WO2017153952A1 - Dérivés de 5-sulfamoyl-2-hydroxybenzamide - Google Patents

Dérivés de 5-sulfamoyl-2-hydroxybenzamide Download PDF

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WO2017153952A1
WO2017153952A1 PCT/IB2017/051399 IB2017051399W WO2017153952A1 WO 2017153952 A1 WO2017153952 A1 WO 2017153952A1 IB 2017051399 W IB2017051399 W IB 2017051399W WO 2017153952 A1 WO2017153952 A1 WO 2017153952A1
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Prior art keywords
sulfamoyl
chloro
hydroxy
fluoro
benzamide
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PCT/IB2017/051399
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English (en)
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Jerry Leroy Adams
Kevin J. Duffy
Todd L. Graybill
Michael Lee Moore
Christopher E. Neipp
Jeffrey M. Ralph
Michael Damien SQUIRE
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Glaxosmithkline Intellectual Property Development Limited
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Publication of WO2017153952A1 publication Critical patent/WO2017153952A1/fr

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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/22—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms
    • C07C311/29—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
    • 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
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
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    • C07C311/30—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/37—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
    • C07C311/38—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring having sulfur atoms of sulfonamide groups and amino groups bound to carbon atoms of six-membered rings of the same carbon skeleton
    • C07C311/44—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring having sulfur atoms of sulfonamide groups and amino groups bound to carbon atoms of six-membered rings of the same carbon skeleton having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
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    • C07C323/23—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
    • C07C323/46—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having at least one of the nitrogen atoms, not being part of nitro or nitroso groups, further bound to other hetero atoms
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    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three 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, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D231/42—Benzene-sulfonamido pyrazoles
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    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
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    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
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    • C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D263/34—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three 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, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D263/48—Nitrogen atoms not forming part of a nitro radical
    • C07D263/50—Benzene-sulfonamido oxazoles
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    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/82—Benzo [b] furans; Hydrogenated benzo [b] furans 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 carbon atoms of the hetero ring
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    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
    • C07D317/62—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring 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 atoms of the carbocyclic ring
    • C07D317/66—Nitrogen atoms not forming part of a nitro radical
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    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur 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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    • C07D333/36—Nitrogen atoms
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    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/62—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes 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 carbon atoms of the hetero ring
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    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
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    • C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
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    • C07C2601/14—The ring being saturated
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    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/08—One of the condensed rings being a six-membered aromatic ring the other ring being five-membered, e.g. indane

Definitions

  • the present invention relates to substituted salicylamide 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.
  • ATP extracellular adenosine triphosphate
  • 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, resulting 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 extracellular adenosine in the tumor microenvironment. Its expression is directly regulated by HIF1 a, consistent with the observed increase in extracellular adenosine under hypoxic conditions.
  • CD73 is overexpressed in multiple solid tumor types and leukaemias, including aggressive and difficult to treat tumours, such as glioblastoma and ovarian tumours.
  • T Reg T-regulatory cells
  • CD73 and CD39 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
  • small-molecule inhibitors of CD73 are expected to have the ability to relieve the adenosine-mediated immunosuppression of the tumor microenvironment and alone, or incombination with other agents, provide a treatment for cancer.
  • CD73 inhibitors are also expected to be useful for other diseases mediated by adenosine and its action on adenosine receptors.
  • CD73 inhibitors could 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 Formula (I):
  • R, R ⁇ and R ⁇ are as defined below; or a pharmaceutically acceptable salt thereof.
  • the present invention also relates to the discovery that the compounds of Formula (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 Formula (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 Formula (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 Formula (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 Formula (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 Formula (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 Formula (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 Formula (I); or a pharmaceutically acceptable salt thereof.
  • This invention also relates to a method of treating a disease state selected from: myocardial infarction, cardiovascular disease, atherosclerosis, ocular diseases, and arrhythmias, which comprises administering to a subject in need thereof an effective amount of a CD73 inhibiting compound of Formula (I); or a pharmaceutically acceptable salt thereof.
  • the invention also relates to a compound of Formula (I) or a pharmaceutically acceptable salt thereof for use in therapy.
  • the invention also relates to a compound of Formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of cancer.
  • the invention also relates to a compound of Formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of pre-cancerous syndromes.
  • the invention also relates to a compound of Formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of AIDS.
  • the invention also relates to a compound of Formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of autoimmune diseases.
  • the invention also relates to a compound of Formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of infections.
  • the invention also relates to a compound of Formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of atherosclerosis.
  • the invention also relates to a compound of Formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of ischemia-reperfusion injury.
  • the invention also relates to a compound of Formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of a disease state selected from: myocardial infarction, cardiovascular disease, atherosclerosis, ocular diseases, and arrhythmias.
  • a disease state selected from: myocardial infarction, cardiovascular disease, atherosclerosis, ocular diseases, and arrhythmias.
  • the invention also relates to the use of a compound of Formula (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 Formula (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 Formula (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 Formula (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 Formula (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 Formula (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 Formula (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 Formula (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 Formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of a disease state selected from: myocardial infarction, cardiovascular disease, atherosclerosis, ocular diseases, and arrhythmias.
  • a disease state selected from: myocardial infarction, cardiovascular disease, atherosclerosis, ocular diseases, and arrhythmias.
  • pharmaceutical compositions that comprise a pharmaceutical carrier and a compound of Formula (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 Formula (I) or a pharmaceutically acceptable salt thereof; and (ii) at least one anti-neoplastic agent.
