WO2020245664A1 - N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-4-(2-(methylsulfonamido)pyrimidin-4-yl) tetrahydro-2h-pyran-4-carboxamide derivatives and related compounds as human ctps1 inhibitors for the treatment of proliferative diseases - Google Patents

N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-4-(2-(methylsulfonamido)pyrimidin-4-yl) tetrahydro-2h-pyran-4-carboxamide derivatives and related compounds as human ctps1 inhibitors for the treatment of proliferative diseases Download PDF

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WO2020245664A1
WO2020245664A1 PCT/IB2020/000559 IB2020000559W WO2020245664A1 WO 2020245664 A1 WO2020245664 A1 WO 2020245664A1 IB 2020000559 W IB2020000559 W IB 2020000559W WO 2020245664 A1 WO2020245664 A1 WO 2020245664A1
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pharmaceutically acceptable
compound
acceptable salt
pyrimidin
formula
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English (en)
French (fr)
Inventor
Abdul Quddus
Andrew Novak
David Cousin
Emma BLACKHAM
Geraint Jones
Joseph WRIGGLESWORTH
Lorna Duffy
Louise BIRCH
Pascal George
Saleh Ahmed
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Step Pharma SAS
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Step Pharma SAS
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Priority to IL288508A priority Critical patent/IL288508B2/en
Priority to JP2021571989A priority patent/JP7595593B2/ja
Priority to US17/615,873 priority patent/US12466810B2/en
Priority to FIEP20749934.4T priority patent/FI3980411T3/fi
Priority to DK20749934.4T priority patent/DK3980411T3/da
Priority to CN202080041337.0A priority patent/CN114008039B/zh
Priority to EP20749934.4A priority patent/EP3980411B1/en
Priority to ES20749934T priority patent/ES3044436T3/es
Publication of WO2020245664A1 publication Critical patent/WO2020245664A1/en
Anticipated expiration legal-status Critical
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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
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    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
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    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • CTP pyrimidine nucleotide cytidine 5’ triphosphate
  • CTP is a precursor required not just for the anabolism of DNA and RNA but also phospholipids and sialyation of proteins.
  • CTP originates from two sources: a salvage pathway and a de novo synthesis pathway that depends on two enzymes, the CTP synthases (or synthetases) 1 and 2 (CTPS1 and CTPS2) (Evans and Guy 2004; Higgins, et al. 2007; Ostrander, et al. 1998).
  • CTPS1 is the critical enzyme in human lymphocyte proliferation
  • a loss-of-function homozygous mutation rs145092287
  • Activated CTPS1-deficient cells were shown to have decreased levels of CTP.
  • Normal T-cell proliferation was restored in CTPS1-deficient cells by expressing wild-type CTPS1 or by addition of cytidine.
  • CTPS1 expression was found to be low in resting lymphocytes, but rapidly upregulated following activation of these cells. Expression of CTPS1 in other tissues was generally low.
  • the invention also provides a compound of formula (I):
  • V, W, R 10 and RI 2 are:
  • the compounds of the invention are provided in a natural isotopic form.
  • R is H, C 1-4 alkyl (e.g. methyl and ethyl) or benzyl.
  • compounds of formula (I) wherein R 1 , X, Y, Z, V, W, R 4 , R 5 , R 10 and R 12 are as defined above may be prepared in five steps from compounds of formula (LVX).
  • P319 may be made using this route.
  • An intermediate of formula (XXXVII) may be coupled to a compound of formula (LVX) in the presence of a base such as LiHMDS to give a compound of formula (XXXIII).
  • R is H, C 1-4 alkyl (e.g. methyl and ethyl) or benzyl, and X, Y and Z are as defined in herein; and
  • the disease or disorder wherein an inhibitor of CTPS1 is beneficial is a disease or disorder wherein a reduction in T-cell and/or B-cell proliferation would be beneficial.
  • the invention also provides a compound of formula (I), or a pharmaceutically acceptable salt and/or solvate (e.g. salt) and/or derivative thereof, for use in the reduction of T-cell and/or B-cell proliferation in a subject.
  • a pharmaceutically acceptable salt and/or solvate e.g. salt
  • prophylaxis or‘preventing’ is used herein to mean preventing symptoms of a disease or disorder in a subject or preventing recurrence of symptoms of a disease or disorder in an afflicted subject and is not limited to complete prevention of an affliction.
  • Chronic idiopathic polyneuritis chronic inflammatory demyelinating polyneuropathy (CIPD), chronic relapsing polyneuropathy (Guillain-Barre syndrome), Miller Fischer syndrome, Stiff man syndrome, Lambert-Eaton myasthenic syndrome, myasthenia gravis.
  • diseases and disorders for which the involvement of B-cells is less clearly characterized although sometimes illustrated by the efficacy of anti-CD20 monoclonal antibodies or intravenous immunoglobulin infusions) and may not correspond or be limited to the production of pathogenic antibodies (nevertheless, non-pathogenic antibodies are sometimes described or even often present and used as a diagnosis biomarker), including:
  • the enzyme converts ATP to ADP and the ADP-GloTM Max reagent subsequently depletes any remaining endogenous ATP in the reaction system.
  • the ADP-GloTM Max detection reagent converts the ADP that has been enzymatically produced back into ATP and using ATP as a substrate together with luciferin for the enzyme luciferase, light is generated which produces a detectable luminescence.
  • the luminescent signal measured is directly proportional to the amount of ADP produced by the enzyme reaction and a reduction in this signal upon compound treatment demonstrates enzyme inhibition. The percentage inhibition produced by each concentration of compound was calculated using the equation shown below:

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PCT/IB2020/000559 2019-06-04 2020-06-04 N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-4-(2-(methylsulfonamido)pyrimidin-4-yl) tetrahydro-2h-pyran-4-carboxamide derivatives and related compounds as human ctps1 inhibitors for the treatment of proliferative diseases Ceased WO2020245664A1 (en)

Priority Applications (8)

Application Number Priority Date Filing Date Title
IL288508A IL288508B2 (en) 2019-06-04 2020-06-04 History of n-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-4-(2-(methylsulfonamido)pyrimidin-4-yl)tetrahydro-h2-pyran-4-carboxamide and related compounds as human CTPS1 inhibitors for the treatment of proliferative diseases
JP2021571989A JP7595593B2 (ja) 2019-06-04 2020-06-04 増殖性疾患の治療のための、ヒトｃｔｐｓ１阻害剤としてのｎ－（５－（６－エトキシピラジン－２－イル）ピリジン－２－イル）－４－（２－（メチルスルホンアミド）ピリミジン－４－イル）テトラヒドロ－２ｈ－ピラン－４－カルボキサミド誘導体及び関連化合物
US17/615,873 US12466810B2 (en) 2019-06-04 2020-06-04 N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-4-(2-(methylsulfonamido)pyrimidin-4-yl) tetrahydro-2H-pyran-4-carboxamide derivatives and related compounds as human CTPS1 inhibitors for the treatment of proliferative diseases
FIEP20749934.4T FI3980411T3 (fi) 2019-06-04 2020-06-04 N-(5-(6-etoksipyratsin-2-yyli)pyridin-2-yyli)-4-(2-(etyylisulfonamido)pyrimidin-4-yyli)tetrahydro-2h-pyran-4-karboksamidi ihmisen ctps1:n estäjänä proliferatiivisten sairauksien hoitoon
DK20749934.4T DK3980411T3 (da) 2019-06-04 2020-06-04 N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-4-(2-(ethylsulfonamido)pyrimidin-4-yl)tetrahydro-2h-pyran-4-carboxamid som en human ctps1-inhibitor til behandling af proliferative sygdomme
CN202080041337.0A CN114008039B (zh) 2019-06-04 2020-06-04 作为人ctps1抑制剂用于治疗增殖性疾病的化合物
EP20749934.4A EP3980411B1 (en) 2019-06-04 2020-06-04 N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-4-(2-(ethylsulfonamido)pyrimidin-4-yl)tetrahydro-2h-pyran-4-carboxamide as a human ctps1 inhibitor for the treatment of proliferative diseases
ES20749934T ES3044436T3 (en) 2019-06-04 2020-06-04 N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-4-(2-(ethylsulfonamido)pyrimidin-4-yl)tetrahydro-2h-pyran-4-carboxamide as a human ctps1 inhibitor for the treatment of proliferative diseases

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
EP19305713 2019-06-04
EP19305713.0 2019-06-04
EP19306144.7 2019-09-20
EP19306144 2019-09-20

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EP (1) EP3980411B1 (cg-RX-API-DMAC7.html)
JP (1) JP7595593B2 (cg-RX-API-DMAC7.html)
CN (1) CN114008039B (cg-RX-API-DMAC7.html)
DK (1) DK3980411T3 (cg-RX-API-DMAC7.html)
ES (1) ES3044436T3 (cg-RX-API-DMAC7.html)
FI (1) FI3980411T3 (cg-RX-API-DMAC7.html)
HU (1) HUE073329T2 (cg-RX-API-DMAC7.html)
IL (1) IL288508B2 (cg-RX-API-DMAC7.html)
WO (1) WO2020245664A1 (cg-RX-API-DMAC7.html)

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022165404A1 (en) * 2021-02-01 2022-08-04 University Of Southern California Enzyme inhibitors and viral infection therapy
US11505547B2 (en) 2017-11-30 2022-11-22 Step Pharma S.A.S. Compounds
US11655246B2 (en) 2017-11-30 2023-05-23 Step Pharma S.A.S. Aminothiazole compounds as inhibitors of CTPS1
WO2023166078A1 (en) 2022-03-01 2023-09-07 Step Pharma S.A.S. Combination treatments comprising a ctps1 inhibitor and a chek1 inhibitor
WO2023166077A1 (en) 2022-03-01 2023-09-07 Step Pharma S.A.S. Combination of a ctps1 inhibitor and a atr inhibitor in cancer therapy
WO2023166080A1 (en) 2022-03-01 2023-09-07 Step Pharma S.A.S. Combination treatments comprising a ctps1 inhibitor and a wee1 inhibitor
WO2023166076A1 (en) 2022-03-01 2023-09-07 Step Pharma S.A.S. Combinations of ctps1 and bcl2 inhibitors for cancer
WO2024133721A1 (en) 2022-12-21 2024-06-27 Step Pharma S.A.S. Combinations of ctps1 inhibitor with iap inhibitor for use in the treatment of cancer
WO2024133730A1 (en) 2022-12-21 2024-06-27 Step Pharma S.A.S. Ctps1 inhibitors for use in the treatment of ctps2 deficient cancer
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