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CN-121986102-A - Pyrimidopyridone and pteridinone derivatives as GCN2 kinase inhibitors, compositions and uses thereof

CN121986102ACN 121986102 ACN121986102 ACN 121986102ACN-121986102-A

Abstract

The present application relates to pyrimidopyridone and pteridinone compounds of formula I, processes for their preparation and compositions containing them. More particularly, the present application relates to compounds of formula I having activity as inhibitors of general regulatory repressor 2 (GCN 2) kinase and their use in the treatment of diseases, disorders or conditions treatable by inhibition of GCN2 kinase, such as cancer and neuronal diseases. (I)。

Inventors

  • R. Al Aval
  • M. Isaac
  • R. LOVELL
  • D Yulin
  • R. K. Rotaper

Assignees

  • 安大略省癌症研究所(OICR)
  • 大学健康网络

Dates

Publication Date
20260505
Application Date
20240829
Priority Date
20230830

Claims (20)

  1. 1. A compound of formula I, or a pharmaceutically acceptable salt, solvate and/or prodrug thereof: (I), Wherein the method comprises the steps of R 1 is selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl and C 3-10 heterocycloalkyl, the latter four groups optionally substituted with one or two R 8 ; X 1 is selected from N and CR 9 ; R 2 is selected from H, C 1-6 alkyl and C 1-6 haloalkyl; X 2 is selected from N and CR 10 ; R 3 、R 4 and R 5 are independently selected from H, halogen, CN, C 1-6 alkyl, and C 1-6 haloalkyl; x 3 is selected from N and CR 11 ; R 6 and R 7 are independently selected from H, halogen, CN, C 1-6 alkyl, C 1-6 haloalkyl, OC 1-6 alkyl and OC 1-6 haloalkyl; Each R 8 is independently selected from OR 12 、NR 12 R 13 、C(O)NR 12 R 13 、C(O)OR 12 , =o, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, and C 3-10 heterocycloalkyl, wherein all alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl are optionally substituted with one OR more substituents selected from halogen, OR 14 、NR 14 R 15 , and C 1-6 alkyl; R 9 、R 10 and R 11 are independently selected from H, halogen, C 1-6 alkyl and C 1-6 haloalkyl; R 12 is selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl and C 3-10 heterocycloalkyl, the latter four groups optionally being substituted with one or two substituents selected from halogen, OH, OC 1-4 alkyl and OC 1-4 fluoroalkyl, and R 13 、R 14 and R 15 are independently selected from H, C 1-6 alkyl and C 1-6 haloalkyl.
  2. 2. The compound of claim 1, wherein R 1 is selected from C 3-10 cycloalkyl and C 3 - 10 heterocycloalkyl, each optionally substituted with one or two R 8 .
  3. 3. The compound of claim 1, wherein R 1 is selected from H, C 1-4 alkyl and C 1-4 fluoroalkyl.
  4. 4. A compound according to claim 3, wherein R 1 is selected from H、CH 3 、CF 3 、CHF 2 、CH 2 CH 3 、CH 2 CH 2 CH 3 、CH(CH 3 ) 2 、CH(CH 3 )CH 2 CH 3 and CH (CH 3 ) 3 ).
  5. 5. The compound of claim 1, wherein R 1 is C 3-10 cycloalkyl optionally substituted with one or two R 8 .
  6. 6. The compound of claim 5, wherein R 1 is monocyclic C 3 - 8 cycloalkyl optionally substituted with one or two R 8 .
  7. 7. The compound of claim 6, wherein R 1 is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl, each of which is optionally substituted with one or two R 8 .
  8. 8. The compound of claim 7, wherein R 1 is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl, each of which is optionally substituted with one R 8 .
  9. 9. The compound of claim 8, wherein R 1 is selected from cyclobutyl and cyclohexyl, each of which is substituted by one R 8 .
  10. 10. The compound of claim 1, wherein R 1 is C 3-10 heterocycloalkyl optionally substituted with one or two R 8 .
  11. 11. The compound of claim 10, wherein R 1 is selected from the group consisting of aziridinyl, oxetanyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, isoxthiolidinyl, thiazolidinyl, isothiazolidinyl, dioxolanyl, dithianyl, piperidinyl, tetrahydropyranyl, diazinoalkyl (diazinanyl) (e.g., piperazinyl), morpholinyl, thiomorpholinyl, dioxanyl, dithianyl, azepanyl, oxepinyl, and thietanyl, each of which is optionally substituted with one or two R 8 .
  12. 12. The compound of claim 11, wherein R 1 is selected from the group consisting of thietanyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, thiomorpholinyl, aziridinyl, azetidinyl, pyrrolidinyl, morpholinyl, piperazinyl, and piperidinyl, each of which is optionally substituted with one R 8 .
  13. 13. The compound of claim 12, wherein R 1 is selected from oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, morpholinyl, piperazinyl, and piperidinyl, each of which is optionally substituted with one R 8 .
  14. 14. The compound of claim 13, wherein R 1 is selected from oxetanyl, tetrahydrofuranyl, and tetrahydropyranyl, each of which is optionally substituted with one R 8 .
  15. 15. The compound of claim 14, wherein R 1 is selected from oxetanyl, tetrahydrofuranyl, and tetrahydropyranyl, each of which is unsubstituted.
  16. 16. The compound according to any one of claims 1 to 15, wherein X 1 is selected from N and CH.
  17. 17. The compound according to any one of claims 1 to 16, wherein R 2 is selected from H and CH 3 .
  18. 18. The compound according to any one of claims 1to 17, wherein X 2 is selected from N and CH.
  19. 19. The compound of any one of claims 1 to 18, wherein R 3 、R 4 and R 5 are independently selected from H, cl, F, br, CN, C 1-4 alkyl and C 1-4 fluoroalkyl.
  20. 20. The compound of claim 19, wherein R 3 、R 4 and R 5 are independently selected from H, cl, F, CN, CH 3 and CF 3 .