  • This invention relates to novel compounds of Formula (I) and to the use of compounds of Formula (I) in the methods of the invention:
  • R is selected from:
  • -N(H)Ci-4alkyl substituted with from 1 to 9 substituents independently selected from: fluoro, chloro, bromo, oxo, -OH, and -CN,
  • R 2 are independently selected from:
  • Ci-6alkyl substituted with from one to five substituents independently selected from: fluoro, chloro, oxo, -OH, and -NH2,
  • -N(H)Ci -6alkyl substituted with from 1 to 9 substituents independently selected from: fluoro, chloro, oxo, -OH, -NH2, phenyl, substituted phenyl, heteroaryl, and substituted heteroaryl;
  • R310 and R320 are independently selected from hydrogen and C-
  • R320 are taken together with the nitrogen to which they are attached to form a 5 to 6 member heterocyclic ring containing up to one other heteroatom selected from oxygen and nitrogen;
  • R 0 is selected from:
  • Ci -6alkyl substituted with from 1 to 5 substituents independently selected from: fluoro, chloro, bromo, iodo, oxo, Cl -4alkyloxy, -OH, -COOH, and
  • -N(H)Ci-4alkyl substituted with from 1 to 5 substituents independently selected from: fluoro, chloro, bromo, oxo, -OH, and -CN,
  • R 2 are independently selected from:
  • Ci-6alkyl substituted with from one to five substituents independently selected from: fluoro, chloro, oxo, -OH, and -NH2,
  • R31 1 and R321 are independently selected from hydrogen and C-
  • R321 are taken together with the nitrogen to which they are attached to form a 5 to 6 member heterocyclic ring containing up to one other heteroatom selected from oxygen and nitrogen;
  • R is selected from:
  • Ci-6alkoxy substituted with from 1 to 5 substituents independently selected from: fluoro and phenyl,
  • -N(H)Ci-4alkyl substituted with from 1 to 5 substituents independently selected from: fluoro, oxo, and -OH, -N(Cl-4alkyl)2,
  • R 22 are independently selected from:
  • Ci-6alkyl substituted with from one to five substituents independently selected from: fluoro, chloro, oxo, -OH, and -NH2,
  • -N(H)Ci -6alkyl substituted with from one to five substituents independently selected from: fluoro, chloro, oxo, -OH, -NH2, phenyl, substituted phenyl, heteroaryl, and substituted heteroaryl; where,
  • R312 an( R322 a re independently selected from hydrogen and C-
  • R322 are taken together with the nitrogen to which they are attached to form a 5 to 6 member heterocyclic ring containing up to one other heteroatom selected from oxygen and nitrogen;
  • R 3 and R 32 are independently selected from:
  • Ci-6alkyl substituted with from one to five substituents independently selected from: fluoro, chloro, oxo, -OH, and -NH2,
  • -N(H)Ci -6alkyl substituted with from one to five substituents independently selected from: fluoro, chloro, oxo, -OH, -NH2, phenyl, substituted phenyl, heteroaryl, and substituted heteroaryl;
  • R323 are taken together with the nitrogen to which they are attached to form a 5 to 6 member heterocyclic ring containing up to one other heteroatom selected from oxygen and nitrogen;
  • R is selected from:
  • Ci-6alkyl substituted with from one to five substituents independently selected from: fluoro, chloro, oxo, -OH, and -NH2,
  • -N(H)Ci -6alkyl substituted with from one to five substituents independently selected from: fluoro, chloro, oxo, -OH, -NH2, phenyl, and phenyl subsitituted with from one to five substituents independently selected from: fluoro, chloro, bromo and iodo; and
  • R 4 , R 42 , and R 43 are independently selected from:
  • Ci-6alkyl substituted with from 1 to 5 substituents independently selected from: fluoro, and -OH,
  • R 4U is selected from:
  • R 4 a is selected from:
  • Ci-6alkyl substituted with from 1 to 5 substituents independently selected from: fluoro, and -OH,
  • R 42a is selected from:
  • Ci-6alkyl substituted with from 1 to 5 substituents independently selected from: fluoro, and -OH,
  • R 43a is selected from:
  • Ci-6alkyl substituted with from 1 to 5 substituents independently selected from: fluoro, and -OH,
  • R 4UD is selected from:
  • R 4 b is selected from:
  • R 42b is selected from:
  • R 43b is selected from: hydrogen,
  • the A ring contains an optional double bond where indicated by the dotted line,
  • R 50 is selected from:
  • Ci -6alkyl substituted with from one to five substituents independently selected from: fluoro, chloro, oxo, -OH, and -NH2,
  • R 5 is selected from:
  • Ci-6alkyl substituted with from 1 to 5 substituents independently selected from: fluoro, and -OH,
  • R 52 is absent or selected from:
  • Ci-6alkyl substituted with from 1 to 5 substituents independently selected from: fluoro, and -OH,
  • R 53 is selected from:
  • the A ring contains an optional double bond where indicated by the dotted line,
  • R 50a is selected from:
  • Ci-6alkyl substituted with from one to five substituents independently selected from: fluoro, chloro, and -OH,
  • R 5 a is selected from:
  • Ci-6alkyl substituted with from 1 to 5 substituents independently selected from: fluoro, and -OH,
  • R 52a is absent or selected from:
  • Ci-6alkyl substituted with from 1 to 5 substituents independently selected from: fluoro, and -OH,
  • R 53a is selected from:
  • Ci-6alkyl substituted with from 1 to 5 substituents independently selected from: fluoro, and -OH,
  • the A ring contains an optional double bond where indicated by the dotted line,
  • R 50b is selected from:
  • R 5 b is selected from:
  • R 52b is absent or selected from:
  • R 53b is selected from:
  • Ci -6alkyl substituted with from one to five substituents independently selected from: fluoro, chloro, oxo, -OH, and -NH2,
  • R 64 are independently selected from:
  • Ci-6alkyl substituted with from 1 to 5 substituents independently selected from: fluoro, and -OH,
  • R 60a is selected from:
  • Ci-6alkyl substituted with from one to five substituents independently selected from: fluoro, chloro, and -OH,
  • R 6i a R 62a R 63a and R 64a gre independently selected from: hydrogen,
  • Ci-6alkyl substituted with from 1 to 5 substituents independently selected from: fluoro, and -OH,
  • R 60b is selected from:
  • R 61 b is selected from:
  • R 63b is selected from:
  • R 64b is selected from:
  • 6-indolyl, 6-indazolyl, and 5-benzimidazolyl each of which are optionall substituted with from one to five substituents independently selected from:
  • R 7 is selected from:
  • -N(H)Ci -6alkyl substituted with from one to five substituents independently selected from: fluoro, chloro, oxo, -OH, -NH2, phenyl, substituted phenyl, heteroaryl, and substituted heteroaryl; and
  • R 72 is selected from:
  • R is selected from 6-indolyl, 6-indazolyl and 5-benzimidazolyl, each of which is substituted with one or two substituents independently selected from Ci- 6 alkyl, hydroxyl and Cl -6alkoxy.
  • R is selected from 6-indolyl, 6-indazolyl and 5-benzimidazolyl, each of which is substituted with one or two substituents independently selected from Ci- 4 alkyl.
  • R is selected from 6-indolyl, 6-indazolyl and 5-benzimidazolyl, each of which is substituted with one or two substituents independently selected from Ci- 2 alkyl.
  • R is selected from 6-indolyl, 6-indazolyl and 5-benzimidazolyl, each of which is substituted with one or two substituents independently selected from Ci- 2 alkyl.
  • R is selected from 6-indolyl, 6-indazolyl and 5-benzimidazolyl each of which is substituted with a Ci_ 2 alkyl group.
