finally, Polθ inhibition could conceivably prevent the MMEJ-dependent functional reversion of BRCA2 mutations that underlies the emergence of cisplatin and PARPi resistance in tumours. There is therefore a need to provide effective Polθ inhibitors for the treatment of cancer. SUMMARY OF THE INVENTION According to a first aspect of the invention, there is provided a compound of formula (I): or a tautomeric or a stereochemically isomeric form, a pharmaceutically acceptable salt or a solvate thereof, wherein:n represents an integer selected from 0, 1, 2, 3 or 4;R1 represents C1-6 alkyl, C2-6 alkenyl, C1-6 alkoxy, hydroxy, halogen, haloC1-6 alkyl, haloC1-6 alkoxy, C3-8 cycloalkyl, cyano or —NRxRy;R2 represents hydrogen, C1-6 alkyl optionally substituted by one or more amino and/or hydroxy groups, C2-6 alkenyl, C1-6 alkoxy optionally substituted by one or more —NRxRy groups, C1-6 alkanol optionally substituted by one or more —NRxRy groups, C1-6 alkyl-NRxRy optionally substituted by one or more hydroxy groups, —X-aryl, —X-heterocyclyl, or —X-heteroaryl, wherein said aryl, heterocyclyl or heteroaryl groups may be optionally substituted with one or more halogen, hydroxy, oxo, cyano, —NRxRy, C1-6 alkyl, haloC1-6 alkyl, C1-6 alkanol, C1-6 alkoxy, C1-6 alkyl-NRxRy, —CO—C1-6 alkyl, —CO—C1-6 alkanol, —CO—C1-6 alkyl-NRxRy, —CONRxRy, —SO2—C1-6 alkyl or a heterocyclyl group optionally substituted by a C1-6 alkyl group,X represents a bond or a linker selected from —C(═O)— or a C1-C4 alkylene group optionally substituted by one or more O, OH, C3-8 cycloalkyl or CO groups;R3 represents hydrogen or C1-6 alkyl;R4, R5, R6 and R7 independently represent hydrogen, C1-6 alkyl, C2-6 alkenyl, C1-6 alkoxy, halogen