WO2019053617A1 - Composés chimiques - Google Patents

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Publication number
WO2019053617A1
WO2019053617A1 PCT/IB2018/056982 IB2018056982W WO2019053617A1 WO 2019053617 A1 WO2019053617 A1 WO 2019053617A1 IB 2018056982 W IB2018056982 W IB 2018056982W WO 2019053617 A1 WO2019053617 A1 WO 2019053617A1
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substituted
fluoro
chloro
independently selected
oxo
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PCT/IB2018/056982
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English (en)
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Kevin J. Duffy
Cynthia Ann Parrish
Laura E. ATOR
Subramanian Baskaran
Michael Gerard Darcy
Jeffrey Alan Oplinger
Jeffrey M. Ralph
Lance Howard Ridgers
Xinrong Tian
Cunyu Zhang
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Glaxosmithkline Intellectual Property Development Limited
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Publication of WO2019053617A1 publication Critical patent/WO2019053617A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D291/00—Heterocyclic compounds containing rings having nitrogen, oxygen and sulfur atoms as the only ring hetero atoms
    • C07D291/08—Heterocyclic compounds containing rings having nitrogen, oxygen and sulfur atoms as the only ring hetero atoms condensed with carbocyclic rings or ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D515/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen, oxygen, and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D515/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen, oxygen, and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D515/04—Ortho-condensed systems

Definitions

  • the present invention relates to substituted macrocycle derivatives that are inhibitors of the activity of CD73.
  • the present invention also relates to pharmaceutical compositions comprising such compounds and methods of using such compounds in the treatment of cancer, pre-cancerous syndromes and other diseases associated with CD73 inhibition, such as AIDS, the treatment of HIV, autoimmune diseases, infections, atherosclerosis, and ischemia-reperfusion injury.
  • Extracel ⁇ Lar adenosine triphosphate ATP
  • Elevated extracel ⁇ Lar ATP is recognized by the immune system as a danger signal to initiate ⁇ pro-inflammatory events, including the recruitment of macrophages and dendritic cells.
  • (1) Successive processing of extracel ⁇ Lar ATP by the extracel ⁇ Lar ectonucleotidases CD73 and CD39 lowers extracel ⁇ Lar ATP levels and can rapidly elevate extracel ⁇ Lar adenosine from a low homeostatic level (20-200 nM) to as much as 1 ,000- 10,000 nM.
  • adenosine A2A and A2B receptors engage the immunosuppressive actions of adenosine A2A and A2B receptors on the infiltrating lymphocytes, shielding cells from an excessive inflammatory response and thereby providing a self-limiting mechanism to resolve the immune response.
  • hypoxia has been shown to increase adenosine levels by 10-20-fold compared with normal levels.
  • adenosine elevation is sufficient to maintain a chronic suppression of the innate immune response, in immune tolerance and, subsequently, uncontrolled malignant growth.
  • CD73 is a glycophosphatidylinositol-anchored di-Zn 2+ metallo-phosphatase specific for the dephosphorylation of purine and pyrimidine ribo- and deoxyribonucleoside monophosphates to the corresponding nucleoside, with adenosine monophosphate (AMP) being the preferred substrate of CD73.
  • AMP adenosine monophosphate
  • CD73-catalyzed conversion of AMP to adenosine is thought to be the major contributor to extracel ⁇ Lar adenosine in the tumor microenvironment. Its expression is directly reg ⁇ Lated by HIF1 , consistent with the observed increase in extracel ⁇ Lar adenosine under hypoxic conditions.
  • CD73 is overexpressed in ⁇ solid tumor types and leukaemias, including aggressive and diff ⁇ Lt to treat tumours, such as glioblastoma and ovarian tumours.
  • T Reg head and neck squamous cell carcinoma
  • cells both cir- and tumor associated express both CD73 and CD39, thus providing a mechanism for the conversion of ATP to adenosine that only depends on T Reg cells.
  • siRNA small-interfering ribonucleic acids
  • transgenic knockouts transgenic knockouts and overexpression models to confirm the involvement of CD73 in the generation of adenosine and promotion of immune tolerance.