  • R is selected from 2-methyl-1 H-indol-6-yl, 2-ethyl-1 H-indol-6-yl, 3-methyl-1 H-indol-6-yl 3-ethyl-1 H-indol-6-yl, 3-methyl-1 H-indazol-6-yl, 3-ethyl-1 H-indazol- 6-yl, 2-methyl-1 /-/-benzo[d]imidazol-5-yl and 2-ethyl-1 /-/-benzo[d]imidazol-5-yl.
  • R is selected from 3-ethoxyphenyl, 4-methoxyphenyl,
  • R is selected from 4-benzyloxyphenyl, 3- phenylsulfonamidophenyl, 4-phenoxyphenyl, oxazol-phenyl, 4-cyclopentyloxyphenyl and cyclohexyloxyphenyl.
  • R is selected from 2,3-dihydro-1 H-inden, naphthalene, quinolin, benzo[b]thiophen, 1 H-pyrazol, benzofuran, indolin, 3,4dihydroisoquinoline-2(1 H)- carboxylate, 1 H-pyrrolo[2,3-b]pyridine-6-yl, thiophen, benzo[d][1 ,3]dioxol-5-yl, 1 ,2,3,4tetrahydroquinolin, 1 H-pyrrolo[2,3-b]pyridine-5-yl, imidazo[1 ,2-a]pyridine, 5- chlorothiophen, 1 -phenyl-1 H-pyrazol, methylthiophen and pyrazol.
  • R is selected from 1 H-indol-6-yl, 1 H-indol-5-yl, 2-methyl-1 H- indol-6-yl, 1 -methyl-1 H-indol-6-yl, 3-methyl-1 H-indol-6-yl, 2-methyl-1 H-indol-5-yl, 1 -methyl- 1 H-indol-5-yl, 3-methyl-1 H-indol-5-yl, 4-fluoro-1 H-indol-5-yl, 2-oxoindolin-6-yl, 4-fluoro-1 H- indol-6-yl, 3-ethyl-1 H-indol-6-yl, 2-ethyl-1 H-indol-6-yl, 7-fluoro-1 H-indol-5-yl, 5-chloro-1 H- indol-6-yl, 2-cyclopropyl-1 H-indol-6-yl, 1 H-indol,
  • R is selected from 1 H-benzo[d]imidazol-5-yl, 2-methyl-1 H- benzo[d]imidazol-5-yl, 2-ethyl-1 H-benzo[d]imidazol-5-yl, 1 H-benzo[d]imidazol-7-yl, 2-ethyl- 4-fluoro-1 H-benzo[d]imidazol-5-yl, 2-amino-1 H-benzo[d]imidazol-5-yl, 4-fluoro-2-methyl- 1 H-benzo[d]imidazol-5-yl, 4-fluoro-1 H-benzo[d]imidazol-5-yl, 2-isopropyl-1 H- benzo[d]imidazol-6-yl, 4-chloro-1 H-benzo[d]imidazol-5-yl, 1 H-benzo[d]imidazol-6-yl and 7- methyl-1 H-benzo[d]imidazol-5--
  • R is selected from 1 H-indazol-5-yl, 1 H-indazol-6-yl and 3-ethyl- 1 H-indazol-6-yl.
  • R 1 is selected from hydrogen, N(H)Ci- 6 alkyl or N(H)Ci- 6 alkyl substituted with from one to five substituents independently selected from F, CI, oxo, OH, NH 2 , phenyl, substituted phenyl, heteroaryl and substituted heteroaryl, where substituted means that the subject chemical moiety has one or two substituents, selected from the group consisting of: -CH3, -CH2F, -CHF2, -CF3, hydroxy, cyano, fluoro, chloro, bromo, iodo, amino, C-
  • R 1 is selected from hydrogen, N(H)Ci- 6 alkyl or N(H)Ci- 6 alkyl substituted with one or two substituents independently selected from F, CI, oxo, OH, NH 2 , phenyl, substituted phenyl, heteroaryl and substituted heteroaryl, where substituted means that the subject chemical moiety has one or two substituents, selected from the group consisting of: -CH3, -CH2F, -CHF2, -CF3, hydroxy, cyano, fluoro, chloro, bromo, iodo, amino, C-
  • R 1 is selected from hydrogen, N(H)Ci- 4 alkyl or N(H)Ci- 4 alkyl substituted with one or two substituents independently selected from F, CI, oxo, OH, NH2, phenyl, substituted phenyl, heteroaryl and substituted heteroaryl, where substituted means that the subject chemical moiety has one or two substituents, selected from the group consisting of: -CH3, -CH2F, -CHF2, -CF3, hydroxy, cyano, fluoro, chloro, bromo, iodo, amino, C-
  • R 1 is selected from hydrogen, N(H)Ci- 4 alkyl or N(H)Ci- 4 alkyl substituted with one substituent selected from F, CI, OH, NH 2 , phenyl, substituted phenyl, heteroaryl and substituted heteroaryl, where substituted means that the subject chemical moiety has one or two substituents, selected from the group consisting of: -CH3, -CH2F, - CHF2, -CF3, hydroxy, cyano, fluoro, chloro, bromo, iodo, amino, C-
  • R 1 is selected from hydrogen, N(H)Ci_ alkyl or N(H)Ci_ alkyl substituted with one substituent selected from OH, NH 2 , phenyl, substituted phenyl, heteroaryl and substituted heteroaryl, where substituted means that the subject chemical moiety has one or two substituents, selected from the group consisting of: -CH3, -CH2F, - CHF2, -CF3, hydroxy, cyano, fluoro, chloro, bromo, iodo, amino, C-
  • R 1 is selected from hydrogen, N(H)Ci- 2 alkyl or N(H)Ci- 2 alkyl substituted with one or two substituents independently selected from fluoro, chloro, oxo, OH, NH 2 , phenyl, substituted phenyl, heteroaryl and substituted heteroaryl, where substituted means that the subject chemical moiety has one or two substituents, selected from the group consisting of: -CH3, -CH2F, -CHF2, -CF3, hydroxy, cyano, fluoro, chloro, bromo, iodo, amino, C-
  • R 1 is selected from hydrogen, N(H)Ci- 2 alkyl or N(H)Ci- 2 alkyl substituted with one substituent selected from fluoro, chloro, OH, NH 2 , phenyl, substituted phenyl, heteroaryl and substituted heteroaryl, where substituted means that the subject chemical moiety has one or two substituents, selected from the group consisting of: -CH3, -CH2F, -CHF2, -CF3, hydroxy, cyano, fluoro, chloro, bromo, iodo, amino, C-
  • R 1 is selected from hydrogen, N(H)Ci- 2 alkyl or N(H)Ci- 2 alkyl substituted with one substituent selected from OH, NH 2 , phenyl or substituted phenyl.