Description

Pyrimidopyridone and pteridinone derivatives as GCN2 kinase inhibitors, compositions and uses thereof The present application claims the benefit of priority from co-pending U.S. provisional patent application 63/535,418 filed 8/30 at 2023, the entire contents of which are incorporated herein by reference. Technical Field The present application relates to pyrimidopyridone and pteridinone compounds having activity as inhibitors of general regulatory repressor protein 2 (GCN 2) kinase, processes for their preparation, compositions comprising them and their use, for example in therapy. More particularly, the present application relates to compounds useful in the treatment of diseases, disorders or conditions treatable by inhibition of GCN2 kinase, such as cancer and neuronal diseases. Background Eukaryotic initiation factor 2α (eif2α) kinase generally regulates repressor 2 (GCN 2) driving adaptation of cells to amino acid restrictions by activating an Integrated Stress Response (ISR) that induces activation of transcription factor 4 (ATF 4). The GCN2 kinase mediated adaptation of cells to amino acid restrictions occurs through translational control of gene expression, which is performed primarily by eif2α phosphorylation. Using quantitative phosphorylation proteomics, dokladal et al recently demonstrated that GCN2 targets assisted, physiologically relevant effectors, including eIF2 beta and Gcn20, were used to fine tune translational control in response to amino acid starvation (Molecular Cell2021; 81 (9), P1879-1889.e6). In addition to phosphorylating the eIF2- α subunit, GCN2 phosphorylates the β -subunit of the trimeric eIF 2G protein complex to facilitate its association with eIF5, which in turn helps to inhibit translation initiation. Under unique stress conditions, cellular ISR is activated by four eukaryotic initiation factor 2 alpha (eIF 2 alpha) kinases, GCN2, protein kinase-like endoplasmic reticulum kinase (PERK), double-stranded RNA-dependent kinase (PKR) and Heme Regulation Inhibitor (HRI) [ Nat Rev Mol Cell Biol2016,17:213-226]. These four eif2α kinases typically phosphorylate eif2α at position S51, thereby reducing overall protein synthesis. However, specific mRNAs with an upstream open reading frame, such as activating transcription factor 4 (ATF 4), are selectively translated by delaying translation reinitiation via eIF 2. Alpha. Phosphorylation. ATF4 is a key transcription factor for stress adaptation and subsequently drives transcription of genes involved in processes such as protein folding, amino acid metabolism and autophagy [ Nat Rev Mol Cell Biol2019, 20:436-450]. Within tumors, cancer cells often undergo amino acid deprivation, in part because abnormal proliferation increases the need for amino acids to produce proteins, lipids, and nucleic acids, and in part because insufficient and disordered angiogenesis leads to amino acid supply shortages. Therefore, GCN2 may be important for cancer cell survival and tumor progression. Furthermore, knockdown of GCN2 or ATF4 has been shown to reduce tumor growth in vivo [ EMBO. J.2010, 29:2082-2096]. Furthermore, the GCN2 arm of ISR has been shown to protect cancer cells from intrinsic stress induced by the c-Myc oncogene [ Nat Cell Biol2019, 21:1413-1424;Nat Cell Biol2019, 21:889-899 ]. GCN2 may also be involved in resistance to cancer chemotherapy because sensitization to the antitumor agent L-asparaginase (L-ASNase) is triggered by inhibition of GCN2 in cancer cells that express low levels of asparagine synthetase (ASNS) [ Proc NATL ACAD SCI USA2018, 115:E 7776-E7785]. ASNS catalyzes the biosynthesis of asparagine (Asn) from aspartic acid and is highly responsive to cellular stress, particularly to intracellular amino acid depletion. ATF4 induces ASNS, [ J Biol chem.2017;292 (49): 19952-19958], which in turn maintains Asn levels and inhibits apoptosis, while depletion of intracellular Asn induces apoptosis. ASNS therefore plays a role in tumor cell accumulation and progression by maintaining cell viability. Elevated ASNS protein expression is also associated with resistance to asparaginase treatment [ J Biol chem.2017;292 (49): 19952-19958]. Thus, tumors with high ASNS expression should be sensitive to inhibition of ASNS activity when used in combination with L-ASNase and GCN2 inhibition. This combination is a viable strategy to control the growth, proliferation and migration of cancer cells, eliminate them, or enhance their sensitivity to existing chemotherapeutic agents or radiation therapy. It has been proposed that the GCN2 mediated ISR pathway provides a promising target for cancer treatment. Therefore, disruption of this oncogenic stress-induced pathway by inhibition of GCN2 is an attractive therapeutic strategy. Another important therapeutic area involving ISR activation is neuronal diseases or neuropathies [ Science2021, 373, 1161-1166 ]. Dominant mutations in the ubiquitously expressed transferred RNA (tRNA) synthetase gene lead to axon