WO2017153952A1 - 5-sulfamoyl-2-hydroxybenzamide derivatives - Google Patents

5-sulfamoyl-2-hydroxybenzamide derivatives 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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French (fr)
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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/en

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    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00Amides 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
    • C07C311/22Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms
    • C07C311/29Sulfonamides, 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
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12Antivirals
    • A61P31/14Antivirals for RNA viruses
    • A61P31/18Antivirals for RNA viruses for HIV
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • C07C311/30Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/37Sulfonamides, 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
    • C07C311/38Sulfonamides, 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
    • C07C311/44Sulfonamides, 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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    • C07C323/46Thiols, 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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    • C07D231/14Heterocyclic 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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    • C07D231/42Benzene-sulfonamido pyrazoles
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    • C07D261/00Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
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    • C07D263/00Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/30Heterocyclic 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
    • C07D263/34Heterocyclic 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
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    • C07D307/77Heterocyclic 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
    • C07D307/78Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/82Benzo [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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    • C07D317/00Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/44Heterocyclic 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
    • C07D317/46Heterocyclic 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
    • C07D317/48Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
    • C07D317/62Methylenedioxybenzenes 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
    • C07D317/66Nitrogen atoms not forming part of a nitro radical
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    • C07D333/00Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04Heterocyclic 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
    • C07D333/26Heterocyclic 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
    • C07D333/30Hetero atoms other than halogen
    • C07D333/36Nitrogen atoms
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    • C07D333/00Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/62Benzo[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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    • C07D471/02Heterocyclic 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
    • C07D471/04Ortho-condensed systems
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    • C07C2602/02Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/04One of the condensed rings being a six-membered aromatic ring
    • C07C2602/08One 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.

Abstract

The invention is directed to substituted salicylamide derivatives. Specifically, the invention is directed to compounds according to Formula (I): wherein R, R1 and R2 are as defined herein, or a pharmaceutically acceptable salt thereof. The compounds of the invention are inhibitors of CD73 and can be useful in the treatment of cancer, pre-cancerous syndromes and diseases associated with CD73 inhibition, such as AIDS, the treatment of HIV, autoimmune diseases, infections, atherosclerosis, and ischemia–reperfusion injury. Accordingly, the invention is further directed to pharmaceutical compositions comprising a compound of the invention. The invention is still further directed to methods of inhibiting CD73 activity and treatment of disorders associated therewith using a compound of the invention or a pharmaceutical composition comprising a compound of the invention.

Description

CHEMICAL COMPOUNDS
FIELD OF THE INVENTION
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.
BACKGROUND OF THE INVENTION
Local levels of extracellular adenosine triphosphate (ATP) are acutely elevated as a consequence of infection, tissue injury, ischaemia or intervention-induced tumor cell death. Elevated extracellular ATP is recognized by the immune system as a danger signal to initiate multiple pro-inflammatory events, including the recruitment of macrophages and dendritic cells. (1) Successive processing of extracellular ATP by the extracellular ectonucleotidases CD73 and CD39 lowers extracellular ATP levels and can rapidly elevate extracellular adenosine from a low homeostatic level (20-200 nM) to as much as 1 ,000- 10,000 nM. (2) These elevated adenosine concentrations 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. Within the context of a solid tumor, hypoxia has been shown to increase adenosine levels by 10-20-fold compared with normal levels. (3) It has been proposed that 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-Zn2+ 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. 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. (4) CD73 is overexpressed in multiple solid tumor types and leukaemias, including aggressive and difficult to treat tumours, such as glioblastoma and ovarian tumours. (5) In patients with head and neck squamous cell carcinoma (HNSCC), T-regulatory cells (TReg) (both circulating and tumor associated) express both CD73 and CD39, thus providing a mechanism for the conversion of ATP to adenosine that only depends on TReg cells. (6) There are multiple reports using small-interfering ribonucleic acids (siRNA), transgenic knockouts and overexpression models to confirm the involvement of CD73 in the generation of adenosine and promotion of immune tolerance. (5)
Thus, 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.
Because inhibiton of CD73 results in decreased extracellular adenosine, CD73 inhibitors are also expected to be useful for other diseases mediated by adenosine and its action on adenosine receptors. Thus, 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)
References
1 . Ghiringhelli, F. et al. Activation of the NLRP3 inflammasome in dendritic cells induces IL-1 p-dependent adaptive immunity against tumors. Nat. Med. 15, 1 170— 1 178 (2009).
2. Chen, J. F., Eltzschig, H. K. & Fredholm, B. B. Adenosine receptors as drug targets — what are the challenges? Nat. Rev. Drug Discov. 12, 265-286 (2013).
3. Blay, J., White, T. D. & Hoskin, D. W. The extracellular fluid of solid carcinomas contains immunosuppressive concentrations of adenosine. Cancer Res. 57, 2602- 2605 (1997).
4. Synnestvedt, K. et al. Ecto-5'-nucleotidase (CD73) regulation by hypoxia-inducible factor-1 mediates permeability changes in intestinal epithelia.
5. Stagg, J. & Smyth, M. J. Extracellular adenosine triphosphate and adenosine in cancer. Oncogene 29, 5346-5358 (2010).
6. Mandapathil, M. et al. Adenosine and prostaglandin e2 cooperate in the suppression of immune responses mediated by adaptive regulatory T cells. J. Biol.
Chem. 285, 27571 -27580 (2010).
7. Antonioli, L. et al. Immunity, inflammation and cancer: a leading role for adenosine.
Nature Rev. Cancer 13, 842-857 (2013).
8. Regateiro, F. S. et al. CD73 and adenosine generation in the creation of regulatory microenvironments. Clin. Exp. Immunol. 171 , 1 -7 (2013).
9. Sorrentino, R. et al. The adenosinergic system in cancer. Oncolmmunology 2, e22448 (2013). 10. Allard, B. et al. CD73-Generated Adenosine: Orchestrating the Tumor-Stroma Interplay to Promote Cancer Growth. J. Biomed. Biotech. 2012, Article ID 485156, 8 pages, doi:10.1 155/2012/485156. It is an object of the present invention to provide novel compounds that are inhibitors of CD73.
It is also an object of the present invention to provide a pharmaceutical composition that comprises a pharmaceutical carrier and a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
It is also an object of the present invention to provide a method for treating cancer, pre-cancerous syndromes, AIDS, HIV, autoimmune diseases, infections, atherosclerosis, and ischemia-reperfusion injury that comprises administering novel inhibitors of CD73 activity.
SUMMARY OF THE INVENTION
The invention is directed to substituted salicylamide derivatives. Specifically, the invention is directed to compounds according to Formula (I):
Figure imgf000005_0001
wherein 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.
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. Included in the present invention are 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.
DETAILED DESCRIPTION OF THE INVENTION
This invention relates to novel compounds of Formula (I) and to the use of compounds of Formula (I) in the methods of the invention:
Figure imgf000009_0001
R is selected from:
aryl,
aryl substituted with from one to five substituents independently selected from:
fluoro,
chloro,
bromo,
iodo,
Cl -6alkyl,
Ci -6alkyl substituted with from 1 to 9 substituents
independently selected from: fluoro, chloro, bromo, iodo, oxo, Cl -4alkyloxy, -OH, -COOH, -NR3 0R320,
-N(H)Cl -4alkyl, -N(Cl -4alkyl)2 and -CN, cycloalkyl,
heteroaryl, Cl-6alkoxy,
Ci-6alkoxy substituted with from 1 to 9 substituents
independently selected from: fluoro, chloro, bromo, oxo, -OH, phenyl and -CN,
-CN,
oxo,
-OH,
-Ocycloalkyl,
-Ophenyl,
-C(0)OC(CH3)3,
-COOH,
-Cl -4alkylOCl -4alkyl,
-NO2,
-IMH2,
-N(H)Cl-4alkyl,
-N(H)Ci-4alkyl substituted with from 1 to 9 substituents independently selected from: fluoro, chloro, bromo, oxo, -OH, and -CN,
-N(Cl-4alkyl)2,
-Cl -4alkylNHBoc,
-N(H)aryl,
-N(H)C(0)aryl,
-N(H)0C(0)Cl-4alkyl,
-N(H)C(0)Cl-4alkyl,
-N(H)S(0)2Cl-4alkyl,
-N(H)S(0)2cycloalkyl,
-N(H)S(0)2phenyl,
-SCl -6alkyl, -SCi -6alkyl substituted with from 1 to 9 substituents independently selected from: fluoro, chloro, bromo, oxo, -OH, and -CN,
-SO2NH2, and
heteroaryl,
heteroaryl substituted with from one to five substituents independently selected from:
fluoro,
chloro,
bromo,
iodo,
Cl-6alkyl,
Ci-6alkyl substituted with from 1 to 9 substituents
independently selected from: fluoro, chloro, bromo, iodo, oxo, -OH, -NR31 0R320, and -CN, aryl,
Cl-4alkoxy,
-CN,
oxo,
-OH,
-COOH,
-NO2,
-IMH2, and
SO2NH2,
bicycloheteroaryl,
bicycloheteroaryl substituted with from one to five substituents
independently selected from:
fluoro,
chloro,
bromo,
iodo, Cl-6alkyl,
Ci-6alkyl substituted with from 1 to 9 substituents
independently selected from: fluoro, chloro, bromo, iodo, oxo, -OH, -COOH, -NR31 0R320, and -CN,
-C(0)OCl-6alkyl,
cycloalkyl,
aryl,
Cl-4alkoxy,
Ci-4alkoxy substituted with from 1 to 5 substituents
independently selected from: fluoro, chloro, bromo, oxo, -OH and -CN,
-CN,
oxo,
-OH,
-Ophenyl,
-COOH,
-Νθ2,
-NH2,
-N(H)Cl-4alkyl,
-N(Cl-4alkyl)2,
-N(H)aryl, and
-N(H)C(0)aryl; and
and R2 are independently selected from:
hydrogen,
Cl-6alkyl,
Ci-6alkyl substituted with from one to five substituents independently selected from: fluoro, chloro, oxo, -OH, and -NH2,
fluoro,
chloro,
bromo, iodo,
-N(H)Cl -6alkyl,
-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;
where,
R310 and R320 are independently selected from hydrogen and C-| -C4alkyl, or R31 0 and
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;
and pharmaceutically acceptable salts thereof.
Included in the compounds of the invention and used in the methods of the invention are compounds of Formula (II):
Figure imgf000013_0001
wherein:
R 0 is selected from:
aryl,
aryl substituted with from one to five substituents independently selected from:
fluoro,
chloro,
bromo,
Cl -6alkyl,
Ci -6alkyl substituted with from 1 to 5 substituents independently selected from: fluoro, chloro, bromo, iodo, oxo, Cl -4alkyloxy, -OH, -COOH, and
-NR311 R321 ,
cycloalkyl,
heteroaryl,
Cl-6alkoxy,
Ci-6alkoxy substituted with from 1 to 5 substituents
independently selected from: fluoro, chloro, bromo, oxo, -OH, phenyl and -CN,
-CN,
oxo,
-OH,
-Ocycloalkyl,
-Ophenyl,
-COOH,
-NO2,
-NH2,
-N(H)Cl-4alkyl,
-N(H)Ci-4alkyl substituted with from 1 to 5 substituents independently selected from: fluoro, chloro, bromo, oxo, -OH, and -CN,
-N(Cl-4alkyl)2,
-N(H)aryl,
-N(H)C(0)aryl,
-N(H)0C(0)Cl-4alkyl,
-N(H)C(0)Cl-4alkyl,
-N(H)S(0)2Cl-4alkyl,
-N(H)S(0)2cycloalkyl,
-N(H)S(0)2phenyl, -SCl -6alkyl,
-SCi -6alkyl substituted with from 1 to 5 substituents
independently selected from: fluoro, chloro, bromo, oxo, -OH, and -CN, and
-SO2NH2,
heteroaryl,
heteroaryl substituted with from one to five substituents independently selected from:
fluoro,
chloro,
bromo,
iodo,
Cl-6alkyl,
Ci-6alkyl substituted with from 1 to 5 substituents
independently selected from: fluoro, chloro, bromo, iodo, oxo, -OH, -NR31 1 R321 and -CN, aryl,
Cl-4alkoxy,
-CN,
oxo,
-OH,
-COOH,
-NO2,
-IMH2, and
SO2NH2,
bicycloheteroaryl,
bicycloheteroaryl substituted with from one to five substituents
independently selected from:
fluoro,
chloro,
bromo, iodo,
Cl-6alkyl,
Ci-6alkyl substituted with from 1 to 5 substituents
independently selected from: fluoro, chloro, bromo, iodo, oxo, -OH, -COOH, -NR31 1 R321 and -CN,
-C(0)OCl-6alkyl,
cycloalkyl,
aryl,
Cl-4alkoxy,
Ci-4alkoxy substituted with from 1 to 5 substituents
independently selected from: fluoro, chloro, bromo, oxo, -OH and -CN,
-CN,
oxo,
-OH,
-Ophenyl,
-COOH,
-NO2,
-NH2, and
-N(H)Cl-4alkyl; and
and R 2 are independently selected from:
hydrogen,
Cl-6alkyl,
Ci-6alkyl substituted with from one to five substituents independently selected from: fluoro, chloro, oxo, -OH, and -NH2,
fluoro,
chloro,
bromo,
iodo,
-N(H)Cl -6alkyl, -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,
R31 1 and R321 are independently selected from hydrogen and C-| -C4alkyl, or R31 1 and
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;
and pharmaceutically acceptable salts thereof.
Included in the compounds of the invention and used in the methods of the invention are compounds of Formula (III):
Figure imgf000017_0001
wherein:
on
R is selected from:
aryl,
aryl substituted with from one to five substituents independently selected from:
fluoro,
Cl -6alkyl,
Cl -6alkyl substituted 1 to 5 times by fluoro,
-CONR3 2R322
heteroaryl,
Cl -6alkoxy, Ci-6alkoxy substituted with from 1 to 5 substituents independently selected from: fluoro and phenyl,
-OH,
-Ocycloalkyl,
-Ophenyl,
-NH2,
-N(H)Cl-4alkyl,
-N(H)Ci-4alkyl substituted with from 1 to 5 substituents independently selected from: fluoro, oxo, and -OH, -N(Cl-4alkyl)2,
-N(H)S(0)2Cl -4alkyl,
-N(H)S(0)2cycloalkyl,
-N(H)S(0)2phenyl,
-SCl -6alkyl,
-SCl -6alkyl substituted 1 to 5 times by fluoro, and
-SO2NH2,
heteroaryl,
heteroaryl substituted with from one to five substituents independently selected from:
fluoro,
chloro,
Cl-6alkyl,
Cl-6alkyl substituted 1 to 5 times by fluoro,
-CONR312R322,
aryl, and
Cl-4alkoxy,
bicycloheteroaryl,
bicycloheteroaryl substituted with from one to five substituents
independently selected from: fluoro,
chloro,
bromo,
Cl-6alkyl,
Ci-6alkyl substituted with from 1 to 5 substituents
independently selected from: fluoro, and -OH, -CONR3 2R322,
-C(0)OCl-6alkyl,
cycloalkyl,
aryl,
Cl-4alkoxy,
Ci-4alkoxy substituted with from 1 to 5 substituents
independently selected from: fluoro, chloro, bromo, oxo, -OH and -CN,
oxo, and
-NH2; and
and R22 are independently selected from:
hydrogen,
Cl-6alkyl,
Ci-6alkyl substituted with from one to five substituents independently selected from: fluoro, chloro, oxo, -OH, and -NH2,
fluoro,
chloro,
bromo,
iodo,
-N(H)Cl -6alkyl,
-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 are independently selected from hydrogen and C-| -C4alkyl, or R312 and
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;
and pharmaceutically acceptable salts thereof.
Included in the compounds of the invention and used in the methods of the invention are compounds of Formula (IV):
Figure imgf000020_0001
is selected from:
aryl substituted with from one to five substituents independently selected from:
fluoro,
Cl -6alkyl,
Cl -6alkyl substituted 1 to 3 times by fluoro,
-CONR3 3R323 ,
heteroaryl,
Cl -6alkoxy,
Ci -6alkoxy substituted with from 1 to 3 substituents
independently selected from: fluoro and phenyl,
-OH,
-Ocycloalkyl, -Ophenyl,
-NH2,
-N(H)Cl-4alkyl,
-N(H)Cl-4alkyl substituted by oxo,
-N(Cl-4alkyl)2,
-N(H)S(0)2Cl-4alkyl,
-N(H)S(0)2cycloalkyl,
-N(H)S(0)2phenyl,
-SCl -6alkyl, and
-SO2NH2,
heteroaryl,
heteroaryl substituted with from one to five substituents independently selected from:
fluoro,
chloro,
Cl-6alkyl,
-CONR3 3R323,
aryl, and
Cl-4alkoxy,
bicycloheteroaryl,
bicycloheteroaryl substituted with from one to five substituents
independently selected from:
fluoro,
chloro,
bromo,
Cl-6alkyl,
Cl-6alkyl substituted by -OH,
-CONR31 3R323 -C(0)OCl-6alkyl,
cycloalkyl,
aryl,
Cl-4alkoxy,
Ci-4alkoxy substituted with from 1 to 5 substituents
independently selected from: fluoro, chloro, bromo, oxo, -OH and -CN,
oxo, and
-NH2; and
R3 and R32 are independently selected from:
hydrogen,
Cl-6alkyl,
Ci-6alkyl substituted with from one to five substituents independently selected from: fluoro, chloro, oxo, -OH, and -NH2,
fluoro,
chloro,
bromo,
iodo,
-N(H)Cl -6alkyl,
-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,
R313 an( R323 are independently selected from hydrogen and C-|-C4alkyl, or R313 and
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;
and pharmaceutically acceptable salts thereof. Included in the compounds of the invention and used in the methods of the invention are compounds of Formula (V):
Figure imgf000023_0001
R is selected from:
hydrogen,
Cl-6alkyl,
Ci-6alkyl substituted with from one to five substituents independently selected from: fluoro, chloro, oxo, -OH, and -NH2,
fluoro,
chloro,
bromo,
iodo,
-N(H)Cl -6alkyl, and
-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
R4 , R42, and R43, are independently selected from:
hydrogen,
fluoro,
chloro,
bromo,
Cl-6alkyl,
Ci-6alkyl substituted with from 1 to 5 substituents independently selected from: fluoro, and -OH,
-CONH2,
heteroaryl,
aryl,
Cl -6alkoxy,
Ci-6alkoxy substituted with from 1 to 3 substituents independently
selected from: fluoro, chloro, bromo, oxo, -OH, -CN, and phe
-OH,
oxo,
-C(0)0Cl -6alkyl,
cycloalkyl,
-Ocycloalkyl,
-Ophenyl,
-NH2,
-N(H)Cl -4alkyl,
-N(H)Cl-4alkyl substituted by oxo,
-N(Cl -4alkyl)2,
-N(H)S(0)2Cl -4alkyl,
-N(H)S(0)2cycloalkyl,
-N(H)S(0)2phenyl,
-SCl-6alkyl, and
-SO2NH2;
and pharmaceutically acceptable salts thereof.
Included in the compounds of the invention and used in the methods of the invention are compounds of Formula (VI):
Figure imgf000025_0001
R4U is selected from:
hydrogen,
Cl-4alkyl,
Ci-4alkyl substituted from one to five times by fluoro,
fluoro,
chloro, and
bromo;
R4 a is selected from:
hydrogen,
fluoro,
chloro,
Cl-6alkyl,
Ci-6alkyl substituted with from 1 to 5 substituents independently selected from: fluoro, and -OH,
-CONH2,
aryl,
Cl-6alkoxy,
-OH,
-C(0)OCl -6alkyl,
cycloalkyl, and
-NH2;
R42a is selected from:
hydrogen,
fluoro, chloro,
bromo,
Cl-6alkyl,
Ci-6alkyl substituted with from 1 to 5 substituents independently selected from: fluoro, and -OH,
-CONH2,
aryl,
Cl-6alkoxy,
-OH,
-C(0)OCl -6alkyl, and
cycloalkyl; and
R43a is selected from:
hydrogen,
fluoro,
chloro,
bromo,
Cl-6alkyl,
Ci-6alkyl substituted with from 1 to 5 substituents independently selected from: fluoro, and -OH,
-CONH2,
aryl,
Cl-6alkoxy,
-OH,
-C(0)OCl -6alkyl, and
cycloalkyl;
and pharmaceutically acceptable salts thereof. Included in the compounds of the invention and used in the methods of the invention are compounds of Formula (VII):
Figure imgf000027_0001
R4UD is selected from:
hydrogen,
methyl, and
chloro;
R4 b is selected from:
hydrogen,
methyl,
ethyl,
isopropyl,
cyclopropyl,
phenyl,
hydroxymethyl,
-C(0)OCH3, and
-CONH2;
R42b is selected from:
hydrogen,
methyl,
ethyl,
phenyl,
chloro,
-C(0)OCH3, and
-CONH2; and
R43b is selected from: hydrogen,
methyl,
chloro,
bromo,
hydroxy methyl,
-C(0)OCH3, and
-CONH2; and
and pharmaceutically acceptable salts thereof.
Included in the compounds of the invention and used in the methods of the invention are compounds of Formula (VIII):
Figure imgf000028_0001
wherein:
the A ring contains an optional double bond where indicated by the dotted line,
R50 is selected from:
hydrogen,
Cl -6alkyl,
Ci -6alkyl substituted with from one to five substituents independently selected from: fluoro, chloro, oxo, -OH, and -NH2,
fluoro,
chloro, bromo,
lodo, and
-N(H)Cl -6alkyl;
R5 is selected from:
hydrogen,
fluoro,
chloro,
Cl-6alkyl,
Ci-6alkyl substituted with from 1 to 5 substituents independently selected from: fluoro, and -OH,
Cl-6alkoxy,
Ci-6alkoxy substituted with from 1 to 3 substituents independently
selected from: fluoro, chloro, bromo, oxo, -OH, -CN, and phenyl, -OH, and
-C(0)OCi -6alkyl;
R52 is absent or selected from:
hydrogen,
fluoro,
chloro,
Cl-6alkyl,
Ci-6alkyl substituted with from 1 to 5 substituents independently selected from: fluoro, and -OH,
Cl-6alkoxy,
Ci-6alkoxy substituted with from 1 to 3 substituents independently
selected from: fluoro, chloro, bromo, oxo, -OH, -CN, and phenyl, -OH, and
-C(0)OCl -6alkyl; and
R53 is selected from:
hydrogen, fluoro,
chloro,
Cl -6alkyl,
Ci -6alkyl substituted with from 1 to 5 substituents independently selected from: fluoro, and -OH,
Cl -6alkoxy,
Ci -6alkoxy substituted with from 1 to 3 substituents independently
selected from: fluoro, chloro, bromo, oxo, -OH, -CN, and phenyl, -OH, and
-C(0)OCl -6alkyl;
and pharmaceutically acceptable salts thereof;
52
provided that when R is not absent, the A ring does not contain a double bond where indicted by the dotted line.
Included in the compounds of the invention and used in the methods of the invention are compounds of Formula (IX):
Figure imgf000030_0001
wherein:
the A ring contains an optional double bond where indicated by the dotted line,
R50a is selected from:
hydrogen, Cl-6alkyl,
Ci-6alkyl substituted with from one to five substituents independently selected from: fluoro, chloro, and -OH,
fluoro, and
chloro;
R5 a is selected from:
hydrogen,
Cl-6alkyl,
Ci-6alkyl substituted with from 1 to 5 substituents independently selected from: fluoro, and -OH,
Cl-6alkoxy, and
-OH;
R52a is absent or selected from:
hydrogen,
Cl-6alkyl,
Ci-6alkyl substituted with from 1 to 5 substituents independently selected from: fluoro, and -OH,
Cl-6alkoxy, and
-OH; and
R53a is selected from:
hydrogen,
Cl-6alkyl,
Ci-6alkyl substituted with from 1 to 5 substituents independently selected from: fluoro, and -OH,
Cl-6alkoxy, and
-OH;
and pharmaceutically acceptable salts thereof; provided that when R is not absent, the A ring does not contain a double bond where indicted by the dotted line.
Included in the compounds of the invention and used in the methods of the invention are compounds of Formula (X):
Figure imgf000032_0001
wherein:
the A ring contains an optional double bond where indicated by the dotted line,
R50b is selected from:
hydrogen,
methyl, and
chloro;
R5 b is selected from:
hydrogen, and
ethyl;
R52b is absent or selected from:
hydrogen,
methyl, and
ethyl; and
R53b is selected from:
hydrogen,
methyl, and ethyl; and
and pharmaceutically acceptable salts thereof;
52h
provided that when R is not absent, the A ring does not contain a double bond where indicted by the dotted line.
Included in the compounds of the invention and used in the methods of the invention are compounds of Formula (XI):
Figure imgf000033_0001
(XI) is selected from:
hydrogen,
Cl -6alkyl,
Ci -6alkyl substituted with from one to five substituents independently selected from: fluoro, chloro, oxo, -OH, and -NH2,
fluoro,
chloro,
bromo,
iodo, and
-N(H)Cl -6alkyl; and
R62 R63 anc| R64 are independently selected from:
hydrogen,
fluoro,
chloro,
bromo,
Cl -6alkyl, Ci-6alkyl substituted with from 1 to 5 substituents independently selected from: fluoro, and -OH,
Cl-6alkoxy,
Ci-6alkoxy substituted with from 1 to 3 substituents independently
selected from: fluoro, chloro, bromo, oxo, -OH, -CN, and phenyl,
-OH,
-C(0)OCl -6alkyl,
-NH2,
-N(H)Cl -4alkyl,
-N(H)C1 -4alkyl substituted by oxo, and
-N(Cl -4alkyl)2;
and pharmaceutically acceptable salts thereof.
Included in the compounds of the invention and used in the methods of the invention compounds of Formula (XII):
Figure imgf000034_0001
wherein:
R60a is selected from:
hydrogen,
Cl-6alkyl,
Ci-6alkyl substituted with from one to five substituents independently selected from: fluoro, chloro, and -OH,
fluoro, and
chloro; and
R6i a R62a R63a and R64a gre independently selected from: hydrogen,
fluoro,
chloro,
bromo,
Cl-6alkyl,
Ci-6alkyl substituted with from 1 to 5 substituents independently selected from: fluoro, and -OH,
Cl-6alkoxy,
-OH,
-NH2,
-N(H)Cl -4alkyl, and
-N(Cl -4alkyl)2;
and pharmaceutically acceptable salts thereof.
Included in the compounds of the invention and used in the methods of the invention are compounds of Formula (XIII):
Figure imgf000035_0001
wherein:
R60b is selected from:
hydrogen,
methyl, and
chloro;
R61 b is selected from:
hydrogen, and
methyl;
is selected from: hydrogen,
methyl,
ethyl,
-NH2,
-N(H)CH3, and
-N(CH3)2;
R63b is selected from:
hydrogen,
fluoro, and
chloro; and
R64b is selected from:
hydrogen,
methyl, and
chloro;
pharmaceutically acceptable salts thereof.
Included in the compounds of the invention and used in the methods of the invention are compounds of Formula (XIV):
Figure imgf000036_0001
wherein:
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:
fluoro,
chloro, bromo,
Cl-6alkyl,
Cl-6alkyl substituted by -OH,
-CONR314R324i
-C(0)OCl-6alkyl,
cycloalkyl,
aryl,
Cl-4alkoxy,
Ci-4alkoxy substituted with from 1 to 5 substituents
independently selected from: fluoro, chloro, bromo, oxo, -OH and -CN,
oxo, and
-NH2; and
R7 is selected from:
hydrogen,
-N(H)Cl -6alkyl,
-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
R72 is selected from:
hydrogen,
methyl,
chloro, and
bromo;
where,
R314 an( R324 are independently selected from hydrogen and C-|-C4alkyl, or R314 and R324 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; and pharmaceutically acceptable salts thereof.
In an embodiment, 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-6alkyl, hydroxyl and Cl -6alkoxy.
In an embodiment, 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-4alkyl.
In an embodiment, 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-2alkyl.
In an embodiment, 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-2alkyl.
In an embodiment, R is selected from 6-indolyl, 6-indazolyl and 5-benzimidazolyl each of which is substituted with a Ci_2alkyl group.
In an embodiment 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.
In an embodiment R is selected from 3-ethoxyphenyl, 4-methoxyphenyl,
3,4diethoxyphenyl, 3,4dimethoxyphenyl, 3-methoxyphenyl, 4-trifluoromethylphenyl, 3- hydroxyphenyl, 4-hydroxyphenyl, 4-trifluoromethoxyphenyl, 4-methylsulfonylphenyl, 2,2,2- trifluoroethoxyphenyl, 4-isopropoxyphenyl, 2-fluorophenyl, 4-methylthiophenyl, tert- butoxyphenyl, 4-dimethylaminophenyl, 4-methylaminophenyl, 4-sulfamoylphenyl, 3- aminophenyl, 4-ethylaminophenyl, 4-aminophenyl, 4-cyclopropanesulfonamidophenyl, 3- cyclopropanesulfonamidophenyl, 4-phenylsulfonamidophenyl, 4- methylsulfonamidophenyl, 3-methylsulfonamidophenyl, 4-acetamidophenyl, 3- acetamidophenyl, 3-isopropoxyphenyl and 4-cyclopropoxyphenyl.
In an embodiment R is selected from 4-benzyloxyphenyl, 3- phenylsulfonamidophenyl, 4-phenoxyphenyl, oxazol-phenyl, 4-cyclopentyloxyphenyl and cyclohexyloxyphenyl.
In an embodiment 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.
In an embodiment 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-indole-2-methylcarboxylate-6-yl, 1 H-indole-3- methylcarboxylate-6-yl, 3-chloro-1 H-indol-6-yl, 2-phenyl-1 H-indol-6-yl, 4-bromo-1 H-indol- 6-yl, 1 H-indole-4-methylcarboxylate-6-yl, 6-fluoro-1 H-indol-5-yl and 2-hydroxymethyl-1 H- indol-6-yl.
In an embodiment 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-yl.
In an embodiment R is selected from 1 H-indazol-5-yl, 1 H-indazol-6-yl and 3-ethyl- 1 H-indazol-6-yl.
In an embodiment R1 is selected from hydrogen, N(H)Ci-6alkyl or N(H)Ci-6alkyl substituted with from one to five 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-| -C4alkylamino, diC-| -C4alkylamino, and diC-| -C4alkylamino where the carbon chains 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 and optionally substituted by methyl.
In an embodiment R1 is selected from hydrogen, N(H)Ci-6alkyl or N(H)Ci-6alkyl 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-| -C4alkylamino, diC-| -C4alkylamino, and diC-| -C4alkylamino where the carbon chains 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 and optionally substituted by methyl.
In an embodiment R1 is selected from hydrogen, N(H)Ci-4alkyl or N(H)Ci-4alkyl 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-| -C4alkylamino, diC-| -C4alkylamino, and diC-| -C4alkylamino where the carbon chains 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 and optionally substituted by methyl.
In an embodiment R1 is selected from hydrogen, N(H)Ci-4alkyl or N(H)Ci-4alkyl substituted with one substituent selected from F, CI, 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-| -C4alkylamino, diC-| - C4alkylamino, and diC-| -C4alkylamino where the carbon chains 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 and optionally substituted by methyl.
In an embodiment R1 is selected from hydrogen, N(H)Ci_ alkyl or N(H)Ci_ alkyl substituted with one substituent selected from 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-| -C4alkylamino, diC-| - C4alkylamino, and diC-| -C4alkylamino where the carbon chains 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 and optionally substituted by methyl.
In an embodiment R1 is selected from hydrogen, N(H)Ci-2alkyl or N(H)Ci-2alkyl substituted with one or two substituents independently selected from fluoro, chloro, 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-| -C4alkylamino, diC-| -C4alkylamino, and diC-| -C4alkylamino where the carbon chains 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 and optionally substituted by methyl.
In an embodiment R1 is selected from hydrogen, N(H)Ci-2alkyl or N(H)Ci-2alkyl substituted with one substituent selected from fluoro, chloro, 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-| -C4alkylamino, diC-| -C4alkylamino, and diC-| -C4alkylamino where the carbon chains 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 and optionally substituted by methyl.
In an embodiment R1 is selected from hydrogen, N(H)Ci-2alkyl or N(H)Ci-2alkyl substituted with one substituent selected from OH, NH2, phenyl or substituted phenyl. In an embodiment R1 is selected from hydrogen, NHCH2CH3, NHCH2CH2OH, NHCH2CH2NH2, NHCH2Ph, NHCH(CH3)Ph or (3-chlorobenzyl)amino.
In a specific embodiment R1 is hydrogen.
In an embodiment R2 is selected from hydrogen, fluoro, chloro, bromo, Ci_6alkyl or
Ci-6alkyl substituted with from one to five substituents independently selected from fluoro, chloro, oxo, OH or NH2.
In an embodiment R2 is selected from hydrogen, fluoro, chloro, bromo, Ci_6alkyl or Ci_6alkyl substituted with from one to three substituents independently selected from fluoro, oxo or NH2.
In an embodiment R2 is selected from hydrogen, fluoro, chloro, bromo, Ci_4alkyl or Ci-4alkyl substituted with from one to five substituents independently selected from fluoro, CI, oxo, OH or NH2.
In an embodiment R2 is selected from hydrogen, fluoro, chloro, bromo, Ci_ alkyl or Ci-4alkyl substituted with from one to three substituents independently selected from fluoro, oxo or NH2.
In an embodiment R2 is selected from hydrogen, fluoro, chloro, bromo, Ci_2alkyl or Ci_2alkyl substituted with from one to five substituents independently selected from fluoro, chloro, oxo, OH or NH2. In an embodiment R2 is selected from hydrogen, fluoro, chloro, bromo, Ci_2alkyl or Ci-2alkyl substituted with from one to three substituents independently selected from F, oxo or NH2.
In an embodiment R2 is selected from hydrogen, fluoro, chloro, bromo, methyl, ethyl, isopropyl, CF3 or CONH2.
In a specific embodiment R2 is hydrogen. In a further specific embodiment R2 is methyl. In a further specific embodiment R2 is chloro.
In an embodiment R1 is hydrogen and R2 is selected from methyl or CI.