  • R 1 is selected from hydrogen, NHCH 2 CH 3 , NHCH 2 CH 2 OH, NHCH 2 CH 2 NH 2 , NHCH 2 Ph, NHCH(CH 3 )Ph or (3-chlorobenzyl)amino.
  • R 1 is hydrogen
  • R 2 is selected from hydrogen, fluoro, chloro, bromo, Ci_ 6 alkyl or
  • Ci- 6 alkyl substituted with from one to five substituents independently selected from fluoro, chloro, oxo, OH or NH 2 .
  • R 2 is selected from hydrogen, fluoro, chloro, bromo, Ci_ 6 alkyl or Ci_6alkyl substituted with from one to three substituents independently selected from fluoro, oxo or NH 2 .
  • R 2 is selected from hydrogen, fluoro, chloro, bromo, Ci_ 4 alkyl or Ci- 4 alkyl substituted with from one to five substituents independently selected from fluoro, CI, oxo, OH or NH 2 .
  • R 2 is selected from hydrogen, fluoro, chloro, bromo, Ci_ alkyl or Ci- 4 alkyl substituted with from one to three substituents independently selected from fluoro, oxo or NH 2 .
  • R 2 is selected from hydrogen, fluoro, chloro, bromo, Ci_ 2 alkyl or Ci_ 2 alkyl substituted with from one to five substituents independently selected from fluoro, chloro, oxo, OH or NH 2 .
  • R 2 is selected from hydrogen, fluoro, chloro, bromo, Ci_ 2 alkyl or Ci- 2 alkyl substituted with from one to three substituents independently selected from F, oxo or NH 2 .
  • R 2 is selected from hydrogen, fluoro, chloro, bromo, methyl, ethyl, isopropyl, CF 3 or CONH 2 .
  • R 2 is hydrogen. In a further specific embodiment R 2 is methyl. In a further specific embodiment R 2 is chloro.
  • R 1 is hydrogen and R 2 is selected from methyl or CI.
  • pharmaceutically acceptable salts, of the compounds according to Formula (I) may be prepared. Indeed, in certain embodiments of the invention pharmaceutically acceptable salts of the compounds according to Formula (I) may be preferred over the respective free or unsalted compound. Accordingly, the invention is further directed to pharmaceutically acceptable salts, of the compounds according to Formula (I). The invention is further directed to free or unsalted compounds of Formula (I).
  • the compounds according to Formula (I) may contain one or more asymmetric centers (also referred to as a chiral center) and may, therefore, exist as individual enantiomers, diastereomers, or other stereoisomeric forms, or as mixtures thereof.
  • Chiral centers such as chiral carbon atoms, may be present in a substituent such as an alkyl group.
  • compounds according to Formula (I) containing one or more chiral centers may be used as racemic mixtures, enantiomerically enriched mixtures, or as enantiomerically pure individual stereoisomers.
  • the compounds according to Formula (I) may also contain double bonds or other centers of geometric asymmetry. Where the stereochemistry of a center of geometric asymmetry present in Formula (I), or in any chemical structure illustrated herein, is not specified, the structure is intended to encompass the trans (E) geometric isomer, the cis (Z) geometric isomer, and all mixtures thereof. Likewise, all tautomeric forms are also included in Formula (I) whether such tautomers exist in equilibrium or predominately in one form.
  • the compounds of Formula (I) or pharmaceutically acceptable salts, thereof may exist in solid or liquid form.
  • the compounds of the invention may exist in crystalline or noncrystalline form, or as a mixture thereof.
  • pharmaceutically acceptable solvates may be formed wherein solvent molecules are incorporated into the crystalline lattice during crystallization. Accordingly, the compounds of Formula (I) and pharmaceutically acceptable salts thereof may exist in solvated and unsolvated forms.
  • polymorphs may have the same chemical composition but differ in packing, geometrical arrangement, and other descriptive properties of the crystalline solid state. Polymorphs, therefore, may have different physical properties such as shape, density, hardness, deformability, stability, and dissolution properties. Polymorphs typically exhibit different melting points, IR spectra, and X-ray powder diffraction patterns, which may be used for identification.
  • polymorphs may be produced, for example, by changing or adjusting the reaction conditions or reagents, used in making the compound. For example, changes in temperature, pressure, or solvent may result in polymorphs. In addition, one polymorph may spontaneously convert to another polymorph under certain conditions. Accordingly, the compounds of Formula (I) and pharmaceutically acceptable salts thereof may exist in a single crystalline form or in different polymorphic forms.
  • Alkyl refers to a hydrocarbon chain having the specified number of "member atoms".
  • C ⁇ -CQ alkyl refers to an alkyl group having from 1 to 6 member atoms.
  • Alkyl groups may be saturated, unsaturated, straight or branched. Representative branched alkyl groups have one, two, or three branches.
  • Alkyl includes but is not limited to: methyl, ethyl, ethylenyl, propyl (n-propyl and isopropyl), butenyl, butyl (n-butyl, isobutyl, and t-butyl), pentyl and hexyl.
  • Alkoxy refers to an -O-alkyl group wherein “alkyl” is as defined herein.
  • -C4alkoxy refers to an alkoxy group having from 1 to 4 carbon member atoms.
  • Examples of such groups include but is not limited to: methoxy, ethoxy, propoxy, butoxy, and t-butoxy.
  • Aryl refers to an aromatic hydrocarbon ring system.
  • Aryl groups are monocyclic, bicyclic, and tricyclic ring systems having a total of five to fourteen ring member atoms, wherein at least one ring system is aromatic and wherein each ring in the system contains 3 to 7 member atoms, such as but no limited to: phenyl, dihydroindene, naphthalene, tetrahydronaphthalene and biphenyl.
  • aryl is selected from: phenyl, dihydroindene and naphthalene.
  • Bicycloheteroaryl refers to two fused ring systems, wherein at least one ring system is aromatic, containing from 1 to 6 heteroatoms as member atoms. Bicycloheteroaryl groups containing more than one heteroatom may contain different heteroatoms. Bicycloheteroaryl rings have from 6 to 1 1 member atoms.