  • 5 ⁇ 3 ⁇ - ⁇ " ⁇ _ ⁇ inhibitors of CD73 are expected to have the ability to relieve the adenosine-mediated immunosuppression of the tumor microenvironment and alone, or in combination with other agents, provide a treatment for cancer.
  • CD73 inhibitors are also expected to be ⁇ . for other diseases mediated by adenosine and its action on adenosine receptors.
  • CD73 inhibitors ⁇ be used for enhancing immune responses, enhancing immunization, and increasing inflammatory responses, as well as treating a wide range of conditions including neurological, neurodegenerative and CNS diseases, including depression, Parkinson's disease, cerebral and cardiac ischemic diseases, sleep disorders, and fibrosis. (7-10)
  • the invention is directed to substituted salicylamide derivatives. Specifically, the invention is directed to compounds according to Forrr ⁇ La (I):
  • R, R1 , P , X, Y, and Z are as defined below; or a pharmaceutically acceptable salt thereof.
  • the present invention also relates to the discovery that the compounds of Forrr ⁇ La (I) are active as inhibitors of CD73.
  • This invention also relates to a method of treating cancer, which comprises administering to a subject in need thereof an effective amount of a CD73 inhibiting compound of Forrr ⁇ La (I); or a pharmaceutically acceptable salt thereof.
  • This invention also relates to a method of treating pre-cancerous syndromes, which comprises administering to a subject in need thereof an effective amount of a CD73 inhibiting compound of Forrr ⁇ La (I); or a pharmaceutically acceptable salt thereof.
  • This invention also relates to a method of treating HIV, which comprises administering to a subject in need thereof an effective amount of a CD73 inhibiting compound of Forrr ⁇ La (I); or a pharmaceutically acceptable salt thereof.
  • This invention also relates to a method of treating autoimmune diseases, which comprises administering to a subject in need thereof an effective amount of a CD73 inhibiting compound of Forrr ⁇ La (I); or a pharmaceutically acceptable salt thereof.
  • This invention also relates to a method of treating infections, which comprises administering to a subject in need thereof an effective amount of a CD73 inhibiting compound of Forrr ⁇ La (I); or a pharmaceutically acceptable salt thereof.
  • This invention also relates to a method of treating atherosclerosis, which comprises administering to a subject in need thereof an effective amount of a CD73 inhibiting compound of Forrr ⁇ La (I); or a pharmaceutically acceptable salt thereof.
  • This invention also relates to a method of treating ischemia-reperfusion injury, which comprises administering to a subject in need thereof an effective amount of a CD73 inhibiting compound of Forrr ⁇ La (I); or a pharmaceutically acceptable salt thereof.
  • This invention also relates to a method of treating a disease state selected from: myocardial infarction, disease, atherosclerosis, oc Lar diseases, and arrhythmias, which comprises administering to a subject in need thereof an effective amount of a CD73 inhibiting compound of Forrr ⁇ La (I); or a pharmaceutically acceptable salt thereof.
  • a disease state selected from: myocardial infarction, disease, atherosclerosis, oc Lar diseases, and arrhythmias
  • the invention also relates to a compound of Forrr ⁇ La (I) or a pharmaceutically acceptable salt thereof for use in therapy.
  • the invention also relates to a compound of Forrr ⁇ La (I) or a pharmaceutically acceptable salt thereof for use in the treatment of cancer.
  • the invention also relates to a compound of Forrr ⁇ La (I) or a pharmaceutically acceptable salt thereof for use in the treatment of pre-cancerous syndromes.
  • the invention also relates to a compound of Forrr ⁇ La (I) or a pharmaceutically acceptable salt thereof for use in the treatment of AIDS.
  • the invention also relates to a compound of Forrr ⁇ La (I) or a pharmaceutically acceptable salt thereof for use in the treatment of autoimmune diseases.
  • the invention also relates to a compound of Forrr ⁇ La (I) or a pharmaceutically acceptable salt thereof for use in the treatment of infections.
  • the invention also relates to a compound of Forrr ⁇ La (I) or a pharmaceutically acceptable salt thereof for use in the treatment of atherosclerosis.
  • the invention also relates to a compound of Forrr ⁇ La (I) or a pharmaceutically acceptable salt thereof for use in the treatment of ischemia-reperfusion injury.