Included in the presently invented compounds of Formula (I) are:
5-(N-(3-ethoxyphenyl)sulfamoyl)-2-hydroxybenzamide;
2-hydroxy-5-(N-(4-methoxyphenyl)sulfamoyl)benzamide;
5-(N-(3,4-diethoxyphenyl)sulfamoyl)-2-hydroxybenzamide;
5-(N-(3,4-dimethoxyphenyl)sulfamoyl)-2-hydroxybenzamide;
2-hydroxy-5-(N-(3-methoxyphenyl)sulfamoyl)benzamide;
2-hydroxy-5-(N-(4-(trifluoromethyl)phenyl)sulfamoyl)benzamide;
2-hydroxy-5-(N-(3-hydroxyphenyl)sulfamoyl)benzamide;
2-hydroxy-5-(N-(4-hydroxyphenyl)sulfamoyl)benzamide;
2-hydroxy-5-(N-(4-(trifluoromethoxy)phenyl)sulfamoyl)benzamide;
2-hydroxy-5-(N-(4-(methylsulfonyl)phenyl)sulfamoyl)benzamide;
2-hydroxy-5-(N-(4-(2,2,2-trifluoroethoxy)phenyl)sulfamoyl)benzamide;
2-hydroxy-5-(N-(4-isopropoxyphenyl)sulfamoyl)benzamide;
5-(N-(2-fluorophenyl)sulfamoyl)-2-hydroxybenzamide;
5-(N-(4-(benzyloxy)phenyl)sulfamoyl)-2-hydroxybenzamide;
2-hydroxy-5-(N-(4-(methylthio)phenyl)sulfamoyl)benzamide;
5-(N-(4-(tert-butoxy)phenyl)sulfamoyl)-2-hydroxybenzamide;
5-(N-(4-(dimethylamino)phenyl)sulfamoyl)-2-hydroxybenzamide;
2-hydroxy-5-(N-(3-(phenylsulfonamido)phenyl)sulfamoyl)benzamide;
2-hydroxy-5-(N-(4-phenoxyphenyl)sulfamoyl)benzamide; 2-hydroxy-5-(N-(4-(methylamino)phenyl)sulfamoyl)benzamide;
2-hydroxy-5-(N-(4-sulfamoylphenyl)sulfamoyl)benzamide;
5-(N-(2,3-dihydro-1 H-inden-5-yl)sulfamoyl)-2-hydroxybenzamide;
5-(N-(3-aminophenyl)sulfamoyl)-2-hydroxybenzamide;
2-hydroxy-5-(N-(naphthalen-2-yl)sulfamoyl)benzamide;
2-hydroxy-5-(N-(quinolin-6-yl)sulfamoyl)benzamide;
5-(N-(1 H-indol-6-yl)sulfamoyl)-2-hydroxybenzamide;
5-(N-(1 H-indol-5-yl)sulfamoyl)-2-hydroxybenzamide;
5-(N-(1 H-benzo[d]imidazol-5-yl)sulfamoyl)-2-hydroxybenzamide;
5-(N-(4-(ethylamino)phenyl)sulfamoyl)-2-hydroxybenzamide;
5-(N-(4-aminophenyl)sulfamoyl)-2-hydroxybenzamide;
5-(N-(benzo[b]thiophen-5-yl)sulfamoyl)-2-hydroxybenzamide;
5-(N-(1 H-pyrazol-5-yl)sulfamoyl)-2-hydroxybenzamide;
2-hydroxy-5-(N-(2-methyl-1 H-indol-6-yl)sulfamoyl)benzamide;
5-(N-(benzofuran-5-yl)sulfamoyl)-2-hydroxybenzamide;
5-(N-(benzo[b]thiophen-6-yl)sulfamoyl)-2-hydroxybenzamide;
2-hydroxy-5-(N-(1 -methyl-1 H-indol-6-yl)sulfamoyl)benzamide;
2-hydroxy-5-(N-(3-(oxazol-2-yl)phenyl)sulfamoyl)benzamide;
2-hydroxy-5-(N-(3-methyl-1 H-indol-6-yl)sulfamoyl)benzamide;
2-hydroxy-5-(N-(4-(oxazol-2-yl)phenyl)sulfamoyl)benzamide;
2-hydroxy-5-(N-(3-(oxazol-4-yl)phenyl)sulfamoyl)benzamide;
2-hydroxy-5-(N-(4-(oxazol-4-yl)phenyl)sulfamoyl)benzamide;
2-hydroxy-5-(N-(indolin-6-yl)sulfamoyl)benzamide;
5-(N-(4-(cyclopropanesulfonamido)phenyl)sulfamoyl)-2-hydroxybenzamide; 5-(N-(3-(cyclopropanesulfonamido)phenyl)sulfamoyl)-2-hydroxybenzamide; 2-hydroxy-5-(N-(4-(phenylsulfonamido)phenyl)sulfamoyl)benzamide;
2-hydroxy-5-(N-(4-(methylsulfonamido)phenyl)sulfamoyl)benzamide; 2-hydroxy-5-(N-(3-(methylsulfonamido)phenyl)sulfamoyl)benzamide;
5-(N-(1 H-indazol-5-yl)sulfamoyl)-2-hydroxybenzamide;
2-hydroxy-5-(N-(2-methyl-1 H-indol-5-yl)sulfamoyl)benzamide;
tert-butyl 7-(3-carbamoyl-4-hydroxyphenylsulfonamido)-3,4-dihydroisoquinoline-(1 H)-carboxylate;
5-(N-(1 H-pyrrolo[2,3-b]pyridin-6-yl)sulfamoyl)-2-hydroxybenzamide;
2-hydroxy-5-(N-(1 -methyl-1 H-indol-5-yl)sulfamoyl)benzamide;
tert-butyl 6-(3-carbamoyl-4-hydroxyphenylsulfonamido)-3,4-dihydroisoquinoline-(1 H)-carboxylate;
2-hydroxy-5-(N-(3-methyl-1 H-indol-5-yl)sulfamoyl)benzamide;
5-(N-(1 H-indol-5-yl)sulfamoyl)-2-hydroxy-3-methylbenzamide;
5-(N-(4-fluoro-1 H-indol-5-yl)sulfamoyl)-2-hydroxybenzamide;
5-(N-(4-acetamidophenyl)sulfamoyl)-2-hydroxybenzamide;
5-(N-(3-acetamidophenyl)sulfamoyl)-2-hydroxybenzamide;
2-hydroxy-5-(N-(2-oxoindolin-6-yl)sulfamoyl)benzamide;
5-(N-(4-fluoro-1 H-indol-6-yl)sulfamoyl)-2-hydroxybenzamide;
5-(N-(1 H-indazol-6-yl)sulfamoyl)-2-hydroxybenzamide;
5-(N-(benzo[d][1 ,3]dioxol-5-yl)sulfamoyl)-2-hydroxybenzamide;
5-(N-(1 H-indol-6-yl)sulfamoyl)-2-hydroxyisophthalamide;
5-(N-(1 H-indol-5-yl)sulfamoyl)-3-chloro-2-hydroxybenzamide;
2-hydroxy-5-(N-(1 ,2,3,4-tetrahydroquinolin-7-yl)sulfamoyl)benzamide, tert-butyl 7-(3-carbamoyl-4-hydroxyphenylsulfonamido)-3,4-dihydroquinoline-(2H)-carboxylate;
5-(N-(1 H-pyrrolo[2,3-b]pyridin-5-yl)sulfamoyl)-2-hydroxybenzamide;
5-(N-(1 H-benzo[d]imidazol-5-yl)sulfamoyl)-2-hydroxy-3-methylbenzamide;
2-hydroxy-5-(N-(3-isopropoxyphenyl)sulfamoyl)benzamide;
2-hydroxy-5-(N-(thiophen-3-yl)sulfamoyl)benzamide; 5-(N-(4-(cyclopentyloxy)phenyl)sulfamoyl)-2-hydroxybenzamide;
2-hydroxy-5-(N-(2-methyl-1 H-benzo[d]imidazol-5-yl)sulfamoyl)benzamide;
tert-butyl 6-(3-carbamoyl-4-hydroxyphenylsulfonamido)-3,4-dihydroquinoline-(2H)-carboxylate;
5-(N-(3-ethyl-1 H-indol-6-yl)sulfamoyl)-2-hydroxybenzamide;
5-(N-(1 H-benzo[d]imidazol-5-yl)sulfamoyl)-3-chloro-2-hydroxybenzamide;
5-(N-(2-ethyl-1 H-benzo[d]imidazol-5-yl)sulfamoyl)-2-hydroxybenzamide;
5-(N-(4-(cyclohexyloxy)phenyl)sulfamoyl)-2-hydroxybenzamide;
2-hydroxy-5-(N-(imidazo[1 ,2-a]pyridin-6-yl)sulfamoyl)benzamide;
5-(N-(1 H-benzo[d]imidazol-7-yl)sulfamoyl)-2-hydroxybenzamide;
2-hydroxy-5-(N-(2-isopropyl-1 H-indol-6-yl)sulfamoyl)benzamide;
5-(N-(2-ethyl-1 H-indol-6-yl)sulfamoyl)-2-hydroxybenzamide;
4- fluoro-2-hydroxy-5-(N-(4-isopropoxyphenyl)sulfamoyl)benzamide;
2-hydroxy-5-(N-(4-isopropoxyphenyl)sulfamoyl)-3-methylbenzamide;
5- (N-(7-fluoro-1 H-indol-5-yl)sulfamoyl)-2-hydroxybenzamide;
5-(N-(1 H-indazol-6-yl)sulfamoyl)-2-hydroxy-3-methylbenzamide;
5-(N-(5-chloro-1 H-indol-6-yl)sulfamoyl)-2-hydroxybenzamide;
5-(N-(2-cyclopropyl-1 H-indol-6-yl)sulfamoyl)-2-hydroxybenzamide;
5-(N-(4-cyclopropoxyphenyl)sulfamoyl)-2-hydroxybenzamide;
5-(N-(2-ethyl-4-fluoro-1 H-benzo[d]imidazol-5-yl)sulfamoyl)-2-hydroxybenzamide; 5-(N-(2-amino-1 H-benzo[d]imidazol-5-yl)sulfamoyl)-2-hydroxybenzamide, 5-(N-(4-fluoro-2-methyl-1 H-benzo[d]imidazol-5-yl)sulfamoyl)-2-hydroxybenzamide; 5-(N-(1 H-indol-6-yl)sulfamoyl)-2-hydroxy-3-methylbenzamide;
2- hydroxy-3-methyl-5-(N-(2-methyl-1 H-indol-6-yl)sulfamoyl)benzamide;
5-(N-(4-fluoro-1 H-benzo[d]imidazol-5-yl)sulfamoyl)-2-hydroxybenzamide;
3- chloro-2-hydroxy-5-(N-(4-isopropoxyphenyl)sulfamoyl)benzamide;
2-hydroxy-5-(N-(2-isopropyl-1 H-benzo[d]imidazol-6-yl)sulfamoyl)benzamide; 2-hydroxy-5-(N-(4-isopropoxyphenyl)sulfamoyl)-4-(methylamino)benzamide; 5-(N-(1 H-benzo[d]imidazol-5-yl)sulfamoyl)-2-hydroxy-3-isopropylbenzamide;
2- hydroxy-3-methyl-5-(N-(3-methyl-1 H-indol-6-yl)sulfamoyl)benzamide;
3- chloro-2-hydroxy-5-(N-(3-methyl-1 H-indol-6-yl)sulfamoyl)benzamide;
5-(N-(4-chloro-1 H-benzo[d]imidazol-6-yl)sulfamoyl)-2-hydroxybenzamide;
4- (ethylamino)-2-hydroxy-5-(N-(4-isopropoxyphenyl)sulfamoyl)benzamide;
5- (N-(2-ethyl-1 H-benzo[d]imidazol-5-yl)sulfamoyl)-2-hydroxy-3-methylbenzamide; 5-(N-(5-chlorothiophen-3-yl)sulfamoyl)-2-hydroxybenzamide;
5-(N-(1 H-indazol-6-yl)sulfamoyl)-2-hydroxy-3-isopropylbenzamide;
3-chloro-5-(N-(2-ethyl-1 H-benzo[d]imidazol-5-yl)sulfamoyl)-2-hydroxybenzamide; 5-(N-(1 H-indazol-6-yl)sulfamoyl)-3-chloro-2-hydroxybenzamide;
3- chloro-2-hydroxy-5-(N-(2-methyl-1 H-indol-6-yl)sulfamoyl)benzamide;
5-(N-(1 H-indol-6-yl)sulfamoyl)-3-chloro-2-hydroxybenzamide;
4- (benzylamino)-2-hydroxy-5-(N-(4-isopropoxyphenyl)sulfamoyl)benzamide;
5- (N-(1 H-indazol-6-yl)sulfamoyl)-3-ethyl-2-hydroxybenzamide;
5-(N-(1 H-benzo[d]imidazol-6-yl)sulfamoyl)-3-ethyl-2-hydroxybenzamide;
2-hydroxy-5-(N-(1 -phenyl-1 H-pyrazol-4-yl)sulfamoyl)benzamide;
2-hydroxy-5-(N-(1 -phenyl-1 H-pyrazol-3-yl)sulfamoyl)benzamide;
methyl 6-(3-carbamoyl-4-hydroxyphenylsulfonamido)-1 H-indole-2-carboxylate; 2-hydroxy-5-(N-(5-methylthiophen-2-yl)sulfamoyl)benzamide;
2- hydroxy-5-(N-(5-methylthiophen-3-yl)sulfamoyl)benzamide;
3- chloro-5-(N-(4-(ethylamino)phenyl)sulfamoyl)-2-hydroxybenzamide;
methyl 6-(3-carbamoyl-4-hydroxyphenylsulfonamido)-1 H-indole-3-carboxylate; 5-(N-(3-chloro-1 H-indol-6-yl)sulfamoyl)-2-hydroxybenzamide;
2-hydroxy-5-(N-(2-phenyl-1 H-indol-6-yl)sulfamoyl)benzamide;
5-(N-(1 H-benzo[d]imidazol-6-yl)sulfamoyl)-3-fluoro-2-hydroxybenzamide; 5-(N-(1 H-benzo[d]imidazol-6-yl)sulfamoyl)-2-hydroxy-3- (trifluoromethyl)benzamide;
2- hydroxy-5-(N-(4-methylthiophen-2-yl)sulfamoyl)benzamide;
3- chloro-5-(N-(3-ethyl-1 H-indol-6-yl)sulfamoyl)-2-hydroxybenzamide;
5-(N-(3-ethyl-1 H-indol-6-yl)sulfamoyl)-2-hydroxy-3-methylbenzamide;
5-(N-(4-bromo-1 H-indol-6-yl)sulfamoyl)-2-hydroxybenzamide;
5-(N-(2-ethyl-1 H-indol-6-yl)sulfamoyl)-2-hydroxy-3-methylbenzamide;
3- chloro-5-(N-(2-ethyl-1 H-indol-6-yl)sulfamoyl)-2-hydroxybenzamide;
2-hydroxy-5-(N-(7-methyl-1 H-benzo[d]imidazol-5-yl)sulfamoyl)benzamide; methyl 6-(3-carbamoyl-4-hydroxyphenylsulfonamido)-1 H-indole-4-carboxylate; 5-(N-(1 H-pyrazol-4-yl)sulfamoyl)-2-hydroxybenzamide;
5-(N-(4-(ethylamino)phenyl)sulfamoyl)-2-hydroxy-3-methylbenzamide;
5-(N-(6-fluoro-1 H-indol-5-yl)sulfamoyl)-2-hydroxybenzamide;
2- hydroxy-5-(N-(2-(hydroxymethyl)-1 H-indol-6-yl)sulfamoyl)benzamide;
5-(N-(1 H-benzo[d]imidazol-6-yl)sulfamoyl)-3-bromo-2-hydroxybenzamide; 5-(N-(3-ethyl-1 H-indol-6-yl)sulfamoyl)-4-(ethylamino)-2-hydroxybenzamide;
4- ((2-chlorobenzyl)amino)-2-hydroxy-5-(N-(4- isopropoxyphenyl)sulfamoyl)benzamide;
methyl 6-(3-carbamoyl-5-chloro-4-hydroxyphenylsulfonamido)-1 H-indole-2- carboxylate;
5- (N-(4-bromo-1 H-indol-6-yl)sulfamoyl)-3-chloro-2-hydroxybenzamide;
3- chloro-5-(N-(3-chloro-1 H-indol-6-yl)sulfamoyl)-2-hydroxybenzamide;
methyl 6-(3-carbamoyl-5-chloro-4-hydroxyphenylsulfonamido)-1 H-indole-4- carboxylate;
3-chloro-2-hydroxy-5-(N-(2-(hydroxymethyl)-1 H-indol-6-yl)sulfamoyl)benzamide;
2-hydroxy-4-((2-hydroxyethyl)amino)-5-(N-(4- isopropoxyphenyl)sulfamoyl)benzamide;
5-(N-(2-ethyl-1 H-indol-6-yl)sulfamoyl)-4-(ethylamino)-2-hydroxybenzamide; methyl 6-(3-carbamoyl-5-chloro-4-hydroxyphenylsulfonamido)-1 H-indole-3- carboxylate;
(S)-2-hydroxy-5-(N-(4-isopropoxyphenyl)sulfamoyl)-4-((1
ylethyl)amino)benzamide;
4-((3-chlorobenzyl)amino)-2-hydroxy-5-(N-(4- isopropoxyphenyl)sulfamoyl)benzamide;
3-chloro-2-hydroxy-5-(N-(2-oxoindolin-6-yl)sulfamoyl)benzamide;
4-((2-aminoethyl)amino)-2-hydroxy-5-(N-(4- isopropoxyphenyl)sulfamoyl)benzamide,
3-chloro-2-hydroxy-5-(N-(1 -methyl-1 H-indol-5-yl)sulfamoyl)benzamide;
4-(benzylamino)-5-(N-(3-ethyl-1 H-indol-6-yl)sulfamoyl)-2-hydroxybenzamide;
3-chloro-5-(N-(3-ethyl-1 H-indazol-6-yl)sulfamoyl)-2-hydroxybenzamide;
2-hydroxy-5-(/V-(4-isopropoxyphenyl)sulfamoyl)-4-((pyridin-4- ylmethyl)amino)benzamide;
4-(((1 /-/-pyrazol-3-yl)methyl)amino)-2-hydroxy-5-(/V-(4- isopropoxyphenyl)sulfamoyl)-benzamide;
2-hydroxy-5-(/V-(4-isopropoxyphenyl)sulfamoyl)-4-((isoxazol-5- ylmethyl)amino)benzamide;
2-hydroxy-5-(/V-(4-isopropoxyphenyl)sulfamoyl)-4-((thiophen-2-ylmethyl)amino)- benzamide;
2-hydroxy-4-((2-hydroxybenzyl)amino)-5-(N-(4- isopropoxyphenyl)sulfamoyl)benzamide;
2-hydroxy-4-((3-hydroxybenzyl)amino)-5-(N-(4- isopropoxyphenyl)sulfamoyl)benzamide;
4-(((4H-1 ,2,4-triazol-3-yl)methyl)amino)-2-hydroxy-5-(N-(4- isopropoxyphenyl)sulfamoyl)benzamide;
2-hydroxy-4-((3-hydroxypropyl)amino)-5-(N-(4- isopropoxyphenyl)sulfamoyl)benzamide;
2-hydroxy-4-((1 -hydroxypropan-2-yl)amino)-5-(N-(4- isopropoxyphenyl)sulfamoyl)benzamide; 6-(3-carbamoyl-5-chloro-4-hydroxyphenylsulfonamido)-1 Hindole-3-carboxamide;
3-chloro-2-hydroxy-5-(N-(3-methyl-1 H-indazol-6-yl)sulfamoyl)benzamide;
3-chloro-2-hydroxy-5-(N-(2-phenyl-1 H-indol-6-yl)sulfamoyl)benzamide;
3-chloro-2-hydroxy-5-(N-(4-(hydroxymethyl)-1 H-indol-6-yl)sulfamoyl)benzamide;
6-(3-carbamoyl-5-chloro-4-hydroxyphenylsulfonamido)-1 H-indole-2-carboxamide;
3-chloro-5-(N-(1 ,2-dimethyl-1 H-indol-5-yl)sulfamoyl)-2-hydroxybenzamide;
3-chloro-5-(N-(2-ethyl-2H-indazol-6-yl)sulfamoyl)-2-hydroxybenzamide;
3-chloro-2-hydroxy-5-(N-(3-phenyl-1 H-indol-6-yl)sulfamoyl)benzamide;
3-chloro-2-hydroxy-5-(N-(4-methyl-1 H-indol-6-yl)sulfamoyl)benzamide;
3-chloro-5-(N-(2-(dimethylamino)-1 Hbenzo[d]imidazol-6-yl)sulfamoyl)-2- hydroxybenzamide;
5- (N-(1 H-benzo[d][1 ,2,3]triazol-6-yl)sulfamoyl)-3-chloro-2-hydroxybenzamide;
6- (3-carbamoyl-5-chloro-4-hydroxyphenylsulfonamido)-1 H-indole-4-carboxamide;
3-chloro-2-hydroxy-5-(N-(2-isopropyl-1 H-indol-6-yl)sulfamoyl)benzamide;
3-chloro-5-(N-(1 -ethyl-1 H-indol-5-yl)sulfamoyl)-2-hydroxybenzamide;
3-chloro-2-hydroxy-5-(N-(2-(methylamino)-1 H-benzo[d]imidazol-6- yl)sulfamoyl)benzamide;
3-chloro-5-(N-(2,3-dimethyl-1 H-indol-6-yl)sulfamoyl)-2-hydroxybenzamide;
3-chloro-5-(N-(1 ,3-dimethyl-1 Hindol-5-yl)sulfamoyl)-2-hydroxybenzamide;
3-chloro-5-(N-(4-chloro-1 H-indol-6-yl)sulfamoyl)-2-hydroxybenzamide;
3-chloro-5-(N-(2-(ethylamino)-1 H-benzo[d]imidazol-6-yl)sulfamoyl)-2- hydroxybenzamide;
3- chloro-2-hydroxy-5-(N-(1 -methyl-1 Hbenzo[d]imidazol-5-yl)sulfamoyl)benzamide;
5-(N-(2-acetamido-1 Hbenzo[d]imidazol-6-yl)sulfamoyl)-3-chloro-2- hydroxybenzamide;
5-(N-(2-amino-1 Hbenzo[d]imidazol-6-yl)sulfamoyl)-3-chloro-2-hydroxybenzamide;
4- (benzylamino)-3-chloro-2-hydroxy-5-(N-(4-isopropoxyphenyl)sulfamoyl)- benzamide; 3-chloro-5-(N-(4-ethoxy-1 H-indol-6-yl)sulfamoyl)-2-hydroxybenzamide;
3-chloro-5-(N-(2,4-diethyl-1 Hbenzo[d]imidazol-6-yl)sulfamoyl)-2- hydroxybenzamide;
3-chloro-5-(N-(4-ethyl-1 Hindol-6-yl)sulfamoyl)-2-hydroxybenzamide;
3-chloro-5-(N-(2-ethyl-4-propyl-1 Hbenzo[d]imidazol-6-yl)sulfamoyl)-2- hydroxybenzamide;
3- chloro-5-(N-(2-ethyl-4-isopropyl-1 H-indol-6-yl)sulfamoyl)-2-hydroxybenzamide;
4- (benzylamino)-3-chloro-5-(N-(2-ethyl-1 H-indol-6-yl)sulfamoyl)-2- hydroxybenzamide;
2-hydroxy-3-(hydroxymethyl)-5-(N-(4-isopropoxyphenyl)sulfamoyl)benzamide;
5- (N-(1 H-indol-6-yl)sulfamoyl)-2-hydroxy-4-((5-hydroxypentyl)amino)benzamide; 5-(N-(1 H-indol-6-yl)sulfamoyl)-2-hydroxy-4-((3-hydroxybutyl)amino)benzamide and pharmaceutically acceptable salts thereof.
The skilled artisan will appreciate that 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 pharmaceutically acceptable salts of the compounds of the invention are readily prepared by those of skill in the art.
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. Where the stereochemistry of a chiral center present in a compound of Formula (I), or in any chemical structure illustrated herein, if not specified the structure is intended to encompass all individual stereoisomers and all mixtures thereof. Thus, 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. In the solid state, the compounds of the invention may exist in crystalline or noncrystalline form, or as a mixture thereof. For compounds of the invention that are in crystalline form, the skilled artisan will appreciate that 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.
The skilled artisan will further appreciate that certain compounds of Formula (I) or pharmaceutically acceptable salts thereof that exist in crystalline form, including the various solvates thereof, may exhibit polymorphism (i.e. the capacity to occur in different crystalline structures). These different crystalline forms are typically known as "polymorphs." Polymorphs 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. The skilled artisan will appreciate that different 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.
DEFINITIONS
"Alkyl" refers to a hydrocarbon chain having the specified number of "member atoms". For example, 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. For example, C-| -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. Suitably 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, azabenzimidazolyl, tetrahydrobenzimidazolyl, benzimidazolyl, benopyranyl, benzoxazolyl, benzofuranyl, isobenzofuranyl, benzothiazolyl, benzothienyl, imidazo[4.5-c]pyridine, imidazo[4.5- b]pyridine, imidazo[1 ,2-a]pyridine, furopyridinyl, napthyridinyl, tetrahydroisoquinoline, tetrahydroquinoline, dihydroisoquinoline, benzothiazole, benzoimidazole, benzodiazole, quinoline, quinoxaline, dihydrobenzodioxine, dihydrobenzodioxol, isoindoline, indazole and indoline.
Suitably "Bicycloheteroaryl" includes: 1 /-/-pyrrolo[2,3-Jb]pyridine, indolyl, benzimidazolyl, benzothienyl, imidazo[1 ,2-a]pyridine, tetrahydroquinoline, dihydroisoquinoline, dihydrobenzodioxol, indazole and indoline.
Suitably "Bicycloheteroaryl" includes benzotriazolyl.
"Cycloalkyl", unless otherwise defined, 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. Suitably heteroaryl is selected from: pyrazolyl, oxazolyl and thienyl.
"Heteroatom" refers to a nitrogen, sulphur or oxygen atom.
The term "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: -CO2R200, -CONR2 °R220, -S02C-| -C4alkyl, -SO2NR21 0R220, -NR230SO2C-| -C4alkyl, C -C4alkyl, hydroxyC-| -
C4alkyl, C-| -C4alkyloxy, amino, C-| -C4alkylamino, aminoC-| -C4alkyl, diC-| -C4alkylamino, diC-| -C4alkylamino where the carbon chains 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 and optionally substituted by methyl, hydroxy, nitro, tetrazole, cyano, oxo, fluoro, chloro, bromo, iodo, -CH2F, -CHF2, and trifluoromethyl, where R200 is selected form hydrogen, C-| -C4alkyl, aryl, heteroaryl, cycloalkyl, bicycloheteroaryl, R2"O and R22^ are independently selected from hydrogen, C-| -C4alkyl, aryl, heteroaryl or R2 "O and R22^ 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, and R2^0 js selected from hydrogen, C-| - C4alkyl, aryl and heteroaryl.
Suitably, the term "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-| -C4alkyl, C-| -C4alkyloxy, amino, C-| -C4alkylamino, diC-| -C4alkylamino, diC-| -C4alkylamino where the carbon chains 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 and optionally substituted by methyl, aminoC-| -C4alkyl, hydroxy, tetrazole, cyano, fluoro, chloro, bromo, iodo, -CH2F, -CHF2, and trifluoromethyl.
Suitably, the term "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-| -C4alkylamino, diC-| - C4alkylamino, and diC-| -C4alkylamino where the carbon chains 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 and optionally substituted by methyl. As used herein the symbols and conventions used in these processes, schemes and examples are consistent with those used in the contemporary scientific literature, for example, the Journal of the American Chemical Society or the Journal of Biological Chemistry. Standard single-letter or three-letter abbreviations are generally used to designate amino acid residues, which are assumed to be in the L-configuration unless otherwise noted. Unless otherwise noted, all starting materials were obtained from commercial suppliers and used without further purification. Specifically, the following abbreviations may be used in the examples and throughout the specification:
Ac (acetyl);
Ac20 (acetic anhydride);
ACN (acetonitrile);
AIBN (azobis(isobutyronitrile));
BINAP (2,2'-bis(diphenylphosphino)-1 ,1 '-binaphthyl);
BMS (borane - dimethyl sulphide complex);
Bn (benzyl);
Boc (tert-Butoxycarbonyl);
Boc20 (di-fe/ -butyl dicarbonate);
BOP (Benzotriazole-l -yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate);
CAN (cerric ammonium nitrate);
Cbz (benzyloxycarbonyl);
CSI (chlorosulfonyl isocyanate);
CSF (cesium fluoride);
DABCO (1 ,4-Diazabicyclo[2.2.2]octane);
DAST (Diethylamino)sulfur trifluoride);
DBU (1 ,8-Diazabicyclo[5.4.0]undec-7-ene);
DCC (Dicyclohexyl Carbodiimide);
DCE (1 ,2-dichloroethane);
DCM (dichloromethane); DDQ (2,3-Dichloro-5,6-dicyano-1 ,4-benzoquinone);
ATP (adenosine triphosphate);
Bis-pinacolatodiboron (4,4,4',4', 5, 5, 5', 5'-Octamethyl-2,2'-bi-1 ,3,2-dioxaborolane);
BSA (bovine serum albumin);
C18 (refers to 18-carbon alkyl groups on silicon in HPLC stationary phase)
CH3CN (acetonitrile) Cy (cyclohexyl);
DCM (dichloromethane);
DIEA (diisopropylethylamine);
DIPEA (Hunig's base, /V-ethyl-W-(1 -methylethyl)-2-propanamine);
Dioxane (1 ,4-dioxane);
DMAP (4-dimethylaminopyridine);
DME (1 ,2-dimethoxyethane);
DMEDA (Λ/,Λ/'-dimethylethylenediamine);
DMF (Λ/,/V-dimethylformamide);
DMSO (dimethylsulfoxide);
DPPA (diphenyl phosphoryl azide);
EDC (/V-(3-dimethylaminopropyl)-/V'ethylcarbodiimide) hydrochloride salt;
EDTA (ethylenediaminetetraacetic acid);
EtOAc (ethyl acetate);
EtOH (ethanol);
Et20 (diethyl ether);
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);
HOBt (1 -hydroxybenzotriazole);
HOAc (acetic acid); HPLC (high pressure liquid chromatography);
HMDS (hexamethyldisilazide);
Hunig's Base (Λ/,/V-Diisopropylethylamine);
IPA (isopropyl alcohol);
Indoline (2,3-dihydro-1 H-indole) ;
KHMDS (potassium hexamethyldisilazide) ;
LAH (lithium aluminum hydride) ;
LDA (lithium diisopropylamide) ;
LHMDS (lithium hexamethyldisilazide)
MeOH (methanol);
MTBE (methyl tert-butyl ether);
mCPBA (m-chloroperbezoic acid);
NaHMDS (sodium hexamethyldisilazide);
NCS (N-chlorosuccinimide);
NBS (/V-bromosuccinimide);
PE (petroleum ether);
Pd2(dba)3 (Tris(dibenzylideneacetone)dipalladium(O);
Pd(dppf)CI2.DCM Complex([1 ,1 '-
Bis(diphenylphosphino)ferrocene]dichloropalladium(ll).dichloromethane complex); PyBOP (benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate);
PyBrOP (bromotripyrrolidinophosphonium hexafluorophosphate);
RPHPLC (reverse phase high pressure liquid chromatography);
RT (room temperature);
Sat. (saturated)
SFC (supercritical fluid chromatography);
SGC (silica gel chromatography);
SM (starting material); TCL (thin layer chromatography);
TEA (triethylamine);
TEMPO (2,2,6,6-Tetramethylpiperidine 1 -oxyl, free radical);
TFA (trifluoroacetic acid); and
THF (tetrahydrofuran).
All references to ether are to diethyl ether and brine refers to a saturated agueous solution of NaCI.
COMPOUND PREPARATION
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.
The skilled artisan will appreciate that if 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). In some instances, 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.
As used in Scheme 1 below, r and r "2 represents all combinations of R, R and R2 disclosed herein.
General procedure for the preparation of salicylamide sulfonamides (A2)
The general procedure for preparation of salicylamide sulfonamides (A2) is shown in Scheme 1 below. 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).
Scheme 1
Figure imgf000059_0001
A2 Methods of Use
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.
Suitably, the present invention relates to a method for treating breast cancer, including inflammatory breast cancer, ductal carcinoma, and lobular carcinoma. Suitably the present invention relates to a method for treating colon cancer.
Suitably the present invention relates to a method for treating pancreatic cancer, including insulinomas, adenocarcinoma, ductal adenocarcinoma, adenosquamous carcinoma, acinar cell carcinoma, and glucagonoma.
Suitably the present invention relates to a method for treating skin cancer, including melanoma, including metastatic melanoma. Suitably 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.
Suitably 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; myeloma; chronic or acute leukemia; lymphocytic lymphomas; primary CNS lymphoma; neoplasms of the CNS; spinal axis tumours; squamous cell carcinomas; synovial sarcoma; malignant pleural mesotheliomas; brain stem glioma; pituitary adenoma; bronchial adenoma; chondromatous hanlartoma; inesothelioma; and Hodgkin's Disease.
Suitably 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, acute lymphoblastic leukemia, acute myelogenous leukemia, chronic neutrophilic leukemia, acute lymphoblastic T cell leukemia, plasmacytoma, Immunoblastic large cell leukemia, mantle cell leukemia, multiple myeloma, megakaryoblastic leukemia, multiple myeloma, acute megakaryocyte leukemia, promyelocytic leukemia, erythroleukemia, malignant lymphoma, hodgkins lymphoma, non- hodgkins lymphoma, lymphoblastic T cell lymphoma, Burkitt's lymphoma, follicular lymphoma, neuroblastoma, bladder cancer, urothelial cancer, vulval cancer, cervical cancer, endometrial cancer, renal cancer, mesothelioma, esophageal cancer, salivary gland cancer, hepatocellular cancer, gastric cancer, nasopharangeal cancer, buccal cancer, cancer of the mouth, GIST (gastrointestinal stromal tumor), neuroendocrine cancers and testicular cancer.
Suitably 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.
In some embodiments, 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. In some embodiments, 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).
In one embodiment, 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). In another embodiment, 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.
In other embodiments, compounds of the invention are used to increase or enhance an immune response to an antigen by providing adjuvant activity. In one embodiment, 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.
Further 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 fibrosis, hepatic fibrosis, liver fibrosis, pulmonary fibrosis, idiopathic pulmonary fibrosis, interstitial fibrosis, cystic fibrosis, emphysema, peritoneal fibrosis, cardiac fibrosis, myocardial fibrosis, endomyocardial fibrosis, atrial fibrosis, alcoholic fatty liver disease, fatty liver, hepatic steatosis, cirrhosis, hepatic cirrhosis, nonalcoholic fatty liver disease (NAFLD), non-alcoholic hepatosteatosis (NASH), mediastinal fibrosis, myelofibrosis, retroperitoneal fibrosis, progressive massive fibrosis, nephrogenic systemic fibrosis, Crohn's disease, keloids, hypertrophic scars, scleroderma, systemic sclerosis, arthrofibrosis, Peyronie's disease, priapism, Dupuytren's contracture, adhesive capsulitis, stroke, psychosis, psychoses of organic origin, dry eye disease, keratoconjunctivitis sicca, keratitis sicca, glaucoma, diabetic retinopathy, retinal ischemia, kidney disease, renal failure, and acute renal failure.
In some embodiments, diseases and disorders treatable with compounds of the invention are insulin resistance, diabetes and risk of diabetes. In some embodiments, 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. In some embodiments, 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. In further aspects, 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.
By the term "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.
As used herein, 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. Furthermore, the term "therapeutically effective amount" and derivatives thereof 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.
As used herein, "patient" or "subject" refers to a human or other animal. Suitably the 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. In addition, 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.
Additionally, the compounds of Formula (I) or pharmaceutically acceptable salts thereof may be administered as prodrugs. As used herein, 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. Where a -COOH or -OH group is present, pharmaceutically acceptable 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.
By the term "co-administration" as used herein 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. The term further active agent or agents, as used herein, includes any compound or therapeutic agent known to or that demonstrates advantageous properties when administered to a patient in need of treatment for cancer. Preferably, if the administration is not simultaneous, the compounds are administered in a close time proximity to each other. Furthermore, it does not matter if 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.
Typically, 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), 6th 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.
Examples of a further active ingredient or ingredients (anti-neoplastic agent) for use in combination or co-administered with the presently invented combinations are 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. Examples of 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 G2/M phases of the cell cycle. It is believed that the diterpenoids stabilize the β-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. Examples of diterpenoids include, but are not limited to, paclitaxel and its analog docetaxel.
Paclitaxel, 5p,20-epoxy-1 ,2α,4,7β,10β,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 δβ-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. The dose limiting toxicity of docetaxel is neutropenia. 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, is commercially available as VELBAN® as an injectable solution. Although, it has possible indication as a second line therapy of various solid tumors, it is primarily indicated in the treatment of testicular cancer and various lymphomas including Hodgkin's Disease; and lymphocytic and histiocytic lymphomas. Myelosuppression is the dose limiting side effect of vinblastine.
Vincristine, vincaleukoblastine, 22-oxo-, sulfate, is commercially available as ONCOVIN® as 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, is commercially available as PLATINOL® as 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. Examples of 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.
Busulfan, 1 ,4-butanediol dimethanesulfonate, is commercially available as MYLERAN® TABLETS. Busulfan is indicated for the palliative treatment of chronic myelogenous leukemia. Bone marrow suppression is the most common dose limiting side effects of busulfan.
Carmustine, 1 ,3-[bis(2-chloroethyl)-1 -nitrosourea, is commercially available as single vials of lyophilized material as BiCNU®. Carmustine is indicated for the palliative treatment as a single agent or in combination with other agents for brain tumors, multiple myeloma, Hodgkin's disease, and non-Hodgkin's lymphomas. Delayed myelosuppression is the most common dose limiting side effects of carmustine.
Dacarbazine, 5-(3,3-dimethyl-1 -triazeno)-imidazole-4-carboxamide, is commercially available as single vials of material as DTIC-Dome®. Dacarbazine is indicated for the treatment of metastatic malignant melanoma and in combination with other agents for the second line treatment of Hodgkin's Disease. Nausea, vomiting, and anorexia are the most common dose limiting side effects of dacarbazine.
Antibiotic anti-neoplastics are non-phase specific agents, which bind or intercalate with DNA. Typically, such action results in stable DNA complexes or strand breakage, which disrupts ordinary function of the nucleic acids, leading to cell death. Examples of antibiotic anti-neoplastic agents include, but are not limited to, actinomycins such as dactinomycin, anthrocyclins such as daunorubicin and doxorubicin; and bleomycins. Dactinomycin, also know as Actinomycin D, is commercially available in injectable form as COSMEGEN®. Dactinomycin is indicated for the treatment of Wilm's tumor and rhabdomyosarcoma. Nausea, vomiting, and anorexia are the most common dose limiting side effects of dactinomycin.
Daunorubicin, (8S-cis-)-8-acetyl-10-[(3-amino-2,3,6-trideoxy-a-L-lyxo- hexopyranosyl)oxy]-7,8,9,10-tetrahydro-6,8,1 1 -trihydroxy-1 -methoxy-5,12
naphthacenedione hydrochloride, is commercially available as a liposomal injectable form as DAUNOXOME® or as an injectable as CERUBIDINE®. Daunorubicin is indicated for remission induction in the treatment of acute nonlymphocytic leukemia and advanced HIV associated Kaposi's sarcoma. Myelosuppression is the most common dose limiting side effect of daunorubicin.
Doxorubicin, (8S, 10S)-10-[(3-amino-2,3,6-trideoxy-a-L-lyxo-hexopyranosyl)oxy]-8- glycoloyl, 7,8,9,10-tetrahydro-6, 8, 1 1 -trihydroxy-1 -methoxy-5, 12 naphthacenedione hydrochloride, is commercially available as an injectable form as RUBEX® or ADRIAMYCIN RDF®. Doxorubicin is primarily indicated for the treatment of acute lymphoblastic leukemia and acute myeloblasts leukemia, but is also a useful component in the treatment of some solid tumors and lymphomas. Myelosuppression is the most common dose limiting side effect of doxorubicin. Bleomycin, a mixture of cytotoxic glycopeptide antibiotics isolated from a strain of
Streptomyces verticillus, is commercially available as BLENOXANE®. Bleomycin is indicated as a palliative treatment, as a single agent or in combination with other agents, of squamous cell carcinoma, lymphomas, and testicular carcinomas. Pulmonary and cutaneous toxicities are the most common dose limiting side effects of bleomycin.
Topoisomerase II inhibitors include, but are not limited to, epipodophyllotoxins.
Epipodophyllotoxins are phase specific anti-neoplastic agents derived from the mandrake plant. Epipodophyllotoxins typically affect cells in the S and G2 phases of the cell cycle by forming a ternary complex with topoisomerase II and DNA causing DNA strand breaks. The strand breaks accumulate and cell death follows. Examples of epipodophyllotoxins include, but are not limited to, etoposide and teniposide. Etoposide, 4'-demethyl-epipodophyllotoxin 9[4,6-0-(R)-ethylidene-p-D- glucopyranoside], is commercially available as an injectable solution or capsules as VePESID® and is commonly known as VP-16. Etoposide is indicated as a single agent or in combination with other chemotherapy agents in the treatment of testicular and non-small cell lung cancers. Myelosuppression is the most common side effect of etoposide. The incidence of leucopenia tends to be more severe than thrombocytopenia.
Teniposide, 4'-demethyl-epipodophyllotoxin 9[4,6-0-(R)-thenylidene-p-D- glucopyranoside], is commercially available as an injectable solution as VUMON® and is commonly known as VM-26. Teniposide is indicated as a single agent or in combination with other chemotherapy agents in the treatment of acute leukemia in children. Myelosuppression is the most common dose limiting side effect of teniposide. Teniposide can induce both leucopenia and thrombocytopenia.
Antimetabolite neoplastic agents are phase specific anti-neoplastic agents that act at S phase (DNA synthesis) of the cell cycle by inhibiting DNA synthesis or by inhibiting purine or pyrimidine base synthesis and thereby limiting DNA synthesis. Consequently, S phase does not proceed and cell death follows. Examples of antimetabolite anti-neoplastic agents include, but are not limited to, fluorouracil, methotrexate, cytarabine, mecaptopurine, thioguanine, and gemcitabine.
5-fluorouracil, 5-fluoro-2,4- (1 H,3H) pyrimidinedione, is commercially available as fluorouracil. Administration of 5-fluorouracil leads to inhibition of thymidylate synthesis and is also incorporated into both RNA and DNA. The result typically is cell death. 5-fluorouracil is indicated as a single agent or in combination with other chemotherapy agents in the treatment of carcinomas of the breast, colon, rectum, stomach and pancreas. Myelosuppression and mucositis are dose limiting side effects of 5-fluorouracil. Other fluoropyrimidine analogs include 5-fluoro deoxyuridine (floxuridine) and 5- fluorodeoxyuridine monophosphate.
Cytarabine, 4-amino-1 -p-D-arabinofuranosyl-2 (1 H)-pyrimidinone, is commercially available as CYTOSAR-U® and is commonly known as Ara-C. It is believed that cytarabine exhibits cell phase specificity at S-phase by inhibiting DNA chain elongation by terminal incorporation of cytarabine into the growing DNA chain. Cytarabine is indicated as a single agent or in combination with other chemotherapy agents in the treatment of acute leukemia. Other cytidine analogs include 5-azacytidine and 2',2'-difluorodeoxycytidine (gemcitabine). Cytarabine induces leucopenia, thrombocytopenia, and mucositis. Mercaptopurine, 1 ,7-dihydro-6H-purine-6-thione monohydrate, is commercially available as PURINETHOL®. Mercaptopurine exhibits cell phase specificity at S-phase by inhibiting DNA synthesis by an as of yet unspecified mechanism. Mercaptopurine is indicated as a single agent or in combination with other chemotherapy agents in the treatment of acute leukemia. Myelosuppression and gastrointestinal mucositis are expected side effects of mercaptopurine at high doses. A useful mercaptopurine analog is azathioprine.
Thioguanine, 2-amino-1 ,7-dihydro-6H-purine-6-thione, is commercially available as TABLOID®. Thioguanine exhibits cell phase specificity at S-phase by inhibiting DNA synthesis by an as of yet unspecified mechanism. Thioguanine is indicated as a single agent or in combination with other chemotherapy agents in the treatment of acute leukemia. Myelosuppression, including leucopenia, thrombocytopenia, and anemia, is the most common dose limiting side effect of thioguanine administration. However, gastrointestinal side effects occur and can be dose limiting. Other purine analogs include pentostatin, erythrohydroxynonyladenine, fludarabine phosphate, and cladribine. Gemcitabine, 2'-deoxy-2', 2'-difluorocytidine monohydrochloride (β-isomer), is commercially available as GEMZAR®. Gemcitabine exhibits cell phase specificity at S- phase and by blocking progression of cells through the G1/S boundary. Gemcitabine is indicated in combination with cisplatin in the treatment of locally advanced non-small cell lung cancer and alone in the treatment of locally advanced pancreatic cancer. Myelosuppression, including leucopenia, thrombocytopenia, and anemia, is the most common dose limiting side effect of gemcitabine administration.
Methotrexate, N-[4[[(2,4-diamino-6-pteridinyl) methyl]methylamino] benzoyl]-L- glutamic acid, is commercially available as methotrexate sodium. Methotrexate exhibits cell phase effects specifically at S-phase by inhibiting DNA synthesis, repair and/or replication through the inhibition of dyhydrofolic acid reductase which is required for synthesis of purine nucleotides and thymidylate. Methotrexate is indicated as a single agent or in combination with other chemotherapy agents in the treatment of choriocarcinoma, meningeal leukemia, non-Hodgkin's lymphoma, and carcinomas of the breast, head, neck, ovary and bladder. Myelosuppression (leucopenia, thrombocytopenia, and anemia) and mucositis are expected side effect of methotrexate administration.
Camptothecins, including, camptothecin and camptothecin derivatives are available or under development as Topoisomerase I inhibitors. Camptothecins cytotoxic activity is believed to be related to its Topoisomerase I inhibitory activity. Examples of camptothecins include, but are not limited to irinotecan, topotecan, and the various optical forms of 7-(4- methylpiperazino-methylene)-10,1 1 -ethylenedioxy-20-camptothecin described below. Irinotecan HCI, (4S)-4,1 1 -diethyl-4-hydroxy-9-[(4-piperidinopiperidino) carbonyloxy]-1 H- pyrano[3',4',6,7]indolizino[1 ,2-b]quinoline-3, 14(41-1, 12H)-dione hydrochloride, is commercially available as the injectable solution CAMPTOSAR®. Irinotecan is a derivative of camptothecin which binds, along with its active metabolite SN-38, to the topoisomerase I - DNA complex. It is believed that cytotoxicity occurs as a result of irreparable double strand breaks caused by interaction of the topoisomerase I : DNA : irintecan or SN-38 ternary complex with replication enzymes. Irinotecan is indicated for treatment of metastatic cancer of the colon or rectum. The dose limiting side effects of irinotecan HCI are myelosuppression, including neutropenia, and Gl effects, including diarrhea.