  • Bicycloheteroaryl includes but is not limited to: 1 /-/-pyrrolo[3,2-c]pyridine, 1 /-/-pyrrolo[2,3-Jb]pyridine, 1 H-pyrazolo[4,3- c] pyridine, 1 H-pyrazolo[3,4-d]pyrimidine, 1 H-pyrrolo[2,3-d]pyrimidine, 7H-pyrrolo[2,3- d]pyrimidine, thieno[3,2-c]pyridine, thieno[2,3-d]pyrimidine, furo[2,3-c]pyridine, furo[2,3- d] pyrimidine, indolyl, isoindolyl, indolizinyl, indazolyl, purinyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, pteridinyl, cinnolinyl, azabenzimidazoly
  • Bicycloheteroaryl includes: 1 /-/-pyrrolo[2,3-Jb]pyridine, indolyl, benzimidazolyl, benzothienyl, imidazo[1 ,2-a]pyridine, tetrahydroquinoline, dihydroisoquinoline, dihydrobenzodioxol, indazole and indoline.
  • Bicycloheteroaryl includes benzotriazolyl.
  • Cycloalkyl refers to a saturated or unsaturated non aromatic hydrocarbon ring having from three to seven carbon atoms. Cycloalkyl groups are monocyclic ring systems. For example, C3-C7 cycloalkyl refers to a cycloalkyl group having from 3 to 7 member atoms. Examples of cycloalkyl as used herein include but is not limited to: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclobutenyl, cyclopentenyl, cyclohexenyl and cycloheptyl. Suitably cycloalkyl is selected from: cyclopropyl, cyclopentyl and cyclohexyl.
  • Heteroaryl refers to a monocyclic aromatic 4 to 8 member ring containing from 1 to 7 carbon atoms and containing from 1 to 4 heteroatoms, provided that when the number of carbon atoms is 3, the aromatic ring contains at least two heteroatoms. Heteroaryl groups containing more than one heteroatom may contain different heteroatoms.
  • Heteroaryl includes but is not limited to: pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, furanyl, furazanyl, thienyl, triazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, tetrazinyl.
  • heteroaryl is selected from: pyrazolyl, oxazolyl and thienyl.
  • Heteroatom refers to a nitrogen, sulphur or oxygen atom.
  • substituted as used herein, unless otherwise defined, is meant that the subject chemical moiety has from one to five substituents, suitably from one to three substituents, selected from the group consisting of: -CO2R 200 , -CONR 2 °R 220 , -S0 2 C-
  • substituted as used herein is meant that the subject chemical moiety has from one to three substituents, selected from the group consisting of: C-
  • C4alkyl hydroxyC-
  • substituted as used herein is meant that the subject chemical moiety has one or two substituents, selected from the group consisting of: -CH3, -CH2F, - CHF2, -CF3, hydroxy, cyano, fluoro, chloro, bromo, iodo, amino, C-
  • ACN acetonitrile
  • AIBN azobis(isobutyronitrile)
  • BINAP (2,2'-bis(diphenylphosphino)-1 ,1 '-binaphthyl
  • BOP Benzotriazole-l -yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate
  • CSF cesium fluoride
  • DCM dichloromethane
  • DDQ 2,3-Dichloro-5,6-dicyano-1 ,4-benzoquinone
  • ATP adenosine triphosphate
  • BSA bovine serum albumin
  • C18 refers to 18-carbon alkyl groups on silicon in HPLC stationary phase
  • DIPEA Human's base, /V-ethyl-W-(1 -methylethyl)-2-propanamine
  • DMEDA ( ⁇ /, ⁇ /'-dimethylethylenediamine
  • DPPA diphenyl phosphoryl azide
  • EDTA ethylenediaminetetraacetic acid
  • HEPES (4-(2-hydroxyethyl)-1 -piperazine ethane sulfonic acid);
  • HATU (0-(7-Azabenzotriazol-1 -yl)-/V,/V,/V',/V'-tetramethyluronium hexafluorophosphate); HOAt (1 -hydroxy-7-azabenzotriazole);
  • HMDS hexamethyldisilazide
  • Hunig's Base ( ⁇ /,/V-Diisopropylethylamine);
  • IPA isopropyl alcohol
  • KHMDS potassium hexamethyldisilazide
  • LAH lithium aluminum hydride
  • mCPBA m-chloroperbezoic acid
  • NaHMDS sodium hexamethyldisilazide
  • NBS (/V-bromosuccinimide
  • PE petroleum ether
  • TFA trifluoroacetic acid
  • the compounds according to Formula (I) are prepared using conventional organic synthetic methods.
  • a suitable synthetic route is depicted below in the following general reaction scheme. All of the starting materials are commercially available or are readily prepared from commercially available starting materials by those of skill in the art.
  • a substituent described herein is not compatible with the synthetic methods described herein, the substituent may be protected with a suitable protecting group that is stable to the reaction conditions.
  • the protecting group may be removed at a suitable point in the reaction sequence to provide a desired intermediate or target compound.
  • suitable protecting groups and the methods for protecting and de-protecting different substituents using such suitable protecting groups are well known to those skilled in the art; examples of which may be found in T. Greene and P. Wuts, Protecting Groups in Organic Synthesis (4th ed.), John Wiley & Sons, NY (2006).
  • a substituent may be specifically selected to be reactive under the reaction conditions used. Under these circumstances, the reaction conditions convert the selected substituent into another substituent that is either useful as an intermediate compound or is a desired substituent in a target compound.
  • r and r "2 represents all combinations of R, R and R 2 disclosed herein.
  • Salicylamide-5-sulfonyl chlorides (A1) are conveniently prepared by chlorosulfonylation of salicylamides with chlorosulfonic acid. Salicylamides are either dissolved in a mixture of chlorosulfonic acid and thionyl chloride at 0 °C, allowed to warm to RT and stirred overnight, or dissolved in excess chlorosulfonic acid at RT and stirred at 55 °C overnight. Quenching the reaction by careful addition of the reaction mixture to ice water affords the sulfonyl chloride as a solid, which is collected by filtration, washed, dried, and used without further purification.
  • the salicylamide sulfonamides (A2) are prepared by treating the sulfonyl chloride (A1) with an appropriate arylamine in either pyridine, DCM, or a mixture of DCM and pyridine. Extractive workup followed by silica gel column chromatography or preparative HPLC as necessary affords the desired salicylamide sulfonamides (A2).
  • the compounds according to Formula (I) and pharmaceutically acceptable salts thereof are inhibitors of CD73. These compounds are potentially useful in the treatment of conditions wherein the underlying pathology is attributable to CD73, for example, cancer and pre-cancerous syndromes. Accordingly, in another aspect the invention is directed to methods of treating such conditions.
  • the present invention relates to a method for treating breast cancer, including inflammatory breast cancer, ductal carcinoma, and lobular carcinoma.
  • the present invention relates to a method for treating colon cancer.
  • the present invention relates to a method for treating pancreatic cancer, including insulinomas, adenocarcinoma, ductal adenocarcinoma, adenosquamous carcinoma, acinar cell carcinoma, and glucagonoma.