  • the invention also relates to a compound of Forrr ⁇ La (I) or a pharmaceutically acceptable salt thereof for use in the treatment of a disease state selected from: myocardial infarction, disease, atherosclerosis, ⁇ , ⁇ diseases, and arrhythmias.
  • a disease state selected from: myocardial infarction, disease, atherosclerosis, ⁇ , ⁇ diseases, and arrhythmias.
  • the invention also relates to the use of a compound of Forrr ⁇ La (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of cancer.
  • the invention also relates to the use of a compound of Forrr ⁇ La (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of pre-cancerous syndromes.
  • the invention also relates to the use of a compound of Forrr ⁇ La (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of AIDS.
  • the invention also relates to the use of a compound of Forrr ⁇ La (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of HIV.
  • the invention also relates to the use of a compound of Forrr ⁇ La (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of autoimmune diseases.
  • the invention also relates to the use of a compound of Forrr ⁇ La (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of infections.
  • the invention also relates to the use of a compound of Forrr ⁇ La (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of atherosclerosis.
  • the invention also relates to the use of a compound of Forrr ⁇ La (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of ischemia-reperfusion injury.
  • the invention also relates to the use of a compound of Forrr ⁇ La (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of a disease state selected from: myocardial infarction, disease, atherosclerosis, ⁇ , ⁇ diseases, and arrhythmias.
  • a disease state selected from: myocardial infarction, disease, atherosclerosis, ⁇ , ⁇ diseases, and arrhythmias.
  • pharmaceutical compositions that comprise a pharmaceutical carrier and a compound of Forrr ⁇ La (I) or a pharmaceutically acceptable salt thereof.
  • the invention also relates to a pharmaceutical composition as defined above for use in therapy. Also included in the present invention are methods of co-administering the presently invented CD73 inhibiting compounds with a further anti-neoplastic agent or agents.
  • the invention also relates to a combination for use in therapy which comprises a therapeutically effective amount of (i) a compound of Forrr ⁇ La (I) or a pharmaceutically acceptable salt thereof; and (ii) at least one anti-neoplastic agent.
  • This invention relates to novel compounds of Forrr ⁇ La (I) and to the use of compounds of Forrr ⁇ La (I) in the methods of the invention:
  • R is selected from:
  • P is selected from: Ci -3alkyl and Ci -3alkyl substituted from 1 to 4 times by fluoro;
  • X is selected from:
  • heterocycloalkyl substituted heterocycloalkyl
  • -OheterocycloalkyI substituted with from 1 to 4 substituents independently selected from: fluoro, chloro, bromo, oxo, -OH, Cl-4alkoxy, -CF3, heterocycloalkyl, substituted heterocycloalkyl, -NR ⁇ RS, -CN, Cl-3alkyl, and Cl-3alkyl substituted with from 1 to 3 substituents independently selected from: fluoro, chloro, oxo, Cl -4alkoxy, -OH, -NH2, and -CN,
  • -N(H)Ci-4alkyl substituted with from 1 to 9 substituents independently selected from: fluoro, chloro, bromo, oxo, -OH, Cl-4alkoxy, heterocycloalkyl, substituted heterocycloalkyl, -NR 5 R 6 , and -CN,
  • Cl-3alkyl and Cl-3alkyl substituted with from 1 to 3 substituents independently selected from: fluoro, chloro, oxo, Cl -2alkoxy, -OH, -NH2, and -CN, -NO2,
  • -N(H)Ci-4alkyl substituted with from 1 to 9 substituents independently selected from: fluoro, chloro, bromo, oxo, -OH, Cl-4alkoxy, heterocycloalkyl, substituted heterocycloalkyl, -NR 5 R 6 , and -CN,