Topotecan HCI, (S)-10-[(dimethylamino)methyl]-4-ethyl-4,9-dihydroxy-1 H- pyrano[3',4',6,7]indolizino[1 ,2-b]quinoline-3,14-(4H,12H)-dione monohydrochloride, is commercially available as the injectable solution HYCAMTIN®. Topotecan is a derivative of camptothecin which binds to the topoisomerase I - DNA complex and prevents religation of singles strand breaks caused by Topoisomerase I in response to torsional strain of the DNA molecule. Topotecan is indicated for second line treatment of metastatic carcinoma of the ovary and small cell lung cancer. The dose limiting side effect of topotecan HCI is myelosuppression, primarily neutropenia.
Also of interest, is the camptothecin derivative of Formula A following, including the racemic mixture (R,S) form as well as the R and S enantiomers:
Figure imgf000072_0001
known by the chemical name "7-(4-methylpiperazino-methylene)-10,1 1 -ethylenedioxy- 20(R,S)-camptothecin (racemic mixture) or "7-(4-methylpiperazino-methylene)-10,1 1 - ethylenedioxy-20(R)-camptothecin (R enantiomer) or "7-(4-methylpiperazino-methylene)- 10,1 1 -ethylenedioxy-20(S)-camptothecin (S enantiomer). Such compound as well as related compounds are described, including methods of making, in U.S. Patent Nos. 6,063,923; 5,342,947; 5,559,235; and 5,491 ,237. Hormones and hormonal analogues are useful compounds for treating cancers in which there is a relationship between the hormone(s) and growth and/or lack of growth of the cancer. Examples of hormones and hormonal analogues useful in cancer treatment include, but are not limited to, adrenocorticosteroids such as prednisone and prednisolone which are useful in the treatment of malignant lymphoma and acute leukemia in children; aminoglutethimide and other aromatase inhibitors such as anastrozole, letrazole, vorazole, and exemestane useful in the treatment of adrenocortical carcinoma and hormone dependent breast carcinoma containing estrogen receptors; progestrins such as megestrol acetate useful in the treatment of hormone dependent breast cancer and endometrial carcinoma; estrogens, androgens, and anti-androgens such as flutamide, nilutamide, bicalutamide, cyproterone acetate and 5a-reductases such as finasteride and dutasteride, useful in the treatment of prostatic carcinoma and benign prostatic hypertrophy; anti- estrogens such as tamoxifen, toremifene, raloxifene, droloxifene, iodoxyfene, as well as selective estrogen receptor modulators (SERMS) such those described in U.S. Patent Nos. 5,681 ,835, 5,877,219, and 6,207,716, useful in the treatment of hormone dependent breast carcinoma and other susceptible cancers; and gonadotropin-releasing hormone (GnRH) and analogues thereof which stimulate the release of leutinizing hormone (LH) and/or follicle stimulating hormone (FSH) for the treatment prostatic carcinoma, for instance, LHRH agonists and antagagonists such as goserelin acetate and luprolide. Signal transduction pathway inhibitors are those inhibitors, which block or inhibit a chemical process which evokes an intracellular change. As used herein this change is cell proliferation or differentiation. Signal tranduction inhibitors useful in the present invention include inhibitors of receptor tyrosine kinases, non-receptor tyrosine kinases, SH2/SH3 domain blockers, serine/threonine kinases, phosphotidylinositol-3 kinases, myo-inositol signaling, and Ras oncogenes.
Several protein tyrosine kinases catalyse the phosphorylation of specific tyrosyl residues in various proteins involved in the regulation of cell growth. Such protein tyrosine kinases can be broadly classified as receptor or non-receptor kinases.
Receptor tyrosine kinases are transmembrane proteins having an extracellular ligand binding domain, a transmembrane domain, and a tyrosine kinase domain. Receptor tyrosine kinases are involved in the regulation of cell growth and are generally termed growth factor receptors. Inappropriate or uncontrolled activation of many of these kinases, i.e. aberrant kinase growth factor receptor activity, for example by over-expression or mutation, has been shown to result in uncontrolled cell growth. Accordingly, the aberrant activity of such kinases has been linked to malignant tissue growth. Consequently, inhibitors of such kinases could provide cancer treatment methods. Growth factor receptors include, for example, epidermal growth factor receptor (EGFr), platelet derived growth factor receptor (PDGFr), erbB2, erbB4, vascular endothelial growth factor receptor (VEGFr), tyrosine kinase with immunoglobulin-like and epidermal growth factor homology domains (TIE-2), insulin growth factor -I (IGFI) receptor, macrophage colony stimulating factor (cfms), BTK, ckit, cmet, fibroblast growth factor (FGF) receptors, Trk receptors (TrkA, TrkB, and TrkC), ephrin (eph) receptors, and the RET protooncogene. Several inhibitors of growth receptors are under development and include ligand antagonists, antibodies, tyrosine kinase inhibitors and anti-sense oligonucleotides. Growth factor receptors and agents that inhibit growth factor receptor function are described, for instance, in Kath, John C, Exp. Opin. Ther. Patents (2000) 10(6):803-818; Shawver et al DDT Vol 2, No. 2 February 1997; and Lofts, F. J. et al, "Growth factor receptors as targets", New Molecular Targets for Cancer Chemotherapy, ed. Workman, Paul and Kerr, David, CRC press 1994, London.
Suitably, the pharmaceutically active compounds of the invention are used in combination with a VEGFR inhibitor, suitably 5-[[4-[(2,3-dimethyl-2H-indazol-6- yl)methylamino]-2-pyrimidinyl]amino]-2-methylbenzenesulfonamide, or a pharmaceutically acceptable salt, suitably the monohydrochloride salt thereof, which is disclosed and claimed in in International Application No. PCT/US01/49367, having an International filing date of December 19, 2001 , International Publication Number WO02/0591 10 and an International Publication date of August 1 , 2002, the entire disclosure of which is hereby incorporated by reference, and which is the compound of Example 69. 5-[[4-[(2,3-dimethyl-2H-indazol-6- yl)methylamino]-2-pyrimidinyl]amino]-2-methylbenzenesulfonamide can be prepared as described in International Application No. PCT/US01/49367.
Suitably, 5-[[4-[(2,3-dimethyl-2H-indazol-6-yl)methylamino]-2-pyrimidinyl]amino]-2- methylbenzenesulfonamide is in the form of a monohydrochloride salt. This salt form can be prepared by one of skill in the art from the description in International Application No. PCT/US01/49367, having an International filing date of December 19, 2001 .
5-[[4-[(2,3-dimethyl-2H-indazol-6-yl)methylamino]-2-pyrimidinyl]amino]-2- methylbenzenesulfonamide is sold commercially as the monohydrochloride salt and is known by the generic name pazopanib and the trade name Votrient®.
Pazopanib is implicated in the treatment of cancer and ocular diseases/angiogenesis. Suitably the present invention relates to the treatment of cancer and ocular diseases/angiogenesis, suitably age-related macular degeneration, which method comprises the administration of a compound of Formula (I) alone or in combination with pazopanib.
Tyrosine kinases, which are not growth factor receptor kinases are termed nonreceptor tyrosine kinases. Non-receptor tyrosine kinases for use in the present invention, which are targets or potential targets of anti-cancer drugs, include cSrc, Lck, Fyn, Yes, Jak, cAbl, FAK (Focal adhesion kinase), Brutons tyrosine kinase, and Bcr-Abl. Such nonreceptor kinases and agents which inhibit non-receptor tyrosine kinase function are described in Sinh, S. and Corey, S.J., (1999) Journal of Hematotherapy and Stem Cell Research 8 (5): 465 - 80; and Bolen, J.B., Brugge, J.S., (1997) Annual review of Immunology. 15: 371 -404. SH2/SH3 domain blockers are agents that disrupt SH2 or SH3 domain binding in a variety of enzymes or adaptor proteins including, PI3-K p85 subunit, Src family kinases, adaptor molecules (She, Crk, Nek, Grb2) and Ras-GAP. SH2/SH3 domains as targets for anti-cancer drugs are discussed in Smithgall, T.E. (1995), Journal of Pharmacological and Toxicological Methods. 34(3) 125-32.
Inhibitors of Serine/Threonine Kinases including MAP kinase cascade blockers which include blockers of Raf kinases (rafk), Mitogen or Extracellular Regulated Kinase (MEKs), and Extracellular Regulated Kinases (ERKs); and Protein kinase C family member blockers including blockers of PKCs (alpha, beta, gamma, epsilon, mu, lambda, iota, zeta). IkB kinase family (IKKa, IKKb), PKB family kinases, akt kinase family members, PDK1 and TGF beta receptor kinases. Such Serine/Threonine kinases and inhibitors thereof are described in Yamamoto, T., Taya, S., Kaibuchi, K., (1999), Journal of Biochemistry. 126 (5) 799-803; Brodt, P, Samani, A., and Navab, R. (2000), Biochemical Pharmacology, 60. 1 101 -1 107; Massague, J., Weis-Garcia, F. (1996) Cancer Surveys. 27:41 -64; Philip, P.A., and Harris, A.L. (1995), Cancer Treatment and Research. 78: 3-27, Lackey, K. et al Bioorganic and Medicinal Chemistry Letters, (10), 2000, 223-226; U.S. Patent No. 6,268,391 ; Pearce, L.R et al. Nature Reviews Molecular Cell Biology (2010) 1 1 , 9-22. and Martinez-lacaci, L., et al, Int. J. Cancer (2000), 88(1), 44-52. Suitably, the pharmaceutically active compounds of the invention are used in combination with a MEK inhibitor. Suitably, N-{3-[3-cyclopropyl-5-(2-fluoro-4-iodo- phenylamino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro-2H-pyrido[4,3-d]pyrimidin-1 - yl]phenyl}acetamide, or a pharmaceutically acceptable salt or solvate, suitably the dimethyl sulfoxide solvate, thereof, which is disclosed and claimed in International Application No. PCT/JP2005/01 1082, having an International filing date of June 10, 2005; International Publication Number WO 2005/121 142 and an International Publication date of December 22, 2005, the entire disclosure of which is hereby incorporated by reference. N-{3-[3- cyclopropyl-5-(2-fluoro-4-iodo-phenylamino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro- 2H-pyrido[4,3-d]pyrimidin-1 -yl]phenyl}acetamide, can be prepared as described in United States Patent Publication No. US 2006/0014768, Published January 19, 2006, the entire disclosure of which is hereby incorporated by reference.
Suitably, the pharmaceutically active compounds of the invention are used in combination with a B-Raf inhibitor. Suitably, /V-{3-[5-(2-Amino-4-pyrimidinyl)-2-(1 ,1 - dimethylethyl)-1 ,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide, or a pharmaceutically acceptable salt thereof, which is disclosed and claimed, in International Application No. PCT/US2009/042682, having an International filing date of May 4, 2009, the entire disclosure of which is hereby incorporated by reference. /V-{3-[5-(2-Amino-4- pyrimidinyl)-2-(1 ,1 -dimethylethyl)-1 ,3-thiazol-4-yl]-2-fluorophenyl}-2,6- difluorobenzenesulfonamide can be prepared as described in International Application No. PCT/US2009/042682.
Suitably, the pharmaceutically active compounds of the invention are used in combination with an Akt inhibitor. Suitably, N-{(1 S)-2-amino-1 -[(3,4- difluorophenyl)methyl]ethyl}-5-chloro-4-(4-chloro-1 -methyl-1 H-pyrazol-5-yl)-2- furancarboxamide or a pharmaceutically acceptable salt thereof, which is disclosed and claimed in International Application No. PCT/US2008/053269, having an International filing date of February 7, 2008; International Publication Number WO 2008/098104 and an International Publication date of August 14, 2008, the entire disclosure of which is hereby incorporated by reference. N-{(1 S)-2-amino-1 -[(3,4-difluorophenyl)methyl]ethyl}-5-chloro- 4-(4-chloro-1 -methyl-1 H-pyrazol-5-yl)-2-furancarboxamide is the compound of example 224 and can be prepared as described in International Application No. PCT/US2008/053269.
Suitably, the pharmaceutically active compounds of the invention are used in combination with an Akt inhibitor. Suitably, /V-{(1 S)-2-amino-1 -[(3- fluorophenyl)methyl]ethyl}-5-chloro-4-(4-chloro-1 -methyl-1 H-pyrazol-5-yl)-2- thiophenecarboxamide or a pharmaceutically acceptable salt thereof, which is disclosed and claimed in International Application No. PCT/US2008/053269, having an International filing date of February 7, 2008; International Publication Number WO 2008/098104 and an International Publication date of August 14, 2008, the entire disclosure of which is hereby incorporated by reference. Λ/-{(1 S)-2-amino-1 -[(3-fluorophenyl)methyl]ethyl}-5-chloro-4-(4- chloro-1 -methyl-1 H-pyrazol-5-yl)-2-thiophenecarboxamide is the compound of example 96 and can be prepared as described in International Application No. PCT/US2008/053269. Suitably, Λ/-{(1 S)-2-amino-1 -[(3-fluorophenyl)methyl]ethyl}-5-chloro-4-(4-chloro-1 -methyl- 1 H-pyrazol-5-yl)-2-thiophenecarboxamide is in the form of a hydrochloride salt. The salt form can be prepared by one of skill in the art from the description in International Application No. PCT/US2010/022323, having an International filing date of January 28, 2010.
Inhibitors of Phosphotidylinositol-3 Kinase family members including blockers of PI3-kinase, ATM, DNA-PK, and Ku may also be useful in the present invention. Such kinases are discussed in Abraham, R.T. (1996), Current Opinion in Immunology. 8 (3) 412- 8; Canman, C.E., Lim, D.S. (1998), Oncogene 17 (25) 3301 -3308; Jackson, S.P. (1997), International Journal of Biochemistry and Cell Biology. 29 (7):935-8; and Zhong, H. et al, Cancer res, (2000) 60(6), 1541 -1545. Also of interest in the present invention are Myo-inositol signaling inhibitors such as phospholipase C blockers and Myoinositol analogues. Such signal inhibitors are described in Powis, G., and Kozikowski A., (1994) New Molecular Targets for Cancer Chemotherapy ed., Paul Workman and David Kerr, CRC press 1994, London.
Another group of signal transduction pathway inhibitors are inhibitors of Ras Oncogene. Such inhibitors include inhibitors of farnesyltransferase, geranyl-geranyl transferase, and CAAX proteases as well as anti-sense oligonucleotides, ribozymes and immunotherapy. Such inhibitors have been shown to block ras activation in cells containing wild type mutant ras, thereby acting as antiproliferation agents. Ras oncogene inhibition is discussed in Scharovsky, O.G., Rozados, V.R., Gervasoni, S.I. Matar, P. (2000), Journal of Biomedical Science. 7(4) 292-8; Ashby, M.N. (1998), Current Opinion in Lipidology. 9 (2) 99 - 102; and BioChim. Biophys. Acta, (19899) 1423(3):19-30.
As mentioned above, antibody antagonists to receptor kinase ligand binding may also serve as signal transduction inhibitors. This group of signal transduction pathway inhibitors includes the use of humanized antibodies to the extracellular ligand binding domain of receptor tyrosine kinases. For example Imclone C225 EGFR specific antibody (see Green, M.C. et al, Monoclonal Antibody Therapy for Solid Tumors, Cancer Treat. Rev., (2000), 26(4), 269-286); Herceptin ® erbB2 antibody (see Tyrosine Kinase Signalling in Breast cancenerbB Family Receptor Tyrosine Kniases, Breast cancer Res., 2000, 2(3), 176-183); and 2CB VEGFR2 specific antibody (see Brekken, R.A. et al, Selective Inhibition of VEGFR2 Activity by a monoclonal Anti-VEGF antibody blocks tumor growth in mice, Cancer Res. (2000) 60, 51 17-5124).
Non-receptor kinase angiogenesis inhibitors may also be useful in the present invention. Inhibitors of angiogenesis related VEGFR and TIE2 are discussed above in regard to signal transduction inhibitors (both receptors are receptor tyrosine kinases). Angiogenesis in general is linked to erbB2/EGFR signaling since inhibitors of erbB2 and EGFR have been shown to inhibit angiogenesis, primarily VEGF expression. Accordingly, non-receptor tyrosine kinase inhibitors may be used in combination with the compounds of the present invention. For example, anti-VEGF antibodies, which do not recognize VEGFR (the receptor tyrosine kinase), but bind to the ligand; small molecule inhibitors of integrin (alphav beta3) that will inhibit angiogenesis; endostatin and angiostatin (non-RTK) may also prove useful in combination with the disclosed compounds. (See Bruns CJ et al (2000), Cancer Res., 60: 2926-2935; Schreiber AB, Winkler ME, and Derynck R. (1986), Science, 232: 1250-1253; Yen L et al. (2000), Oncogene 19: 3460-3469). Agents used in immunotherapeutic regimens may also be useful in combination with the compounds of Formula (I). There are a number of immunologic strategies to generate an immune response. These strategies are generally in the realm of tumor vaccinations. The efficacy of immunologic approaches may be greatly enhanced through combined inhibition of signaling pathways using a small molecule inhibitor. Discussion of the immunologic/tumor vaccine approach against erbB2/EGFR are found in Reilly RT et al. (2000), Cancer Res. 60: 3569-3576.
Agents used in proapoptotic regimens (e.g., bcl-2 antisense oligonucleotides) may also be used in the combination of the present invention. Members of the Bcl-2 family of proteins block apoptosis. Upregulation of bcl-2 has therefore been linked to chemoresistance. Studies have shown that the epidermal growth factor (EGF) stimulates anti-apoptotic members of the bcl-2 family (i.e., mcl-1). Therefore, strategies designed to downregulate the expression of bcl-2 in tumors have demonstrated clinical benefit and are now in Phase ll/lll trials, namely Genta's G3139 bcl-2 antisense oligonucleotide. Such proapoptotic strategies using the antisense oligonucleotide strategy for bcl-2 are discussed in Water JS et al. (2000), J. Clin. Oncol. 18: 1812-1823.
Cell cycle signalling inhibitors inhibit molecules involved in the control of the cell cycle. A family of protein kinases called cyclin dependent kinases (CDKs) and their interaction with a family of proteins termed cyclins controls progression through the eukaryotic cell cycle. The coordinate activation and inactivation of different cyclin/CDK complexes is necessary for normal progression through the cell cycle. Several inhibitors of cell cycle signalling are under development. For instance, examples of cyclin dependent kinases, including CDK2, CDK4, and CDK6 and inhibitors for the same are described in, for instance, Rosania et al, Exp. Opin. Ther. Patents (2000) 10(2):215-230. Further, p21 WAF1/CIP1 has been described as a potent and universal inhibitor of cyclin-dependent kinases (Cdks) (Ball et al., Progress in Cell Cycle Res., 3: 125 (1997)). Compounds that are known to induce expression of p21 WAF1/CIP1 have been implicated in the suppression of cell proliferation and as having tumor suppressing activity (Richon et al., Proc. Nat Acad. Sci. U.S.A. 97(18): 10014-10019 (2000)), and are included as cell cycle signaling inhibitors. Histone deacetylase (HDAC) inhibitors are implicated in the transcriptional activation of p21 WAF1/CIP1 (Vigushin et al., Anticancer Drugs, 13(1): 1 -13 (Jan 2002)), and are suitable cell cycle signaling inhibitors for use in combination herein.
Examples of such HDAC inhibitors include: 1 . Vorinostat, including pharmaceutically acceptable salts thereof. Marks et al., Nature Biotechnology 25, 84 to 90 (2007); Stenger, Community Oncology 4, 384-386 (2007). Vorinostat has the following chemical structure and name:
Figure imgf000078_0001
/V-hydroxy-/V'-phenyl-octanediamide 2. Romidepsin, including pharmaceutically acceptable salts thereof.
Vinodhkumar et al., Biomedicine & Pharmacotherapy 62 (2008) 85-93.
Romidepsin, has the following che ame:
Figure imgf000079_0001
(1 S,4S,7Z,10S,16E,21 R)-7-ethylidene-4,21 -di(propan-2-yl)-2-oxa-12,13-dithia-5, 8,20,23- tetrazabicyclo[8.7.6]tricos-16-ene-3,6,9,19,22-pentone
3. Panobinostat, including pharmaceutically acceptable salts thereof. Drugs of the Future 32(4): 315-322 (2007).
Panobinostat, has the following chemical structure and name:
Figure imgf000079_0002
(2£)-/V-hydroxy-3-[4-({[2-(2-methyl-1 /-/-indol-3-yl)ethyl]amino}methyl)phenyl]acrylamide
4. Valproic acid, including pharmaceutically acceptable salts thereof. Gottlicher, et al. EMBO J. 20(24): 6969-6978 (2001 ).
Valproic acid, has the following chemical structure and name:
Figure imgf000079_0003
2-propylpentanoic acid
5. Mocetinostat (MGCD0103), including pharmaceutically acceptable salts thereof. Balasubramanian et al., Cancer Letters 280: 21 1 -221 (2009).
Mocetinostat, has the following chemical structure and name:
Figure imgf000080_0001
A/-(2-Aminophenyl)-4-[[(4-pyridin-3-ylpyrimidin-2-yl)amino]meth benzamide
Further examples of such HDAC inhibitors are included in Bertrand European Journal of Medicinal Chemistry 45, (2010) 2095-21 16, particularly the compounds of table 3 therein as indicated below.
Figure imgf000081_0001
Proteasome inhibitors are drugs that block the action of proteasomes, cellular complexes that break down proteins, like the p53 protein. Several proteasome inhibitors are marketed or are being studied in the treatment of cancer. Suitable proteasome inhibitors for use in combination herein include: 1 . Bortezomib (Velcade®), including pharmaceutically acceptable salts thereof. Adams J, Kauffman M (2004), Cancer Invest 22 (2): 304-1 1 .
Bortezomib has the following chemical structure and name.
Figure imgf000082_0001
[(1 f?)-3-methyl-1 -({(2S)-3-phenyl-2-[(pyrazin-2- ylcarbonyl)amino]propanoyl}amino)butyl]boronic acid
2. Disulfiram, including pharmaceutically acceptable salts thereof.
Bouma et al. (1998). J. Antimicrob. Chemother. 42 (6): 817-20.
Disulfiram has the following chemical structure and name.
Figure imgf000082_0002
1 ,1 ',1 ",1 "'-[disulfanediylbis(carbonothioylnitrilo)]tetraethane
3. Epigallocatechin gallate (EGCG), including pharmaceutically acceptable salts thereof. Williamson et al., (December 2006), The Journal of Allergy and Clinical Immunology 1 18 (6): 1369-74.
Epigallocatechin gallate has t and name.
Figure imgf000082_0003
[(2R,3R)-5,7-dihydroxy-2-(3,4,5-trihydroxyphenyl)chroman-3-yl]3,4,5-trihydroxybenzoate
4. Salinosporamide A, including pharmaceutically acceptable salts thereof. Feling et at., (2003), Angew. Chem. Int. Ed. Engl. 42 (3): 355-7.
Salinosporamide A has the following chemical structure and name.
Figure imgf000083_0001
(4R,5S)-4-(2-chloroethyl)-1 -((1 S)-cyclohex-2-enyl(hydroxy)methyl) -5-methyl-6-oxa-2- azabicyclo3.2.0heptane-3,7-dione 5. Carfilzomib, including pharmaceutically acceptable salts thereof. Kuhn DJ, et al, Blood, 2007, 1 10:3281 -3290.
Carfilzomib has the following chemical structure and name.
Figure imgf000083_0002
(S)-4-methyl-N-((S)-1 -(((S)-4-methyl-1 -((R)-2-methyloxiran-2-yl)-1 -oxopentan-2-yl)amino)-
1 -oxo-3-phenylpropan-2-yl)-2-((S)-2-(2-morpholinoacetamido)-4- phenylbutanamido)pentanamide
The 70 kilodalton heat shock proteins (Hsp70s) and 90 kilodalton heat shock proteins (Hsp90s) are a family of ubiquitously expressed heat shock proteins. Hsp70s and Hsp90s are over expressed certain cancer types. Several Hsp70s and Hsp90s inhibitors are being studied in the treatment of cancer. Suitable Hsp70s and Hsp90s inhibitors for use in combination herein include:
1 . 17-AAG(Geldanamycin), including pharmaceutically acceptable salts thereof. Jia W et al. Blood. 2003 Sep 1 ;102(5):1824-32.
17-AAG(Geldanamycin) has the following chemical structure and name.
Figure imgf000084_0001
17-(Allylamino)-17-demethoxygeldanamycin
2. Radicicol, including pharmaceutically acceptable salts thereof. (Lee et al.,
Mol Cell Endocrinol. 2002, 188,47-54)
Radicicol has the following chemical structure and name.
Figure imgf000084_0002
(1 aR,2Z,4E,14R,15aR)-8-chloro-9,1 1 -dihydroxy-14-methyl-15,15a-dihydro-1 aH- benzo[c]oxireno[2,3-k][1 ]oxacyclotetradecine-6,12(7H,14H)-dione
Inhibitors of cancer metabolism - Many tumor cells show a markedly different metabolism from that of normal tissues. For example, the rate of glycolysis, the metabolic process that converts glucose to pyruvate, is increased, and the pyruvate generated is reduced to lactate, rather than being further oxidized in the mitochondria via the tricarboxylic acid (TCA) cycle. This effect is often seen even under aerobic conditions and is known as the Warburg Effect.
Lactate dehydrogenase A (LDH-A), an isoform of lactate dehydrogenase expressed in muscle cells, plays a pivotal role in tumor cell metabolism by performing the reduction of pyruvate to lactate, which can then be exported out of the cell. The enzyme has been shown to be upregulated in many tumor types. The alteration of glucose metabolism described in the Warburg effect is critical for growth and proliferation of cancer cells and knocking down LDH-A using RNA-i has been shown to lead to a reduction in cell proliferation and tumor growth in xenograft models.
D. A. Tennant et. al., Nature Reviews, 2010, 267.
P. Leder, et. al., Cancer Cell, 2006, 9, 425. High levels of fatty acid synthase (FAS) have been found in cancer precursor lesions. Pharmacological inhibition of FAS affects the expression of key oncogenes involved in both cancer development and maintenance. Alii et al. Oncogene (2005) 24, 39-46. doi:10.1038
Inhibitors of cancer metabolism, including inhibitors of LDH-A and inhibitors of fatty acid biosynthesis (or FAS inhibitors), are suitable for use in combination with the compounds of this invention. Additional examples of a further active ingredient or ingredients (anti-neoplastic agent) for use in combination or co-administered with the presently invented CD73 inhibiting compounds are anti-PD-L1 agents.
Anti-PD-L1 antibodies and methods of making the same are known in the art. Such antibodies to PD-L1 may be polyclonal or monoclonal, and/or recombinant, and/or humanized.
Exemplary PD-L1 antibodies are disclosed in:
US Patent No. 8,217,149; 12/633,339;
US Patent No. 8,383,796; 13/091 ,936;
US Patent No 8,552,154; 13/120,406;
US patent publication No. 201 10280877; 13/068337;
US Patent Publication No. 20130309250; 13/892671 ;
WO2013019906;
WO2013079174;
US Application No. 13/51 1 ,538 (filed August 7, 2012), which is the US National Phase of International Application No. PCT/US10/58007 (filed 2010);
and
US Application No. 13/478,51 1 (filed May 23, 2012).
Additional exemplary antibodies to PD-L1 (also referred to as CD274 or B7-H1) and methods for use are disclosed in US Patent No. 7,943,743; US20130034559, WO2014055897, US Patent No. 8,168,179; and US Patent No. 7,595,048. PD-L1 antibodies are in development as immuno-modulatory agents for the treatment of cancer.
In one embodiment, the antibody to PD-L1 is an antibody disclosed in US Patent No. 8,217,149. In another embodiment, the anti-PD-L1 antibody comprises the CDRs of an antibody disclosed in US Patent No. 8,217,149. In another embodiment, the antibody to PD-L1 is an antibody disclosed in US Application No. 13/51 1 ,538. In another embodiment, the anti-PD-L1 antibody comprises the CDRs of an antibody disclosed in US Application No. 13/51 1 ,538.
In another embodiment, the antibody to PD-L1 is an antibody disclosed in Application No. 13/478,51 1 . In another embodiment, the anti-PD-L1 antibody comprises the CDRs of an antibody disclosed in US Application No. 13/478,51 1 .
In one embodiment, the anti-PD-L1 antibody is BMS-936559 (MDX-1 105). In another embodiment, the anti-PD-L1 antibody is MPDL3280A (RG7446). In another embodiment, the anti-PD-L1 antibody is MEDI4736.
Additional examples of a further active ingredient or ingredients (anti-neoplastic agent) for use in combination or co-administered with the presently invented CD73 inhibiting compounds are PD-1 antagonist.
"PD-1 antagonist" means any chemical compound or biological molecule that blocks binding of PD-L1 expressed on a cancer cell to PD-1 expressed on an immune cell (T cell, B cell or NKT cell) and preferably also blocks binding of PD-L2 expressed on a cancer cell to the immune-cell expressed PD-1 . Alternative names or synonyms for PD- 1 and its ligands include: PDCD1 , PD1 , CD279 and SLEB2 for PD-1 ; PDCD1 L1 , PDL1 , B7H1 , B7-4, CD274 and B7-H for PD-L1 ; and PDCD1 L2, PDL2, B7-DC, Btdc and CD273 for PD-L2. In any embodiments of the aspects or embodiments of the present invention in which a human individual is to be treated, the PD-1 antagonist blocks binding of human PD-L1 to human PD-1 , and preferably blocks binding of both human PD-L1 and PD-L2 to human PD-1 . Human PD-1 amino acid sequences can be found in NCBI Locus No.: NP_005009. Human PD-L1 and PD-L2 amino acid sequences can be found in NCBI Locus No.: NP_054862 and NP_079515, respectively.
PD-1 antagonists useful in the any of the aspects of the present invention include a monoclonal antibody (mAb), or antigen binding fragment thereof, which specifically binds to PD-1 or PD-L1 , and preferably specifically binds to human PD-1 or human PD-L1 . The mAb may be a human antibody, a humanized antibody or a chimeric antibody, and may include a human constant region. In some embodiments, the human constant region is selected from the group consisting of lgG1 , lgG2, lgG3 and lgG4 constant regions, and in preferred embodiments, the human constant region is an lgG1 or lgG4 constant region. In some embodiments, the antigen binding fragment is selected from the group consisting of Fab, Fab'-SH, F(ab')2, scFv and Fv fragments.
Examples of mAbs that bind to human PD-1 , and useful in the vario us aspects and embodiments of the present invention, are described in US7488802, US7521051 , US8008449, US8354509, US8168757, WO2004/004771 , WO2004/072286, WO2004/056875, and US201 1/0271358.
Specific anti-human PD-1 mAbs useful as the PD-1 antagonist in any of the aspects and embodiments of the present invention include: MK-3475, a humanized lgG4 mAb with the structure described in WHO Drug Information, Vol. 27, No. 2, pages 161 -162 (2013) and which comprises the heavy and light chain amino acid sequences shown in Figure 6; nivolumab, a human lgG4 mAb with the structure described in WHO Drug Information, Vol. 27, No. 1 , pages 68-69 (2013) and which comprises the heavy and light chain amino acid sequences shown in Figure 7; the humanized antibodies h409A1 1 , h409A16 and h409A17, which are described in WO2008/156712, and AMP-514, which is being developed by Medimmune.
Other PD-1 antagonists useful in the any of the aspects and embodiments of the present invention include an immunoadhesin that specifically binds to PD-1 , and preferably specifically binds to human PD-1 , e.g., a fusion protein containing the extracellular or PD-1 binding portion of PD-L1 or PD-L2 fused to a constant region such as an Fc region of an immunoglobulin molecule. Examples of immunoadhesion molecules that specifically bind to PD-1 are described in WO2010/027827 and WO201 1 /066342. Specific fusion proteins useful as the PD-1 antagonist in the treatment method, medicaments and uses of the present invention include AMP-224 (also known as B7-DCIg), which is a PD-L2-FC fusion protein and binds to human PD-1 . Other examples of mAbs that bind to human PD-L1 , and useful in the treatment method, medicaments and uses of the present invention, are described in WO2013/019906, W02010/077634 A1 and US8383796. Specific anti-human PD-L1 mAbs useful as the PD-1 antagonist in the treatment method, medicaments and uses of the present invention include MPDL3280A, BMS-936559, MEDI4736, MSB0010718C. KEYTRUDA/pembrolizumab is an anti-PD-1 antibody marketed for the treatment of lung cancer by Merck. The amino acid sequence of pembrolizumab and methods of using are disclosed in US Patent No. 8,168,757. Opdivo/nivolumab is a fu M human monoclonal antibody marketed by Bristol Myers Squibb directed against, the negative immunoreguiatory human ce!! surface receptor PD-1 (programmed death-1 or programmed ceil death- 1 /PCD-1) with immunopotentiation activity. Nivo!umab binds to and blocks the activation of PD-1 , an ig superfamiiy transmembrane protein, by its ligands PD-L1 and PD-L2 resulting in the activation of T- celis and cell-mediated immune responses against tumor ceiis or pathogens. Activated PD-1 negatively regulates T-ceil activation and effector function through the suppression of P1 3k/Akt pathway activation. Other names for nivoiumab include: B S-936558, DX- 1 106, and ONO-4538. The amino acid sequence for nivoiumab and methods of using and making are disclosed in US Patent No. US 8,008,449.
Additional examples of a further active ingredient or ingredients (anti-neoplastic agent) for use in combination or co-administered with the presently invented CD73 inhibiting compounds are immuno-modulators.
As used herein "immuno-modulators" refer to any substance including monoclonal antibodies that affects the immune system. The ICOS binding proteins of the present invention can be considered immune-modulators. Immuno-modulators can be used as anti-neoplastic agents for the treatment of cancer. For example, immune-modulators include, but are not limited to, anti-CTLA-4 antibodies such as ipilimumab (YERVOY) and anti-PD-1 antibodies (Opdivo/nivolumab and Keytruda/pembrolizumab). Other immuno- modulators include, but are not limited to, OX-40 antibodies, PD-L1 antibodies, LAG3 antibodies, TIM-3 antibodies, 41 BB antibodies and GITR antibodies.
Yervoy (ipilimumab) is a fully human CTLA-4 antibody marketed by Bristol Myers Squibb. The protein structure of ipilimumab and methods are using are described in US Patent Nos. 6,984,720 and 7,605,238. CD134, also known as OX40, is a member of the TNFR-superfamily of receptors which is not constitutively expressed on resting naive T cells, unlike CD28. OX40 is a secondary costimulatory molecule, expressed after 24 to 72 hours following activation; its ligand, OX40L, is also not expressed on resting antigen presenting cells, but is following their activation. Expression of OX40 is dependent on full activation of the T cell; without CD28, expression of OX40 is delayed and of fourfold lower levels. OX-40 antibodies, OX- 40 fusion proteins and methods of using them are disclosed in US Patent Nos: US 7,504,101 ; US 7,758,852; US 7,858,765; US 7,550,140; US 7,960,515; WO2012027328; WO2013028231 .
Additional examples of a further active ingredient or ingredients (anti-neoplastic agent) for use in combination or co-administered with the presently invented CD73 inhibiting compounds are Toll-like Receptor 4 (TLR4) antagonists.
Aminoalkyl glucosaminide phosphates (AGPs) are known to be useful as vaccine adjuvants and immunostimulatory agents for stimulating cytokine production, activating macrophages, promoting innate immune response, and augmenting antibody production in immunized animals. Aminoalkyl glucosaminide phosphates (AGPs) are synthetic ligands of the Toll-like Receptor 4 (TLR4). AGPs and their immunomodulating effects via TLR4 are disclosed in patent publications such as WO 2006/016997, WO 2001 /090129, and/or U.S. Patent No. 6,1 13,918 and have been reported in the literature. Additional AGP derivatives are disclosed in U.S. Patent No. 7,129,219, U.S. Patent No. 6,525,028 and U.S. Patent No 6,91 1 ,434. Certain AGPs act as agonists of TLR4, while others are recognized as TLR4 antagonists.
Additional examples of a further active ingredient or ingredients (anti-neoplastic agent) for use in combination or co-administered with the presently invented CD73 inhibiting compounds are antibodies to ICOS.
CDRs for murine antibodies to human ICOS having agonist activity are shown in PCT/EP2012/055735 (WO 2012/131004). Antibodies to ICOS are also disclosed in WO 2008/137915, WO 2010/056804, EP 1374902, EP1374901 , and EP1 125585.
Additional examples of a further active ingredient or ingredients (anti-neoplastic agent) for use in combination or co-administered with the presently invented compound of Formula (I) are STING modulating compounds, CD39 inhibitors and A2a and A2a adenosine antagonists.
In one embodiment, the cancer treatment method of the claimed invention includes the co-administration a compound of Formula (I) and/or a pharmaceutically acceptable salt thereof and at least one anti-neoplastic agent, such as one selected from the group consisting of anti-microtubule agents, platinum coordination complexes, alkylating agents, antibiotic agents, topoisomerase II inhibitors, antimetabolites, topoisomerase I inhibitors, 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. Compositions
The pharmaceutically active compounds within the scope of this invention are useful as CD73 inhibitors in mammals, particularly humans, in need thereof. The present invention provides a pharmaceutical composition containing a pharmaceutically acceptable excipient and an effective amount of a compound of Formula (I) as described above or a pharmaceutically acceptable salt thereof.
The present invention provides a process for preparing a pharmaceutical composition containing a pharmaceutically acceptable excipient and an effective amount of a compound of Formula (I) as described above or a pharmaceutically acceptable salt thereof, which process comprises bringing the compound of Formula (I) or a pharmaceutically acceptable salt thereof into association with a pharmaceutically acceptable excipient.
The present invention therefore provides a method of treating cancer, precancerous syndromes and other conditions requiring CD73 inhibition, which comprises administering an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof. The compounds of Formula (I) also provide for a method of treating the above indicated disease states because of their demonstrated ability to act as CD73 inhibitors. The drug may be administered to a patient in need thereof by any conventional route of administration, including, but not limited to, intravenous, intramuscular, oral, topical, subcutaneous, intradermal, intraocular and parenteral. The pharmaceutically active compounds of the present invention are incorporated into convenient dosage forms such as capsules, tablets, or injectable preparations. Solid or liquid pharmaceutical carriers are employed. Solid carriers include, starch, lactose, calcium sulfate dihydrate, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid. Liquid carriers include syrup, peanut oil, olive oil, saline, and water. Similarly, the carrier or diluent may include any prolonged release material, such as glyceryl monostearate or glyceryl distearate, alone or with a wax. The amount of solid carrier varies widely but, preferably, will be from about 25 mg to about 1 g per dosage unit. When a liquid carrier is used, the preparation will be in the form of a syrup, elixir, emulsion, soft gelatin capsule, sterile injectable liquid such as an ampoule, or an aqueous or nonaqueous liquid suspension.
The pharmaceutical compositions are made following conventional techniques of a pharmaceutical chemist involving mixing, granulating, and compressing, when necessary, for tablet forms, or mixing, filling and dissolving the ingredients, as appropriate, to give the desired oral or parenteral products.
Doses of the presently invented pharmaceutically active compounds in a pharmaceutical dosage unit as described above will be an efficacious, nontoxic quantity preferably selected from the range of 0.001 - 500 mg/kg of active compound, preferably 0.01 - 100 mg/kg. When treating a human patient in need of a CD73 inhibitor, the selected dose is administered preferably from 1 -6 times daily, orally or parenterally. Preferred forms of parenteral administration include topically, rectally, transdermal^, by injection and continuously by infusion. Oral dosage units for human administration preferably contain from 0.5 to 3500 mg of active compound. Oral administration, which uses lower dosages, is preferred. Parenteral administration, at high dosages, however, also can be used when safe and convenient for the patient.
Optimal dosages to be administered may be readily determined by those skilled in the art, and will vary with the particular CD73 inhibitor in use, the strength of the preparation, the mode of administration, and the advancement of the disease condition. Additional factors depending on the particular patient being treated will result in a need to adjust dosages, including patient age, weight, diet, and time of administration.
The method of this invention of inducing CD73 inhibitory activity in mammals, including humans, comprises administering to a subject in need of such activity an effective CD73 inhibiting amount of a pharmaceutically active compound of the present invention.