  • the present invention relates to a method for treating skin cancer, including melanoma, including metastatic melanoma.
  • the present invention relates to a method for treating lung cancer including small cell lung cancer, non-small cell lung cancer, squamous cell carcinoma, adenocarcinoma, and large cell carcinoma.
  • the present invention relates to a method for treating cancers selected from the group consisting of: cancers of the lung, bone, pancreas, skin, head, neck, uterus, ovaries, stomach, colon, breast, esophagus, small intestine, bowel, endocrine system, thyroid glad, parathyroid gland, adrenal gland, urethra, prostate, penis, testes, ureter, bladder, kidney or liver; rectal cancer; cancer of the anal region; carcinomas of the fallopian tubes, endometrium, cervix, vagina, vulva, renal pelvis, renal cell; sarcoma of soft tissue; myxoma; rhabdomyoma; fibroma; lipoma; teratoma; cholangiocarcinoma; hepatoblastoma; angiosarcoma; hemagioma; hepatoma; fibrosarcoma; chondrosarcoma; myelom
  • the present invention relates to a method for treating cancers selected from the group consisting of brain (gliomas), glioblastomas, astrocytomas, glioblastoma multiforme, Bannayan-Zonana syndrome, Cowden disease, Lhermitte-Duclos disease, Wilm's tumor, Ewing's sarcoma, Rhabdomyosarcoma, ependymoma, medulloblastoma, head and neck, kidney, liver, melanoma, ovarian, pancreatic, adenocarcinoma, ductal adenocarcinoma, adenosquamous carcinoma, acinar cell carcinoma, glucagonoma, insulinoma, prostate, sarcoma, osteosarcoma, giant cell tumor of bone, thyroid, lymphoblastic T cell leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia, hairy-cell leukemia
  • the present invention relates to a method for treating pre-cancerous syndromes in a mammal, including a human, wherein the pre-cancerous syndrome is selected from: cervical intraepithelial neoplasia, monoclonal gammapathy of unknown significance (MGUS), myelodysplasia syndrome, aplastic anemia, cervical lesions, skin nevi (pre-melanoma), prostatic intraepithleial (intraductal) neoplasia (PIN), Ductal Carcinoma in situ (DCIS), colon polyps and severe hepatitis or cirrhosis.
  • MGUS monoclonal gammapathy of unknown significance
  • MUS monoclonal gammapathy of unknown significance
  • myelodysplasia syndrome aplastic anemia
  • cervical lesions aplastic anemia
  • cervical lesions skin nevi
  • pre-melanoma pre-melanoma
  • PIN prostatic intraepithlei
  • the compounds of the invention can be used to overcome Tcell tolerance.
  • Compounds of the invention can also be used to increase or enhance an immune response, including increasing the immune response to an antigen; to improve immunization, including increasing vaccine efficacy; and to increase inflammation.
  • the compounds of the invention can be used to enhance the immune response to vaccines including, but not limited, Listeria vaccines, oncolytic viarl vaccines, and cancer vaccines such as GV AX® (granulocyte-macrophage colony-stimulating factor (GM-CF) gene-transfected tumor cell vaccine).
  • GV AX® granulocyte-macrophage colony-stimulating factor (GM-CF) gene-transfected tumor cell vaccine.
  • compounds of the invention are used to enhance the immune response in an immunosuppressed subject, such as a subject infected with an immunodeficiency virus (e.g., HIV-1 or HIV-2).
  • an immunodeficiency virus e.g., HIV-1 or HIV-2
  • compounds of the invention are used to enhance the immune response in a subject infected with a pathogen such as a bacterial, viral, or fungal pathogen, to facilitate destruction of the pathogen in the subject.
  • Immune deficiencies associated with immune deficiency diseases, immune suppressive medical treatment, acute and/or chronic infection, and aging can be treated using the compounds disclosed herein.
  • Compounds of the invention can be used to stimulate the immune system of patients suffering from medical treatment or iatrogenically induced immune suppression, including those who have undergone bone marrow transplants, chemotherapy, and/or radiotherapy.
  • compounds of the invention are used to increase or enhance an immune response to an antigen by providing adjuvant activity.
  • at least one antigen or vaccine is administered to a subject in conjunction with at least one compound of the invention to prolong an immune response to the antigen or vaccine.
  • Therapeutic compositions are also provided which include at least one antigenic agent or vaccine component, including, but not limited to, viruses, bacteria, and fungi, or portions thereof, proteins, peptides, tumor-specific antigens, and nucleic acid vaccines, in combination with a compound of the invention.
  • Compounds of the invention can be used as antidepressants, to stimulate cognitive functions, and to improve motor impairment due to neurodegenerative diseases such as Parkinson's disease.
  • Compounds of the present invention can be used to treat infections, in particular infections caused by pathogens that exploit extonucleotidases in order to generate adenosine-rich environments to escape immune surveillance and infections associated with inflammation.
  • Diseases and disorders treatable with compounds of the invention include infections, including but not limited to, parasitic, fungal, bacterial, and viral infections, including, but not limited to, Leishmania, Trypanosoma, Toxoplasma, Trichomonas, Giardia, Candida, Legionellapneumophila, Staphylococcus aureus, Bacillus anthracis, Streptococcus sanguinis, Pseudomonas aeruginosa, and AIDS.
  • Compounds of the invention can be used to treat sepsis, decrease or inhibit bacterial growth, reduce inflammatory cytokine levels, and lessen organ injury.
  • diseases and disorders treatable with compounds of the invention include, but are not limited to, neurological, CNS, respiratory, neurodegenerative, inflammatory, cardiovascular, gastrointestinal, ophthalmologic, connective tissue, and renal diseases and disorders.
  • Diseases and disorders treatable with compounds of the invention also include, but are not limited to, AIDS, HIV infection, extra pyramidal syndrome (EPS), dystonia, primary (idiopathic) dystonia, akathisia, pseudoparkinsonism, tardive dyskinesia, restless leg syndrome (RLS), periodic limb movement in sleep (PLMS), attention deficit disorders, including attention deficit hyperactivity disorder (ADHD), depression, anxiety, cognitive function diseases, cognitive decline, Parkinson's disease, senile dementia, Alzheimer's disease, Huntington's disease, Wilson's disease, psychiatric disorders, Hallervorden-Spatz disease, progressive pallidal atrophy, cerebral ischemia, hemorrhagic stroke, neonatal ischemia and hypoxia, subarachnoid hemorrhage, traumatic brain injury, cardiac arrest, multiple sclerosis, diabetes, type II diabetes, diabetes mellitus, insulin resistance, risk of diabetes, epilepsy, asthma, chronic obstructive pulmonary disease (COPD), fibrosis, dermal
  • diseases and disorders treatable with compounds of the invention are insulin resistance, diabetes and risk of diabetes.