  • -OheterocycloalkyI substituted with from 1 to 4 substituents independently selected from: fluoro, chloro, bromo, oxo, -OH, Cl -4alkoxy, -CF3, heterocycloalkyl, substituted heterocycloalkyl, -NR5R6, -CN,
  • Cl -3alkyl and Cl -3alkyl substituted with from 1 to 3 substituents independently selected from: fluoro, chloro, oxo, Cl -2alkoxy, -OH, -NH2, and -CN,
  • -N(H)Ci -4alkyl substituted with from 1 to 9 substituents independently selected from: fluoro, chloro, bromo, oxo, -OH, Cl -4alkoxy, heterocycloalkyl, substituted heterocycloalkyl, -NR ⁇ RS, and -CN, -N(H)C(0)OCl-4alkyl,
  • Z is absent or selected from:
  • Ci-6alkoxy substituted with from 1 to 9 substituents independently selected from: fluoro, chloro, bromo, oxo, -OH, Cl -4alkoxy, heterocycloalkyl, substituted heterocycloalkyl, -NR 5 R 6 , and -CN,
  • -OheterocycloalkyI substituted with from 1 to 4 substituents independently selected from: fluoro, chloro, bromo, oxo, -OH, Cl -4alkoxy, -CF3, heterocycloalkyl, substituted heterocycloalkyl, -NR5R6, -CN,
  • Cl -3alkyl and Cl -3alkyl substituted with from 1 to 3 substituents independently selected from: fluoro, chloro, oxo, Cl -2alkoxy, -OH, -NH2, and -CN,
  • -N(H)Ci -4alkyl substituted with from 1 to 9 substituents independently selected from: fluoro, chloro, bromo, oxo, -OH, Cl -4alkoxy, heterocycloalkyl, substituted heterocycloalkyl, -NR 5 R 6 , -N(H)Cl -4alkyl,
  • -OheterocycloalkyI substituted with from 1 to 4 substituents independently selected from: fluoro, chloro, bromo, oxo, -OH, Cl -4alkoxy, -CF3, heterocycloalkyl, substituted heterocycloalkyl, -NR ⁇ RS, -CN, Cl -3alkyl, and Cl -3alkyl substituted with from 1 to 3 substituents independently selected from: fluoro, chloro, oxo, Cl -2alkoxy, -OH, -NH2, and -CN,
  • -N(H)Ci -4alkyl substituted with from 1 to 9 substituents independently selected from: fluoro, chloro, bromo, oxo, -OH, Cl -4alkoxy, heterocycloalkyl, substituted heterocycloalkyl, -NR 5 R 6 , and -CN,
  • -OheterocycloalkyI substituted with from 1 to 4 substituents independently selected from: fluoro, chloro, bromo, oxo, -OH, Cl-4alkoxy, -CF3, heterocycloalkyl, substituted heterocycloalkyl, -NR5R6, -CN,
  • Cl-3alkyl and Cl-3alkyl substituted with from 1 to 3 substituents independently selected from: fluoro, chloro, oxo, Cl -2alkoxy, -OH, -NH2, and -CN,
  • -N(H)Ci-4alkyl substituted with from 1 to 9 substituents independently selected from: fluoro, chloro, bromo, oxo, -OH, Cl-4alkoxy, heterocycloalkyl, substituted heterocycloalkyl, -NR5R6, and -CN,
  • Y is a 2 to 18 atom saturated or unsaturated alkylene chain, optionally containing one ring selected from: aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, and optionally containing from 1 to 7 additional heteroatoms independently selected from: O, S, B, P, N + (Cl -4alkyl)(Cl -4alkyl), and N-R 7 , where:
  • R 7 is H, Cl -6alkyl, C3-6cycloalkyl, or -C(0)-R 8 ,
  • R 8 is Cl -6alkyl, C3-6cycloalkyl, or aryl
  • R is H, or one or two substituents at any carbon atom of said chain Y, or one or two substituents at any ⁇ atom of said chain Y, or one or two substituents at any nitrogen atom of said chain Y, or one or two substituents at any boron atom of said chain Y, or one or two substituents at any phosphorus atom of said chain Y,
  • substituents are independently selected from the group consisting of: fluoro, chloro, bromo, iodo, cyano, -NR ⁇ RS, Cl -6alkoxy, -OH, oxo, thio, Cl -6thioalkyl, Cl -6alkyl, and
  • Ci -6alkyl substituted with from 1 to 9 substituents independently selected from: fluoro, chloro, bromo, iodo, oxo, -OH, -IMH2, Cl -4alkoxy, -NR 5 R 6 , and -CN;
  • R5 and R6 are independently selected from hydrogen and C-
  • R is selected from:
  • X is selected from:
  • -N(H)Ci -4alkyl substituted with from 1 to 9 substituents independently selected from: fluoro, chloro, oxo, -OH, -NH2, -N(H)Cl -4alkyl, and -N(Cl -4alkyl)2, and
  • P is selected from: Ci-2alkyl and Ci -2alkyl substituted one or two times by fluoro.