The invention also provides for the use of a compound of Formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use as a CD73 inhibitor. The invention also provides a compound of Formula (I) or a pharmaceutically acceptable salt thereof for use in therapy. The invention also provides a compound of Formula (I) or a pharmaceutically acceptable salt thereof for use in treating cancer and pre-cancerous syndromes.
The invention also provides the use of a compound of Formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating cancer and pre-cancerous syndromes.
The invention also provides for a pharmaceutical composition for use as a CD73 inhibitor which comprises a compound of Formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
The invention also provides for a pharmaceutical composition for use in the treatment of cancer which comprises a compound of Formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. In addition, the pharmaceutically active compounds of the present invention can be co-administered with further active ingredients, such as other compounds known to treat cancer, or compounds known to have utility when used in combination with a CD73 inhibitor. Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. The following Examples are, therefore, to be construed as merely illustrative and not a limitation of the scope of the present invention in any way.
EXAMPLES
The following Examples illustrate the invention. These examples are not intended to limit the scope of the present invention, but rather to provide guidance to the skilled artisan to prepare and use the compounds, compositions, and methods of the present invention. While particular embodiments of the present invention are described, the skilled artisan will appreciate that various changes and modifications can be made without departing from the spirit and scope of the invention.
Abbreviations: DBU, 1 ,8 diazabicyclo[5.4.0]undec-7-ene; DCM, dichloromethane; DDQ, 4,5-dichloro-3,6-dioxocyclohexa-1 ,4-diene-1 ,2-carbonitrile; DIPEA, diisopropylethylamine; DMAP. Λ/,/V-dimethylaminopyridine; DMF, Λ/,/V-dimethylformamide; EtOAc, ethyl acetate; EtOH, ethanol; LAH, lithium aluminum hydride; LiHMDS, lithium hexamethyldisilazide; MeOH, methanol; NIS, N-iodosuccinimide; T3P, propylphosphonic anhydride; TBAF, tetrabutylammonium fluoride; TFA, trifluoroacetic acid; THF, tetrahydrofuran.
Intermediates 3-Carbamoyl-4-hydroxybenzene-1 -sulfonyl chloride (lnt-1 )
To a solution of chlorosulfonic acid (220 ml_) and thionyl chloride (80 ml_) stirred at 0 °C was added 2-hydroxybenzamide (150 g). The reaction mixture was allowed to warm to RT and was stirred for 6 hr. Ice cold water (4000 ml_) was added to the reaction mixture with stirring. The resulting solid was isolated by filtration, washed with water (1000 ml_) and acetone (200 mL) and dried to afford the titled compound (105 g). LCMS m/z 233.8 (M-H)-. Ή NMR after D20 exchange (400 MHz, DMSO-c/6) δ ppm 6.85 (d, J=8.55 Hz, 1 H) 7.65 (dd, J=8.55, 1 .97 Hz, 1 H) 8.15 (d, J=2.19 Hz, 1 H).
5-Carbamoyl-2-fluoro-4-hydroxybenzene-1 -sulfonyl chloride (lnt-2)
(a) Methyl 4-fluoro-2-hydroxybenzoate
To a solution of 4-fluoro-2-hydroxybenzoic acid (20 g) in MeOH (300 mL) at 0 °C was added sulfuric acid (20.49 mL) dropwise. The reaction mixture was heated to 60 °C and was stirred for 2 days. The reaction mixture was concentrated under reduced pressure and the residue poured into water and extracted with EtOAc (2 x 200 mL). The combined EtOAc extracts were washed with saturated brine (50 mL), dried over sodium sulfate and concentrated under reduced pressure to afford the titled compound (17 g). GSMS m/z 170.1 (M+). Alternatively, the title compound can be prepared by the following method. A mixture of 4- fluoro-2-hydroxybenzoic acid (0.800 g) in thionyl chloride (3.0 mL) was stirred at room temperature for 10 min and then heated at 70 °C for 30 min. The reaction mixture was then concentrated in vacuo to yield a light yellow semi-solid (857 mg). The solid was cooled to 0 °C and MeOH (6.0 mL) was carefully added (gas evolution observed). The reaction mixture was warmed to room temperature and then concentrated in vacuo to afford the crude title product as a white solid (754 mg). LCMS m/z 171 .1 (M+H)+.
(b) 4-Fluoro-2-hydroxybenzamide Methyl 4-fluoro-2-hydroxybenzoate (10 g) was dissolved in ammonia (7 M in MeOH, 150 mL) and the reaction mixture was heated to 80 °C and stirred for 16 hr. The reaction mixture was allowed to cool to RT and was concentrated under reduced pressure to afford the titled compound (7.8 g) LCMS m/z 156.0 (M+H)+.
Alternatively, the title compound can be prepared by the following method. A suspension of methyl 4-fluoro-2-hydroxybenzoate (22.4 g) in aq NH4OH solution (175 mL) was stirred at room temperature for 5 days. The reaction mixture was partially concentrated in vacuo, resulting in a white, basic suspension. The reaction flask was immersed in an ice bath and cone HCI was added until the mixture was pH 4. The resulting suspension was filtered, washed with water, and dried in vacuo to afford the title product as a white solid (18.87 g). LCMS m/z 156.0 (M+H)+.
(c) 5-Carbamoyl-2-fluoro-4-hydroxybenzene-1 -sulfonyl chloride
To a solution of chlorosulfonic acid (5.15 mL) and thionyl chloride (2.82 mL) at 0 °C was added 4-fluoro-2-hydroxybenzamide (4 g). The reaction mixture was allowed to warm to RT and was stirred for 16 hr. The reaction mixture was poured into ice water (20 mL) and the resulting solid collected by filtration and dried under vacuum to afford the titled compound (5.2 g). LCMS m/z 254.06 (M+H)+.
Alternatively, the title compound can be prepared using the following method. To an ice- chilled round bottom flask containing chlorosulfonic acid (60 mL) was added, portionwise over 25 min, 4-fluoro-2-hydroxybenzamide (18.87 g). After addition was complete, the ice bath was removed and the reaction mixture was heated at 60 °C for 15 h. The homogeneous reaction was cooled and carefully added dropwise via pipet into an oversized beaker half full with ice (gas evolution observed). Upon complete addition, the ice was allowed to melt. The resulting suspension was filtered, washing with water, and then dried in vacuo to yield the title product as a white solid (24.71 g). LCMS m/z 254.0 (M+H)+.
3-Bromo-5-carbamoyl-4-hydroxybenzene-1 -sulfonyl chloride (lnt-3)
A 20 mL reaction vial equipped with a stirbar and vented septum cap was charged with 3- bromo-2-hydroxybenzamide (215 mg). The solid material was taken up in chlorosulfonic acid (0.467 mL) and the resulting reaction mixture warmed to 55 °C with stirring overnight. The mixture was then cooled to room temperature and added dropwise to approximately 20 mL of water-saturated crushed ice. The resulting suspension was stirred for 20 minutes and the precipitate collected by filtration, washed with water, and dried to afford the titled compound as an off-white solid (290 mg). 1H NMR (400 MHz, DICHLOROMETHANE-cfe) δ ppm 6.07 (br. s., 1 H) 6.64 (br. s., 1 H) 8.14 (d, J=2.27 Hz, 1 H) 8.36 (d, J=2.27 Hz, 1 H) 14.27 (br. s., 1 H).
3-Carbamoyl-4-hydroxy-5-methylbenzene-1 -sulfonyl chloride (lnt-4)
(a) Methyl 2-hydroxy-3-methylbenzoate
To a solution of 2-hydroxy-3-methylbenzoic acid (10 g) in MeOH (200 mL) was added sulfuric acid (3.50 mL). The reaction mixture was heated to 70 °C and stirred for 48 hr. The reaction mixture was concentrated under reduced pressure, neutralized with saturated sodium bicarbonate (aq) (100 mL) and extracted with EtOAc (2 x 200 mL). The combined EtOAc extracts were dried over sodium sulfate and concentrated under reduced pressure to afford the titled compound (9 g). GCMS m/z 166.2 (M+).
(b) 2-Hydroxy-3-methylbenzamide
Methyl 2-hydroxy-3-methylbenzoate (8 g) was dissolved in ammonia (7 M in MeOH, 120 mL) in a sealed reaction vessel and stirred at 80 °C for 24 hr. The reaction mixture was allowed to cool to RT and was concentrated under reduced pressure. The resulting solid was washed with pentane (100 mL) and dried under vacuum to afford the titled compound (6 g). LCMS m/z 151 .97 (M+H)+.
(c) 3-Carbamoyl-4-hydroxy-5-methylbenzene-1 -sulfonyl chloride
To a solution of chlorosulfonic acid (2.66 mL) and thionyl chloride (1 .159 mL) at 0 °C under nitrogen was added 2-hydroxy-3-methylbenzamide (2 g) and the reaction mixture was allowed to warm to RT and was stirred for 2 hr. The reaction mixture was poured into ice water and the resulting solid was collected by filtration and dried under vacuum to afford the titled compound (500 mg). LCMS m/z 250.03 (M+H)+.
3-Carbamoyl-5-chloro-4-hydroxybenzene-1 -sulfonyl chloride (lnt-5)
(a) Methyl 3-chloro-2-hydroxybenzoate
To a solution of 3-chloro-2-hydroxybenzoic acid (9 g) in MeOH (100 mL) under nitrogen was slowly added sulfuric acid (3 mL). The reaction mixture was heated to 75 °C and stirred for 48 hr. The reaction mixture was allowed to cool to RT and concentrated under reduced pressure. The residue was neutralized by the addition of saturated potassium carbonate and then was diluted with water (30 mL) and extracted with DCM (2 x 200 mL). The combined DCM extracts were dried over sodium sulfate and concentrated under reduced pressure to afford the titled compound (10 g), which was used without further purification. GCMS m/z 186.1 (M+).
(b) 3-Chloro-2-hydroxybenzamide
3-Chloro-2-hydroxybenzamide (2 g) and ammonia (7 N in MeOH, 30 mL) were heated to 70 °C in a sealed reaction vessel and stirred for 48 hr. The reaction mixture was concentrated under reduced pressure and the resulting solid was triturated with pentane (3 x 15 mL) and dried to afford the titled compound (1 .8 g), which was used without further purification. LCMS m/z 170.0 (M-H)~.
(c) 3-Carbamoyl-5-chloro-4-hydroxybenzene-1 -sulfonyl chloride
To a solution of chlorosulfonic acid (0.585 mL) and thionyl chloride (0,213 mL) under nitrogen at 0 °C was added 3-chloro-2-hydroxybenzamide (0.5 g) portionwise over 5 min. The reaction mixture was allowed to warm to RT and was stirred for 16 hr. The reaction mixture was diluted with EtOAc (30 mL) and washed with cold water (15 mL) and saturated brine (15 mL). The EtOAc layer was dried over sodium sulfate and concentrated under reduced pressure to afford the titled compound (700 mg). LCMS m/z (M-H)-.
3-Carbamoyl-4-hydroxy-5-isopropylbenzene-1 -sulfonyl chloride (lnt-6)
(a) 2-Hydroxy-3-isopropylbenzamide A 20 mL reaction vial equipped with a stirbar and needle-vented septum cap was charged with 2-hydroxy-3-isopropylbenzoic acid (500 mg) and 1 ,1 '-carbonyldiimidazole (900 mg). The solid materials were taken up in Ν,Ν-dimethylformamide (DMF) (2.0 mL) and treated with 30% aqueous ammonium hydroxide (2.0 mL), and after the foaming subsided, the resulting mixture was stirred 30 minutes at room temperature. The reaction mixture was then poured transferred to a 100 mL round bottom flask and diluted with water to approximately 30 mL total volume. The reaction mixture was then treated with glacial acetic acid until the pH was approximately 6-7 and the resulting precipitate collected by suction filtration. The precipitate was taken up in a minimum amount of ethyl acetate and injected onto a 25 gram SNAP Ultra silica cartridge for purification (0-50% EtOAc/heptane over 20 CV). Fractions containing the desired product were pooled and concentrated to afford the titled compound as a white solid (337 mg). LCMS m/z 180.1 (M+H)+. 1H NMR (400 MHz, DMSO-c/e) δ ppm 1 .16 (d, J=6.82 Hz, 6 H) 3.24 (spt, J=6.91 Hz, 1 H) 6.80 (t, J=7.71 Hz, 1 H) 7.33 (dd, J=7.58, 1 .26 Hz, 1 H) 7.68 (dd, J=8.08, 1 .52 Hz, 1 H) 7.91 (br. s., 1 H) 8.42 (br. s., 1 H) 13.68 (s, 1 H).
(b) 3-Carbamoyl-4-hydroxy-5-isopropylbenzene-1 -sulfonyl chloride (lnt-6)
A 20 mL reaction vial equipped with a stirbar and needle-vented septum cap was charged with 2-hydroxy-3-isopropylbenzamide (321 mg). The material was taken up in chlorosulfonic acid (0.840 mL) and the resulting mixture warmed to 55 °C with stirring overnight. The reaction mixture was then cooled to room temperature and added dropwise to a 125 mL conical flask containing approximately 50 mL of water-saturated crushed ice. The resulting mixture was stirred, allowing the ice to melt completely, and the resulting precipitate was isolated by suction filtration to afford the titled compound as an off-white solid (337 mg). LCMS m/z 278.1 , 280.1 (M+H, chloride). Ή NMR (400 MHz, DICHLOROMETHANE-c/2) δ ppm 1 .28 (d, J=6.82 Hz, 6 H) 3.40 (dquin, J=13.82, 6.90, 6.90, 6.90, 6.90 Hz, 1 H) 5.90 (br. s., 1 H) 6.48 (br. s., 1 H) 7.95 (dd, J=2.27, 0.51 Hz, 1 H) 8.01 (d, J=2.27 Hz, 1 H) 13.79 (br. s., 1 H).
3-Carbamoyl-5-ethyl-4-hydroxybenzene-1 -sulfonyl chloride (lnt-7)
(a) 3-Ethyl-2-hydroxybenzamide
A 40 mL reaction vial equipped with a stirbar and needle-vented septum cap was charged with 3-ethyl-2-hydroxybenzoic acid (900 mg) and N,N'-carbonyldiimidazole (1 .756 g). The solids were then quickly taken up in anhydrous Ν,Ν-dimethylformamide (DMF) (7.5 mL) and the mixture stirred rapidly. The resulting mixture was stirred for 1 hour and then treated with a 30 wt% aqueous ammonia solution (7.03 mL) and the resulting reaction mixture stirred overnight at room temperature. The mixture was then concentrated under high vacuum to a residue of 3-4 mL total volume and then taken up in 30 mL of water slowly with rapid stirring. The resulting brilliant yellow suspension was allowed to stir at room temperature for 1 hour and the resulting precipitate collected by and dried by suction filtration to afford the titled compound as a brilliant yellow solid (678 mg). LCMS m/z 166.1 (M+H)+. Ή NMR (400 MHz, DMSO-c/6) δ ppm 1 .13 (t, J=7.45 Hz, 3 H) 2.56 (q, J=7.41 Hz, 2 H) 6.73 - 6.82 (m, 1 H) 7.29 (dd, J=7.33, 1 .01 Hz, 1 H) 7.68 (dd, J=8.08, 1 .52 Hz, 1 H) 7.90 (br. s., 1 H) 8.41 (br. s., 1 H) 13.56 (s, 1 H).
(b) 3-Carbamoyl-5-ethyl-4-hydroxybenzene-1 -sulfonyl chloride (lnt-7)
A 20 mL reaction vial equipped with a stirbar and needle-vented septum cap was charged with the solid 3-ethyl-2-hydroxybenzamide (678 mg). The solid material was then taken up in chlorosulfonic acid (2.54 mL) and the resulting mixture warmed to 55 °C with stirring overnight The mixture was then slowly added dropwise to a 250 mL conical flask charged with 100 mL of water-saturated crushed ice. The resulting slurry was stirred until the ice melted entirely and the precipitate collected by suction filtration and dried by the same to afford the title compound as an off white solid (959 mg). LCMS m/z 264.1 , 266.1 (M+H, chloride]. Ή NMR (400 MHz, DICHLOROMETHANE-cfc) δ ppm 1 .27 (t, J=7.45 Hz, 3 H) 2.76 (q, J=7.58 Hz, 2 H) 5.62 - 6.89 (m, 2 H) 7.93 (d, J=2.27 Hz, 1 H) 8.03 (d, J=2.53 Hz, 1 H) 13.66 (br. s., 1 H). 3-Carbamoyl-4-hydroxy-5-(trifluoromethyl)benzene-1 -sulfonyl chloride (lnt-8) 2-Hydroxy-3-(trifluoromethyl)benzamide
A 20 mL reaction vial equipped with a stirbar and needle-vented septum cap was charged with 2-hydroxy-3-(trifluoromethyl)benzoic acid (0.750 g) and 1 ,1 '-carbonyldiimidazole (1 .180 g). The solid material were taken up in Ν,Ν-dimethylformamide (DMF) (2.65 mL) and treated with cone, aqueous ammonia (2.62 mL) after the foaming had subsided. The resulting mixture was stirred 30 minutes at room temperature. The mixture was then transferred to a 100 mL conical flask and diluted with water to approximately 30 mL total volume. The mixture was then treated with glacial acetic acid until the pH was approximately 6-7. The mixture was then extracted with ethyl acetate, twice, and the organics pooled, dried over sodium sulfate, filtered, and concentrated to a residue. The residue was then injected onto a 25 gram SNAP Ultra silica cartridge for purification (0-65% EtOAc into Heptane over 26 CV). Fractions containing the desired material were pooled and concentrated to a yellow solid significantly enriched in the desired material by LCMS. The solid was then subjected to a second injection onto a 25 gram SNAP Ultra silica cartridge for purification (15-65% EtOAc into Heptane over 15 CV). Fractions containing the desired material were then pooled and concentrated to afford the title compound as a bright yellow solid at 90% purity (215 mg). LCMS m/z 206.1 (M+H)+. 1H NMR (400 MHz, DICHLOROMETHANE-c/2) δ ppm 5.79 - 6.63 (m, 2 H) 6.85 - 7.07 (m, 1 H) 7.63 (dd, J=8.08, 1 .01 Hz, 1 H) 7.74 (dq, J=7.71 , 0.72 Hz, 1 H) 13.21 (s, 1 H).
3-Carbamoyl-4-hydroxy-5-(trifluoromethyl)benzene-1 -sulfonyl chloride (lnt-8)
A 20 mL reaction vial equipped with a stirbar and vented septum cap was charged with 2- hydroxy-3-(trifluoromethyl)benzamide (215 mg). The solid material was taken up in chlorosulfonic acid (0.491 mL) and the resulting reaction mixture warmed to 55 °C with stirring overnight. The mixture was then cooled to room temperature and added dropwise to approximately 30 mL of water-saturated crushed ice. The resulting suspension was stirred for 20 minutes and then the precipitate collected by suction filtration to afford the titled compound as an off-white solid (250 mg). Ή NMR (400 MHz, DICHLOROMETHANE- <k) δ ppm 6.13 (br. s., 1 H) 6.73 (br. s., 1 H) 8.34 - 8.37 (m, 1 H) 8.37 - 8.40 (m, 1 H) 14.50 (br. s., 1 H).
Example 1
5-(N-(3-Ethoxyphenyl)sulfamoyl)-2-hvdroxybenzamide
Figure imgf000098_0001
To a solution of 3-carbamoyl-4-hydroxybenzene-1 -sulfonyl chloride (lnt-1 , 500 mg) in pyridine (5 mL) at 0 °C was added 3-ethoxyaniline (291 mg). The reaction mixture was allowed to warm to RT and was stirred for 12 hr. The reaction mixture was diluted with ice water (20 mL) and extracted with EtOAc (2 x 20 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to afford the crude product (635 mg). The crude product was purified by preparative reversed phase HPLC (Kromasil C-18, 21 .2 x 250 mm) using acetonitrile in 5 mM ammonium bicarbonate (aq). The desired fractions were combined and lyophilized to afford the titled compound (122 mg). LCMS m/z 337.00 (M+H)+. 1H NMR after D20 exchange (400 MHz, DMSO-c/6) δ ppm 1 .27 (t, J=6.91 Hz, 3 H) 3.92 (q, J=6.94 Hz, 2 H) 6.51 - 6.72 (m, 3 H) 6.96 (d, J=8.77 Hz, 1 H) 7.12 (t, J=8.22 Hz, 1 H) 7.69 (dd, J=8.77, 2.63 Hz, 1 H) 8.31 (d, J=2.41 Hz, 1 H).
Example 2
2-Hvdroxy-5-(N-(4-methoxyphenyl)sulfamoyl)benzamide
Figure imgf000098_0002
To a solution of 3-carbamoyl-4-hydroxybenzene-1 -sulfonyl chloride (lnt-1 , 500 mg) in pyridine (5 mL) under nitrogen at 0 °C was added 4-methoxyaniline (261 mg). The reaction mixture was allowed to warm to RT and stirred for 12 hr. Solvent was removed under vacuum and the residue was diluted with water (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic extracts were washed with saturated brine (50 mL), dried over sodium sulfate, and concentrated under reduced pressure to afford the crude product (502 mg). The crude product was purified by silica gel column chromatography, eluting with 25% EtOAc in hexanes. The appropriate fractions were combined and concentrated under reduced pressure to afford the titled compound (134 mg). LCMS m/z 322.99 (M+H)+. 1H NMR after D20 exchange (400 MHz, DMSO-c/6) δ ppm 2.09 (s, 1 H) 3.67 (s, 3 H) 6.70 - 6.89 (m, 2 H) 6.89 - 7.07 (m, 3 H) 7.67 (dd, J=8.77, 2.41 Hz, 1 H) 8.24 (d, J=2.19 Hz, 1 H).
Example 3
5-(N-(3.4-Diethoxyphenyl)sulfamoyl)-2-hvdroxybenzamide
Figure imgf000099_0001
To a solution of 3-carbamoyl-4-hydroxybenzene-1 -sulfonyl chloride (lnt-1 , 500 mg) in pyridine (5 mL) under nitrogen at 0 °C was added 3,4-diethoxyaniline (385 mg). The reaction mixture was allowed to warm to RT and stirred for 12 hr. Solvent was removed under vacuum and the residue was diluted with water (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic extracts were washed with saturated brine (50 mL), dried over sodium sulfate, and concentrated under reduced pressure to afford the crude product (570 mg). The crude product was purified by silica gel column chromatography, eluting with 25% EtOAc in hexanes. The appropriate fractions were combined and concentrated under reduced pressure to afford the titled compound (148 mg). LCMS m/z 381 .03 (M+H)+. 1H NMR after D20 exchange(400 MHz, DMSO-c/6) δ ppm 1 .25 (td, J=7.02, 3.29 Hz, 6 H) 3.89 (dq, J=9.65, 6.94 Hz, 4 H) 6.54 (dd, J=8.66, 2.52 Hz, 1 H) 6.65 (d, J=2.41 Hz, 1 H) 6.78 (d, J=8.77 Hz, 1 H) 7.03 (d, J=8.77 Hz, 1 H) 7.68 (dd, J=8.66, 2.30 Hz, 1 H) 8.25 - 8.41 (m, 1 H). Example 4
5-(N-(3,4-Dimethoxyphenyl)sulfamoyl)-2-hvdroxybenzamide
Figure imgf000100_0001
To a solution of 3-carbamoyl-4-hydroxybenzene-1 -sulfonyl chloride (lnt-1 , 500 mg) in pyridine (10 ml_) was added 3,4-dimethoxyaniline (325 mg) and the reaction mixture was stirred under nitrogen for 16 hr. The solvent was removed under reduced pressure and the residue diluted with water (20 ml_) and then extracted with EtOAc (2 x 40 ml_). The combined organic extracts were washed with water (40 ml_) and saturated brine (40 ml_), dried over sodium sulfate and concentrated under reduced pressure to afford the crude product (700 mg). The crude product was purified by silica gel column chromatography on a 40 g column eluting with a gradient of 0-1 % MeOH in DCM. The desired fractions were concentrated under reduced pressure and the residue was triturated with pentane and dried to afford the titled compound (200 mg). LCMS m/z 350.97 (M-H)~. 1H NMR after D20 exchange (400 MHz, DMSO-c/6) δ ppm 3.65 (d, J=9.21 Hz, 6 H) 6.57 (dd, J=8.55, 2.41 Hz, 1 H) 6.66 (d, J=2.63 Hz, 1 H) 6.80 (d, J=8.55 Hz, 1 H) 7.05 (d, J=8.77 Hz, 1 H) 7.70 (dd, J=8.77, 2.41 Hz, 1 H) 8.26 (d, J=2.41 Hz, 1 H).
Example 5
2-Hvdroxy-5-(N-(3-methoxyphenyl)sulfamoyl)benzamide
Figure imgf000100_0002
To a solution of 3-carbamoyl-4-hydroxybenzene-1 -sulfonyl chloride (lnt-1 , 200 mg) in pyridine (2 ml_) at 0 °C under nitrogen was added 3-methoxyaniline (105 mg). The reaction mixture was allowed to warm to RT and stirred for 12 hr. The solvent was removed under reduced pressure and the residue was diluted with water (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to obtain the crude product (640 mg). The crude product was purified by silica gel column chromatography on a 60 g column eluting with hexane followed by 30% EtOAc/hexane. The desired fractions were concentrated under reduced pressure to afford the titled compound (151 mg). LCMS m/z 320.93 (M-H)~. Ή NMR after D20 exchange (400 MHz, DMSO-c/6) δ ppm 3.67 (s, 3 H) 6.53 - 6.72 (m, 3 H) 7.05 (d, J=8.77 Hz, 1 H) 7.15 (t, J=8.1 1 Hz, 1 H) 7.76 (dd, J=8.77, 2.41 Hz, 1 H) 8.33 (d, J=2.41 Hz, 1 H).
Example 6
2-Hvdroxy-5-(N-(4-(trifluoromethyl)phenyl)sulfamoyl)benzamide
Figure imgf000101_0001
To a solution of 3-carbamoyl-4-hydroxybenzene-1 -sulfonyl chloride (lnt-1 , 200 mg) in pyridine (2 mL) at 0 °C under nitrogen was added 4-(trifluoromethyl)aniline (137 mg). The reaction mixture was allowed to warm to RT and stirred for 12 hr. The solvent was removed under reduced pressure and the residue was diluted with water (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to obtain the crude product (580 mg). The crude product was purified by silica gel column chromatography on a 30 g column eluting with hexane followed by 30% EtOAc/hexane. The desired fractions were concentrated under reduced pressure to afford the titled compound (121 mg). LCMS m/z 358.94 (M-H)~. 1H NMR after D20 exchange(400 MHz, DMSO-c/6) δ ppm 7.07 (d, J=8.77 Hz, 1 H) 7.30 (d, J=8.33 Hz, 2 H) 7.61 (d, J=8.55 Hz, 2 H) 7.82 (dd, J=8.77, 2.41 Hz, 1 H) 8.39 (d, J=2.41 Hz, 1 H).
Example 7
2-Hvdroxy-5-(N-(3-hvdroxyphenyl)sulfamoyl)benzamide
Figure imgf000102_0001
To a solution of 3-carbamoyl-4-hydroxybenzene-1 -sulfonyl chloride (lnt-1 , 200 mg) in pyridine (2 mL) at 0 °C under nitrogen was added 3-aminophenol (93 mg). The reaction mixture was allowed to warm to RT and stirred for 12 hr. The solvent was removed under reduced pressure and the residue was diluted with water (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to obtain the crude product (480 mg). The crude product was purified by silica gel column chromatography on a 30 g column eluting with DCM followed by 2% MeOH/DCM. The desired fractions were concentrated under reduced pressure to afford the titled compound (140 mg). LCMS m/z 306.93 (M-H)~. Ή NMR after D20 exchange (400 MHz, DMSO-c/6) δ ppm 6.28 - 6.48 (m, 1 H) 6.49 - 6.75 (m, 2 H) 6.93 - 7.13 (m, 2 H) 7.74 (dd, J=8.77, 2.41 Hz, 1 H) 8.32 (d, J=2.41 Hz, 1 H).
Example 8
2-Hvdroxy-5-(N-(4-hvdroxyphenyl)sulfamoyl)benzamide
Figure imgf000102_0002
To a solution of 3-carbamoyl-4-hydroxybenzene-1 -sulfonyl chloride (lnt-1 , 200 mg) in pyridine (2 mL) at 0 °C under nitrogen was added 4-aminophenol (93 mg). The reaction mixture was allowed to warm to RT and stirred for 12 hr. The solvent was removed under reduced pressure and the residue was diluted with water (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to obtain the crude product (490 mg). The crude product was purified by silica gel column chromatography on a 30 g column eluting with DCM followed by 2% MeOH/DCM. The desired fractions were concentrated under reduced pressure to afford the titled compound (120 mg). LCMS m/z 308.98 (M+H)+. Ή NMR after D20 exchange (400 MHz, DMSO-c/6) δ ppm 6.52 - 6.67 (m, 2 H) 6.74 - 6.92 (m, 2 H) 7.03 (d, J=8.77 Hz, 1 H) 7.65 (dd, J=8.77, 2.41 Hz, 1 H) 8.20 (d, J=2.19 Hz, 1 H).
Example 9
2-Hydroxy-5-(N-(4-(trifluoromethoxy)phenyl)sulfamoyl)benzamide
Figure imgf000103_0001
To a solution of 3-carbamoyl-4-hydroxybenzene-1 -sulfonyl chloride (lnt-1 , 200 mg) in pyridine (2 mL) at 0 °C under nitrogen was added 4-(trifluoromethoxy)aniline (150 mg). The reaction mixture was allowed to warm to RT and stirred for 12 hr. The solvent was removed under reduced pressure and the residue was diluted with water (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to obtain the crude product (590 mg). The crude product was purified by silica gel column chromatography on a 30 g column eluting with DCM followed by 1 .5% MeOH/DCM. The desired fractions were concentrated under reduced pressure to afford the titled compound (145 mg). LCMS m/z 376.97 (M+H)+. 1H NMR (400 MHz, DMSO-c/6) δ ppm 7.04 (d, J=8.99 Hz, 1 H) 7.12 - 7.29 (m, 3 H) 7.73 (dd, J=8.77, 2.41 Hz, 1 H) 8.03 (br. s., 1 H) 8.35 (d, J=2.41 Hz, 1 H) 8.55 (br. s., 1 H) 10.36 (s, 1 H) 13.48 (s, 1 H).
Example 10
2-Hvdroxy-5-(N-(4-(2,2,2-trifluoroethoxy)phenyl)sulfamoyl)benzamide
Figure imgf000104_0001
To a solution of 3-carbamoyl-4-hydroxybenzene-1 -sulfonyl chloride (lnt-1 , 500 mg) in pyridine (5 mL) at 0 °C under nitrogen was added 4-(2,2,2-trifluoroethoxy)aniline (406 mg). The reaction mixture was allowed to warm to RT and stirred for 12 hr. The solvent was removed under reduced pressure and the residue was diluted with water (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to obtain the crude product (410 mg). The crude product was purified by silica gel column chromatography on a 30 g column eluting with hexane followed by 30% EtOAc/hexane. The desired fractions were concentrated under reduced pressure to afford the titled compound (131 mg). LCMS m/z 389.00 (M-H)~. 1H NMR (400 MHz, DMSO-c/6) δ ppm 4.65 (q, J=8.92 Hz, 2 H) 6.71 - 6.97 (m, 3 H) 6.99 - 7.05 (m, 2 H) 7.67 (dd, J=8.66, 2.30 Hz, 1 H) 8.00 (br. s., 1 H) 8.29 (d, J=2.41 Hz, 1 H) 8.52 (br. s., 1 H) 9.90 (s, 1 H) 13.42 (s, 1 H).
Example 11
2-Hvdroxy-5-(N-(4-isopropoxyphenyl)sulfamoyl)benzamide
Figure imgf000104_0002
To a solution of 3-carbamoyl-4-hydroxybenzene-1 -sulfonyl chloride (lnt-1 , 500 mg) in pyridine (5 mL) at 0 °C under nitrogen was added 4-isopropoxyaniline (321 mg). The reaction mixture was allowed to warm to RT and stirred for 12 hr. The solvent was removed under reduced pressure and the residue was diluted with water (50 mL) and extracted with EtOAc (3 x 50 ml_). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to obtain the crude product (508 mg). The crude product was purified by silica gel column chromatography on a 30 g column eluting with hexane followed by 30% EtOAc/hexane. The desired fractions were concentrated under reduced pressure to afford the titled compound (158 mg). LCMS m/z 348.98 (M-H)-. 1H NMR (400 MHz, DMSO-c/6) δ ppm 1 .19 (d, J=5.92 Hz, 6 H) 4.37 - 4.59 (m, 1 H) 6.72 - 6.82 (m, 2 H) 6.90 - 6.98 (m, 2 H) 7.01 (d, J=8.77 Hz, 1 H) 7.66 (dd, J=8.77, 2.19 Hz, 1 H) 7.99 (br. s., 1 H) 8.25 (d, J=2.41 Hz, 1 H) 8.50 (br. s., 1 H) 9.71 (s, 1 H) 13.41 (br. s., 1 H).
Example 12
5-(N-(2-Fluorophenyl)sulfamoyl)-2-hvdroxybenzamide
Figure imgf000105_0001
To a solution of 3-carbamoyl-4-hydroxybenzene-1 -sulfonyl chloride (lnt-1 , 500 mg) in pyridine (5 ml_) at 0 °C was added 2-fluoroaniline (236 mg). The reaction mixture was allowed to warm to RT and stirred for 12 hr. The reaction mixture was diluted with water (20 ml_) and extracted with EtOAc (2 x 20 ml_). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to obtain the crude product (800 mg). The crude product was purified by silica gel column chromatography on an 8 g column eluting with hexane followed by 30% EtOAc/hexane. The desired fractions were combined and concentrated under reduced pressure to afford the titled compound (173 mg). LCMS m/z 308.95 (M-H)~. Ή NMR (400 MHz, DMSO-c/6) δ ppm 7.04 (d, J=8.77 Hz, 1 H) 7.07 - 7.27 (m, 3 H) 7.72 (dd, J=8.88, 2.30 Hz, 1 H) 8.00 (br. s., 1 H) 8.27 (d, J=2.41 Hz, 1 H) 8.53 (br. s., 1 H) 9.96 (br. s., 1 H) 13.49 (br. s., 1 H).
Example 13
2-Hydroxy-5-(N-(4-(methylsulfonyl)phenyl)sulfamoyl)benzamide
Figure imgf000106_0001
To a solution of 3-carbamoyl-4-hydroxybenzene-1 -sulfonyl chloride (lnt-1 , 500 mg) in pyridine (5 ml_) at 0 °C was added 4-(methylsulfonyl)aniline (363 mg). The reaction mixture was allowed to warm to RT and stirred for 12 hr. The reaction mixture was diluted with ice cold water (20 ml_) and extracted with EtOAc (2 x 20 ml_). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to obtain the crude product (800 mg). The crude product was purified by silica gel column chromatography on a 10 g column eluting with hexane followed by 40% EtOAc/hexane. The desired fractions were combined and concentrated under reduced pressure to afford the titled compound (62 mg). LCMS 368.91 (M-H)~. 1H NMR (400 MHz, DMSO-cfe) δ ppm 3.1 1 (s, 3 H) 7.07 (d, J=8.77 Hz, 1 H) 7.32 (d, J=8.77 Hz, 2 H) 7.69 - 7.95 (m, 3 H) 8.07 (br. s., 1 H) 8.46 (d, J=2.41 Hz, 1 H) 8.61 (br. s., 1 H) 10.91 (br. s., 1 H) 13.55 (br. s., 1 H).
Example 14
5-(N-(4-(Benzyloxy)phenyl)sulfamoyl)-2-hvdroxybenzamide
Figure imgf000106_0002
To a solution of 3-carbamoyl-4-hydroxybenzene-1 -sulfonyl chloride (lnt-1 , 500 mg) in pyridine (5 ml_) at 0 °C was added 4-(benzyloxy)aniline (423 mg). The reaction mixture was allowed to warm to RT and stirred for 12 hr. The reaction mixture was diluted with ice cold water (20 ml_) and extracted with EtOAc (2 x 20 ml_). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to obtain the crude product (800 mg). The crude product was purified by silica gel column chromatography on an 8 g column eluting with hexane followed by 30% EtOAc/hexane. The desired fractions were combined and concentrated under reduced pressure to afford the titled compound (103 mg). LCMS m/z 397.02 (M-H)~. Ή NMR (400 MHz, DMSO-c/6) δ ppm 4.99 (s, 2 H) 6.83 - 6.92 (m, 2 H) 6.93 - 7.05 (m, 3 H) 7.26 - 7.44 (m, 5 H) 7.66 (dd, J=8.88, 2.30 Hz, 1 H) 8.00 (br. s., 1 H) 8.26 (d, J=2.19 Hz, 1 H) 8.51 (br. s., 1 H) 9.77 (s, 1 H) 13.41 (br. s., 1 H).
Example 15
2-Hvdroxy-5-(N-(4-(methylthio)phenyl)sulfamoyl)benzamide
Figure imgf000107_0001
To a solution of 3-carbamoyl-4-hydroxybenzene-1 -sulfonyl chloride (lnt-1 , 500 mg) in pyridine (5 mL) at 0 °C was added 4-(methylthio)aniline (295 mg). The reaction mixture was allowed to warm to RT and stirred for 12 hr. The reaction mixture was diluted with ice cold water (20 mL) and extracted with EtOAc (2 x 20 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to obtain the crude product (750 mg). The crude product was purified by silica gel column chromatography on an 8 g column eluting with hexane followed by 30% EtOAc/hexane. The desired fractions were combined and concentrated under reduced pressure to afford the titled compound (166 mg). LCMS m/z 336.91 (M-H)~. Ή NMR (400 MHz, DMSO-c/6) δ ppm 2.38 (s, 3 H) 6.84 - 7.08 (m, 3 H) 7.13 (d, J=8.55 Hz, 2 H) 7.70 (dd, J=8.77, 2.41 Hz, 1 H) 8.01 (br. s., 1 H) 8.32 (d, J=2.19 Hz, 1 H) 8.53 (br. s., 1 H) 10.07 (s, 1 H) 13.43 (s, 1 H).
Example 16
5-(N-(4-(tert-Butoxy)phenyl)sulfamoyl)-2-hvdroxybenzamide
Figure imgf000107_0002
To a solution of 3-carbamoyl-4-hydroxybenzene-1 -sulfonyl chloride (lnt-1 , 500 mg) in pyridine (10 mL) was added 4-(tert-butoxy)aniline (351 mg) and the reaction mixture was stirred at RT for 16 hr. The solvent was evaporated under reduced pressure and the residue was diluted with water (20 mL) and extracted with EtOAc (2 x40 mL). The combined organic layers were washed with water (40 mL) and saturated brine (40 mL), dried over sodium sulfate and concentrated under reduced pressure to obtain the crude product (700 mg). The crude product was purified by silica gel column chromatography on a 40 g column eluting with a gradient of 0-40% EtOAc/hexane. The desired fraction was concentrated under reduced pressure, triturated with n-pentane, and dried to afford the titled compound (97 mg). LCMS m/z 362.97 (M-H)~. Ή NMR (400 MHz, DMSO-c/6) δ ppm 1 .21 (s, 9 H) 6.71 - 6.89 (m, 2 H) 6.89 - 7.13 (m, 3 H) 7.66 (dd, J=8.77, 2.19 Hz, 1 H) 7.98 (br. s, 1 H) 8.24 (d, J=2.19 Hz, 1 H) 8.49 (br. s, 1 H) 9.84 (s, 1 H) 13.44 (s, 1 H).