  • compounds of the invention are used to reduce insulin resistance, reduce the risk of diabetes, decrease or inhibit statin-induced adenosine production, or reduce or decrease increases in blood glucose caused by a statin in a subject taking a statin.
  • compounds of the invention are used to treat diabetes in a subject taking a statin or to prevent diabetes in a subject taking a statin.
  • Methods of the invention include decreasing, reducing, inhibiting, suppressing, limiting or controlling in the subject elevated blood glucose levels.
  • methods of the invention include increasing, stimulating, enhancing, promoting, inducing or activating in the subject insulin sensitivity.
  • Statins include, but are not limited to atorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin, pitavastatin, pravastatin, rousuvastatin and simvastatin.
  • the methods of treatment of the invention comprise administering an effective amount of a compound according to Formula (I) or a pharmaceutically acceptable salt, thereof to a patient in need thereof.
  • treating and derivatives thereof as used herein, is meant therapeutic therapy.
  • Prophylactic therapy is appropriate when a subject has, for example, a strong family history of cancer or is otherwise considered at high risk for developing cancer, or when a subject has been exposed to a carcinogen.
  • the term "effective amount” and derivatives thereof means that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal or human that is being sought, for instance, by a researcher or clinician.
  • therapeutically effective amount means any amount which, as compared to a corresponding subject who has not received such amount, results in improved treatment, healing, prevention, or amelioration of a disease, disorder, or side effect, or a decrease in the rate of advancement of a disease or disorder.
  • the term also includes within its scope amounts effective to enhance normal physiological function.
  • patient or “subject” refers to a human or other animal.
  • patient or subject is a human.
  • the compounds of Formula (I) or pharmaceutically acceptable salts thereof may be administered by any suitable route of administration, including systemic administration.
  • Systemic administration includes oral administration, and parenteral administration, Parenteral administration refers to routes of administration other than enteral, transdermal, or by inhalation, and is typically by injection or infusion.
  • Parenteral administration includes intravenous, intramuscular, and subcutaneous injection or infusion.
  • the compounds of Formula (I) or pharmaceutically acceptable salts thereof may be administered once or according to a dosing regimen wherein a number of doses are administered at varying intervals of time for a given period of time. For example, doses may be administered one, two, three, or four times per day. Doses may be administered until the desired therapeutic effect is achieved or indefinitely to maintain the desired therapeutic effect. Suitable dosing regimens for a compound of the invention depend on the pharmacokinetic properties of that compound, such as absorption, distribution, and half- life, which can be determined by the skilled artisan.
  • suitable dosing regimens including the duration such regimens are administered, for a compound of the invention depend on the condition being treated, the severity of the condition being treated, the age and physical condition of the patient being treated, the medical history of the patient to be treated, the nature of concurrent therapy, the desired therapeutic effect, and like factors within the knowledge and expertise of the skilled artisan. It will be further understood by such skilled artisans that suitable dosing regimens may require adjustment given an individual patient's response to the dosing regimen or over time as individual patient needs change.
  • a prodrug of a compound of the invention is a functional derivative of the compound which, upon administration to a patient, eventually liberates the compound of the invention in vivo.
  • Administration of a compound of the invention as a prodrug may enable the skilled artisan to do one or more of the following: (a) modify the onset of the compound in vivo; (b) modify the duration of action of the compound in vivo; (C) modify the transportation or distribution of the compound in vivo; (d) modify the solubility of the compound in vivo; and (e) overcome or overcome a side effect or other difficulty encountered with the compound.
  • esters can be employed, for example methyl, ethyl, and the like for -COOH, and acetate maleate and the like for -OH, and those esters known in the art for modifying solubility or hydrolysis characteristics.
  • the compounds of Formula (I) and pharmaceutically acceptable salts thereof may be co-administered with at least one other active agent known to be useful in the treatment of cancer or pre-cancerous syndromes.
  • co-administration is meant either simultaneous administration or any manner of separate sequential administration of a CD73 inhibiting compound, as described herein, and a further active agent or agents, known to be useful in the treatment of cancer, including chemotherapy and radiation treatment.
  • further active agent or agents includes any compound or therapeutic agent known to or that demonstrates advantageous properties when administered to a patient in need of treatment for cancer.
  • the compounds are administered in a close time proximity to each other.
  • the compounds are administered in the same dosage form, e.g. one compound may be administered by injection and another compound may be administered orally.
  • any anti-neoplastic agent that has activity versus a susceptible tumor being treated may be co-administered in the treatment of cancer in the present invention.
  • examples of such agents can be found in Cancer Principles and Practice of Oncology by V.T. Devita and S. Hellman (editors), 6 th edition (February 15, 2001), Lippincott Williams & Wlkins Publishers.
  • Typical anti-neoplastic agents useful in the present invention include, but are not limited to, anti-microtubule agents such as diterpenoids and vinca alkaloids; platinum coordination complexes; alkylating agents such as nitrogen mustards, oxazaphosphorines, alkylsulfonates, nitrosoureas, and triazenes; antibiotic agents such as anthracyclins, actinomycins and bleomycins; topoisomerase II inhibitors such as epipodophyllotoxins; antimetabolites such as purine and pyrimidine analogues and anti- folate compounds; topoisomerase I inhibitors such as camptothecins; hormones and hormonal analogues; signal transduction pathway inhibitors; non-receptor tyrosine kinase angiogenesis inhibitors; immunotherapeutic agents; proapoptotic agents; cell cycle signaling inhibitors; proteasome inhibitors; and inhibitors of cancer metabolism.
  • anti-microtubule agents such as di
  • chemotherapeutic agents examples include chemotherapeutic agents.
  • Anti-microtubule or anti-mitotic agents are phase specific agents active against the microtubules of tumor cells during M or the mitosis phase of the cell cycle.
  • anti-microtubule agents include, but are not limited to, diterpenoids and vinca alkaloids.
  • Diterpenoids which are derived from natural sources, are phase specific anti-cancer agents that operate at the G 2 /M phases of the cell cycle. It is believed that the diterpenoids stabilize the ⁇ -tubulin subunit of the microtubules, by binding with this protein. Disassembly of the protein appears then to be inhibited with mitosis being arrested and cell death following.
  • diterpenoids include, but are not limited to, paclitaxel and its analog docetaxel.