  • Y is a 2 to 10 atom saturated or unsaturated alkylene chain optionally containing from 1 to 3 additional heteroatoms independently selected from: O,
  • Z is absent or selected from:
  • -N(H)Ci-4alkyl substituted with from 1 to 9 substituents independently selected from: fluoro, chloro, oxo, -OH, -NH2, -N(H)Cl-4alkyl, and -N(Cl -4alkyl)2, and
  • R is H, or one or two substituents at any carbon atom of said chain Y, or one or two substituents at any nitrogen atom of said chain Y, wherein said substituents are independently selected from the group consisting of: Cl -3alkyl, Cl -3alkyl substituted with from 1 to 4 substituents independently selected from: fluoro, chloro, oxo, -OH, -IMH2, and
  • R is hydrogen or chloro. Part ⁇ Larly suitably, R is hydrogen.
  • P is Ci-3alkyl. Part ⁇ Larly suitably, P is Ci-2alkyl.
  • X is selected from:
  • X is selected from:
  • Z is absent, aryl or heteroaryl.
  • Z is absent, phenyl, 5- membered heteroaryl or 6-membered heteroaryl.
  • Y is a 2 to 8 atom saturated or unsaturated alkylene chain optionally containing 1 or 2 heteroatoms independently selected from O, N + (Ci -4alkyl)(Ci -4alkyl) and N-R 7 , wherein R 7 is H.
  • R 1 is H, or a substituent which is oxo.
  • R 0 is selected from:
  • P is selected from: Ci -2alkyl and Ci -2alkyl substituted one or two times by fluoro;
  • X 1 is selected from:
  • -N(H)Ci -4alkyl substituted with from 1 to 9 substituents independently selected from: fluoro, chloro, oxo, -OH, -NH2, -N(H)Cl -4alkyl, and -N(Cl -4alkyl)2, and
  • Ci-6alkyl substituted with from 1 to 6 substituents independently selected from: fluoro, chloro, bromo, iodo, oxo, -OH, -NH2, and -CN, cycloalkyl,
  • -N(H)Ci-4alkyl substituted with from 1 to 9 substituents independently selected from: fluoro, chloro, bromo, oxo, -OH, -IMH2, -N(H)Cl-4alkyl, -N(Cl -4alkyl)2, and -CN, and
  • Ci-3alkoxy substituted with from 1 to 4 substituents independently selected from: fluoro, chloro, oxo, -OH, and -CN,
  • -N(H)Ci-2alkyl substituted with from 1 to 3 substituents independently selected from: fluoro, chloro, oxo, -OH, and -CN, and
  • Ci-3alkyl substituted with from 1 to 4 substituents independently selected from: fluoro, chloro, iodo, oxo, -OH, -NH2, and -CN,
  • Y is a 2 to 14 atom saturated or unsaturated alkylene chain optionally containing from 1 to 3 additional heteroatoms independently selected from: O, S, B, P, N + (Cl-4alkyl)(Cl-4alkyl), and N-R 7 ,
  • R 7 is H, Cl-6alkyl, C3-6cycloalkyl, or -C(0)-R 18 ,
  • R 8 is Cl-6alkyl, C3-6cycloalkyl, or aryl
  • R is H, or one or two substituents at any carbon atom of said chain Y, or one or two substituents at any ⁇ atom of said chain Y, or one or two substituents at any nitrogen atom of said chain Y,
  • substituents are independently selected from the group consisting of: Ci-6alkyl, Ci-6alkyl substituted with from 1 to 9 substituents independently selected from: fluoro, chloro, bromo, iodo, oxo, -OH, -IMH2, and -CN, Cl-6alkoxy, -OH, amino, oxo, thio, and Ci -6thioalkyl; or a pharmaceutically acceptable salt thereof.