Example 17
5-(N-(4-(Dimethylamino)phenyl)sulfamoyl)-2-hvdroxybenzamide
Figure imgf000108_0001
To a solution of 3-carbamoyl-4-hydroxybenzene-1 -sulfonyl chloride (lnt-1 , 500 mg) in pyridine (10 mL) was added Λ/1 ,/V1 -dimethylbenzene-1 ,4-diamine (289 mg) and the reaction mixture was stirred at RT under nitrogen for 16 hr. The solvent was evaporated under reduced pressure and the residue was diluted with water (20 mL) and extracted with EtOAc (2 x 40 mL). The combined organic layers were washed with water (40 mL) and saturated brine (40 mL), dried over sodium sulfate and concentrated under reduced pressure to obtain the crude product (700 mg). The crude product was purified by silica gel column chromatography on a 40 g column eluting with a gradient of 0-40% EtOAc/hexane. The desired fraction was concentrated under reduced pressure, triturated with n-pentane, and dried to afford the titled compound (50 mg). LCMS m/z 333.90 (M-H)~. 1H NMR (400 MHz, DMSO-c/e) δ ppm 2.80 (s, 6 H) 6.49 - 6.68 (m, 2 H) 6.73 - 6.92 (m, 2 H) 7.00 (d, J=8.77 Hz, 1 H) 7.64 (dd, J=8.77, 2.19 Hz, 1 H) 7.98 (br. s., 1 H) 8.23 (d, J=2.19 Hz, 1 H) 8.50 (br. s., 1 H) 9.47 (s, 1 H) 13.37 (br. s., 1 H). Example 18
2-Hvdroxy-5-(N-(4-phenoxyphenyl)sulfamoyl)benzamide
Figure imgf000109_0001
To a solution of 3-carbamoyl-4-hydroxybenzene-1 -sulfonyl chloride (lnt-1 , 500 mg) in pyridine (5 mL) at 0 °C was added 4-phenoxyaniline (393 mg). The reaction mixture was allowed to warm to RT and stirred for 12 hr. The reaction mixture was diluted with ice cold water (20 mL) and extracted with EtOAc (2 x 20 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to obtain the crude product (800 mg). The crude product was purified by silica gel column chromatography on an 8 g column eluting with hexane followed by 30% EtOAc/hexane. The desired fractions were combined and concentrated under reduced pressure to afford the titled compound (103 mg). LCMS m/z 385.0 (M+H)+. 1H NMR (400 MHz, DMSO-cfe) δ ppm 6.90 (d, J=8.77 Hz, 4 H) 6.97 - 7.17 (m, 4 H) 7.23 - 7.43 (m, 2 H) 7.71 (dd, J=8.77, 2.19 Hz, 1 H) 8.01 (br. s., 1 H) 8.26 (d, J=2.19 Hz, 1 H) 8.54 (br. s., 1 H) 9.97 (s, 1 H) 13.46 (s, 1 H).
Example 19
2-Hvdroxy-5-(N-(4-(methylamino)phenyl)sulfamoyl)benzamide
Figure imgf000109_0002
To a solution of 3-carbamoyl-4-hydroxybenzene-1 -sulfonyl chloride (lnt-1 , 500 mg) in pyridine (5 mL) at 0 °C under nitrogen was added /V1 -methylbenzene-1 ,4-diamine (259 mg). The reaction mixture was allowed to warm to RT and stirred for 12 hr. The solvent was removed under reduced pressure and the residue was diluted with water (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to obtain the crude product (380 mg). The crude product was purified by silica gel column chromatography on a 30 g column eluting with hexane followed by 30% EtOAc/hexane. The desired fractions were concentrated under reduced pressure and further purified by preparative reversed phase HPLC (Sunfire C18, 19 x 150 mm) eluting with a 10-50% gradient of acetonitrile in 0.1 % formic acid (aq). The desired fraction was lyophilized to afford the titled compound (107 mg). LCMS m/z 322.01 (M+H)+. Ή NMR (400 MHz, DMSO-c/6) δ ppm 2.59 (s, 3 H) 6.29 - 6.50 (m, 2 H) 6.58 - 6.85 (m, 2 H) 6.99 (d, J=8.77 Hz, 1 H) 7.61 (dd, J=8.77, 2.41 Hz, 1 H) 8.18 (d, J=2.41 Hz, 1 H).
Example 20
2-Hvdroxy-5-(N-(4-sulfamoylphenyl)sulfamoyl)benzamide
Figure imgf000110_0001
To a solution of 3-carbamoyl-4-hydroxybenzene-1 -sulfonyl chloride (lnt-1 , 500 mg) in pyridine (10 ml_) was added 4-aminobenzenesulfonamide (365 mg) and the reaction mixture was stirred at RT under nitrogen for 16 hr. The solvent was evaporated under reduced pressure and the residue was diluted with water (20 ml_) and extracted with EtOAc (2 x 40 ml_). The combined organic layers were washed with water (40 ml_) and saturated brine (40 ml_), dried over sodium sulfate and concentrated under reduced pressure to obtain the crude product (700 mg). The crude product was purified by silica gel column chromatography on a 40 g column eluting with a gradient of 0-1 % MeOH/DCM. The desired fraction was concentrated under reduced pressure, and further purified by preparative reversed phase HPLC (XBridge C18, 4.6 x 74 mm) using a gradient of 5-50% acetonitrile in 0.01 M ammonium bicarbonate (aq) to afford the titled compound (50 mg). LCMS m/z 369.93 (M-H)~. Ή NMR after D20 exchange (400 MHz, DMSO-c/6) δ ppm 7.05 (d, J=8.77 Hz, 1 H) 7.26 (d, J=8.77 Hz, 2 H) 7.69 (d, J=8.77 Hz, 2 H) 7.81 (dd, J=8.88, 2.52 Hz, 1 H) 8.40 (d, J=2.41 Hz, 1 H). Example 21
5-(N-(2,3-Dihvdro-1 /y-inden-5-yl)sulfamoyl)-2-hvdroxybenzamide
Figure imgf000111_0001
(a) Methyl 5-(N-(2,3-Dihydro-1 H-inden-5-yl)sulfamoyl)-2-hydroxybenzoate
Methyl 5-(chlorosulfonyl)-2-hydroxybenzoate (150 mg) was added to a solution of DMAP (7.31 mg) and m-toluidine (64.1 mg) in anhydrous pyridine (3 mL). The reaction vessel was sealed, and the reaction mixture was stirred at room temperature. After 40 min, water (3 mL) and DCM (2 mL) were added to the reaction mixture. The layers were separated, and the aqueous layerwas extracted with DCM (2 x2 mL). Isolute-SI loading sorbent was added to the combined organic layers, and the mixture was concentrated under a stream of nitrogen at 50 °C. The crude product was purified by silica gel flash chromatography using a gradient of 0- 70% EtOAc/hexanes to afford the titled compound (153 mg). LCMS m/z 348.0 (M+H)+.
(b) 5-(N-(2,3-Dihydro-1 H-inden-5-yl)sulfamoyl)-2-hydroxybenzoic acid
Lithium hydroxide hydrate (77 mg) was added to a solution of methyl 5-(/V-(2,3-dihydro-1 H- inden-5-yl)sulfamoyl)-2-hydroxybenzoate (154 mg) in THF (1 mL), MeOH (1 mL), and water (1 mL) in a 20 mL vial. The vial was capped, and the reaction was stirred at 50 °C for approximately 3 hr. The heat bath was removed, and a solution of 1 M HCI (2 mL) was added. The mixture was extracted with EtOAc (3 x 2 mL). The combined organic layers were washed with saturated brine (1 mL), dried over Na2S04, concentrated under reduced pressure, and dried under high vacuum to afford the titled compound (152 mg), which was used without further purification. LCMS m/z 333.9 (M+H)
(c) 5-(N-(2,3-Dihydro-1 H-inden-5-yl)sulfamoyl)-2-hydroxybenzamide ( N34646-55)
A solution of 50 wt% T3P in EtOAc (0.32 mL, 0.538 mmol) and was added to a solution of 5-(N-(2,3-dihydro-1 /-/-inden-5-yl)sulfamoyl)-2-hydroxybenzoic acid (150 mg), ammonium chloride (48.8 mg) and DIPEA (0.33 mL) in DMF (1 mL). The reaction mixture was stirred at room temperature for approximately 17 h. A solution of 0.5 M ammonia in dioxane (2 mL, 1 .000 mmol) was then added, and stirring was continued at room temperature. After another 10 min, the reaction mixture was concentrated over 2 days under a stream of nitrogen. Isolute-SI-SI loading sorbent was added to the combined organic layers, and the mixture was concentrated under a stream of nitrogen at 50 °C. The crude product was then purified by silica gel flash chromatography using a gradient of 0-10% MeOH/DCM over 35 min. Removal of solvent under reduced pressure followed by lyophilization afforded the titled compound (9.1 mg). LCMS m/z 332.9 (M+H)+. 1H NMR (400MHz, M ETHAN OL-d4) δ = 8.21 (d, J=2.3 Hz, 1 H), 7.67 (dd, J=2.3, 8.6 Hz, 1 H), 7.03 (d, J=7.8 Hz, 1 H), 6.96 - 6.87 (m, 2H), 6.80 (d, J=6.1 Hz, 1 H), 2.88 - 2.71 (m, 4H), 2.10 - 1 .92 (m, 2H).
Example 22
5-(N-(3-Aminophenyl)sulfamoyl)-2-hvdroxybenzamide
Figure imgf000112_0001
(a) tert-Butyl (3-(3-carbamoyl-4-hydroxyphenylsulfonamido)phenyl)carbamate To a solution of 3-carbamoyl-4-hydroxybenzene-1 -sulfonyl chloride (lnt-1 , 1 .2 g) in pyridine (10 mL) at 0 °C under nitrogen was added tert-butyl (3-aminophenyl)carbamate (1 .061 g). The reaction mixture was allowed to warm to RT and stirred for 4 days. The solvent was removed under reduced pressure and the residue was diluted with water (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to obtain the crude product (1 .8 g). The crude product was purified by silica gel column chromatography on a 60 g column elution with a gradient from 0-30% EtOAc/hexane. The desired fractions were combined and concentrated under reduced pressure to afford the titled compound (750 mg). LCMS 408.36 (M+H)+.
(b) 5-(N-(3-Aminophenyl)sulfamoyl)-2-hydroxybenzamide
To a solution of tert-butyl (3-(3-carbamoyl-4-hydroxyphenylsulfonamido)phenyl)carbamate (400 mg) in DCM (4 mL) under nitrogen at 0 °C was added TFA (1 .33 mL). The reaction mixture was allowed to warm to RT and stirred for 2 hr. The solvent was removed under reduced pressure and the residue was dissolved in EtOAc (50 mL), neutralized by the addition of saturated sodium bicarbonate (aq), and then extracted with EtOAc (3 x 50 mL). The combined EtOAc extracts were washed with saturated brine (50 mL), dried over sodium sulfate, concentrated under reduced pressure and then lyophilized to afford the titled compound (131 mg). LCMS 307.98 (M+H)+. Ή NMR after D20 exchange (400 MHz, DMSO-c/e) δ ppm 6.16 - 6.32 (m, 2 H) 6.38 (t, J=2.08 Hz, 1 H) 6.83 (t, J=8.00 Hz, 1 H) 7.03 (d, J=8.77 Hz, 1 H) 7.73 (dd, J=8.77, 2.41 Hz, 1 H) 8.32 (d, J=2.19 Hz, 1 H). Example 23
2-Hvdroxy-5-(N-(naphthalen-2-yl)sulfamoyl)benzamide
Figure imgf000113_0001
DMAP (5.18 mg) was added to a solution of 3-carbamoyl-4-hydroxybenzene-1 -sulfonyl chloride (lnt-1 , 100 mg) and naphthalen-2-amine (60.8 mg) in anhydrous pyridine (1 ml_). The reaction vessel was sealed, and the reaction mixture was stirred at room temperature for 90 min. The reaction mixture was then concentrated under a stream of nitrogen. 1 M HCI (2 ml_) and EtOAc (2 ml_) were added to the reaction mixture. The layers were separated, and the aqueous layer was extracted with EtOAc (2 x 2 ml_). The combined organic layers were washed with 1 M HCI (3 x 2 ml_) and then concentrated under a stream of nitrogen. The residue was taken up in EtOAc (3 ml_), and the mixture was washed with 1 M HCI (1 x 2 ml_). Isolute-SI loading sorbent was added to the organic layer, and the mixture was concentrated under a stream of nitrogen. The crude product was then purified by silica gel flash chromatography using a gradient of 0-10% MeOH/DCM. Removal of solvent under reduced pressure and lyophilization of the residue afforded the titled compound (51 mg). LCMS m/z 342.9 (M+H)+. 1 H NMR (400MHz, METHANOL-d4) δ = 8.32 (d, J=2.3 Hz, 1 H), 7.80 - 7.65 (m, 4H), 7.53 (s, 1 H), 7.47 - 7.31 (m, 2H), 7.25 (dd, J=2A , 8.7 Hz, 1 H), 6.91 (d, J=8.8 Hz, 1 H).
Example 24
2-Hvdroxy-5-(N-(quinolin-6-yl)sulfamoyl)benzamide
Figure imgf000113_0002
DMAP (5.18 mg) was added to a solution of 3-carbamoyl-4-hydroxybenzene-1 -sulfonyl chloride (lnt-1 , 100 mg, 0.424 mmol) and quinolin-6-amine (61 .2 mg,) in anhydrous pyridine (1 ml_). The reaction vessel was sealed, and the reaction mixture was stirred at room temperature for 80 min. The reaction mixture was then concentrated under a stream of nitrogen. 1 M HCI (2 mL) and EtOAc (2 mL) were added to the residue. The layers were separated, and the pH of the aqueous layer was adjusted to ~5 by pH paper and extracted again with EtOAc (2 x 2 mL). Isolute-SI loading sorbent was added to the combined organic layers, and the mixture was concentrated under reduced pressure and dried under high vacuum. The crude product was then purified by silica gel flash chromatography using a gradient of 0-10% MeOH/DCM. Removal of solvent under reduced pressure and lyophilization of the residue afforded the titled compound (37.8 mg). LCMS m/z 343.9 (M+H)+. Ή NMR (400MHz, METHANOL-d4) δ = 8.70 (dd, J=1 .8, 4.3 Hz, 1 H), 8.34 (d, J=2.5 Hz, 1 H), 8.17 (d, J=8.1 Hz, 1 H), 7.89 (d, J=9.1 Hz, 1 H), 7.77 (dd, J=2.4, 8.7 Hz, 1 H), 7.61 (d, J=2.5 Hz, 1 H), 7.52 (dd, J=2.3, 9.1 Hz, 1 H), 7.43 (dd, J=4.3, 8.3 Hz, 1 H), 6.92 (d, J=8.8 Hz, 1 H).
Example 25
5-(N-(1 H-lndol-6-yl)sulfamoyl)-2-hvdroxybenzamide
Figure imgf000114_0001
DMAP (5.18 mg) was added to a solution of 3-carbamoyl-4-hydroxybenzene-1 -sulfonyl chloride (lnt-1 , 100 mg) and 1 H-indol-6-amine (56.1 mg) in anhydrous pyridine (1 mL). The reaction vessel was sealed, and the reaction mixture was stirred at room temperature for 80 min. The reaction mixture was then concentrated under a stream of nitrogen. Water (3 mL) and EtOAc (2 mL) were added to the reaction mixture. The layers were separated, and the aqueous layer was extracted with EtOAc (2 x 2 mL). The combined organic layers were washed with 1 M HCI (3 x 2 mL) and then concentrated under a stream of nitrogen. The residue was taken up in EtOAc (3 mL), and the mixture was washed with 1 M HCI (1 x 2 mL). Isolute-SI loading sorbent was added to the organic layer, and the mixture was concentrated under a stream of nitrogen. The crude product was then purified by silica gel flash chromatography using a gradient of 0-10% MeOH/DCM over 35 min. Removal of solvent under reduced pressure and lyophilization of the residue afforded the titled compound (57.2 mg). LCMS m/z 331 .9 (M+H)+. Ή NMR (400MHz, METHANOL-d4) δ = 8.19 (d, J=2.0 Hz, 1 H), 7.62 (dd, J=2.3, 8.6 Hz, 1 H), 7.37 (d, J=8.3 Hz, 1 H), 7.16 (dd, J=2.0, 6.3 Hz, 2H), 6.89 (d, J=8.6 Hz, 1 H), 6.67 (dd, J=2.0, 8.3 Hz, 1 H), 6.40 - 6.30 (m, 1 H). Example 26
5-(N-(1 H-lndol-5-yl)sulfamoyl)-2-hvdroxybenzamide
Figure imgf000115_0001
The titled compound was prepared from 1 H-indol-5-amine (56.1 mg) according to the method of Example 25, affording 40.6 mg of the desired product. LCMS m/z 332.0 (M+H)+. Ή NMR (400MHz, METHANOL-d4) δ = 8.15 (d, J=2.0 Hz, 1 H), 7.59 (dd, J=2.3, 8.6 Hz, 1 H), 7.28 - 7.17 (m, 3H), 6.89 (d, J=8.8 Hz, 1 H), 6.78 (dd, J=1 .8, 8.6 Hz, 1 H), 6.35 (d, J=3.0 Hz, 1 H).
Example 27
5-(N-(1 H-Benzord1imidazol-5-yl)sulfamoyl)-2-hvdroxybenzamide
Figure imgf000115_0002
DMAP (5.18 mg) was added to a solution of 3-carbamoyl-4-hydroxybenzene-1 -sulfonyl chloride (lnt-1 , 100 mg) and 1 H-benzo[d]imidazol-5-amine (56.5 mg) in anhydrous pyridine (1 ml_). The reaction vessel was sealed, and the reaction mixture was stirred at room temperature. After 1 h, 20 min, the reaction mixture was concentrated under a stream of nitrogen. Water (3 ml_) and EtOAc (2 ml_) were added to the reaction mixture. The layers were separated, and the aqueous layer was extracted with EtOAc (2 x 2 ml_). Isolute-SI loading sorbent was added to the combined organic layers, and the mixture was concentrated under reduced pressure and dried under high vacuum. The crude product was then purified by silica gel flash chromatography using a gradient of 0-10% MeOH/DCM. Removal of the solvent under reduced pressure and lyophilization of the residue afforded the titled compound (22.9 mg). LCMS m/z 332.9 (M+H)+. 1H NMR (400MHz, METHANOL- d4) δ = 8.21 (d, J=2.3 Hz, 1 H), 8.12 (s, 1 H), 7.65 (dd, J=2.4, 8.7 Hz, 1 H), 7.46 (d, J=8.3 Hz, 1 H), 7.35 (d, J=1 .5 Hz, 1 H), 6.99 (d, J=6.3 Hz, 1 H), 6.91 (d, J=8.8 Hz, 1 H). Example 28
5-(N-(4-(Ethylamino)phenyl)sulfamoyl)-2-hvdroxybenzamide
Figure imgf000116_0001
(a) tert-Butyl (4-(3-carbamoyl-4- hydroxyphenylsulfonamido)phenyl)(ethyl)carbamate
To a solution of 3-carbamoyl-4-hydroxybenzene-1 -sulfonyl chloride (lnt-1 , 500 mg) in pyridine (10 ml_) under nitrogen was added tert-butyl 4-(aminophenyl)(ethyl)carbamate (501 mg) and the reaction mixture was stirred at RT for 16 hr. The solvent was removed under reduced pressure and the residue diluted with water (20 ml_) and extracted with EtOAc (2 x 40 ml_). The combined organic layers were washed with water (40 ml_) and saturated brine (40 ml_), dried over sodium sulphate, and concentrated under reduced pressure to obtain the crude product (700 mg). The crude, product was purified by silica gel column chromatography on a 15 g column eluting with 0.2% EtOAc/hexane. The desired fraction was concentrated under reduced pressure to afford the titled compound (400 mg). LCMS m/z 436.13 (M+H)+.
(b) 5-(N-(4-(Ethylamino)phenyl)sulfamoyl)-2-hydroxybenzamide
To a solution of tert-butyl (4-(3-carbamoyl-4- hydroxyphenylsulfonamido)phenyl)(ethyl)carbamate (400 mg) in 1 ,4-dioxane (2 ml_) under nitrogen at 0 °C was added HCI (4 M in 1 ,4 dioxane, 2.5 ml_) and the reaction mixture was allowed to stir for 1 hr. The solvent was removed under reduced pressure and the residue was neutralized by the addition of saturated sodium bicarbonate (aq) (20 ml_), then extracted with EtOAc (2 x 50 ml_). The combined extracts were washed with water (25 ml_) and saturated brine (25 ml_), dried over sodium sulphate, and concentrated under reduced pressure. The resulting solid was washed with 2% DCM/hexane and diethyl ether and dried to afford the titled compound (1 10 mg). LCMS 336.03 (M+H)+. 1H NMR (400 MHz, DMSO-c/6) δ ppm 1 .10 (t, J=7.13 Hz, 3 H) 2.93 (q, J=7.16 Hz, 2 H) 5.44 (br. s., 1 H) 6.39 (d, J=8.77 Hz, 2 H) 6.74 (d, J=8.77 Hz, 2 H) 7.00 (d, J=8.77 Hz, 1 H) 7.62 (dd, J=8.77, 2.41 Hz, 1 H) 7.97 (br. s., 1 H) 8.21 (d, J=2.41 Hz, 1 H) 8.48 (br. s., 1 H) 9.33 (s, 1 H) 13.38 (br. s., 1 H). Example 29
5-(N-(4-Aminophenyl)sulfamoyl)-2-hvdroxybenzamide
Figure imgf000117_0001
(a) tert-Butyl (4-(3-carbamoyl-4-hydroxyphenylsulfonamido)phenyl)carbamate
To a solution of 3-carbamoyl-4-hydroxybenzene-1 -sulfonyl chloride (lnt-1 , 372 mg) in pyridine (4 mL) at 0 °C under nitrogen was added tert-butyl (4-aminophenyl)carbamate (329 mg). The reaction mixture was allowed to warm to RT and was stirred for 4 days. The solvent was removed under reduced pressure and the residue was diluted with water (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to obtain the crude product (390 mg). The crude product was purified by silica gel column chromatography on a 40 g column eluting with a gradient of 0-30% EtOAc/hexane. The desired fractions were concentrated under reduced pressure to afford the titled compound (172 mg). LCMS m/z 406.41 (M-H)-.
(b) 5-(N-(4-Aminophenyl)sulfamoyl)-2-hydroxybenzamide (N35794-70)
To a solution of tert-butyl (4-(3-carbamoyl-4-hydroxyphenylsulfonamido)phenyl)carbamate (172 mg) in DCM (2 mL) under nitrogen at 0 °C was added TFA (0.6 mL). The reaction mixture was allowed to warm to RT and stirred for 2 hr. The solvent was removed under reduced pressure and the residue was dissolved in EtOAc (25 mL), neutralized by the addition of saturated sodium carbonate (aq), and then extracted with EtOAc (3 x 50 mL). The combined EtOAc extracts were washed with water (50 mL) and saturated brine (50 mL), dried over sodium sulfate and concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative reversed phase HPLC (Kromasil phenyl, 25 x 150 mm) using a gradient of 10-35% acetonitrile in 10 mM ammonium acetate (aq). The desired fraction was lyophilized to afford the titled compound (20 mg). LCMS 307.94 (M+H)+. Ή NMR after D20 exchange (400 MHz, DMSO-c/6) δ ppm 6.35 - 6.44 (m, 2 H) 6.56 - 6.72 (m, 2 H) 6.76 (d, J=8.55 Hz, 1 H) 7.44 (d, J=7.89 Hz, 1 H) 8.14 (d, J=2.41 Hz, 1 H). Example 30
5-(N-(Benzorb1thiophen-5-yl)sulfamoyl)-2-hvdroxybenzamide
Figure imgf000118_0001
To a solution of benzo[b]thiophen-5-amine (100 mg) in pyridine under nitrogen at 0 °C was added a suspension of 3-carbamoyl-4-hydroxybenzene-1 -sulfonyl chloride (lnt-1 , 237 mg) in DCM (2 ml_) dropwise over 5 min. The reaction mixture was allowed to warm to RT and was stirred for 16 hr. The solvent was removed under reduced pressure and the residue quenched by the addition of ice cold water (5 ml_). The supernatant was decanted to afford the crude product (450 mg). The crude product was purified by preparative reversed phase HPLC (XBridge C18, 19x150 mm) using a gradient of 10-25% acetonitrile in 5 mM ammonium bicarbonate. The desired fractions were lyophilized to afford the titled compound (52 mg). LCMS m/z 348.99 (M+H)+. Ή NMR (400 MHz, DMSO-c/6) δ ppm 6.97 - 7.04 (m, 1 H) 7.04 - 7.14 (m, 1 H) 7.37 (d, J=5.48 Hz, 1 H) 7.62 (d, J=2.19 Hz, 1 H) 7.68 - 7.77 (m, 2 H) 7.84 (d, J=8.55 Hz, 1 H) 8.00 (br. s., 1 H) 8.36 (d, J=2.41 Hz, 1 H) 8.53 (br. s., 1 H) 10.18 (s, 1 H) 13.43 (br. s., 1 H).
Example 31
5-(N-(1 H-Pyrazol-5-yl)sulfamoyl)-2-hvdroxybenzamide
Figure imgf000118_0002
(a) tert-Butyl 5-nitro-1 H-pyrazole-1 -carboxylate
To a solution of 5-nitro-1 H-pyrazole (2.0 g) and triethylamine (7.40 ml_) in THF (20 ml_) under nitrogen at 0 °C was added di-t-butyl dicarbonate (4.93 ml_) in THF (20 ml_). The reaction was allowed to warm to room temperature and stirred for 3 hr. The reaction mixture was diluted with water (100 ml_) and extracted with EtOAc (3 x 100 ml_). The combined EtOAc extracts were washed with saturated brine (100 ml_), dried over sodium sulfate and concentrated under reduced pressure to give the crude product (4.2 g). The crude product was purified by silica gel column chromatography on a 60 g column eluting with a gradient of 0-30% EtOAc/hexane. The desired fractions were concentrated under reduced pressure to afford the titled compound (2.0 g). LCMS m/z 1 13 (M+H-Boc).
(b) tert-Butyl 5-amino-1 H-pyrazole-1 -carboxylate
To a solution of tert-butyl 5-nitro-1 H-pyrazole-1 -carboxylate (1 .9 g) in MeOH (80 ml_) was added Pd/C (500 mg). The reaction mixture was stirred at RT under an atmosphere of hydrogen gas. The reaction mixture was filtered through a bed of Celite and the filtrate was concentrated under reduced pressure to afford the titled compound (1 .7 g), which was used without further purification. LCMS m/z 183.96 (M+H)+.
(c) tert-Butyl 5-(3-carbamoyl-4-hydroxyphenylsulfonamido)-1 H-pyrazole-1 - carboxylate
To a solution of 3-carbamoyl-4-hydroxybenzene-1 -sulfonyl chloride (lnt-1 , 2.187 g) in pyridine (20 ml_) at 0 °C under nitrogen was added tert-butyl 5-amino-1 H-pyrazole-1 - carboxylate (1 .70 g). The reaction mixture was allowed to warm to RT and stirred for 16 hr. The solvent was removed under reduced pressure and the residue was diluted with water (100 ml_) and extracted with EtOAc (3 x 100 ml_). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to obtain the crude product (1 .8 g). The crude product was purified by silica gel column chromatography on a 50 g column eluting with a gradient of 0-2% MeOH/DCM. The desired fractions were concentrated under reduced pressure to afford the titled compound (750 mg). LCMS m/z 383.18 (M+H)+.
(d) 5-(N-(1 H-Pyrazol-5-yl)sulfamoyl)-2-hydroxybenzamide
To a solution of tert-butyl 5-(3-carbamoyl-4-hydroxyphenylsulfonamido)-1 H-pyrazole-1 - carboxylate (750 mg) in DCM (10 mL) under nitrogen at 0 °C was added TFA (0.756 mL). The reaction mixture was allowed to warm to RT and stirred for 2 hr. The solvent was removed under reduced pressure to obtain the crude product (410 mg). The crude product was purified by preparative reversed phase HPLC (Kromosil phenylhexyl, 25x250 mm) using a gradient of 10-45% acetonitrile in 10 mM ammonium acetate (aq). The desired fractions were lyophilized to afford the titled compound (165 mg). LCMS m/z 283.00 (M+H)+. Ή NMR after D20 exchange (400 MHz, DMSO-c/6) δ ppm 5.89 (d, J=2.19 Hz, 1 H) 6.46 (d, J=8.77 Hz, 1 H) 7.36 (d, J=6.58 Hz, 1 H) 7.45 (d, J=2.19 Hz, 1 H) 8.16 (d, J=2.41 Hz, 1 H).
Example 32
2-Hvdroxy-5-(N-(2-methyl-1 /y-indol-6-yl)sulfamoyl)benzamide
Figure imgf000120_0001
To a solution of 2-methyl-1 /-/-indol-6-amine (200 mg) and pyridine (2.213 mL) in DCM (4 mL) under nitrogen at 0 °C was added 3-carbamoyl-4-hydroxybenzene-1 -sulfonyl chloride (lnt-1 , 387 mg) portionwise over 5 min. The reaction mixture was allowed to warm to RT and was stirred for 16 hr. The solvent was removed under reduced pressure and the residue quenched by the addition of ice cold water (10 mL), which resulted in the formation of a precipitate. The supernatant was decanted to afford the crude product (500 mg). The crude product was purified by preparative reversed phase HPLC (XBridge C18, 30x250 mm) using a gradient of 10-55% acetonitrile in 10 mM ammonium bicarbonate (aq). The desired fractions were concentrated under reduced pressure and the resulting precipitate was collected by filtration and air-dried to afford the titled compound (51 mg). LCMS m/z 346.0 (M+H)+. Ή NMR (400 MHz, DMSO-c/6) δ ppm 2.30 (s, 3 H) 5.90 - 6.05 (m, 1 H) 6.67 (dd, J=8.33, 1 .97 Hz, 1 H) 6.86 - 7.08 (m, 2 H) 7.19 (d, J=8.33 Hz, 1 H) 7.64 (dd, J=8.77, 2.41 Hz, 1 H) 7.95 (br. s., 1 H) 8.27 (d, J=2.19 Hz, 1 H) 8.47 (br. s., 1 H) 9.67 (s, 1 H) 10.76 (s, 1 H) 13.32 (br. s., 1 H).
Example 33
5-(N-(Benzofuran-5-yl)sulfamoyl)-2-hvdroxybenzamide
Figure imgf000120_0002
To a solution of benzofuran-5-amine (200 mg) and pyridine (0.607 mL) in DCM (4 mL) under nitrogen at 0 °C was added 3-carbamoyl-4-hydroxybenzene-1 -sulfonyl chloride (Int- 1 , 425 mg) portionwise over 5 min. The reaction mixture was allowed to warm to RT and was stirred for 16 hr. The solvent was removed under reduced pressure and the residue quenched by the addition of ice cold water (15 mL), which resulted in the formation of a precipitate. The supernatant was decanted to afford the crude product (600 mg). The crude product was purified by preparative reversed phase HPLC (Kinetex C18, 30x150 mm) using a gradient of 70-100% acetonitrile in 10 mM ammonium bicarbonate (aq). The desired fractions were concentrated under reduced pressure and the resulting precipitate was collected by filtration and air-dried to afford the titled compound (250 mg). LCMS m/z 331 .1 (M-H)~. Ή NMR (400 MHz, DMSO-c/6) δ ppm 6.89 (dd, J=2.19, 0.88 Hz, 1 H) 6.94 - 7.15 (m, 2 H) 7.37 (d, J=2.19 Hz, 1 H) 7.45 (d, J=8.77 Hz, 1 H) 7.68 (dd, J=8.77, 2.41 Hz, 1 H) 7.86 - 8.12 (m, 2 H) 8.29 (d, J=2.41 Hz, 1 H) 8.50 (br. s., 1 H) 9.98 (s, 1 H) 13.40 (s, 1 H).
Example 34
5-(N-(Benzorb1thiophen-6-yl)sulfamoyl)-2-hvdroxybenzamide
Figure imgf000121_0001
To a solution of benzo[b]thiophen-6-amine (200 mg) and pyridine (0.542 mL) in DCM (4 mL) under nitrogen at 0 °C was added 3-carbamoyl-4-hydroxybenzene-1 -sulfonyl chloride (lnt-1 , 379 mg) portionwise over 5 min. The reaction mixture was allowed to warm to RT and was stirred for 16 hr. The solvent was removed under reduced pressure and the residue quenched by the addition of ice cold water (15 mL), which resulted in the formation of a precipitate. The supernatant was decanted to afford the crude product (550 mg). The crude product was purified by preparative reversed phase HPLC (Kromosil phenylhexyl, 25x150 mm) using 78% acetonitrile in 10 mM ammonium bicarbonate (aq). The desired fractions were concentrated under reduced pressure and the resultant precipitate was collected by filtration and air-dried to afford the titled compound (149 mg). LCMS m/z 348.95 (M+H)+. 1H NMR (400 MHz, DMSO-c/6) δ ppm 7.01 (d, J=8.77 Hz, 1 H) 7.1 1 (dd, J=8.55, 1 .97 Hz, 1 H) 7.33 (d, J=5.48 Hz, 1 H) 7.62 (d, J=5.48 Hz, 1 H) 7.67 - 7.84 (m, 3 H) 8.01 (br. s., 1 H) 8.39 (d, J=2.19 Hz, 1 H) 8.57 (br. s., 1 H) 10.25 (s, 1 H) 13.48 (br. s., 1 H). Example 35
2-Hvdroxy-5-(N-(1 -methyl-1 /y-indol-6-yl)sulfamoyl)benzamide
Figure imgf000122_0001
To a solution of 1 -methyl-1 /-/-indol-6-amine (200 mg) and pyridine (0.553 mL) in DCM (4 mL) under nitrogen at 0 °C was added 3-carbamoyl-4-hydroxybenzene-1 -sulfonyl chloride (lnt-1 , 387 mg) portionwise over 5 min. The reaction mixture was allowed to warm to RT and was stirred for 16 hr. The solvent was removed under reduced pressure and the residue quenched by the addition of ice cold water (15 mL), which resulted in the formation of a precipitate. The supernatant was decanted to afford the crude product (600 mg). The crude product was purified by preparative reversed phase HPLC (XBridge C18, 19x250 mm) using a gradient of 10-55% acetonitrile in 10 mM ammonium acetate (aq). The desired fractions were concentrated under reduced pressure and the resulting precipitate was collected by filtration and air-dried to afford the titled compound (245 mg). LCMS m/z 346.00 (M+H)+. Ή NMR (400 MHz, DMSO-c/6) δ ppm 3.68 (s, 3 H) 6.30 (dd, J=3.07, 0.88 Hz, 1 H) 6.73 (dd, J=8.44, 1 .86 Hz, 1 H) 6.99 (d, J=8.77 Hz, 1 H) 7.08 - 7.18 (m, 1 H) 7.23 (d, J=3.07 Hz, 1 H) 7.35 (d, J=8.55 Hz, 1 H) 7.71 (dd, J=8.77, 2.41 Hz, 1 H) 7.97 (br. s., 1 H) 8.33 (d, J=2.41 Hz, 1 H) 8.52 (br. s., 1 H) 9.88 (s, 1 H) 13.40 (br. s., 1 H).
Example 36
2-Hvdroxy-5-(N-(3-(oxazol-2-yl)phenyl)sulfamoyl)benzamide
Figure imgf000122_0002
To a solution of 3-(oxazol-2-yl)aniline (136 mg) and pyridine (0.343 mL) in DCM (10 mL) under nitrogen at 0 °C was added 3-carbamoyl-4-hydroxybenzene-1 -sulfonyl chloride (Int- 1 , 200 mg) portionwise over 5 min. The reaction mixture was allowed to warm to RT and stirred for 16 hr. The reaction mixture was concentrated under reduced pressure and diluted with cold water (10 mL), which resulted in the formation of a precipitate. The water layer was decanted to obtain the crude product (200 mg). The crude product was purified by preparative reversed phase HPLC (XBridge C18, 19x150 mm) using a gradient of 10-55% acetonitrile in 5 mM ammonium bicarbonate (aq). The desired fraction was lyophilized to afford the titled compound (1 10 mg). LCMS m/z 360.00 (M+H)+. Ή NMR (400 MHz, DMSO- cfe) δ ppm 7.03 (d, J=8.77 Hz, 1 H) 7.26 (ddd, J=8.1 1 , 1 .97, 0.88 Hz, 1 H) 7.32 - 7.49 (m, 2 H) 7.53 - 7.68 (m, 1 H) 7.69 - 7.85 (m, 2 H) 7.99 (br. s., 1 H) 8.19 (s, 1 H) 8.38 (d, J=2.19 Hz, 1 H) 8.57 (br. s., 1 H) 10.40 (br. s., 1 H) 13.45 (br. s., 1 H).
Example 37
2-Hvdroxy-5-(N-(3-methyl-1 /y-indol-6-yl)sulfamoyl)benzamide
Figure imgf000123_0001
To a solution of 3-methyl-1 /-/-indol-6-amine (200 mg) and pyridine (0.553 mL) under nitrogen at 0 °C was added 3-carbamoyl-4-hydroxybenzene-1 -sulfonyl chloride (lnt-1 , 258 mg) in DCM (2 mL) dropwise over 5 min. The reaction mixture was allowed to warm to RT and stirred for 16 hr. The reaction mixture was concentrated under reduced pressure and diluted with cold water (5 mL), which resulted in the formation of a precipitate. The water layer was decanted to obtain the crude product (250 mg). The crude compound was triturated with n-pentane, then dissolved in EtOAc, filtered and evaporated to dryness, then taken into acetonitrile (10 mL) and water (10 mL) and stirred for 2 hr. The acetonitrile was removed under reduced pressure and the solid collected by filtration and dried under vacuum to afford the titled compound (145 mg). LCMS m/z 346.03 (M+H)+. 1H NMR (400 MHz, DMSO-c/e) δ ppm 2.17 (d, J=1 .10 Hz, 3 H) 6.75 (dd, J=8.44, 1 .86 Hz, 1 H) 6.88 - 7.03 (m, 2 H) 7.06 (d, J=1 .75 Hz, 1 H) 7.28 (d, J=8.55 Hz, 1 H) 7.65 (dd, J=8.77, 2.19 Hz, 1 H) 7.94 (br. s., 1 H) 8.28 (d, J=2.41 Hz, 1 H) 8.50 (br. s., 1 H) 9.75 (s, 1 H) 10.59 (s, 1 H) 13.33 (br. s., 1 H). Example 38
2-Hvdroxy-5-(N-(4-(oxazol-2-yl)phenyl)sulfamoyl)benzamide
Figure imgf000124_0001
To a solution of 4-(oxazol-2-yl)aniline (200 mg) in DCM (10 mL) at 0 °C was added pyridine (0.631 mL) followed by 3-carbamoyl-4-hydroxybenzene-1 -sulfonyl chloride (lnt-1 , 368 mg). The reaction mixture was allowed to warm to RT and stirred for 16 hr. The reaction mixture was diluted with water (15 mL) and filtered to obtain the crude product. The crude product was purified by preparative reversed phase HPLC (Xterra C18, 19x250 mm) using a gradient of 16-98% acetonitrile in 10 mM ammonium bicarbonate (aq). The desired fractions were concentrated under reduced pressure to afford the titled compound (88 mg). LCMS m/z 359.97 (M+H)+. Ή NMR (400 MHz, DMSO-c/6) δ ppm 7.05 (d, J=8.77 Hz, 1 H) 7.16 - 7.38 (m, 3 H) 7.73 - 7.95 (m, 3 H) 8.04 (br. s., 1 H) 8.14 (s, 1 H) 8.42 (d, J=1 .75 Hz, 1 H) 8.59 (br. s., 1 H) 10.55 (br. s., 1 H) 13.50 (br. s., 1 H).
Example 39
2-Hvdroxy-5-(N-(3-(oxazol-4-yl)phenyl)sulfamoyl)benzamide
Figure imgf000124_0002
To a solution of 3-(oxazol-4-yl)aniline (250 mg) in DCM (10 mL) at 0 °C was added pyridine (0.631 mL) followed by 3-carbamoyl-4-hydroxybenzene-1 -sulfonyl chloride (lnt-1 , 368 mg). The reaction mixture was allowed to warm to RT and stirred for 16 hr. The reaction mixture was diluted with water (20 mL) and filtered to obtain the crude product. The crude product was purified by preparative reversed phase HPLC (Xterra C18, 19x250 mm) using a gradient of 10-100% acetonitrile in 10 mM ammonium bicarbonate (aq). The desired fractions were concentrated under reduced pressure to afford the titled compound (103 mg). LCMS m/z 360.04 (M+H)+. Ή NMR (400 MHz, DMSO-c/6) δ ppm 7.05 (dd, J=14.69, 8.1 1 Hz, 2 H) 7.28 (t, J=7.78 Hz, 1 H) 7.43 (d, J=7.02 Hz, 1 H) 7.55 (br. s., 1 H) 7.75 (d, J=7.67 Hz, 1 H) 8.01 (br. s., 1 H) 8.41 (d, J=18.64 Hz, 2 H) 8.56 (br. s., 2 H) 10.25 (br. s., 1 H) 13.44 (br. s., 1 H).