  • Paclitaxel 5p,20-epoxy-1 ,2 ⁇ ,4,7 ⁇ ,10 ⁇ ,13a-hexa-hydroxytax-1 1 -en-9-one 4,10- diacetate 2-benzoate 13-ester with (2R,3S)-N-benzoyl-3-phenylisoserine; is a natural diterpene product isolated from the Pacific yew tree Taxus brevifolia and is commercially available as an injectable solution TAXOL®. It is a member of the taxane family of terpenes. Paclitaxel has been approved for clinical use in the treatment of refractory ovarian and breast cancer in the United States.
  • Docetaxel (2R.3S)- N-carboxy-3-phenylisoserine,N-fe/if-butyl ester, 13-ester with ⁇ -20-epoxy-l ,2a,4,7p,10p,13a-hexahydroxytax-1 1 -en-9-one 4-acetate 2-benzoate, trihydrate; is commercially available as an injectable solution as TAXOTERE®.
  • Docetaxel is indicated for the treatment of breast cancer.
  • Docetaxel is a semisynthetic derivative of paclitaxel q.v. , prepared using a natural precursor, 10-deacetyl-baccatin III, extracted from the needle of the European Yew tree.
  • Vinca alkaloids are phase specific anti-neoplastic agents derived from the periwinkle plant. Vinca alkaloids act at the M phase (mitosis) of the cell cycle by binding specifically to tubulin. Consequently, the bound tubulin molecule is unable to polymerize into microtubules. Mitosis is believed to be arrested in metaphase with cell death following. Examples of vinca alkaloids include, but are not limited to, vinblastine, vincristine, and vinorelbine.
  • Vinblastine vincaleukoblastine sulfate
  • VELBAN® an injectable solution.
  • Myelosuppression is the dose limiting side effect of vinblastine.
  • Vincristine vincaleukoblastine, 22-oxo-, sulfate
  • ONCOVIN® an injectable solution.
  • Vincristine is indicated for the treatment of acute leukemias and has also found use in treatment regimens for Hodgkin's and non-Hodgkin's malignant lymphomas.
  • Alopecia and neurologic effects are the most common side effect of vincristine and to a lesser extent myelosupression and gastrointestinal mucositis effects occur.
  • Vinorelbine 3',4'-didehydro -4'-deoxy-C'-norvincaleukoblastine [R-(R*,R*)-2,3- dihydroxybutanedioate (1 :2)(salt)], commercially available as an injectable solution of vinorelbine tartrate (NAVELBINE®), is a semisynthetic vinca alkaloid.
  • Vinorelbine is indicated as a single agent or in combination with other chemotherapeutic agents, such as cisplatin, in the treatment of various solid tumors, particularly non-small cell lung, advanced breast, and hormone refractory prostate cancers. Myelosuppression is the most common dose limiting side effect of vinorelbine.
  • Platinum coordination complexes are non-phase specific anti-cancer agents, which are interactive with DNA.
  • the platinum complexes enter tumor cells, undergo, aquation and form intra- and interstrand crosslinks with DNA causing adverse biological effects to the tumor.
  • Examples of platinum coordination complexes include, but are not limited to, cisplatin and carboplatin.
  • Cisplatin cis-diamminedichloroplatinum
  • PLATINOL® an injectable solution
  • Cisplatin is primarily indicated in the treatment of metastatic testicular and ovarian cancer and advanced bladder cancer.
  • the primary dose limiting side effects of cisplatin are nephrotoxicity, which may be controlled by hydration and diuresis, and ototoxicity.
  • Carboplatin, platinum, diammine [1 ,1 -cyclobutane-dicarboxylate(2-)-0,0'] is commercially available as PARAPLATIN® as an injectable solution.
  • Carboplatin is primarily indicated in the first and second line treatment of advanced ovarian carcinoma. Bone marrow suppression is the dose limiting toxicity of carboplatin.
  • Alkylating agents are non-phase anti-cancer specific agents and strong electrophiles. Typically, alkylating agents form covalent linkages, by alkylation, to DNA through nucleophilic moieties of the DNA molecule such as phosphate, amino, sulfhydryl, hydroxyl, carboxyl, and imidazole groups. Such alkylation disrupts nucleic acid function leading to cell death.
  • alkylating agents include, but are not limited to, nitrogen mustards such as cyclophosphamide, melphalan, and chlorambucil; alkyl sulfonates such as busulfan; nitrosoureas such as carmustine; and triazenes such as dacarbazine.
  • Cyclophosphamide 2-[bis(2-chloroethyl)amino]tetrahydro-2H-1 ,3,2- oxazaphosphorine 2-oxide monohydrate, is commercially available as an injectable solution or tablets as CYTOXAN®. Cyclophosphamide is indicated as a single agent or in combination with other chemotherapeutic agents, in the treatment of malignant lymphomas, multiple myeloma, and leukemias. Alopecia, nausea, vomiting and leukopenia are the most common dose limiting side effects of cyclophosphamide.
  • Melphalan 4-[bis(2-chloroethyl)amino]-L-phenylalanine, is commercially available as an injectable solution or tablets as ALKERAN®. Melphalan is indicated for the palliative treatment of multiple myeloma and non-resectable epithelial carcinoma of the ovary. Bone marrow suppression is the most common dose limiting side effect of melphalan.
  • Chlorambucil 4-[bis(2-chloroethyl)amino]benzenebutanoic acid, is commercially available as LEUKERAN® tablets. Chlorambucil is indicated for the palliative treatment of chronic lymphatic leukemia, and malignant lymphomas such as lymphosarcoma, giant follicular lymphoma, and Hodgkin's disease. Bone marrow suppression is the most common dose limiting side effect of chlorambucil.

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Abstract

L'invention concerne des dérivés salicylamide substitués. Spécifiquement, l'invention concerne des composés représentés par la formule I : (I) dans laquelle R, R1 et R2 sont tels que définis dans la description, ou un sel de ceux-ci pharmaceutiquement acceptable. Les composés de 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, les maladies auto-immunes, les infections, l'athérosclérose, et une lésion de reperfusion ischémique. Par conséquent, l'invention concerne en outre des compositions pharmaceutiques comprenant un composé de l'invention. L'invention concerne enfin des procédés d'inhibition de l'activité de CD73 et le traitement de troubles associés à celui-ci à l'aide d'un composé de l'invention ou d'une composition pharmaceutique comprenant un composé de l'invention.
PCT/IB2017/051399 2016-03-10 2017-03-09 Dérivés de 5-sulfamoyl-2-hydroxybenzamide WO2017153952A1 (fr)

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WO2020120576A1 (fr) * 2018-12-11 2020-06-18 Fundació Institut De Recerca Biomèdica (Irb Barcelona) INHIBITEURS DE L'AUTOPHOSPHORYLATION DE P38α
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