  • R 0 is selected from:
  • -N(H)Ci -4alkyl substituted with from 1 to 9 substituents independently selected from: fluoro, chloro, oxo, -OH, -IMH2, -N(H)Cl -4alkyl, and -N(Cl -4alkyl)2, and
  • P is selected from: Ci-2alkyl and Ci-2alkyl substituted one ortwo times by fluoro.
  • Y is a 2 to 10 atom saturated or unsaturated alkylene chain optionally containing from 1 to 3 additional heteroatoms independently selected from: O,
  • -N(H)Ci-4alkyl substituted with from 1 to 9 substituents independently selected from: fluoro, chloro, oxo, -OH, -NH2, -N(H)Cl-4alkyl, and -N(Cl -4alkyl)2, and
  • R is H, or one or two substituents at any carbon atom of said chain Y, or one or two substituents at any nitrogen atom of said chain Y, wherein said substituents are independently selected from the group consisting of: Cl-3alkyl, Cl-3alkyl substituted with from 1 to 4 substituents independently selected from: fluoro, chloro, oxo, -OH, -IMH2, and -CN, Cl -3alkoxy, -OH, amino, and oxo.
  • R 10 is hydrogen or chloro. Part ⁇ Larly suitably, R 10 is hydrogen.
  • P 1 is Ci-3alkyl. Part ⁇ Larly suitably, P 1 is Ci-2alkyl.
  • X 1 is selected from:
  • X 1 is selected from:
  • Z 1 is absent, aryl or heteroaryl.
  • Z 1 is absent, phenyl, 5- membered heteroaryl or 6-membered heteroaryl.
  • Y 1 is a 2 to 8 atom saturated or unsaturated alkylene chain optionally containing 1 or 2 heteroatoms independently selected from O, N + (Ci-4alkyl)(Ci-4alkyl) and N-R 17 , wherein R 17 is H.
  • R 11 is H, or a substituent which is oxo.
  • R is selected from:
  • -N(H)Ci -4alkyl substituted with from 1 to 9 substituents independently selected from: fluoro, chloro, oxo, -OH, -IMH2, -N(H)Cl -4alkyl, and -N(Cl -4alkyl)2, and
  • Ci-4alkoxy substituted with from 1 to 3 substituents independently selected from: fluoro, chloro, oxo, -OH, -NH2, -N(H)Cl-4alkyl, and -N(Cl -4alkyl)2, oxo,
  • -N(H)Ci-4alkyl substituted with from 1 to 9 substituents independently selected from: fluoro, chloro, oxo, -OH, -NH2, -N(H)Cl-4alkyl, and -N(Cl -4alkyl)2, and
  • Y 2 is a 2 to 10 atom saturated or unsaturated alkylene chain optionally containing from 1 to 3 additional heteroatoms independently selected from: O, N + (CH3)(CH3), and N-R 25 , wherein R 25 is H or Ci -4alkyl;
  • R 2 is H, or one or two substituents at any carbon atom of said chain Y 2 , or one or two substituents at any nitrogen atom of said chain Y 2 ,
  • substituents are independently selected from the group consisting of: Ci -3alkyl, Ci -3alkyl substituted with from 1 to 4 substituents independently selected from: fluoro, chloro, oxo, -OH, -IMH2, and -CN, Cl -3alkoxy, -OH, amino, and oxo; or a pharmaceutically acceptable salt thereof.
  • R' is selected from:
  • Ci -2alkyl substituted from 1 to 3 times by fluoro
  • Ci -2alkoxy substituted from 1 to 3 times by fluoro.
  • X 2 is selected from:
  • -N(H)Ci -4alkyl substituted with from 1 to 9 substituents independently selected from: fluoro, chloro, oxo, -OH, -NH2, -N(H)Cl-4alkyl, and -N(Cl -4alkyl)2, and -N(Cl-4alkyl)2,
  • P 2 is selected from: Ci-2alkyl and Ci-2alkyl substituted one ortwo times by fluoro.