Example 40
2-Hvdroxy-5-(N-(4-(oxazol-4-yl)phenyl)sulfamoyl)benzamide
Figure imgf000125_0001
To a solution of 4-(oxazol-4-yl)aniline (381 mg) and pyridine (1 .201 mL) under nitrogen at 0 °C was added 3-carbamoyl-4-hydroxybenzene-1 -sulfonyl chloride (lnt-1 , 700 mg) portionwise over 5 min. The reaction mixture was allowed to warm to RT and stirred for 16 hr. The reaction mixture was concentrated under reduced pressure and diluted with ice- cold water (15 mL), which resulted in the formation of a precipitate. The water layer was decanted to obtain the crude product (800 mg). The crude product was purified by preparative reversed phase HPLC (Xterra C18, 25x250 mm) using a gradient of 17-100% acetonitrile in 10 mM ammonium bicarbonate (aq). The desired fractions were concentrated under reduced pressure and the resulting solid was collected by filtration and air-dried to afford the titled compound (195 mg). LCMS m/z 360.00 (M+H)+. 1H NMR (400 MHz, DMSO- c/6) δ ppm 7.03 (d, J=8.77 Hz, 1 H) 7.09 - 7.34 (m, 2 H) 7.51 - 7.69 (m, 2 H) 7.74 (dd, J=8.77, 2.41 Hz, 1 H) 8.02 (br. s., 1 H) 8.22 - 8.46 (m, 2 H) 8.49 (d, J=0.88 Hz, 1 H) 8.57 (br. s., 1 H) 10.25 (s, 1 H) 13.46 (br. s., 1 H).
Example 41
2-Hvdroxy-5-(N-(indolin-6-yl)sulfamoyl)benzamide
Figure imgf000126_0001
(a) tert-Butyl 6-(3-carbamoyl-4-hydroxyphenylsulfonamido)indoline-1 -carboxylate
To a solution of tert-butyl 6-aminoindoline-1 -carboxylate (398 mg) and pyridine (0.858 mL) under nitrogen at 0 °C was added 3-carbamoyl-4-hydroxybenzene-1 -sulfonyl chloride (Int- 1 , 500 mg) portionwise over 5 min. The reaction mixture was allowed to warm to RT and stirred for 16 hr. The reaction mixture was concentrated under reduced pressure and diluted with ice-cold water (15 mL). The resulting precipitate was collected by filtration, washed with pentane (2 x 5 mL) and diethyl ether (2 x 5 mL), and air-dried to afford the titled compound (900 mg), which was used without further purification. LCMS m/z 434.16 (M+H)+.
(b) 2-Hydroxy-5-(N-(indolin-6-yl)sulfamoyl)benzamide
To a solution of tert-butyl 6-(3-carbamoyl-4-hydroxyphenylsulfonamido)indoline-1 - carboxylate (900 mg) in DCM (8 mL) under nitrogen at 0 °C was added TFA (3.20 mL) dropwise over 5 min. The reaction mixture was allowed to warm to RT and was stirred for 16 hr. The reaction mixture was concentrated under reduced pressure to obtain the crude product (680 mg). The crude product was purified by preparative reversed phase HPLC (XBridge C18, 4.6x75 mm) using a gradient of 5-50% acetonitrile in 5 mM ammonium bicarbonate (aq). The desired fractions were concentrated under reduced pressure and the resulting solid was collected by filtration and air-dried to afford the titled compound (58 mg). LCMS 334.05 (M+H)+. 1H NMR (400 MHz, DMSO-c/6) δ ppm 2.76 (t, J=8.44 Hz, 2 H) 3.34 (t, J=8.55 Hz, 2 H) 5.49 (br. s., 1 H) 6.16 - 6.31 (m, 2 H) 6.80 (d, J=7.45 Hz, 1 H) 7.01 (d, J=8.77 Hz, 1 H) 7.70 (dd, J=8.77, 2.41 Hz, 1 H) 7.99 (br. s., 1 H) 8.31 (d, J=2.41 Hz, 1 H) 8.51 (br. s., 1 H) 9.71 (s, 1 H) 13.37 (br. s., 1 H).
Example 42
5-(N-(4-(Cvclopropanesulfonamido)phenyl)sulfamoyl)-2-hvdroxybenzamide
Figure imgf000127_0001
To a solution of N-(4-aminophenyl)cyclopropanesulfonamide (216 mg) and pyridine (0.515 ml_) in DCM (10 ml_) under nitrogen at 0 °C was added 3-carbamoyl-4-hydroxybenzene-1 - sulfonyl chloride (lnt-1 , 300 mg) portionwise over 5 min. The reaction mixture was allowed to warm to RT and was stirred for 16 hr. The reaction mixture was concentrated under reduced pressure, diluted with cold water (10 ml_), resulting in the formation of a precipitate, and the water was decanted to obtain the crude product (400 mg). The crude product was purified by preparative reversed phase HPLC (Kromosil phenylhexyl) using a gradient of 10-40% acetonitrile in 10 mM ammonium bicarbonate (aq). The desired fraction was lyophilized to afford the titled compound (200 mg). LCMS m/z 412.1 (M+H)+. 1H NMR (400 MHz, DMSO-c/e) δ ppm 0.74 - 0.94 (m, 4 H) 2.32 - 2.48 (m, 1 H) 6.97 - 7.21 (m, 4 H) 7.69 (dd, J=8.77, 2.41 Hz, 1 H) 8.00 (br. s., 1 H) 8.27 (d, J=2.41 Hz, 1 H) 8.52 (br. s., 1 H) 9.50 (s, 1 H) 9.97 (s, 1 H) 13.44 (s, 1 H).
Example 43
5-(N-(3-(Cvclopropanesulfonamido)phenyl)sulfamoyl)-2-hvdroxybenzamide
Figure imgf000127_0002
To a solution of N-(3-aminophenyl)cyclopropanesulfonamide (216 mg) and pyridine (0.515 ml_) in DCM (10 ml_) under nitrogen at 0 °C was added 3-carbamoyl-4-hydroxybenzene-1 - sulfonyl chloride (lnt-1 , 300 mg) portionwise over 5 min. The reaction mixture was allowed to warm to RT and was stirred for 16 hr. The reaction mixture was concentrated under reduced pressure, diluted with cold water (10 ml_), resulting in the formation of a precipitate, and the water was decanted to obtain the crude product (300 mg). The crude product was purified by preparative reversed phase HPLC (Kromosil phenylhexyl) using a gradient of 10-40% acetonitrile in 10 mM ammonium bicarbonate (aq). The desired fraction was lyophilized to afford the titled compound (103 mg). LCMS m/z 412.02 (M+H)+. 1H NMR (400 MHz, DMSO-c/e) δ ppm 0.75 - 0.90 (m, 4 H) 2.37 - 2.46 (m, 1 H) 6.73 - 6.87 (m, 3 H) 7.03 - 7.17 (m, 2 H) 7.51 - 7.73 (m, 2 H) 8.26 (d, J=2.41 Hz, 1 H) 9.09 (br. s., 2 H).
Example 44
2-Hvdroxy-5-(N-(4-(phenylsulfonamido)phenyl)sulfamoyl)benzamide
Figure imgf000128_0001
(a) tert-Butyl (4-(phenylsulfonamido)phenyl)carbamate
To a solution of tert-butyl (4-aminophenyl)carbamate (0.5 g) and pyridine (0.971 mL) in DCM (10 mL) at 0 °C under nitrogen was added benzenesulfonyl chloride (0.370 mL) dropwise over 5 min. The reaction mixture was allowed to warm to RT and stirred for 16 hr. The reaction mixture was concentrated under reduced pressure, diluted with cold water (10 mL) and filtered to afford the titled compound (720 mg), which was used without further purification. LCMS m/z 349.12 (M+H), 697.21 (2M+H).
(b) N-(4-Aminophenyl)benzenesulfonamide, hydrochloride salt
To a solution of tert-butyl (4-(phenylsulfonamido)phenyl)carbamate (720 mg) in 1 ,4-dioxane (10 mL) at 0 °C under nitrogen was added HCI (4 M in 1 ,4 dioxane, 5.17 mL) dropwise over 3 min. The reaction mixture was allowed to warm to RT and stirred for 16 hr. The reaction mixture was concentrated under reduced pressure to afford the titled compound (670 mg). LCMS m/z 247.1 (M-H)~.
(c) 2-Hydroxy-5-(N-(4-(phenylsulfonamido)phenyl)sulfamoyl)benzamide
To a solution of N-(4-Aminophenyl)benzenesulfonamide, hydrochloride salt (253 mg) and pyridine (0.515 mL) in DCM (10 mL) at 0 °C under nitrogen was added 3-carbamoyl-4- hydroxybenzene-1 -sulfonyl chloride (lnt-1 , 300 mg) portionwise over 5 min. The reaction mixture was allowed to warm to RT and was stirred for 16 hr. The reaction mixture was concentrated under reduced pressure, diluted with cold water (10 mL), resulting in the formation of a precipitate, and the water layer was decanted to obtain the crude product (350 mg). The crude product was purified by preparative reversed phase HPLC (Kromosil phenylhexyl, 25x250 mm) using a gradient of 10-50% acetonitrile in 10 mM ammonium bicarbonate (aq). The desired fraction was lyophilized to afford the titled compound (145 mg). LCMS m/z 448.06 (M+H)+. Ή NMR (400 MHz, DMSO-c/6) δ ppm 6.86 - 7.02 (m, 4 H) 7.26 - 7.53 (m, 2 H) 7.53 - 7.77 (m, 3 H) 8.00 (br. s., 1 H) 8.26 (d, J=2.41 Hz, 1 H) 8.57 (br. s., 1 H) 9.94 (s, 1 H) 10.02 (s, 1 H) 13.48 (br. s., 1 H).
Example 45
2-Hvdroxy-5-(N-(4-(methylsulfonamido)phenyl)sulfamoyl)benzamide
Figure imgf000129_0001
(a) tert-Butyl (4-(methylsulfonamido)phenyl)carbamate
To a solution of tert-butyl (4-aminophenyl)carbamate (2.0 g) in DCM (20 mL) was added TEA (4.02 mL). The reaction mixture was cooled to 0 °C and methanesulfonyl chloride (0.743 mL) was added. The reaction mixture was allowed to warm to RT and stirred for 16 hr. The reaction mixture was diluted with water (30 mL) and extracted with EtOAc (3 x 60 mL). The combined EtOAc extracts were washed with saturated brine (60 mL) and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography using 40% EtOAc/hexane. The desired fractions were concentrated under reduced pressure to afford the titled compound (1 .78 g). LCMS m/z 285.2 (M-H)~.
(b) N-(4-Aminophenyl)methanesulfonamide
To a solution of tert-butyl (4-(methylsulfonamido)phenyl)carbamate (1 .7 g) in 1 ,4-dixoane (20 mL) at 0 °C was added HCI (4 M in 1 ,4-dioxane, 7.42 mL). The reaction mixture was allowed to warm to RT and stirred for 16 hr. The reaction mixture was diluted with EtOAc (100 mL) and washed with saturated sodium bicarbonate (aq) (2 x 80 mL) followed by water. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to afford the titled compound (950 mg). LCMS 187.22 (M+H)+.
(c) 2-Hydroxy-5-(N-(4-(methylsulfonamido)phenyl)sulfamoyl)benzamide
To a solution of N-(4-aminophenyl)methanesulfonamide (250 mg) in DCM (10 mL) was added pyridine (0.543 mL). The reaction mixture was cooled to 0 °C and 3-carbamoyl-4- hydroxybenzene-1 -sulfonyl chloride (lnt-1 , 316 mg) was added portionwise over 5 min. The reaction mixture was allowed to warm to RT and stirred 16 hr. The reaction mixture was diluted with water and the resulting solid was collected by filtration to obtain the crude product (520 mg). The crude product was purified by preparative reversed phase HPLC (XBridge C18, 19x150 mm) using a gradient of 10-55% acetonitrile in 5 mM ammonium bicarbonate (aq). The desired fractions were concentrated under reduced pressure to afford the titled compound (149 mg). LCMS m/z 386.03 (M+H)+. 1H NMR (400 MHz, DMSO-c/6) δ ppm 2.89 (br. s., 3 H) 7.05 (d, J=5.26 Hz, 5 H) 7.70 (d, J=8.33 Hz, 1 H) 8.00 (br. s., 1 H) 8.28 (br. s., 1 H) 8.53 (br. s., 1 H) 9.53 (br. s., 1 H) 10.00 (br. s., 1 H) 13.45 (br. s., 1 H).
Example 46
2-Hvdroxy-5-(N-(3-(methylsulfonamido)phenyl)sulfamoyl)benzamide
Figure imgf000130_0001
(a) tert-Butyl (3-(methylsulfonamido)phenyl)carbamate
To a solution of tert-butyl (3-aminophenyl)carbamate (2 g) in DCM (20 mL) was added TEA (4.02 mL). The reaction mixture was cooled to 0 °C and methanesulfonyl chloride (0.743 mL) was added. The reaction mixture was allowed to warm to RT and stirred for 16 hr. The reaction mixture was diluted with water (40 mL) and extracted with EtOAc (3 x 60 mL). The combined EtOAc extracts were washed with saturated brine (100 mL), dried over sodium sulfate, and concentrated under reduced pressure to afford the crude product. The crude product was purified by silica gel column chromatography, eluting with 40% EtOAc/hexane. The desired fractions were concentrated under reduced pressure to afford the titled compound (1 .0g). LCMS 285.16 (M-H)~
(b) N-(3-Aminophenyl)methanesulfonamide
To a solution of tert-butyl (3-(methylsulfonamido)phenyl)carbamate (1 .0 g) in 1 ,4-dioxane (10 mL) at 0 °C was added HCI (4 M in 1 ,4-dioxane, 4.37 mL). The reaction mixture was allowed to warm to RT and stirred for 3 hr. The reaction mixture was diluted with EtOAc (80 mL) and washed with saturated sodium bicarbonate (aq) (2 x 100 mL) followed by saturated brine. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to afford the titled compound (600 mg). LCMS m/z 186.90 (M+H)+.
(c) 2-Hydroxy-5-(N-(3-(methylsulfonamido)phenyl)sulfamoyl)benzamide
To a solution of N-(3-aminophenyl)methanesulfonamide (200 mg) in DCM wad added pyridine (0.434 mL). The reaction mixture was cooled to 0 °C and 3-carbamoyl-4- hydroxybenzene-1 -sulfonyl chloride (lnt-1 , 253 mg) was added portionwise. The reaction mixture was allowed to warm to RT and stirred for 16 hr. The reaction mixture was diluted with water and the resulting solid was collected by filtration to afford the crude product. The crude product was purified by preparative reversed phase HPLC (Kromosil phenylhexyl, 25x150 mm) using a gradient of 10-40% acetonitrile in 5 mM ammonium bicarbonate (aq). The desired fractions were concentrated under reduced pressure to afford the titled compound (162 mg). LCMS m/z 386.03 (M+H)+. Ή NMR (400 MHz, DMSO-c/6) δ ppm 2.70 - 3.06 (m, 3 H) 6.83 (t, J=8.33 Hz, 2 H) 6.95 - 7.09 (m, 2 H) 7.16 (t, J=7.34 Hz, 1 H) 7.74 (d, J=8.1 1 Hz, 1 H) 7.90 - 8.17 (m, 1 H) 8.33 (br. s., 1 H) 8.49 (br. s., 1 H) 9.71 (br. s., 1 H) 10.18 (br. s., 1 H) 13.39 (br. s., 1 H).
Example 47
2-Hvdroxy-5-(N-(3-(phenylsulfonamido)phenyl)sulfamoyl)benzamide
Figure imgf000131_0001
(a) tert-Butyl (3-(phenylsulfonamido)phenyl)carbamate
To a solution of tert-butyl (3-aminophenyl)carbamate (500 mg) and pyridine (0.971 mL) in DCM (10 mL) at 0 °C under nitrogen was added benzenesulfonyl chloride (0.381 mL) dropwise over 5 min. The reaction mixture was allowed to warm to RT and stirred for 16 hr. The reaction mixture was concentrated under reduced pressure, dilute with cold water (10 mL) and the resulting solid was collected by filtration to afford the titled compound (700 mg), which was used without further purification. LCMS m/z 347.07 (M-H)-.
(b) N-(3-Aminophenyl)benzenesulfonamide, Hydrochloride
To a solution of tert-butyl (3-(phenylsulfonamido)phenyl)carbamate (700 mg) in 1 ,4-dioxane (10 mL) at 0 °C under nitrogen was added HCI (4 M in 1 ,4-dioxane, 5.02 mL) dropwise over 3 min. The reaction mixture was allowed to warm to RT and stirred for 16 hr. The reaction mixture was concentrated under reduced pressure and the resulting solid was collected by filtration and washed with n=pentane (20 mL) to afford the titled compound (650 mg), which was used without further purification. LCMS m/z 249.1 (M+H)+.
(c) 2-Hydroxy-5-(N-(3-(phenylsulfonamido)phenyl)sulfamoyl)benzamide
To a solution of N-(3-aminophenyl)benzenesulfonamide (253 mg) and pyridine (0.515 mL) in DCM (10 mL) at 0 °C under nitrogen was added 3-carbamoyl-4-hydroxybenzene-1 - sulfonyl chloride (lnt-1 , 300 mg) portionwise over 5 min. The reaction mixture was allowed to warm to RT and stirred for 16 hr. The reaction mixture was concentrated under reduced pressure, diluted with cold water (10 mL), resulting in the formation of a precipitate, and the water decanted to obtain the crude product (450 mg). The crude product was purified by preparative reversed phase HPLC (XBridge C18, 19x150 mm) using a gradient of 10-55% acetonitrile in 5 mM ammonium bicarbonate (aq). The desired fraction was lyophilized to afford the titled compound (135 mg). LCMS m/z 448.10 (M+H)+. Ή NMR after D20 exchange (400 MHz, DMSO-c/6) δ ppm 6.62 - 6.83 (m, 2 H) 6.93 (d, J=8.77 Hz, 1 H) 6.99 - 7.25 (m, 2 H) 7.30 - 7.54 (m, 2 H) 7.55 - 7.70 (m, 4 H) 8.30 (d, J=2.41 Hz, 1 H).
Example 48
5-(N-(4-Acetamidophenyl)sulfamoyl)-2-hvdroxybenzamide
Figure imgf000132_0001
(a) tert-Butyl (4-acetamidophenyl)carbamate
To a solution of tert-butyl (4-aminophenyl)carbamate (300 mg) and triethylamine (1 .004 ml_) in DCM (2 ml_) under nitrogen at 0 °C was added acetyl chloride (0.206 ml_) dropwise over 1 min. The reaction mixture was allowed to warm to RT and stirred for 6 hr. The reaction mixture was concentrated under reduced pressure, diluted with ice-cold water (15 ml_) and the resulting solid was collected by filtration to afford the titled compound (350 mg), which was used without further purification. LCMS m/z 268.35 (M+H)+.
(b) tert-Butyl (4-acetamidophenyl)carbamate, trifluoroacetic acid salt
To a solution of tert-butyl (4-acetamidophenyl)carbamate (350 mg) in DCM (2.5 ml_) at 0 ° C under nitrogen was added TFA (0.708 ml_) dropwise over 1 min. The reaction mixture was allowed to warm to RT and stirred for 16 hr. The reaction mixture was concentrated under reduced pressure, then suspended in toluene and evaporated 2X to obtain the titled compound (300 mg), which was used without further purification. LCMS m/z 151 .17 (M+H)+. (c) 5-(N-(4-Acetamidophenyl)sulfamoyl)-2-hydroxybenzamide
To a solution of N-(4-aminophenyl)acetamide, trifluoroacetic acid salt (300 mg) and pyridine (0.459 ml_) in DCM (4 ml_) under nitrogen at 0 °C was added 3-carbamoyl-4- hydroxybenzene-1 -sulfonyl chloride (lnt-1 , 321 mg) portionwise over 5 min. The reaction mixture was allowed to warm to RT and stirred for 16 hr. The reaction mixture was concentrated under reduced pressure, diluted with ice-cold water (15 ml_), resulting in the formation of a precipitate, and the water was decanted to afford the crude product. The crude product was purified by preparative reversed phase HPLC (Sunfire C18, 30x250 mm) using a gradient of 10-50% acetonitrile in 0.1 % formic acid (aq). The desired fractions were lyophilized to afford the titled compound (91 mg). LCMS m/z 350.03 (M+H)+. 1H NMR (400 MHz, DMSO-c/e) δ ppm 1 .98 (s, 3 H) 6.96 - 7.03 (m, 2 H) 7.41 (d, J=8.77 Hz, 2 H) 7.66 (dd, J=8.77, 2.41 Hz, 1 H) 7.98 (br. s., 1 H) 8.29 (d, J=2.19 Hz, 1 H) 8.55 (br. s., 1 H) 9.81 (s, 1 H) 9.89 (s, 1 H) 13.42 (br. s., 1 H). Example 49
5-(N-(3-Acetamidophenyl)sulfamoyl)-2-hvdroxybenzamide
Figure imgf000133_0001
(a) tert-Butyl (3-acetamidophenyl)carbamate
To a solution of tert-butyl (3-aminophenyl)carbamate (300 mg) and triethylamine (1 .004 mL) in DCM (2 mL) under nitrogen at 0 °C was added acetyl chloride (0.123 mL) dropwise over 1 min. The reaction mixture was allowed to warm to RT and stirred for 16 hr. The reaction mixture was concentrated under reduced pressure, diluted with ice-cold water (15 mL) and the resultant precipitate was isolated by filtration and air-dried to afford the titled compound (350 mg), which was used without further purification. LCMS 249.34 (M+H)+.
(b) N-(3-Aminophenyl)acetamide, trifluoroacetic acid salt
To a solution of tert-butyl (3-acetamidophenyl)carbamate (330 mg) in DCM (2.5 mL) under nitrogen at 0 °C was added TFA (0.708 mL) dropwise over 1 min. The reaction mixture was allowed to warm to RT and stirred for 16 hr. The reaction mixture was concentrated under reduced pressure and the residue evaporated from toluene 2X to afford the titled compound (300 mg), which was used without further purification. LCMS m/z 151 .17 (M+H)+.
(c) 5-(N-(3-Acetamidophenyl)sulfamoyl)-2-hydroxybenzamide
To a solution of N-(3-aminophenyl)acetamide, trifluoroacetic acid salt (300 mg) and pyridine (0.459 mL) in DCM (4 mL) under nitrogen at 0 °C was added 3-carbamoyl-4- hydroxybenzene-1 -sulfonyl chloride (lnt-1 , 321 mg) portionwise over 5 min. The reaction mixture was allowed to warm to RT and stirred for 16 hr. The reaction mixture was concentrated under reduced pressure, diluted with ice-cold water (15 mL) and the resulting precipitate was collected by filtration to afford the crude product (600 mg). The crude product was purified by preparative reversed phase HPLC (Kromosil phenylhexyl, 25x150 mm) eluting with a 38% acetonitrile in 10 mM ammonium bicarbonate (aq). The desired fractions were concentrated under reduced pressure and the resulting solid was collected by filtration and air-dried to afford the titled compound (40 mg). LCMS m/z 350.07 (M+H)+. Ή NMR (400 MHz, DMSO-c/6) δ ppm 2.00 (s, 3 H) 6.62 - 6.88 (m, 1 H) 7.01 (d, J=8.77 Hz, 1 H) 7.10 (t, J=8.00 Hz, 1 H) 7.21 (d, J=8.33 Hz, 1 H) 7.46 (s, 1 H) 7.73 (dd, J=8.88, 2.30 Hz, 1 H) 8.01 (br. s., 1 H) 8.33 (d, J=2.41 Hz, 1 H) 8.50 (br. s., 1 H) 9.88 (s, 1 H) 10.1 1 (s, 1 H) 13.40 (br. s., 1 H). Example 50
2-Hvdroxy-5-(N-(2-oxoindolin-6-yl)sulfamoyl)benzamide
Figure imgf000134_0001
DIPEA (0.371 mL) was added to a solution of 3-carbamoyl-4-hydroxybenzene-1 -sulfonyl chloride (lnt-1 , 500 mg), 6-aminoindolin-2-one hydrochloride (392 mg), and DMAP (12.96 mg) in anhydrous pyridine (4 mL). The reaction vessel was sealed, and the reaction mixture was stirred at room temperature. After 1 h, 55 min, the reaction was concentrated under reduced pressure at 70 °C. 2 M HCI (5 mL) and EtOAc (2 mL) were added to the residue. A thick oily precipitate was present, so the mixture was filtered. The layers were separated, and the aqueous layer was extracted with EtOAc (4 x 2 mL). LC/MS showed product in both the organic layers and the precipitate, so these were combined. Isolute-SI loading sorbent was added, and the mixture was concentrated under a stream of nitrogen. The crude product was then purified by silica gel flash chromatography using a gradient of 0- 10% MeOH/DCM, followed by purification by HPLC, providing 20 mg of the titled compound as a white solid. LCMS m/z 348.1 (M+H)+. Ή NMR (400MHz, DMSO-d6) δ = 13.40 (s, 1 H), 10.29 (s, 1 H), 10.08 (s, 1 H), 8.55 (br. s., 1 H), 8.32 (d, J=2.3 Hz, 1 H), 8.03 (br. s., 1 H), 7.69 (dd, J=2.4, 8.7 Hz, 1 H), 7.02 (d, J=8.6 Hz, 2H), 6.74 - 6.53 (m, 2H).
Example 51
5-(N-(4-Fluoro-1 H-indol-6-yl)sulfamoyl)-2-hvdroxybenzamide
Figure imgf000134_0002
3-Carbamoyl-4-hydroxybenzene-1 -sulfonyl chloride (lnt-1 , 100 mg) was added to a solution of 4-fluoro-1 /-/-indol-6-amine (65 mg) and DMAP (5.18 mg) in anhydrous pyridine (2 mL), forming an orange solution. The reaction vessel was capped, and the reaction mixture was stirred at room temperature. After 3 h, the reaction was concentrated under reduced pressure. 1 M HCI (3 mL) and EtOAc (2 mL) were added to the residue. The layers were separated, and the aqueous layer was extracted with EtOAc (2 x 2 mL). Isolute-SI loading sorbent was added to the combined organic layers, and the mixture was concentrated under reduced pressure and dried under high vacuum. The crude product was then purified by silica gel flash chromatography using a gradient of 0-10% MeOH/DCM. After removal of solvent under reduced pressure and lyophilization of the purified material, 49.9 mg of the titled compound was obtained as an off-white solid. LCMS m/z 350.1 (M+H)+. Ή NMR (400MHz, METHANOL-d4) δ = 8.25 (d, J=2.3 Hz, 1 H), 7.71 (dd, J=2.3, 8.8 Hz, 1 H), 7.09 (d, J=3.3 Hz, 1 H), 6.91 - 6.84 (m, 2H), 6.80 (dd, J=2.1 , 1 1 .2 Hz, 1 H), 6.36 (dd, J=0.8, 3.3 Hz, 1 H).
Example 52
5-(N-(1 H-lndazol-6-yl)sulfamoyl)-2-hvdroxybenzamide
Figure imgf000135_0001
To a solution of 1 /-/-indazol-6-amine (300 mg) and pyridine (0.91 1 mL) in DCM (4 mL) under nitrogen at 0 °C was added 3-carbamoyl-4-hydroxybenzene-1 -sulfonyl chloride (lnt-1 , 637 mg) portionwise over 5 min. The reaction mixture was allowed to warm to RT and stirred for 16 hr. The reaction mixture was concentrated under reduced pressure and dilute with ice-cold water (15 mL). The resulting precipitate was collected by filtration to afford the crude product (500 mg). The crude product was purified by preparative reversed phase HPLC (XBridge C18, 19x150 mm) using a gradient of 10-55% acetonitrile in 5 mM ammonium bicarbonate (aq). The desired fractions were concentrated under reduced pressure and the resulting solid was collected by filtration and air-dried to afford the titled compound (238 mg). LCMS m/z 333.07 (M+H)+. Ή NMR (400 MHz, DMSO-c/6) δ ppm 6.90 (dd, J=8.77, 1 .75 Hz, 1 H) 7.01 (d, J=8.77 Hz, 1 H) 7.22 (s, 1 H) 7.60 (d, J=8.77 Hz, 1 H) 7.72 (dd, J=8.88, 2.30 Hz, 1 H) 7.93 (s, 1 H) 7.99 (br. s., 1 H) 8.37 (d, J=2.19 Hz, 1 H) 8.50 (br. s., 1 H) 10.24 (s, 1 H) 12.83 (s, 1 H) 13.35 (br. s., 1 H). Example 53
5-(N-(Benzordiri ,31dioxol-5-yl)sulfamoyl)-2-hvdroxybenzamide
Figure imgf000136_0001
To a solution of benzo[d][1 ,3]dioxol-5-amine (140 mg) and pyridine (0.515 mL) in DCM (10 mL) under nitrogen at 0 °C was added 3-carbamoyl-4-hydroxybenzene-1 -sulfonyl chloride (lnt-1 , 300 mg) portionwise over 5 min. The reaction mixture was allowed to warm to RT and stirred for 16 hr. The reaction mixture was concentrated under reduced pressure, diluted with cold water (10 mL) and the water layer was decanted to afford the crude product (350 mg). The crude product was purified by preparative reversed phase HPLC (XBridge C18, 30x250 mm) using a gradient of 20-50% acetonitrile in 10 mM ammonium bicarbonate (aq). The desired fraction was lyophilized to afford the titled compound (125 mg). LCMS m/z 337.00 (M+H)+. Ή NMR (400 MHz, DMSO-c/6) δ ppm 5.95 (s, 2 H) 6.47 (dd, J=8.33, 2.19 Hz, 1 H) 6.66 (d, J=2.19 Hz, 1 H) 6.75 (d, J=8.33 Hz, 1 H) 7.02 (d, J=8.77 Hz, 1 H) 7.67 (dd, J=8.77, 2.41 Hz, 1 H) 7.99 (br. s., 1 H) 8.27 (d, J=2.41 Hz, 1 H) 8.55 (br. s., 1 H) 9.81 (s, 1 H) 13.44 (br. s., 1 H).
Example 54
5-(N-(1 /y-lndazol-5-yl)sulfamoyl)-2-hvdroxybenzamide
Figure imgf000136_0002
To a solution of 1 /-/-indazol-5-amine (170 mg) and pyridine (0.515 mL) in DCM (10 mL) under nitrogen at 0 °C was added 3-carbamoyl-4-hydroxybenzene-1 -sulfonyl chloride (Int- 1 , 300 mg) portionwise over 5 min. The reaction mixture was allowed to warm to RT and stirred for 16 hr. The reaction mixture was concentrated under reduced pressure, diluted with ice water (5 mL) and the water layer was decanted to afford the crude product (300 mg). The crude product was purified by preparative reversed phase HPLC (XBridge C18, 19x150 mm) using a gradient of 10-55% acetonitrile in 0.1 % TFA (aq). The desired fraction was concentrated under reduced pressure and the resulting solid was triturated with water and collected by filtration to afford the titled compound (70 mg). LCMS m/z 333.0 (M+H)+. Ή NMR after D20 exchange(400 MHz, DMSO-c/6) δ ppm 7.00 (d, J=8.77 Hz, 1 H) 7.08 (dd, J=8.77, 1 .97 Hz, 1 H) 7.27 - 7.54 (m, 2 H) 7.67 (dd, J=8.77, 2.41 Hz, 1 H) 7.99 (s, 1 H) 8.25 (d, J=2.41 Hz, 1 H).
Example 55
2-Hvdroxy-5-(N-(2-methyl-1 /y-indol-5-yl)sulfamoyl)benzamide
Figure imgf000137_0001
To a solution of 2-methyl-1 /-/-indol-5-amine (186 mg) in DCM (10 mL) at 0 °C was added pyridine (0.515 mL) followed by 3-carbamoyl-4-hydroxybenzene-1 -sulfonyl chloride (lnt-1 , 300 mg). The reaction mixture was allowed to warm to RT and stirred for 16 hr. The reaction mixture was diluted with water (15 mL) and the resulting solid was collected by filtration to afford the crude product. The crude product was purified by preparative reversed phase HPLC (Kromosil phenylhexyl, 25x150 mm) using a gradient of 10-45% acetonitrile in 10 mM ammonium bicarbonate (aq). The desired fractions were concentrated under reduced pressure to afford the titled compound (160 mg). LCMS m/z 346.0 (M+H)+. 1H NMR (400 MHz, DMSO-c/e) δ ppm 2.31 (s, 3 H) 6.00 (s, 1 H) 6.69 (dd, J=8.55, 1 .97 Hz, 1 H) 6.96 (d, J=8.77 Hz, 1 H) 7.02 - 7.20 (m, 2 H) 7.63 (dd, J=8.77, 2.19 Hz, 1 H) 7.94 (br. s., 1 H) 8.24 (d, J=2.19 Hz, 1 H) 8.49 (br. s., 1 H) 9.55 (s, 1 H) 10.81 (s, 1 H) 13.36 (br. s., 1 H).
Example 56
tert-Butyl 7-(3-carbamoyl-4-hvdroxyphenylsulfonamido)-3,4-dihvdroisoquinoline-
2(1 H)-carboxylate
Figure imgf000138_0001
To a solution of tert-butyl 7-amino-3,4-dihydroisoquinoline-2(1 H)-carboxylate (253 mg) and pyridine (0.515 mL) in DCM (10 mL) under nitrogen at 0 °C was added 3-carbamoyl-4- hydroxybenzene-1 -sulfonyl chloride (lnt-1 , 300 mg) portionwise over 5 min. The reaction mixture was allowed to warm to RT and stirred for 16 hr. The reaction mixture was concentrated under reduced pressure, diluted with ice water (15 mL) and the water layer was decanted to afford the crude product (400 mg). The crude product was purified by silica gel column chromatography, eluting with 30% EtOAc/hexane. The desired fractions were concentrated under reduced pressure to afford the titled compound (300 mg). LCMS m/z 448.10 (M+H)+. 1H NMR (400 MHz, DMSO-c/6) δ ppm 1 .40 (s, 9 H) 2.64 (t, J=5.81 Hz, 2 H) 3.47 (t, J=5.92 Hz, 2 H) 4.37 (s, 2 H) 6.88 (d, J=6.36 Hz, 2 H) 6.94 - 7.13 (m, 2 H) 7.74 (dd, J=8.77, 2.19 Hz, 1 H) 7.92 - 8.13 (m, 1 H) 8.36 (d, J=2.19 Hz, 1 H) 8.50 - 8.67 (m, 1 H) 10.06 (s, 1 H) 13.50 (s, 1 H).
Example 57
5-(A/-(1 /y-Pyrrolor2,3-blpyridin-6-yl)sulfamoyl)-2-hvdroxybenzamide
Figure imgf000138_0002
To a solution of 1 /-/-pyrrolo[2,3-b]pyridin-6-amine (200 mg) in DCM (10 mL) was added pyridine (0.607 mL). The reaction mixture was cooled to 0 °C and 3-carbamoyl-4- hydroxybenzene-1 -sulfonyl chloride (lnt-1 , 354 mg) was added portionwise. The reaction mixture was allowed to warm to RT and stirred for 16 hr. The reaction mixture was concentrated under reduced pressure and diluted with water. The resulting solid was collected by filtration and washed with ether to obtain the crude product (150 mg). The crude product was purified by preparative reversed phase HPLC (XBridge C18, 19x150 mm) using a gradient of 10-55% acetonitrile in 5 mM ammonium bicarbonate (aq). The desired fractions were concentrated under reduced pressure to afford the titled compound (71 .9 mg). LCMS m/z 333.0 (M+H)+. Ή NMR (400 MHz, DMSO-c/6) δ ppm 6.32 (dd, J=3.40, 1 .86 Hz, 1 H) 6.84 (d, J=8.33 Hz, 1 H) 7.00 (d, J=8.99 Hz, 1 H) 7.16 - 7.31 (m, 1 H) 7.82 (d, J=8.33 Hz, 1 H) 7.89 - 8.17 (m, 2 H) 8.45 (d, J=2.41 Hz, 1 H) 8.55 (br. s., 1 H) 10.58 (s, 1 H) 1 1 .35 (br. s., 1 H) 13.43 (s, 1 H).
Example 58
2-Hvdroxy-5-(N-(1 -methyl-1 /y-indol-5-yl)sulfamoyl)benzamide
Figure imgf000139_0001
To a solution of 1 -methyl-1 /-/-indol-5-amine (200 mg) in DCM (10 mL) was added pyridine (0.553 mL). The reaction mixture was cooled to 0 °C and 3-carbamoyl-4-hydroxybenzene- 1 -sulfonyl chloride (lnt-1 , 322 mg) was added portionwise. The reaction mixture was allowed to warm to RT and stirred for 16 hr. The reaction mixture was concentrated under reduced pressure and diluted with water. The resulting solid was collected by filtration and washed with ether to obtain the titled compound (280 mg). LCMS m/z 346.00 (M+H)+. 1H NMR after D20 exchange (400 MHz, DMSO-c/6) δ ppm 3.71 (s, 3 H) 6.32 (dd, J=3.07, 0.66 Hz, 1 H) 6.86 (dd, J=8.77, 1 .97 Hz, 1 H) 6.99 (d, J=8.77 Hz, 1 H) 7.13 - 7.34 (m, 3 H) 7.67 (dd, J=8.66, 2.30 Hz, 1 H) 8.25 (d, J=2.41 Hz, 1 H).
Example 59
tert-Butyl 6-(3-carbamoyl-4-hvdroxyphenylsulfonamido)-3,4-dihvdroisoquinoline-
2(1 H)-carboxylate
Figure imgf000140_0001
To a solution of tert-butyl 6-amino-3,4-dihydroisoquinoline-2(1 H)-carboxylate (422 mg) and pyridine (0.858 mL) in DCM (10 mL) under nitrogen at 0 °C was added 3-carbamoyl-4- hydroxybenzene-1 -sulfonyl chloride (lnt-1 , 500 mg) portionwise over 5 min. The reaction mixture was allowed to warm to RT and stirred for 16 hr. The reaction mixture was concentrated under reduced pressure, diluted with ice water (15 mL) and the water layer was decanted to afford the crude product (700 mg). A 300 mg aliquot of the crude product was purified by silica gel column chromatography, eluting with a gradient of 30-50% EtOAc/hexane. The desired fractions were concentrated under reduced pressure to afford the titled compound (200 mg). LCMS m/z 448.10 (M+H)+. 1H NMR (400 MHz, DMSO-c/6) δ ppm 1 .40 (s, 9 H) 2.66 (t, J=5.81 Hz, 2 H) 3.47 (t, J=5.92 Hz, 2 H) 4.36 (s, 2 H) 6.70 - 6.96 (m, 2 H) 6.96 - 7.13 (m, 2 H) 7.73 (dd, J=8.88, 2.30 Hz, 1 H) 8.01 (br. s., 1 H) 8.36 (d, J=2.19 Hz, 1 H) 8.56 (br. s., 1 H) 10.06 (s, 1 H) 13.47 (s, 1 H).
Example 60
2-Hvdroxy-5-(N-(3-methyl-1 tf-indol-5-yl)sulfamoyl)benzamide
Figure imgf000140_0002
To a solution of 3-methyl-1 /-/-indol-5-amine (186 mg) in DCM 5 mL at 0 °C was added pyridine (0.515 mL) and 3-carbamoyl-4-hydroxybenzene-1 -sulfonyl chloride (lnt-1 , 300 mg). The reaction mixture was allowed to warm to RT and stirred for 16 hr. The reaction mixture was concentrated under reduced pressure and poured into ice water (10 mL). The water layer was decanted to afford the crude product (300 mg). The crude product was purified by silica gel column chromatography, eluting with 40% EtOAc/hexane, followed by preparative reversed phase HPLC (Kromosil phenylhexyl, 25x150 mm), using a gradient of 10-50% acetonitrile in 10 mM ammonium bicarbonate (aq). The desired fraction was concentrated under reduced pressure and the resulting solid was collected by filtration, washed with water and dried under vacuum to afford the titled compound (23 mg). LCMS 346.03 (M+H)+. Ή NMR (400 MHz, DMSO-c/6) δ ppm 2.07 - 2.25 (m, 3 H) 6.76 (dd, J=8.55, 1 .97 Hz, 1 H) 6.98 (d, J=8.77 Hz, 1 H) 7.06 (s, 1 H) 7.10 - 7.34 (m, 2 H) 7.67 (dd, J=8.77, 2.41 Hz, 1 H) 7.95 (br. s., 1 H) 8.26 (d, J=2.19 Hz, 1 H) 8.50 (br. s., 1 H) 9.61 (s, 1 H) 10.66 (br. s., 1 H) 13.39 (br. s., 1 H).