  • Y is a 2 to 10 atom saturated or unsaturated alkylene chain optionally containing from 1 to 3 additional heteroatoms independently selected from: O, N + (CH3)(CH3), and N-R 25 , wherein R 25 is H or Ci-4alkyl.
  • Z 2 is absent or selected from:
  • -N(H)Ci-4alkyl substituted with from 1 to 9 substituents independently selected from: fluoro, chloro, oxo, -OH, -NH2, -N(H)Cl-4alkyl, and -N(Cl -4alkyl)2, and -N(Cl-4alkyl)2,
  • R is H, or one or two substituents at any carbon atom of said chain Y, or one or two substituents at any nitrogen atom of said chain Y, wherein said substituents are independently selected from the group consisting of: Cl -3alkyl, Cl -3alkyl substituted with from 1 to 4 substituents independently selected from: fluoro, chloro, oxo, -OH, -IMH2, and
  • R 20 is hydrogen or chloro. Part ⁇ Larly suitably, R 20 is hydrogen.
  • P 2 is d- 3 alkyl. Part ⁇ Larly suitably, P 2 is Ci_ 2 alkyl.
  • X 2 is selected from:
  • X 2 is selected from:
  • Z 2 is absent, aryl or heteroaryl.
  • Z 2 is absent, phenyl, 5- membered heteroaryl or 6-membered heteroaryl.
  • Y 2 is a 2 to 8 atom saturated or unsaturated alkylene chain optionally containing 1 or 2 heteroatoms independently selected from O, N + (Ci -4alkyl)(Ci -4alkyl) and N-R 17 , wherein R 17 is H.
  • R 21 is H, or a substituent which is oxo.
  • X 3 is selected from:
  • Z 3 is absent or selected from:
  • Y 3 is a 2 to 7 atom saturated or unsaturated alkylene chain optionally containing 1 or 2 additional heteroatoms independently selected from: O, N + (CH3)(CH3), and N-H,
  • R 3 is H, or one or two substituents at any carbon atom of said chain Y 3 , or one or two substituents at any nitrogen atom of said chain Y 3 ,
  • substituents are independently selected from the group consisting of: -CH3, and oxo; or a pharmaceutically acceptable salt thereof.
  • X 3 is selected from:
  • Z 3 is absent or selected from:
  • Y is a 2 to 7 atom saturated or unsaturated alkylene chain optionally containing
  • R 3 is H, or one or two substituents at any carbon atom of said chain Y 3 , or one or two substituents at any nitrogen atom of said chain Y 3 , wherein said substituents are independently selected from the group consisting of: -CH3, and oxo.

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  • Immunology (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des dérivés salicylamide substitués. L'invention concerne particulièrement, des composés représentés par la formule (I) : dans laquelle R, R1, P, X, Y, et Z sont tels que définis dans la description; ou un sel pharmaceutiquement acceptable de ceux-ci. Les composés selon l'invention sont des inhibiteurs de CD73 et peuvent être utiles dans le traitement du cancer, de syndromes précancéreux et de maladies associées à l'inhibition de CD73, telles que le SIDA, le traitement du VIH, des maladies auto-immunes, des infections, l'athérosclérose, et une lésion de reperfusion ischémique. Par conséquent, l'invention concerne en outre des compositions pharmaceutiques comprenant un composé selon l'invention. L'invention concerne par ailleurs des procédés d'inhibition de l'activité de CD73 et le traitement de troubles associés à celui-ci à l'aide d'un composé selon l'invention ou d'une composition pharmaceutique comprenant un composé selon l'invention.
PCT/IB2018/056982 2017-09-12 2018-09-12 Composés chimiques WO2019053617A1 (fr)

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WO2023148129A1 (fr) * 2022-02-02 2023-08-10 F. Hoffmann-La Roche Ag Macrocycles d'imidazole pour le traitement d'une maladie auto-immune
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WO2022094012A1 (fr) * 2020-11-02 2022-05-05 Merck Sharp & Dohme Corp. Agonistes du récepteur de l'orexine d'urée macrocyclique
WO2023148129A1 (fr) * 2022-02-02 2023-08-10 F. Hoffmann-La Roche Ag Macrocycles d'imidazole pour le traitement d'une maladie auto-immune
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