Example 61
tert-Butyl 7-(3-carbamoyl-4-hvdroxyphenylsulfonamido)-3.4-dihvdroquinoline-
1 (2H)-carboxylate
Figure imgf000141_0001
To a solution of tert-butyl 7-amino-3,4-dihydroquinoline-1 (2H)-carboxylate (527 mg) and pyridine (0.172 mL) in DCM (10 mL) under nitrogen at 0 °C was added 3-carbamoyl-4- hydroxybenzene-1 -sulfonyl chloride (lnt-1 , 300 mg) portionwise over 5 min. The reaction mixture was allowed to warm to RT and stirred for 16 hr. The reaction mixture was concentrated under reduced pressure, diluted with ice water (15 mL) and the water layer was decanted to afford the crude product. The crude product was purified by silica gel column chromatography, eluting with a gradient of 30-50% EtAOc/hexane. The desired fractions were concentrated under reduced pressure to afford the titled compound (500 mg). LCMS m/z 448.13 (M+H)+. Ή NMR (400 MHz, DMSO-c/6) δ ppm 1 .42 (s, 9 H) 1 .57 - 1 .83 (m, 2 H) 2.60 (t, J=6.58 Hz, 2 H) 3.32 - 3.59 (m, 2 H) 6.64 - 6.87 (m, 1 H) 6.87 - 7.14 (m, 2 H) 7.17 - 7.43 (m, 1 H) 7.60 - 7.77 (m, 1 H) 7.99 (br. s., 1 H) 8.32 (d, J=2.19 Hz, 1 H) 8.52 (br. s., 1 H) 9.97 (s, 1 H) 13.41 (br. s., 1 H). Example 62
2-Hvdroxy-5-(N-(1 ,2,3,4-tetrahvdroquinolin-7-yl)sulfamoyl)benzamide,
Hydrochloride
Figure imgf000142_0001
To a solution of tert-butyl 7-(3-carbamoyl-4-hydroxyphenylsulfonamido)-3,4- dihydroquinoline-1 (2H)-carboxylate (Example 61 , 200 mg) in 1 ,4-dioxane (5 mL) under nitrogen at 0 °C was added HCI (4 M in 1 ,4-dioxane, 0.559 mL) dropwise over 1 min. The reaction mixture was allowed to warm to RT and was stirred for 16 hr. The reaction mixture was concentrated under reduced pressure and the resulting solid was washed with n- pentane (20 mL) and diethyl ether (10 mL) and dried to afford the titled compound (65 mg). LCMS m/z 348.09 (M+H)+. Ή NMR (400 MHz, DMSO-c/6) δ ppm 1 .73 - 1 .86 (m, 2 H) 2.60 (t, J=6.36 Hz, 2 H) 3.14 - 3.22 (m, 2 H) 6.87 (s, 2 H) 6.95 - 7.19 (m, 2 H) 7.74 (dd, J=8.77, 2.41 Hz, 1 H) 8.33 (d, J=2.41 Hz, 1 H).
Example 63
5-(N-(1 H-Pyrrolor2.3-blpyridin-5-yl)sulfamoyl)-2-hvdroxybenzamide
Figure imgf000142_0002
To a solution of 1 H-pyrrolo[2,3-b]pyridin-5-amine (0.364 mL) in DCM (15 mL) stirred under nitrogen at 0 °C was added 3-carbamoyl-4-hydroxybenzene-1 -sulfonyl chloride (lnt-1 , 708 mg) portionwise over 5 min. The reaction mixture was allowed to warm to RT and stirred for 16 hr. The reaction mixture was concentrated under reduced pressure and the residue was triturated with water (3 x 15 mL), collected by filtration, washed with diethyl ether (3 x 20 mL), n-pentane (3 x 15 mL), and 10% acetonitrile in water, and dried under vacuum to obtain the crude product. This was purified by preparative HPLC (Sunfire C18, 30x150 mm) using a gradient of 10-50% acetonitrile in 0.1 % formic acid (aq). The desired fraction was concentrated under reduced pressure to remove the acetonitrile and the resulting slurry was filtered on a Buchner funnel. The precipitate was washed with water (3 x 15 mL) and dried under vacuum to afford the titled compound (129.8 mg). LCMS m/z 333.0 (M+H)+. 1H NMR (400 MHz, DMSO-c/6) δ ppm 6.38 (dd, J=3.40, 1 .86 Hz, 1 H) 7.01 (d, J=8.77 Hz, 1 H) 7.32 - 7.53 (m, 1 H) 7.62 (d, J=2A 9 Hz, 1 H) 7.66 (dd, J=8.77, 2.41 Hz, 1 H) 7.85 (d, J=2.41 Hz, 1 H) 7.91 - 8.1 1 (m, 1 H) 8.23 (d, J=2.41 Hz, 1 H) 8.48 (br. s., 1 H) 9.84 (s, 1 H) 1 1 .60 (br. s., 1 H) 13.42 (s, 1 H).
Example 64
2-Hvdroxy-5-(N-(3-isopropoxyphenyl)sulfamoyl)benzamide
Figure imgf000143_0001
To a solution of 3-siopropoxyaniline (200 mg) in DCM (10 mL) at 0 °C was added pyridine (0.535 mL) followed by 3-carbamoyl-4-hydroxybenzene-1 -sulfonyl chloride (lnt-1 , 312 mg). The reaction mixture was allowed to warm to RT and stirred for 16 hr. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2 x 100 mL). The combined EtOAc extracts were dried over sodium sulfate, filtered and concentrated under reduced pressure to afford the crude product (250 mg). The crude product was purified by silica gel column chromatography, eluting with 45% EtOAc in hexane. The desired fractions were concentrated under reduced pressure to afford the titled compound (238 mg). LCMS m/z 351 .07 (M+H)+. Ή NMR (400 MHz, DMSO-c/6) δ ppm 1 .18 (d, J=5.92 Hz, 6 H) 4.44 (dt, J=12.06, 6.03 Hz, 1 H) 6.45 - 6.70 (m, 3 H) 6.88 - 7.14 (m, 2 H) 7.72 (dd, J=8.77, 2.41 Hz, 1 H) 8.01 (br. s., 1 H) 8.36 (d, J=2.41 Hz, 1 H) 8.55 (br. s., 1 H) 10.09 (s, 1 H) 13.44 (br. s., 1 H). Example 65
2-Hvdroxy-5-(N-(thiophen-3-yl)sulfamoyl)benzamide
Figure imgf000144_0001
To a stirred solution of thiophen-3-amine (200 mg) in DCM (10 mL) at 0 °C was added pyridine (0.816 mL) followed by 3-carbamoyl-4-hydroxybenzene-1 -sulfonyl chloride (lnt-1 , 475 mg). The reaction mixture was allowed to warm to RT and stirred for 16 hr. The reaction mixture was concentrated under reduced pressure and diluted with water. The resulting solid was collected by filtration and dried under vacuum to afford the crude product (280 mg). The crude product was purified by preparative reversed phase HPLC (XBridge C18, 19 x 150 mm) using a gradient of 10-100% acetonitrile in 10 mM ammonium bicarbonate (aq). The desired fractions were concentrated under reduced pressure to afford the titled compound (139 mg). LCMS m/z 298.94 (M+H)+. Ή NMR (400 MHz, DMSO-c/6) δ ppm 6.81 (dd, J=5.04, 1 .32 Hz, 1 H) 6.90 (dd, J=3.07, 1 .32 Hz, 1 H) 7.02 (d, J=8.77 Hz, 1 H) 7.39 (dd, J=5.04, 3.07 Hz, 1 H) 7.72 (dd, J=8.77, 2.19 Hz, 1 H) 8.02 (br. s., 1 H) 8.34 (d, J=2.19 Hz, 1 H) 8.57 (br. s., 1 H) 10.24 (s, 1 H) 13.48 (s, 1 H).
Example 66
5-(N-(4-(Cvclopentyloxy)phenyl)sulfamoyl)-2-hvdroxybenzamide
Figure imgf000144_0002
(a) 1 -(Cyclopentyloxy)-4-nitrobenzene
To a stirred solution of 4-nitrophenol (4 g) in DMF (80 mL) was added potassium carbonate (1 1 .92 g), potassium iodide (0.955 g) and bromocylopentane (6.43 g). The temperature was raised to 1 10 °C and the reaction mixture was stirred for 16 hr. The reaction mixture was allowed to cool to RT and then was diluted with cold water (100 mL) and extracted with EtOAc (3 x 100 mL). The combined EtOAc extracts were washed with saturated brine, dried over sodium sulfate and concentrated under reduced pressure to afford the titled compound (4 g). GCMS m/z 207.2 (M+).
(b) 4-(Cyclopentyloxy)aniline
A stirred solution of 1 -(cyclopentyloxy)-4-nitrobenzene (2.5 g) in MeOH (25 mL) was purged with nitrogen for 10 min, followed by addition of 10% Pd/C (Degussa catalyst, 50% w/w water, 0.5 g). The reaction mixture was stirred under a hydrogen atmosphere (balloon) for 16 hr. The reaction mixture was filtered through Celite and the precipitate washed with MeOH (50 mL). The combined MeOH filtrates were concentrated under reduced pressure to afford the titled compound (2 g). LCMS m/z 178.2 (M+H)+.
(c) 5-(N-(4-(Cyclopentyloxy)phenyl)sulfamoyl)-2-hydroxybenzamide
To a stirred solution of 4-(cyclopentyloxy)aniline (200 mg) and pyridine (0.456 mL) in DCM (10 mL) at 0 °C was added 3-carbamoyl-4-hydroxybenzene-1 -sulfonyl chloride (lnt-1 , 266 mg) portionwise. The reaction mixture was allowed to warm to RT and stirred for 16 hr. The reaction mixture was concentrated under reduced pressure and diluted with ice water (100 mL). The resulting solid was collected by filtration, dried under vacuum, and triturated with diethyl ether and n-pentane to afford the titled compound (318 mg). LCMS m/z 377.10 (M+H)+. Ή NMR after D20 exchange (400 MHz, DMSO-c/6) δ ppm 1 .45 - 1 .73 (m, 6 H) 1 .77 - 1 .95 (m, 2 H) 4.59 - 4.82 (m, 1 H) 6.63 - 6.85 (m, 2 H) 6.87 - 7.00 (m, 2 H) 7.04 (d, J=8.77 Hz, 1 H) 7.68 (dd, J=8.77, 2.19 Hz, 1 H) 8.23 (d, J=2.41 Hz, 1 H).
Example 67
2-Hvdroxy-5-(N-(2-meth -1 /y-benzord1imidazol-5-yl)sulfamoyl)benzamide
Figure imgf000145_0001
To a stirred solution of 2-methyl-1 H-benzo[d]imidazol-5-amine (187 mg) in DCM (5 mL) at 0 °C was added 3-carbamoyl-4-hydroxybenzene-1 -sulfonyl chloride (lnt-1 , 300 mg). The reaction mixture was allowed to warm to RT and stirred for 16 hr. The reaction mixture was diluted with water (30 mL) and extracted with DCM (2 x 50 mL). The combined DCM extracts were washed with saturated brine (25 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to afford the crude product (300 mg). The crude product was purified by reversed phase preparative HPLC (Sunfire C18, 30 x 250 mm) using a gradient of 10-100% acetonitrile in 10 mM ammonium bicarbonate (aq). The desired fraction was concentrated under reduced pressure and the resulting solid was collected by filtration, washed with water (10 mL) and dried under vacuum to afford the titled compound (55.6. mg). LCMS m/z 347.04 (M+H)+. Ή NMR after D20 exchange (400 MHz, DMSO-c/6) δ ppm 2.27 - 2.50 (m, 3 H) 6.76 (d, J=8.33 Hz, 1 H) 6.85 (dd, J=8.55, 1 .75 Hz, 1 H) 7.02 - 7.21 (m, 1 H) 7.28 (d, J=8.33 Hz, 1 H) 7.40 - 7.61 (m, 1 H) 8.19 (d, J=2.19 Hz, 1 H).
Example 68
tert-Butyl 6-(3-carbamoyl-4-hvdroxyphenylsulfonamido)-3,4-dihvdroquinoline-
1 (2H)-carboxylate
Figure imgf000146_0001
To a solution of tert-butyl 6-amino-3,4-dihydroquinoline-1 (2H)-carboxylate (316 mg) and pyridine (0.309 mL) in DCM (10 mL) at RT under nitrogen was added 3-carbamoyl-4- hydroxybenzene-1 -sulfonyl chloride (lnt-1 , 300 mg) portionwise over 5 min. The reaction mixture was stirred for 16 hr at RT. The reaction mixture was concentrated under reduced pressure to afford the crude product (400 mg). The crude product was purified by silica gel column chromatography, eluting with 50% EtOAc/hexane. The desired fractions were concentrated under reduced pressure and the resulting solid was suspended in water (20 mL) and evaporated 2X. The solid was collected by filtration and dried under vacuum to afford the titled compound (320 mg). LCMS m/z 448.13 (M+H)+. Ή NMR (400 MHz, DMSO- cfe) δ ppm 1 .42 (s, 9 H) 1 .64 - 1 .84 (m, 2 H) 2.61 (t, J=6.58 Hz, 2 H) 3.47 - 3.61 (m, 1 H) 6.83 (dd, J=4.71 , 2.08 Hz, 2 H) 7.03 (d, J=8.77 Hz, 1 H) 7.40 (d, J=9.65 Hz, 1 H) 7.72 (dd, J=8.77, 2.41 Hz, 1 H) 8.00 (br. s., 1 H) 8.33 (d, J=2.41 Hz, 1 H) 8.54 (br. s., 1 H) 9.93 (s, 1 H) 13.48 (s, 1 H).
Example 69
5-(N-(3-Ethyl-1 /y-indol-6-yl)sulfamoyl)-2-hvdroxybenzamide
Figure imgf000147_0001
(a) 3-Ethyl-6-nitro-1 H-indole
To a stirred solution of 6-nitro-1 /-/-indole (5 g), zinc trifluoromethanesulfonate (1 1 .21 g) and tetrabutylammonium iodide (13.67 g) in dry toluene (50 mL) under nitrogen was added DIEA (10.77 mL). The reaction mixture was heated to 120 °C and stirred for 10 min. Bromoethane (2.69 g) was then added and the reaction mixture was stirred at 120 °C for 48 hr. The reaction mixture was allowed to cool to RT and then concentrated under reduced pressure to afford the crude product. The crude product was purified by silica gel column chromatography, eluting with 10% EtOAc/hexane. The desired fractions were concentrated under reduced pressure to afford the titled compound (1 .5 g). LCMS m/z 189.17 (M-H)~. (b) 3-Ethyl-1 H-indol-6-amine
Raney Ni (500 mg) was added to a stirred solution of 3-ethyl-6-nitro-1 /-/-indole (1 .4 g) in MeOH (15 mL) and the reaction mixture was stirred for 16 hr at RT under an atmosphere of hydrogen. The reaction mixture was filtered through Celite and the filtrate was concentrated under reduced pressure to afford the titled compound (1 .0 g). LCMS m/z 161 .1 (M+H)+.
(c) 5-(N-(3-Ethyl-1 H-indol-6-yl)sulfamoyl)-2-hydroxybenzamide
To a stirred solution of 3-ethyl-1 /-/-indol-6-amine (348 mg) and pyridine (0.206 mL) in DCM (15 mL) at 0 °C under nitrogen was added 3-carbamoyl-4-hydroxybenzene-1 -sulfonyl chloride (lnt-1 , 200 mg). The reaction mixture was allowed to warm to RT and stirred for 16 hr. The reaction mixture was concentrated under reduced pressure to afford the crude product (300 mg). The crude product was purified by silica gel column chromatography, eluting with 40% EtOAc/hexane. The desired fractions were concentrated under reduced pressure to afford the titled compound (212 mg). LCMS m/z 360.1 1 (M+H)+. 1H NMR (400 MHz, DMSO-c/e) δ ppm 1 .42 (s, 9 H) 1 .64 - 1 .84 (m, 2 H) 2.61 (t, J=6.58 Hz, 2 H) 3.47 - 3.61 (m, 1 H) 6.83 (dd, J=4.71 , 2.08 Hz, 2 H) 7.03 (d, J=8.77 Hz, 1 H) 7.40 (d, J=9.65 Hz, 1 H) 7.72 (dd, J=8.77, 2.41 Hz, 1 H) 8.00 (br. s., 1 H) 8.33 (d, J=2.41 Hz, 1 H) 8.54 (br. s., 1 H) 9.93 (s, 1 H) 13.48 (s, 1 H). Example 70
5-(N-(2-Ethyl-1 /y-benzorcnimidazol-5-yl)sulfamoyl)-2-hvdroxybenzamide
Figure imgf000148_0001
To a stirred solution of 2-ethyl-1 H-benzo[d]imidazol-5-amine (205 mg) in DCM (5 mL) at 0 °C was added pyridine (0.309 mL) followed by 3-carbamoyl-4-hydroxybenzene-1 -sulfonyl chloride (lnt-1 , 300 mg). The reaction mixture was allowed to warm to RT and was stirred for 16 hr. The reaction mixture was diluted with water (30 mL) and extracted with DCM (2 x 50 mL). The combined DCM extracts were washed with saturated brine (25 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to afford the crude product (300 mg). The crude product was purified by preparative reversed phase HPLC (XBridge C-19, 19 x 150 mm), using a gradient of 10-55% acetonitrile in 0.1 % formic acid (aq). The desired fraction was concentrated under reduced pressure and the resulting solid was collected by filtration, washed with water (10 mL) and dried under vacuum to afford the titled compound (38.3 mg). LCMS m/z 361 .07 (M+H)+. 1H NMR (400 MHz, DMSO-c/6) δ ppm 1 .26 (t, J=7.67 Hz, 3 H) 2.76 (q, J=7.67 Hz, 2 H) 6.69 - 6.91 (m, 1 H) 6.97 (d, J=8.55 Hz, 1 H) 7.14 (br. s., 1 H) 7.28 (d, J=8.55 Hz, 1 H) 7.59 - 7.69 (m, 1 H) 7.93 (br. s., 1 H) 8.14 (s, 1 H) 8.27 (d, J=2.19 Hz, 1 H) 8.52 (br. s., 1 H) 9.79 (br. s., 1 H) 12.08 (br. s., 1 H).
Example 71
5-(N-(4-(Cvclohexyloxy)phenyl)sulfamoyl)-2-hvdroxybenzamide
Figure imgf000148_0002
(a) 1 -(Cyclohexyloxy)-4-nitrobenzene
To a stirred solution of 4-nitrophenol in DMF (30 mL) were added potassium carbonate (8.94 g), potassium iodide (0.716 g) and bromocyclohexane (5.27 g). The temperature was raised to 1 10 °C and the reaction mixture was stirred for 16 hr. The reaction mixture was allowed to cool to RT and then was diluted with cold water (300 mL), and extracted with EtOAc (3 x 100 mL). The combined EtOAc extracts were washed with chilled saturated brine (3 x 150 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to afford the titled compound, which was used without further purification. GCMS m/z 221 .2 (M+).
(b) 4-(Cyclohexyloxy)aniline
A stirred solution of 1 -(cyclohexyloxy)-4-nitrobenzene (1 g) in MeOH (15 mL) was purged with nitrogen and 10% Pd/C (0.721 g) was added. The reaction mixture was stirred for 16 ht under a hydrogen atmosphere (balloon). The reaction mixture was filtered through Celite and the filtrate was concentrated under reduced pressure to afford the titled compound (700 mg). LCMS m/z 192.1 (M+H)+.
(c) 5-(N-(4-(Cyclohexyloxy)phenyl)sulfamoyl)-2-hydroxybenzamide
To a solution of 4-(cyclohexyloxy)aniline (200 mg) in DCM (10 mLO was added pyridine (0.423 mL) followed by 3-carbamoyl-4-hydroxybenzene-1 -sulfonyl chloride (lnt-1 , 246 mg), and the reaction was stirred at RT for 16 hr. The reaction mixture was concentrated under reduced pressure and diluted with water. The resultant solid was collected by filtration to afford the crude product (200 mg). The crude product was purified by preparative reversed phase HPLC (Sunfire C18, 30 x 250 mm) using a 50% acetonitrile in 10 mM ammonium bicarbonate (aq). The desired fractions were concentrated under reduced pressure to afford the titled compound (1 14 mg). LCMS m/z 391 .19 (M+H)+.1H NMR after D20 exchange(400 MHz, DMSO-c/e) δ ppm 1 .17 - 1 .43 (m, 5 H) 1 .44 - 1 .57 (m, 1 H) 1 .58 - 1 .75 (m, 2 H) 1 .76 - 1 .93 (m, 2 H) 4.1 1 - 4.27 (m, 1 H) 6.66 - 6.85 (m, 2 H) 6.87 - 6.99 (m, 2 H) 7.03 (d, J=8.77 Hz, 1 H) 7.68 (dd, J=8.77, 2.41 Hz, 1 H) 8.22 (d, J=2.19 Hz, 1 H).
Example 72
2-Hvdroxy-5-(N-(imidazori ,2-alpyridin-6-yl)sulfamoyl)benzamide
Figure imgf000149_0001
To a stirred solution of imidazo[1 ,2-a]pyridin-6-amine (200 mg) in DCM (10 mL) was added 3-carbamoyl-4-hydroxybenzene-1 -sulfonyl chloride (lnt-1 , 354 mg), and the reaction mixture was stirred for 16 hr at RT. The reaction mixture was concentrated under reduced pressure to afford the crude product (290 mg). The crude product was purified by silica gel column chromatography, eluting with 3% MeOH/DCM to afford partially purified product (60 mg). The partially purified product was purified by preparative reversed phase HPLC (XBridge C18, 30 x 250 mm) using a gradient of 10-30% acetonitrile in 5 mM ammonium bicarbonate (aq). The desired fractions were concentrated under reduced pressure to afford the titled compound (1 1 mg). LCMS 333.10 (M+H)+. Ή NMR after D20 exchange(400 MHz, DMSO-c/e) δ ppm 6.74 (d, J=8.77 Hz, 1 H) 6.96 (dd, J=9.43, 1 .97 Hz, 1 H) 7.35 - 7.63 (m, 3 H) 7.94 (br. s., 1 H) 8.21 (d, J=2.63 Hz, 1 H) 8.26 - 8.42 (m, 1 H).
Example 73
5-(N-(1 H-Benzord1imidazol-7-yl)sulfamoyl)-2-hvdroxybenzamide
Figure imgf000150_0001
To a stirred solution of 1 H-benzo[d]imidazol-7-amine (300 mg) in DCM (10 mL) at 0 °C under nitrogen was added a solution of 3-carbamoyl-4-hydroxybenzene-1 -sulfonyl chloride (lnt-1 , 531 mg) in DCM (10 mL) dropwise over 5 min. The reaction mixture was allowed to warm to RT and was stirred for 16 hr. The reaction mixture was concentrated under reduced pressure and diluted with ice water (100 mL). The resulting solid was collected by filtration, dried, and triturated with diethyl ether and n-pentane to afford the crude product (400 mg). The crude product was purified by preparative reversed phase HPLC (Sunfire C18, 19 x 150 mm) using a gradient of 10-100% acetonitrile in 10 mM ammonium bicarbonate (aq). The desired fractions were lyophilized to afford the titled compound (130 mg). LCMS 333.06 (M+H)+. Ή NMR after D20 exchange(400 MHz, DMSO-c/6) δ ppm 6.87 - 7.17 (m, 3 H) 7.34 (br. s., 1 H) 7.80 (br. s., 1 H) 8.16 (s, 1 H) 8.35 (br. s., 1 H).
Example 74
2-Hvdroxy-5-(N-(2-isopropyl-1 /y-indol-6-yl)sulfamoyl)benzamide
Figure imgf000151_0001
(a) 1 -(2,4-Dinitrophenyl)-3-methylbutan-2-one
To a stirred solution of 1 ,3 dinitrobenzene (1 g) and 3-methylbutan-2-one (10 mL) at RT under argon was added KMn04 (0.940 g) and tetrabutylammonium fluoride trihydrate( 9.38 g) and the reaction mixture was stirred for 16 hr. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (50 mL). The EtOAc layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to afford the crude product (1 .5 g). The crude product was purified by silica gel column chromatography, eluting with 20% EtOAc/hexane to afford the titled compound (900 mg). LCMS m/z 251 .23 (M-H)".
(b) 2-lsopropyl-1 H-indol-6-amine
1 -(2,4-Dinitrophenyl)-3-methylbutan-2-one (900 mg) was added to a stirred solution of 10% Pd/C (380 mg) in MeOH (10 mL) followed by ammonium formate (675 mg). The reaction mixture was heated to 60 °C and stirred for 16 hr. The reaction mixture was filtered through Celite and the filtrate was concentrated under reduced pressure to afford the titled compound (1 g), which was used without further purification. LCMS m/z 175.07 (M+H)+.
(c) 2-Hydroxy-5-(N-(2-isopropyl-1 H-indol-6-yl)sulfamoyl)benzamide
To a stirred solution of 2-isopropyl-1 /-/-indol-6-amine (310 mg) in DCM (15 mL) at 0 °C under nitrogen was added pyridine (0.206 mL) followed by 3-carbamoyl-4- hydroxybenzene-1 -sulfonyl chloride (lnt-1 , 200 mg). The reaction mixture was allowed to warm to RT and was stirred for 16 hr. The reaction mixture was then concentrated under reduced pressure to afford the crude product (300 mg). The crude product was purified by silica gel column chromatography, eluting with 50% EtOAc/hexane. The desired fractions were concentrated under reduced pressure to afford the titled compound (195 mg). LCMS m/z 374.10 (M+H)+. Ή NMR (400 MHz, DMSO-c/6) δ ppm 1 .19 - 1 .34 (m, 6 H) 2.89 - 3.05 (m, 1 H) 5.94 - 6.12 (m, 1 H) 6.68 (dd, J=8.33, 1 .97 Hz, 1 H) 6.83 - 7.09 (m, 2 H) 7.22 (d, J=8.33 Hz, 1 H) 7.66 (dd, J=8.77, 2.19 Hz, 1 H) 7.95 (br. s., 1 H) 8.28 (d, J=2.19 Hz, 1 H) 8.46 (br. s., 1 H) 9.70 (s, 1 H) 10.77 (s, 1 H) 13.30 (br. s., 1 H). Example 75
5-(N-(2-Ethyl-1 /y-indol-6-yl)sulfamoyl)-2-hvdroxybenzamide
Figure imgf000152_0001
(a) 1 -(2,4-Dinitrophenyl)butan-2-one
To a stirred solution of 1 ,3-dinitrobenzene (10 g) and butan-2-one (100 mL) at RT was added Kmn04 (9.40 g) and tetrabutylammonium fluoride trihydrate (94 g) and the reaction mixture was allowed to stir for 1 hr. The reaction mixture was poured into ice water (100 mL) and extracted with EtOAc (2 x 200 mL). The combined EtOAc extracts were washed with saturated brine (100 mL), dried over sodium sulfate and concentrated under reduced pressure to afford the crude product. The crude product was purified by silica gel column chromatography, eluting with 20% EtOAc/hexane. The desired fractions were concentrated under reduced pressure to afford the titled compound (2.2 g). LCMS 236.88 (M-H)~.
(b) 2-Ethyl-1 H-indol-6-amine
To a stirred solution of 1 -(2,4-dinitrophenyl)butan-2-one (1 g) in MeOH (10 mL) was added 10% Pd/C (0.894 g) and ammonium formate (1 .324 g). The reaction vessel was sealed and the reaction mixture stirred at 65 °C for 16 hr. The reaction mixture was allowed to cool to RT and was filtered through Celite. The filtrate was poured into ice water, extracted with EtOAc (2 x 30 mL) and the combined EtOAc extracts were washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure to afford the titled compound (500 mg), which was used without further purification. LCMS m/z 161 .03 (M+H)+.
(c) 5-(N-(2-Ethyl-1 H-indol-6-yl)sulfamoyl)-2-hydroxybenzamide
To a stirred solution of 2-ethyl-1 /-/-indol-6-amine (306 mg) in DCM (5 mL) at 0 °C was added pyridine (0.515 mL) followed by 3-carbamoyl-4-hydroxybenzene-1 -sulfonyl chloride (lnt-1 , 300 mg). The reaction mixture was allowed to warm to RT and was stirred for 16 hr. The reaction mixture was diluted with water (30 mL) and extracted with DCM (2 x 50 mL). The combined DCM extracts were dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford the crude product (500 mg). The crude product was purified by preparative reversed phase HPLC (Kromosil phenyl, 25 x 150 mm) using a gradient of 20- 55% acetonitrile in 0.1 % TFA (aq). The desired fractions were concentrated under reduced pressure and the resulting solids were collected by filtration, washed with water (10 mL) and dried under vacuum to afford the titled compound (196.6 mg). LCMS m/z 360.09 (M+H)+. 1H NMR (400 MHz, DMSO-c/6) δ ppm 1 .22 (t, J=7.56 Hz, 3 H) 2.58 - 2.73 (m, 2 H) 6.01 (d, J=0.88 Hz, 1 H) 6.68 (dd, J=8.33, 1 .97 Hz, 1 H) 6.83 - 7.08 (m, 2 H) 7.21 (d, J=8.33 Hz, 1 H) 7.65 (dd, J=8.66, 2.30 Hz, 1 H) 7.96 (br. s., 1 H) 8.27 (d, J=2.41 Hz, 1 H) 8.46 (br. s., 1 H) 9.69 (s, 1 H) 10.78 (s, 1 H) 13.31 (s, 1 H).
Example 77
5-(N-(4-Fluoro-1 H-indol-5-yl)sulfamoyl)-2-hydroxybenzamide
Figure imgf000153_0001
(a) 4-Fluoroindoline
To a stirred solution of 4-fluoro-1 /-/-indole (25 g) in acetic acid (250 ml_) at 0 °C was added sodium cyanoborohydride (23.25 g) portionwise over 15 min. The reaction mixture was allowed to warm to RT and was stirred for 16 hr. The reaction mixture was quenched with water and concentrated under reduced pressure. The residue was dissolved in EtOAc (200 ml_) and washed with water ( 2 x 200 ml_) and saturated ammonium bicarbonate ( 2 x 200 ml_), dried over sodium sulfate, filtered and concentrated under reduced pressure to afford the crude product (30 g). The crude product was purified by column chromatography on neutral alumina, eluting with 5% EtOAc in hexane. The desired fractions were concentrated under reduced pressure to afford the titled compound (15 g). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 3.06 (t, J=8.44 Hz, 2 H) 3.60 (t, J=8.44 Hz, 2 H) 6.28 - 6.48 (m, 2 H) 6.95 (td, J=7.89, 5.92 Hz, 1 H).
(b) 1 -(4-Fluoroindolin-1 -yl)ethanone
4-Fluoroindoline (10 g) was dissolved in acetic anhydride (100 ml_) and stirred at RT for 2 hr. The reaction was diluted with water 100 ml_ and extracted with EtOAc (200 ml_). The EtOAc layer was washed with saturated sodium bicarbonate and saturated brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to afford the titled compound (9.6 g). GCMS m/z 179.0 (M+).
(c) 1 -(4-Fluoro-5-nitroindolin-1 -yl)ethanone
To a stirred solution of 1 -(4-fluoroindolin-1 -yl)ethanone (8.6 g) in sulfuric acid (131 ml_) at - 10 °C was added fuming nitric acid (1 .644 ml_) dropwise. The reaction mixture was allowed to warm to 0 °C and was stirred for 3 hr. The reaction mixture was quenched with water (10 ml_) and the resulting solid was collected by filtration, dried under vacuum and dissolved in EtOAc (100 ml_), which was then dried over sodium sulfate and concentrated under reduced pressure to afford the crude product. The crude product was purified by flash chromatography on neutral alumina, eluting with 20% EtOAc in hexane. The desired fractions were concentrated under reduced pressure to afford the titled compound (4.0 g). Ή NMR (400 MHz, DMSO-c/6) δ ppm 2.23 (s, 3 H) 3.24 (t, J=8.66 Hz, 2 H) 4.27 (t, J=8.66 Hz, 2 H) 7.93 (d, J=7.67 Hz, 1 H) 8.08 (t, J=8.44 Hz, 1 H).
(d) 4-Fluoro-5-nitroindoline
A solution of 1 -(4-fluoro-5-nitroindolin-1 -yl)ethanone (4 g) in concentrated HCI (80 mL) was stirred at 100 °C for 1 hr. The reaction mixture was allowed to cool to RT and was concentrated under reduced pressure. The residue was diluted with water (20 mL) and the resulting solid was collected by filtration and dried under vacuum to afford the titled compound (3.1 g). 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 3.17 (t, J=8.66 Hz, 2 H) 3.82 (t, J=8.77 Hz, 2 H) 6.28 (d, J=8.77 Hz, 1 H) 7.92 (t, J=8.1 1 Hz, 1 H).
(e) 4-Fluoro-5-nitro-1 H-indole
To a stirred solution of 4-fluoro-5-nitroindoline (3.1 g) in benzene (40 mL) at RT was added DDQ (7.14 mL), and the reaction mixture was then stirred at 80 °C for 7 hr. The reaction mixture was concentrated under reduced pressure to afford the crude product, which was purified by column chromatography on neutral alumina, eluting with 15% EtOAc/hexane. The desired fractions were concentrated under reduced pressure to afford the titled compound (2 g). GCMS m/z 180.1 (M+).
(f) 4-Fluoro-1 H-indol-5-amine
To a stirred solution of 4-fluoro-5-nitro-1 /-/-indole (200 mg) in EtOAc (15 mL) and water (15 mL) was added iron (310 mg) followed by ammonium chloride (238 mg). The reaction mixture was heated to 60 °C and stirred for 4 hr. The reaction mixture was filtered through Celite and the filtrate was diluted with EtOAc (20 mL). The EtOAc layer was separated, dried over sodium sulfate, filtered and concentrated under reduced pressure to afford the titled compound (100 mg). GCMS m/z 150.1 (M+).
(g) 5-(N-(4-Fluoro-1 H-indol-5-yl)sulfamoyl)-2-hydroxybenzamide
To a stirred solution of 4-fluoro-1 /-/-indol-5-amine (100 mg) in DCM (10 mL) was added pyridine (158 mg) followed by 3-carbamoyl-4-hydroxybenzene-1 -sulfonyl chloride (lnt-1 , 157 mg), and the reaction mixture was stirred at RT for 16 hr. The reaction mixture was concentrated under reduced pressure to afford the crude product. The crude product was purified by silica gel column chromatography, eluting with 65% EtOAc/hexane to afford the titled compound (1 10 mg). LCMS m/z 350.09 (M+H)+. 1H NMR (400 MHz, DMSO-c/6) δ ppm 6.41 (t, J=2.08 Hz, 1 H) 6.62 - 6.89 (m, 1 H) 6.90 - 7.06 (m, 1 H) 7.10 (d, J=8.55 Hz, 1 H) 7.35 (t, J=2.74 Hz, 1 H) 7.66 (dd, J=8.77, 2.19 Hz, 1 H) 7.94 (br. s., 1 H) 8.07 - 8.31 (m, 1 H) 8.50 (br. s., 1 H) 9.53 (s, 1 H) 1 1 .38 (br. s., 1 H) 13.46 (br. s., 1 H).
Example 78
5-(N-(7-Fluoro-1 /y-indol-5-yl)sulfamoyl)-2-hvdroxybenzamide
Figure imgf000155_0001
(a) 7-Fluoroindoline
To a stirred solution of 7-fluoro-1 /-/-indole (20 g) in acetic acid (200 mL) at 0 °C was added sodium cyanoborohydride (18.6 g) portionwise. The reaction mixture was allowed to warm to RT and was stirred for 16 hr. The reaction mixture was quenched with water and concentrated under reduced pressure. The residue was dissolved in EtOAc (200 mL) and washed with water ( 2 x 250 mL) and saturated ammonium bicarbonate ( 2 x 250 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to afford the crude product (15 g). The crude product was purified by neutral alumina column chromatography, eluting with 5% EtOAc/hexane. The desired fractions were concentrated under reduced pressure to afford the titled compound (1 1 .6 g). Ή NMR (400 MHz, CHLOROFORM-d) δ ppm 3.06 (t, J=8.44 Hz, 2 H) 3.61 (t, J=8.33 Hz, 2 H) 6.62 (td, J=7.78, 4.60 Hz, 1 H) 6.74 - 6.85 (m, 1 H) 6.89 (dd, J=7.23, 0.66 Hz, 1 H).
(b) 1 -(7-Fluoroindolin-1 -yl)ethanone
A solution of 7-fluoroindoline (1 1 .6 g) in acetic anhydride (100 mL) was stirred at RT for 1 hr. The reaction mixture was diluted with EtOAc (100 mL), washed with water (2 x 100 mL) and saturated sodium bicarbonate, dried over sodium sulfate, filtered and concentrated under reduced pressure to afford the crude product. The crude product was purified by column chromatography on neutral alumina, eluting with 2% EtOAc/hexane. The desired fractions were concentrated under reduced pressure to afford the titled compound (8.0 g). GSMS m/z 179.1 (M+).
(c) 1 -(7-Fluoro-5-nitroindolin-1 -yl)ethanone
To a stirred solution of 1 -(7-fluoroindolin-1 -yl)ethanone (8.0 g) in acetic acid (60 mL) was added fuming nitric acid (3.4 mL) dropwise. The reaction mixture was stirred at RT for 16 hr. The reaction mixture was quenched with ice cold water (50 mL) and the resulting solid was collected by filtration. The solid was dissolved in EtOAc (100 mL), washed with water (2 x 100 mL) and saturated sodium bicarbonate, dried over sodium sulfate, filtered and concentrated to afford the titled compound (5.2 g). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.32 (d, J=4.38 Hz, 3 H) 3.19 (t, J=8.1 1 Hz, 2 H) 4.27 (t, J=8.1 1 Hz, 2 H) 7.84 - 8.06 (m, 2 H)
(d) 7-Fluoro-5-nitroindoline
A solution of 1 -(7-fluoro-5-nitroindolin-1 -yl)ethanone (5.2 g) in concentrated HCI (60 ml_) was stirred at 100 °C for 16 hr. The reaction mixture was concentrated under reduced pressure and diluted with water. The resulting solid was collected by filtration and dried under vacuum to afford the titled compound (3.5 g). 1H NMR (400 MHz, CHLOROFORM- d) δ ppm 3.18 (t, J=8.77 Hz, 2 H) 3.83 (t, J=8.77 Hz, 2 H) 7.76 - 7.86 (m, 2 H).
(e) 7-Fluoro-5-nitro-1 H-indole
To a stirred solution of 7-fluoro-5-nitroindoline (3.5 g) in benzene (100 ml_) at RT was added DDQ (8.72 g). The reaction mixture was heated to 80 °C and stirred for 7 hr. The reaction mixture was concentrated under reduced pressure to afford the crude product, which was purified by column chromatography on neutral alumina, eluting with 25% EtOAc/hexane. The desired fractions were concentrated under reduced pressure to afford the titled compound (1 .6 g). GCMS m/z 180.1 (M+).
(f) 7-Fluoro-1 H-indol-5-amine
To a stirred solution of 7-fluoro-5-nitro-1 /-/-indole (300 mg) in EtOAc (15 ml_) and water (15 ml_) was added iron (465 mg) followed by ammonium chloride (356 mg). The reaction mixture was heated to 60 °C and stirred for 4 hr. The reaction mixture was filtered through Celite and extracted with EtOAc (20 ml_). The EtOAc extract was dried over sodium sulfate, filtered and concentrated under reduced pressure to afford the title compound (200 mg). GCMS m/z 150.1 (M+).
(g) 5-(N-(7-Fluoro-1 H-indol-5-yl)sulfamoyl)-2-hydroxybenzamide
To a stirred solution of 7-fluoro-1 /-/-indol-5-amine (153 mg) in DCM (10 ml_) was added pyridine (201 mg) followed by 3-carbamoyl-4-hydroxybenzene-1 -sulfonyl chloride (lnt-1 , 200 mg), and the reaction mixture was stirred for 16 hr at RT. The reaction mixture was concentrated under reduced pressure to afford the crude product, which was purified by silica gel column chromatography, eluting with 65% EtOAc/hexane. The desired fractions were concentrated under reduced pressure to afford the titled compound (218 mg). LCMS m/z 350.09 (M+H)+. Ή NMR (400 MHz, DMSO-c/6) δ ppm 6.28 - 6.54 (m, 1 H) 6.71 (d, J=1 .53 Hz, 1 H) 6.68 (d, J=1 .75 Hz, 1 H) 7.00 (d, J=8.77 Hz, 1 H) 7.07 (d, J=1 .53 Hz, 1 H) 7.35 (t, J=2.74 Hz, 1 H) 7.57 (br. s., 1 H) 7.68 (dd, J=8.77, 2.41 Hz, 1 H) 7.97 (br. s., 1 H) 8.28 (d, J=2.41 Hz, 1 H) 8.50 (br. s., 1 H) 9.85 (s, 1 H) 1 1 .52 (br. s., 1 H) 13.40 (s, 1 H).
Example 79
5-(N-(5-Chloro-1 /y-indol-6-yl)sulfamoyl)-2-hvdroxybenzamide
Figure imgf000157_0001
(a) (E)-2-(5-Chloro-2,4-dinitrophenyl)-N,N-dimethylethenamine
To a solution of 1 -chloro-5-metyl-2,4-dinitrobenzene (6 g) in DMF (50 mL) was added 1 ,1 - dimethoxy-N,N-dimethylmethanamine (7.36 mL), and the reaction mixture was stirred at 100 °C fir 4 hr. The reaction mixture was allowed to cool to RT and was then poured onto crushed ice. The resulting solid was collected by filtration, washed with water (2 x 20 mL) and n-pentane (2 x 20 mL) and dried under vacuum to afford the titled compound (5 g). LCMS m/z 272.02 (M+H)+.
(b) 5-Chloro-1 H-indol-6-amine
To a solution of (E)-2-(5-Chloro-2,4-dinitrophenyl)-N,N-dimethylethenamine (5 g) in EtOH (250 mL) under nitrogen was added Rainey nickel (5 g). The reaction mixture was degassed and stirred under an atmosphere of hydrogen (balloon) at RT for 16 hr. The reaction mixture was filtered through Celite and the precipitate was washed with MeOH (3 x 150 mL). The combined filtrates were concentrated under reduced pressure to afford the crude product (4 g). The crude product was purified by silica gel column chromatography, eluting with 10% EtOAc/petroleum ether. The desired fractions were concentrated under reduced pressure to afford the titled compound (230 mg). LCMS m/z 167.02 (M+H)+.
(c) 5-(N-(5-chloro-1 H-indol-6-yl)sulfamoyl)-2-hydroxybenzamide
To a solution of 5-chloro-1 /-/-indol-6-amine (89 mg) and pyridine (0.048 mL) in DCM (5 mL) under nitrogen at 0 °C was added 3-carbamoyl-4-hydroxybenzene-1 -sulfonyl chloride (Int- 1 , 140 mg). The reaction mixture was allowed to warm to RT and was stirred for 16 hr. The reaction mixture was concentrated under reduce pressure and the residue was dissolved in EtOAc (100 mL), washed with water (3 x 20 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to afford the crude product (180 mg). The crude product was washed with 10% acetonitrile/water (2 x 5 mL) and 2.5% MeOH/DCM and dried under vacuum. The crude product was then purified by preparative reversed phase HPLC (XBridge C18, 19 x 150 mm) using a gradient of 10-50% acetonitrile in 10 mM ammonium bicarbonate (aq). The desired fractions were concentrated under reduced pressure and the resulting solid was washed with water (2 x 10 mL) and dried under vacuum to afford the titled compound (57.1 mg). LCMS m/z 366.0 (M+H)+. 1 H NMR (400MHz, DMSO-c/e) δ = 13.49 (s, 1 H), 1 1 .22 (s, 1 H), 9.52 (s, 1 H), 8.51 (br s, 1 H), 8.23 (d, J=2.2 Hz, 1 H), 7.95 (br s, 1 H), 7.65 (dd, J=2.2, 8.8 Hz, 1 H), 7.55 (s, 1 H), 7.40 (t, J=2.7 Hz, 1 H), 7.20 (s, 1 H), 7.02 (d, J=8.8 Hz, 1 H), 6.36 (br s, 1 H).
Example 80
5-(N-(2-Cvclopropyl-1 /y-indol-6-yl)sulfamoyl)-2-hvdroxybenzamide
Figure imgf000158_0001
(a) 1 -Cyclopropyl-2-(2,4-dinitrophenyl)ethanone
To a solution of 1 ,3-dinitrobenzene (1 g) and 1 -cyclopropylethanone (10 mL) was added Kmn04 (0.94 g) and tetrabutylammonium fluoride (9.38 g). The reaction mixture was stirred at RT for 1 hr. The reaction mixture was then poured into ice water (30 mL) and extracted with EtOAc (2 x 20 mL). The combined EtOAc extracts were washed with saturated brine, dried over sodium sulfate and concentrated under reduced pressure to afford the crude product. The crude product was purified by silica gel column chromatography, eluting with 2-% EtOAc/hexane. The desired fractions were concentrated under reduced pressure to afford the titled compound (1 g). LCMS m/z (M-H)".
(b) 2-Cyclopropyl-1 H-indol-6-amine
To a stirred solution of 1 -cyclopropyl-2-(2,4-dinitrophenyl)ethanone (1 g) in MeOH (5 mL) was added 10% Pd/C (0.851 g) and ammonium formate (1 .260 g). The reaction vessel was sealed and heated at 65 °C fir 16 hr. The reaction mixture was filtered through Celite, poured into ice water and extracted with EtOAc (3 x 30 mL). The combined EtOAc extracts were washed with saturated brine (20 mL), dried over sodium sulfate, and concentrated under reduced pressure to afford the titled compound (500 mg), which was used without further purification. LCMS m/z 173.15 (M+H)+.
(c) 5-(N-(2-Cyclopropyl-1 H-indol-6-yl)sulfamoyl)-2-hydroxybenzamide
To a stirred solution of 2-cyclopropyl-1 /-/-indol-6-amine (320 mg) in DCM (5 mL) at 0 °C was added pyridine (0.309 mL) followed by 3-carbamoyl-4-hydroxybenzene-1 -sulfonyl chloride (lnt-1 , 300 mg). The reaction mixture was allowed to warm to RT and was stirred for 16 hr. The reaction mixture was diluted with water (30 mL) and extracted with DCM (2 x 50 mL). The combined DCM extracts were washed with saturated brine (25 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to afford the crude product (500 mg). The crude product was purified by preparative reversed phase HPLC (Kinetex C8, 30 xO 150 mm) using a gradient of 35-100% acetonitrile in 10 mM ammonium bicarbonate (aq). The desired fraction was concentrated to a slurry under reduced pressure and the solid was collected by filtration, washed with water (10 mL) and dried under vacuum to afford the titled compound (1675 mg). LCMS m/z 372.05 (M+H)+. H NMR (400MHz, DMSO-c/e) δ =13.33 (s, 1 H), 10.73 (s, 1 H), 9.68 (s, 1 H), 8.45 (br s, 1 H), 8.27 (d, J = 2.2 Hz, 1 H), 7.95 (br s, 1 H), 7.64 (dd, J = 2.4, 8.8 Hz, 1 H), 7.17 (d, J = 8.3 Hz, 1 H), 7.01 - 6.90 (m, 2H), 6.67 (dd, J = 2.0, 8.3 Hz, 1 H), 5.97 (d, J = 2.0 Hz, 1 H), 2.00 - 1 .87 (m, 1 H), 0.95 - 0.85 (m, 2H), 0.76 - 0.65 (m, 2H).
Example 81
5-(N-(4-Cvclopropoxyphenyl)sulfamoyl)-2-hvdroxybenzamide
Figure imgf000159_0001
(a) 1 -Cyclopropoxy-4-nitrobenzene
To a stirred solution of cyclopropanol (0.122 mL) in DMF (8 mL) at 0 °C was carefully added NaH (191 mg). The reaction mixture was stirred at 0 °C for 30 min. 1 -Fluoro-4-nitrobenzene (450 mg) was then added slowly. The reaction mixture was allowed to warm to RT and was stirred for 16 hr. The reaction mixture was diluted with ice water (10 mL) and extracted with EtOAc (3 x 20 mL). The combined EtOAc extracts were washed with saturated brine, dried over sodium sulfate and concentrated under reduced pressure to afford the titled compound (460 mg). GCMS m/z 179.1 (M+).
(b) 4-Cyclopropoxyaniline
To a stirred solution of 1 -cyclopropoxy-4-nitrobenzene (400 mg) in EtOH (8 mL) and water (2 mL) were added iron (623 mg) and ammonium chloride (597 mg). The reaction was heated to 80 °C and stirred for 3 hr. The reaction mixture was allowed to cool to RT and was then filtered through Celite. The filtrate was concentrated under reduced pressure, diluted with water (20 mL) and extracted with EtOAc (3 x 50 mL). The combined EtOAc extracts were washed with saturated brine (50 mL), dried over sodium sulfate and concentrated under reduced pressure to afford the titled compound (300 mg). LCMS m/z 150.02 (M+H)+.
(c) 5-(N-(4-Cyclopropoxyphenyl)sulfamoyl)-2-hydroxybenzamide
To a stirred solution of 4-cyclopropoxyaniline (200 mg) in DCM (10 mL) was added pyridine (0.542 mL) followed by 3-carbamoyl-4-hydroxybenzene-1 -sulfonyl chloride (lnt-1 , 316 mg). The reaction mixture was stirred at RT for 16 hr. The reaction mixture was concentrated under reduced pressure and the residue diluted with water. The resulting solid was collected by filtration to afford the crude product (200 mg). The crude product was purified by preparative reversed phase HPLC (XBridge C18, 19 x 150 mm) using a gradient of 10- 50% acetonitrile in 10 mM ammonium bicarbonate (aq). The desired fractions were concentrated under reduced pressure to afford the titled compound (160 mg). LCMS m/z 349.20 (M+H)+. 1H NMR (400MHz, DMSO-c/6) δ = 13.41 (s, 1 H), 9.77 (s, 1 H), 8.51 (br s, 1 H), 8.26 (d, J = 2.4 Hz, 1 H), 7.99 (br s, 1 H), 7.67 (dd, J = 2.2, 8.8 Hz, 1 H), 7.04 - 6.95 (m, 3H), 6.93 - 6.87 (m, 2H), 3.73 (tt, J = 3.0, 6.0 Hz, 1 H), 0.74 - 0.68 (m, 2H), 0.61 - 0.55 (m, 2H).
Example 82
5-(N-(2-Ethyl-4-fluoro-1 tf-benzord1imidazol-5-yl)sulfamoyl)-2-hvdroxybenzamide
Figure imgf000160_0001
(a) N-(2-Ethyl-4-fluoro-1 H-benzo[d]imidazol-5-yl)propionamide
To a solution of 2-fluoro-4-nitrobenzene-1 ,3-diamine (2 g) in propionic acid (30 mL) was slowly added iron (3.26 g). The reaction mixture was heated to 100 °C and stirred for 24 hr. The reaction mixture was allowed to cool to RT and was concentrated under reduced pressure, diluted with water, neutralized with saturated sodium bicarbonate, and extracted with EtOAc (3 x 900 mL). The combined EtOAc extracts were dried over sodium sulfate, filtered and concentrated under reduced pressure to afford the titled compound (1 .8 g). LCMS m/z 236.10 (M+H)+.
(b) 2-Ethyl-4-fluoro-1 H-benzo[d]imidazol-5-amine
A solution of N-(2-ethyl-4-fluoro-1 /-/-benzo[d]imidazol-5-yl)propionamide (1 .8 g) in concentrated HCI (32.3 mL) was heated to 100 °C and stirred for 4 hr. The reaction mixture was concentrated under reduced pressure and the residue diluted with water, neutralized with saturated sodium bicarbonate (aq) and extracted with EtOAc (3 x 800 mL). The combined EtOAc extracts were dried over sodium sulfate, filtered and concentrated under reduced pressure to afford the titled compound (900 mg). LCMS m/z 180.0 (M+H)+.
(c) 5-(N-(2-Ethyl-4-fluoro-1 H-benzo[d]imidazol-5-yl)sulfamoyl)-2-hydroxybenzamide
To a solution of 2-ethyl-4-fluoro-1 H-benzo[d]imidazol-5-amine (183 mg) in DCM (5 ml_) was added 3-carbamoyl-4-hydroxybenzene-1 -sulfonyl chloride (lnt-1 , 200 mg) and the reaction mixture was stirred at RT for 16 hr. The reaction mixture was concentrated under reduced pressure, diluted with water, and the resulting solids were collected by filtration to afford the crude product (170 mg). The crude product was purified by preparative reversed phase HPLC (Atlantis T3, 19 x 250 mm) using a gradient of 15-100% acetonitrile in 10 mM ammonium bicarbonate (aq). The desired fractions were concentrated under reduced pressure to afford the titled compound (103 mg). LCMS m/z 379.10 (M+H)+. 1H NMR (400MHz, DMSO-c/e) δ = 13.46 (br s, 1 H), 12.45 (br s, 1 H), 9.64 (br s, 1 H), 8.49 (br s, 1 H), 8.20 (br s, 1 H), 7.95 (br s, 1 H), 7.68 - 7.65 (m, 1 H), 7.13 - 7.00 (m, 2H), 6.80 (br t, J=7.2 Hz, 1 H), 2.79 (q, J=7.7 Hz, 2H), 1 .29 (t, J=7.7 Hz, 3H).
Example 83
5-(N-(2-Amino-1 /y-benzord1imidazol-5-yl)sulfamoyl)-2-hvdroxybenzamide, Formic acid salt
Figure imgf000161_0001
(a) 1 H-Benzo[d]imidazole-2,5-diamine
To a stirred solution of 5-nitro-1 H-benzo[d]imidazol-2-amine (500 mg) in MeOH (15 ml_) was added 10% Pd/C (149 mg) and the reaction mixture was stirred under a hydrogen atmosphere (balloon pressure) for 6 hr. The reaction mixture was filtered through Celite and the precipitate washed with MeOH (2 x 15 ml_). The combined filtrate was concentrated under reduced pressure to afford the titled compound (450 mg). LCMS m/z 149.0 )M+H). (b) 5-(N-(2-Amino-1 H-benzo[d]imidazol-5-yl)sulfamoyl)-2-hydroxybenzamide, Formic acid salt
To a suspension of 1 H-benzo[d]imidazole-2,5-diamine (126 mg) in DCM (4 mL) at 0 °C under nitrogen was added 3-carbamoyl-4-hydroxybenzene-1 -sulfonyl chloride (lnt-1 , 200 mg) portionwise over 5 min. The reaction mixture was allowed to warm to RT and was stirred for 16 hr. The reaction mixture was concentrated under reduced pressure, diluted with water, and the resulting precipitate was collected by filtration to afford the crude product (200 mg). The crude product was purified by preparative reversed phase HPLC (Kromasil phenyl, 25 x 150 mm) using a gradient of 10-30% acetonitrile in 0.1 % formic acid (aq). The desired fractions were lyophilized to afford the titled compound (22 mg). LCMS m/z 348.04 (M+H)+. 1H NMR after D20 exchange (400 MHz, DMSO-c/6) δ ppm 6.66 (dd, J=8.33, 1 .97 Hz, 1 H) 6.81 - 7.08 (m, 2 H) 7.61 (dd, J=8.77, 2.41 Hz, 1 H) 8.17 (s, 1 H) 8.22 (d, J=2.41 Hz, 1 H).
Example 84
5-(N-(4-Fluoro-1 /y-benzorcnimidazol-5-yl)sulfamoyl)-2-hvdroxybenzamide
Figure imgf000162_0001
(a) 2-Fluoro-4-nitrobenzene-1 ,3-diamine
To a solution of 1 ,2,3-trifluoro-4-nitrobenzene (5 g) in isopropanol (10 ml_) was added concentrated ammonium hydroxide (105 ml_) dropwise at RT. The reaction vessel was sealed and the reaction mixture was heated to 100 °C and stirred for 16 hr. The reaction mixture was allowed to cool to RT and the resulting solid was collected by filtration and dried under vacuum to afford the titled compound (4.5 g). LCMS m/z 172.07 (M+H)+.
(b) N-(4-Fluoro-1 H-benzo[d]imidazol-5-yl)formamide
To a solution of 2-fluoro-4-nitrobenzene-1 ,3-diamine (1 .8 g) in formic acid (20 ml_) was added iron (2.94 g) portionwise at RT. The reaction mixture was heated to 90 °C and stirred for 16 hr. The reaction mixture was allowed to cool to RT and was concentrated under reduced pressure. The residue was diluted with water and the pH adjusted to 8 with saturated sodium bicarbonate (aq) and extracted with EtOAc (3 x 800 ml_). The combined EtOAc extracts were dried over sodium sulfate, filtered and concentrated under reduced pressure to afford the titled compound (900 mg). LCMS m/z 180.0 (M+H)+.
(c) 4-Fluoro-1 H-benzo[d]imidazol-5-amine
A solution of N-(4-fluoro-1 H-benzo[d]imidazol-5-formamide (0.5 g) in concentrated HCI (7.07 mL) was heated at 100 °C for 4 hr. The reaction mixture was allowed to cool to RT and was diluted with water and neutralized by the addition of saturated sodium bicarbonate (aq). The reaction mixture was then extracted with EtOAc and the combined EtOAc extracts were dried over sodium sulfate, filtered and concentrated under reduced pressure to afford the titled compound, 400 mg). LCMS m/z 152.0 (M+H)+. (d) 5-(N-(4-Fluoro-1 H-benzo[d]imidazol-5-yl)sulfamoyl)-2-hydroxybenzamide
To a solution of 4-fluoro-1 H-benzo[d]imidazol-5-amine (128 mg) in DCM (5 mL) was added 3-carbamoyl-4-hydroxybenzene-1 -sulfonyl chloride (lnt-1 , 250 mg). The reaction mixture was stirred at RT for 16 hr. The reaction mixture was concentrated under reduced pressure and the residue was diluted with water. The resulting solid was collected by filtration to afford the crude product (300 mg). The crude product was purified by preparative reversed phase HPLC (Atlantis T3, 19 x 250 mm) using a gradient of 10-40% acetonitrile in 0.1 % formic acid (aq). The desired fractions were concentrated under reduced pressure to afford the titled compound (79 mg). LCMS m/z 351 .06 (M+H)+. Ή NMR (400MHz, DMSO-c/6) δ = 13.47 (s, 1 H), 12.74 (br s, 1 H), 9.72 (s, 1 H), 8.48 (br s, 1 H), 8.26 - 8.18 (m, 2H), 7.95 (br s, 1 H), 7.68 (dd, J = 2.2, 8.8 Hz, 1 H), 7.27 (d, J = 8.6 Hz, 1 H), 7.03 (d, J = 8.8 Hz, 1 H), 6.92 - 6.85 (m, 1 H).
Example 85
5-(N-(4-Fluoro-2-methyl-1 /y-benzord1imidazol-5-yl)sulfamoyl)-2-hvdroxybenzamide
Figure imgf000163_0001
(a) N-(4-Fluoro-2-methyl-1 H-benzo[d]imidazol-5-yl)acetamide
To a solution of 2-fluoro-4-nitrobenzene-1 ,3-diamine (Example 84 (a), 1 .8 g) in glacial acetic acid (30 mL) was added iron (0.587 g) portionwise. The reaction mixture was heated to 90 °C and stirred for 16 hr. The reaction mixture was allowed to cool to RT and was concentrated under reduced pressure. The residue was diluted with water, neutralized with saturated sodium bicarbonate (aq) and extracted with EtOAc (3 x 800 mL). The combined EtOAc extracts were dried over sodium sulfate, filtered and concentrated under reduced pressure to afford the titled compound (1 g), which was used without further purification. LCMS m/z 207.99 (M+H)+.
(b) 4-Fluoro-2-methyl-1 H-benzo[d]imidazol-5-amine
A solution of N-(4-fluoro-2-methyl-1 /-/-benzo[d]imidazol-5-yl)acetamide (1 g) in concentrated HCI (20.37 mL) was heated to 100 °C and stirred for 4 hr. The reaction mixture was allowed to cool to RT and was diluted with water and neutralized by the addition of saturated sodium bicarbonate (aq). The reaction mixture was then extracted with EtOAc (3 x 900 mL) and the combined EtOAc extracts were dried over sodium sulfate, filtered and concentrated under reduced pressure to afford the titled compound (1 g). LCMS m/z 166.1 MM+H). (c) 5-(N-(4-Fluoro-2-methyl-1 H-benzo[d]imidazol-5-yl)sulfamoyl)-2- hyd roxy be nzam ide
To a solution of 4-fluoro-2-methyl-1 /-/-benzo[d]imidazol-5-amine (140 mg) in DCM (5 ml_) was added 3-carbamoyl-4-hydroxybenzene-1 -sulfonyl chloride (lnt-1 , 250 mg) and the reaction mixture was stirred at RT for 16 hr. The reaction mixture was concentrated under reduced pressure and the residue was diluted with water. The resulting solids were collected by filtration to afford the crude product (140 mg). The crude product was purified by preparative reversed phase HPLC (Atlantis T3, 19 x 250 mm) using a gradient of 10- 45% acetonitrile in 0.1 % formic acid (aq). The desired fractions were concentrated under reduced pressure to afford the titled compound (19 mg). LCMS m/z 365.10 (M+H)+. 1 H NMR (400MHz, DMSO-c/6) δ = 13.46 (s, 1 H), 12.50 (br s, 1 H), 9.66 (s, 1 H), 8.48 (br s, 1 H), 8.19 (d, J = 2.2 Hz, 1 H), 7.95 (br s, 1 H), 7.66 (dd, J = 2.2, 8.8 Hz, 1 H), 7.14 (d, J = 8.6 Hz, 1 H), 7.02 (d, J = 8.8 Hz, 1 H), 6.81 (dd, J = 7.2, 8.3 Hz, 1 H), 2.46 (s, 3H). Example 86
2-Hvdroxy-5-(N-(2-isopropyl-1 tf-benzord1imidazol-6-yl)sulfamoyl)benzamide
Figure imgf000164_0001
(a) 2-lsopropyl-6-nitro-1 H-benzo[d]imidazole
A solution of 4-nitrobenzene-1 ,2-diamine (4 g) in isobutyric acid (24 ml_) was heated to 160 °C and stirred for 16 hr. The reaction mixture was allowed to cool to RT and was concentrated under reduced pressure. The residue was diluted with water (30 ml_) and the pH was adjusted to 8 by addition of 1 N NaOH (aq). The resulting precipitate was collected by filtration, washed with water (3 x 15 ml_) and dried under vacuum to afford the titled compound (3.3 g). LCMS m/z 206.10 (M+H)+.
(b) 2-lsopropyl-1 H-benzo[d]imidazol-6-amine
To a stirred solution of 2-isopropyl-5-nitro-1 /-/-benzo[d]imidazole (1 g) in MeOH (15 mL) was carefully added 10% Pd/C (0.59 g), and the reaction mixture was stirred under a hydrogen atmosphere (balloon) for 6 hr at RT. The reaction mixture was filtered through Celite and the precipitate washed with MeOH (2 x 10 mL). The combined MeOH filtrates were concentrated under reduced pressure to afford the titled compound (700 mg). LCMS m/z 176.14 (M+H)+. (c) 2-Hydroxy-5-(N-(2-isopropyl-1 H-benzo[d]imidazol-6-yl)sulfamoyl)benzamide
To a solution of 2-isopropyl-1 /-/-benzo[d]imidazol-6-amine (200 mg) in DCM (4 mL) under nitrogen at 0 °C was added 3-carbamoyl-4-hydroxybenzene-1 -sulfonyl chloride (lnt-1 , 223 mg) portionwise over 5 min. The reaction mixture was allowed to warm to RT and was stirred for 16 hr. The reaction mixture was concentrated under reduced pressure and diluted with water. The resulting solid was collected by filtration to afford the crude product (300 mg). The crude product was purified by preparative reversed phase HPLC (Durashell C18, 21 x 150 mm) using a gradient Of 10-55% acetonitrile in 5 mM ammonium bicarbonate (aq). The desired fraction was lyophilized to afford the titled compound (52 mg). LCMS m/z 375.1 (M+H)+. Ή NMR (400MHz, DMSO-c/6) δ = 13.33 (br s, 1 H), 12.05 (br s, 1 H), 9.82 (br s, 1 H), 8.48 (br s, 1 H), 8.28 (d, J=2.2 Hz, 1 H), 7.96 (br s, 1 H), 7.67 (dd, J=2.2, 8.8 Hz, 1 H), 7.29 (br d, J=7.5 Hz, 1 H), 7.15 (br s, 1 H), 6.99 (d, J=8.6 Hz, 1 H), 6.85 (dd, J=2.0, 8.6 Hz, 1 H), 3.07 (td, J=7.0, 13.9 Hz, 1 H), 1 .29 (d, J=6.8 Hz, 6H). Example 88
5-(N-(4-Chloro-1 /y-benzorcnimidazol-6-yl)sulfamoyl)-2-hvdroxybenzamide
Figure imgf000165_0001
(a) N-(4-chloro-1 H-benzo[d]imidazol-6-yl)formamide
To a solution of 2-chloro-4,6-dinitroaniline (2 g) in formic acid (30 mL) under nitrogen was added iron (5.13 g) portionwise over 5 min. The reaction mixture was heated to 1 10 °C and stirred for 16 hr. The reaction mixture was allowed to cool to RT, concentrated under reduced pressure, taken into MeOH (50 mL) and filtered. The filtrate was concentrated under reduced pressure to afford the titled compound (3 g). LCMS m/z 194.14 (M+H)+. (b) 4-Chloro-1 H-benzo[d]imidazol-6-amine
A solution of N-(4-chloro-1 H-benzo[d]imidazol-6-yl)formamide (3 g) in concentrated HCI (20 mL) was heated to 1 10 °C and stirred for 6 hr. The reaction mixture was concentrated under reduced pressure, the pH adjusted to 8-9 by the addition of 1 N NaOH, and extracted with EtOAc (3 x 25 mL). The combined EtOAc extracts were dried over sodium sulfate, filtered and concentrated under reduced pressure to afford the crude product. The crude product was triturated with diethyl ether (3 x 15 mL) and dried under vacuum to afford the titled compound (700 mg). LCMS m/z 167.89 (M+H)+. (c) 5-(N-(4-Chloro-1 H-benzo[d]imidazol-6-yl)sulfamoyl)-2-hydroxybenzamide
To a solution of 4-chloro-1 H-benzo[d]imidazol-6-amine (213 mg) in DCM under nitrogen at 0 °C was added 3-carbamoyl-4-hydroxybenzene-1 -sulfonyl chloride (lnt-1 , 200 mg) portionwise over 5 min. The reaction mixture was allowed to warm to RT and was stirred for 16 hr. The reaction mixture was concentrated under reduced pressure and the residue diluted with water (15 mL). The resulting solid was collected by filtration to afford the crude product (300 mg). The crude product was purified by preparative reversed phase HPLC (XBridge C18, 19 x 150 mm) using a gradient of 10-55% acetonitrile in 5 mM ammonium bicarbonate (aq). The desired fraction was lyophilized to afford the titled compound (1 15 mg). LCMS m/z 367.0 (M+H)+. Ή NMR (400 MHz, DMSO-c/6) δ 13.40 (br s, 1 H), 12.57 (br s, 1 H), 10.10 (br s, 1 H), 8.62 (br s, 1 H), 8.31 (d, J=2.19 Hz, 1 H), 8.10 - 8.27 (m, 1 H), 7.90 (br s, 1 H), 7.66 (br d, J=8.99 Hz, 1 H), 7.20 (d, J=1 .53 Hz, 1 H), 6.87 - 7.1 1 (m, 2 H).
Example 91
2-Hvdroxy-5-(N-(1 -phenyl-1 tf-pyrazol-4-yl)sulfamoyl)benzamide
Figure imgf000166_0001
A 20 mL reaction vial equipped with a septum cap and stirbar was charged with 1 -phenyl- 1 /-/-pyrazol-4-amine (405 mg). The solid material was taken up in dichloromethane (DCM) (8.5 mL) and the mixture treated with a portionwise addition of 3-carbamoyl-4- hydroxybenzene-1 -sulfonyl chloride (lnt-1 , 200 mg) and the resulting mixture stirred overnight at room temperature. The mixture was then diluted with ethyl acetate up to approximately 20 mL total volume and filtered to remove the precipitate. The filtrate was then concentrated to a residue and loaded onto a 30 gram SNAP C-18 HS reverse phase silica cartridge for purification (0-50% Ethanol into 0.1 % aqueous formic acid over 17.5 CV). Fractions containing the desired material were pooled and concentrated to afford a deep purple solid. The solid was then triturated with ethanol to afford the titled compound as a pale pink solid (212 mg). LCMS m/z 359.3 (M+H)+. Ή NMR (400 MHz, DMSO-d6) δ ppm 7.06 (d, J=8.84 Hz, 1 H) 7.28 (tt, J=7.42, 1 .04 Hz, 1 H) 7.39 (d, J=0.76 Hz, 1 H) 7.41 - 7.50 (m, 2 H) 7.70 - 7.80 (m, 3 H) 8.06 (br. s., 1 H) 8.23 (s, 1 H) 8.33 (d, J=2.27 Hz, 1 H) 8.60 (br. s., 1 H) 9.89 (s, 1 H) 13.58 (s, 1 H). Example 92
5-(N-(5-Chlorothiophen-3-yl)sulfamoyl)-2-hvdroxybenzamide
Figure imgf000167_0001
To a solution of 5-chlorothiophen-3-amine hydrochloride (217 mg) in DCM (10 mL) was added pyridine (0.309 mL) followed by 3-carbamoyl-4-hydroxybenzene-1 -sulfonyl chloride (lnt-1 , 300 mg), and the reaction mixture was stirred at RT for 16 hr. The reaction mixture was diluted with water (30 mL) and extracted with DCM ( 2 x 50 mL). The combined DCM extracts were washed with saturated brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to afford the crude product. The crude product was triturated with DCM (2 x 10 mL) and dried under vacuum to afford the titled compound (144 mg). LCMS m/z 332.99 (M+H)+. Ή NMR (400MHz, DMSO-c/6) δ = 13.53 (br s, 1 H), 10.35 (br s, 1 H), 8.58 (br s, 1 H), 8.34 (d, J=2.2 Hz, 1 H), 8.04 (br s, 1 H), 7.73 (dd, J=2.2, 8.8 Hz, 1 H), 7.05 (d, J=8.8 Hz, 1 H), 6.81 (d, J=1 .8 Hz, 1 H), 6.77 (d, J=1 .8 Hz, 1 H).
Example 93
Figure imgf000167_0002
A 20 mL reaction vial equipped with a septum cap and stirbar was charged with 1 -phenyl- 1 /-/-pyrazol-3-amine (405 mg). The solid material was taken up in dichloromethane (DCM) (8.5 mL) and the mixture treated with a portionwise addition of 3-carbamoyl-4- hydroxybenzene-1 -sulfonyl chloride (lnt-1 , 200 mg) and the resulting mixture stirred for 3 days at room temperature. The mixture was then diluted with ethyl acetate up to ~20 mL total volume and filtered to remove the precipitate. The filtrate was then concentrated to a residue and loaded onto a 30 gram SNAP C-18 HS reversed phase silica cartridge for purification (0-40% EtOH in 0.1 % aqueous formic acid over 17.5 CV). Fractions containing the desired material were pooled, concentrated to a residue, and triturated with ethanol to afford the title compound as an off white solid (184 mg). LCMS m/z 359.1 (M+H)+. 1H NMR (400 MHz, DMSO-c/e) δ ppm 6.28 (d, J=2.53 Hz, 1 H) 7.06 (d, J=8.84 Hz, 1 H) 7.19 - 7.28 (m, 1 H) 7.37 - 7.48 (m, 2 H) 7.60 - 7.71 (m, 2 H) 7.84 (dd, J=8.72, 2.40 Hz, 1 H) 8.09 (br. s., 1 H) 8.34 (d, J=2.53 Hz, 1 H) 8.46 (d, J=2.27 Hz, 1 H) 8.64 (br. s., 1 H) 10.83 (s, 1 H) 13.55 (s, 1 H).
Example 94
2-Hvdroxy-5-(N-(5-methylthiophen-2-yl)sulfamoyl)benzamide
Figure imgf000168_0001
To a stirred solution of 5-methylthiophen-2-amine, hydrochloride (191 mg) in DCM (10 ml_) was added pyridine (0.309 ml_) followed by 3-carbamoyl-4-hydroxybenzene-1 -sulfonyl chloride (lnt-1 , 300 mg), and the reaction mixture was stirred at RT for 16 hr. The reaction mixture was diluted with water (30 ml_) and extracted with EtOAc ( 2 x 50 ml_). The combined EtOAc extracts were washed with saturated brine, filtered and concentrated under reduced pressure to afford the crude product. The crude product was triturated with DCM (2 x 10 ml_) and dried under vacuum to afford the titled compound (125 mg). LCMS m/z 313.05 (M+H)+. 1H NMR (400MHz, DMSO-c/6) δ = 13.48 (br s, 1 H), 10.17 (br s, 1 H), 8.54 (br s, 1 H), 8.27 (d, J=2.2 Hz, 1 H), 8.01 (br s, 1 H), 7.70 (dd, J=2.3, 8.7 Hz, 1 H), 7.06 (d, J=8.8 Hz, 1 H), 6.48 (dd, J=1 .1 , 3.7 Hz, 1 H), 6.35 (d, J=3.5 Hz, 1 H), 2.28 (s, 3H).
Example 95
2-Hvdroxy-5-(N-(5-methylthiophen-3-yl)sulfamoyl)benzamide
Figure imgf000169_0001
To a stirred solution of 5-methylthiophen-3-amine hydrochloride (200mg) in DCM (20 ml_) under nitrogen was added pyridine (0.324 ml_) followed by 3-carbamoyl-4- hydroxybenzene-1 -sulfonyl chloride (lnt-1 , 315 mg), and the reaction mixture was stirred at RT for 16 hr. The reaction mixture was diluted with water (30 ml_) and extracted with EtOAc ( 2 x 50 ml_). The combined EtOAc extracts were washed with saturated brine, filtered and concentrated under reduced pressure to afford the crude product (250 mg). The crude product was purified by preparative reversed phase HPLC (Durashell C18, 21 x 150 mm) using a gradient of 10-27% acetonitrile in 10 mM ammonium bicarbonate (aq). The desired fractions were lyophilized to afford the titled compound (66 mg). LCMS m/z 313.01 (M+H)+. Ή NMR (400MHz, DMSO-c/6) δ = 13.49 (br s, 1 H), 10.13 (s, 1 H), 8.62 (br s, 1 H), 8.33 (d, J=2.4 Hz, 1 H), 7.99 (br s, 1 H), 7.71 (dd, J=2.4, 8.8 Hz, 1 H), 7.01 (d, J=8.8 Hz, 1 H), 6.60 (d, J=1 .5 Hz, 1 H), 6.54 (t, J=1 .2 Hz, 1 H), 2.31 (s, 3H).
Example 96
Methyl 6-(3-carbamoyl-4-hvdroxyphenylsulfonamido)-1 tf-indole-3-carboxylate
Figure imgf000169_0002
(a) 6-Nitro-1 H-indole-3-carboxylic acid
To a solution of 6-nitro-1 /-/-indole-3-carboxylic acid (2 g) in glacial acetic acid (20 mL) at 0 °C was added nitric acid (70%, 2.218 mL). The reaction mixture was allowed to warm to RT and was stirred for 16 hr. The reaction mixture was diluted with water (30 mL) and extracted with EtOAc (2 x 30 mL). The combined EtOAc extracts were washed with saturated brine, dried over sodium sulfate and concentrated under reduced pressure to afford the crude product. The crude product was purified by silica gel flash chromatography, eluting with 50% EtOAc/hexane. The desired fractions were concentrated under reduced pressure to afford the titled compound (800 mg). LCMS m/z 206.99 (M+H)+.
(b) Methyl 6-nitro-1 H-indole-3-carboxylate
To a solution of 6-nitro-1 /-/-indole-3-carboxylic acid (800 mg) in MeOH (10 mL) was added p-toluenesulfonic acid monohydrate (738 mg). The reaction mixture was heated to 80 °C and was stirred for 16 hr. The reaction mixture was allowed to cool to RT and was diluted with water (30 mL) and extracted with EtOAc (2 x 30 mL). The combined EtOAc extracts were washed with sodium bicarbonate (aq), dried over sodium sulfated and concentrated under reduced pressure to afford the titled compound (500 mg). LCMS m/z 219.54 (M-H)~.
(c) Methyl 6-amino-1 H-indole-3-carboxylate
To a stirred solution of methyl 6-nitro-1 /-/-indole-3-carboxylate (500 mg) in EtOH (10 mL) and water (10 mL) were added iron (634 mg) and ammonium chloride (607 mg). The reaction mixture was heated to 80 °C and stirred for 2 hr. The reaction mixture was allowed to cool to RT and was then filtered through Celite. The filtrate was extracted with EtOAc (2 x 20 mL) and the combined EtOAc extracts were washed with saturated brine, dried over sodium sulfate and concentrated under reduced pressure to afford the crude product. The crude product was purified by silica gel column chromatography, eluting with 60% EtOAc/hexane. The desired fractions were concentrated under reduced pressure to afford the titled compound (150 mg). LCMS 191 .0 (M+H)+.
(d) Methyl 6-(3-carbamoyl-4-hydroxyphenylsulfonamido)-1 H-indole-3-carboxylate
To a solution of methyl 6-amino-1 /-/-indole-3-carboxylate (161 mg) in DCM (10 mL) at 0 °C was added pyridine (0.206 mL) followed by 3-carbamoyl-4-hydroxybenzene-1 -sulfonyl chloride (lnt-1 , 200 mg). The reaction mixture was allowed to warm to RT and was stirred for 16 hr. The reaction mixture was diluted with water (20 mL) and extracted with DCM (2 x 50 mL). The combined DCM extracts were washed with saturated brine (25 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to afford the crude product (300 mg). The crude product was purified by preparative reversed phase HPLC (Kromasil C-18, 21 x 150 mm) using a gradient of 40-100% acetonitrile in 0.1 % TFA (aq). The desired fraction was lyophilized to afford the titled compound (91 .4 mg). LCMS m/z 390.08 (M+H)+. Ή NMR (400MHz, DMSO-c/6) δ = 13.33 (s, 1 H), 1 1 .76 (br d, J=2.2 Hz, 1 H), 9.97 (s, 1 H), 8.47 (br s, 1 H), 8.30 (d, J=2.4 Hz, 1 H), 7.98 (d, J=2.9 Hz, 2H), 7.79 (d, J=8.6 Hz, 1 H), 7.67 (dd, J=2.2, 8.8 Hz, 1 H), 7.21 (d, J=1 .5 Hz, 1 H), 7.02 - 6.90 (m, 2H), 3.76 (s, 3H). Example 97
5-(N-(3-Chloro-1 /y-indol-6-yl)sulfamoyl)-2-hvdroxybenzamide
Figure imgf000171_0001
(a) 3-Chloro-6-nitro-1 H-indole
To a solution of 6-nitro-1 /-/-indole (2 g) in DCM (20 ml_) was added N-chlorosuccinimide (1 .976 g). The reaction mixture was heated to 45 °C and was stirred for 48 hr. The reaction mixture was diluted with water (30 ml_) and extracted with DCM (2 x 50 ml_). The combined DCM extracts were washed with brine, dried over sodium sulfate and concentrated under reduced pressure to afford the titled compound (2 g). LCMS m/z 194.97 (M-H)~.
(b) 3-Chloro-1 H-indol-6-amine
To a solution of 3-chloro-6-nitro-1 /-/-indole (500 mg) in EtOH (10 ml_) and water (10 ml_) were added iron (710 mg) and ammonium chloride (680 mg). The reaction mixture was heated to 80 °C and stirred for 2 hr. The reaction mixture was allowed to cool to RT and filtered through Celite. The filtrate was extracted with EtOAc (2 x 20 ml_) and the combined EtOAc extracts were washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure to afford the titled compound (166 mg). LCMS m/z 167.06 (M+H)+.
(c) 5-(N-(3-Chloro-1 H-indol-6-yl)sulfamoyl)-2-hydroxybenzamide
To a solution of 3-chloro-1 /-/-indol-6-amine (212 mg) in DCM (10 mL) at 0 °C was added pyridine (0.309 mL) followed by 3-carbamoyl-4-hydroxybenzene-1 -sulfonyl chloride (lnt-1 , 300 mg). The reaction mixture was allowed to warm to RT and was stirred for 16 hr. The reaction mixture was diluted with water (30 mL) and extracted with DCM (2 x 50 mL). The combined DCM extracts were washed with saturated brine (25 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to afford the crude product (500 mg). The crude product was purified by preparative reversed phase HPLC (Kromosil C-18, 21 x 150 mm) using a gradient of 10-40% acetonitrile in 10 mM ammonium bicarbonate (aq). The desired fraction was concentrated under reduced pressure to afford the titled compound (157.7 mg). LCMS m/z 366.0 (M+H)+. Ή NMR (400MHz, DMSO-c/6) δ = 13.33 (br s, 1 H), 1 1 .20 (br s, 1 H), 9.95 (s, 1 H), 8.47 (br s, 1 H), 8.30 (d, J=2.2 Hz, 1 H), 7.97 (br s, 1 H), 7.66 (dd, J=2.2, 8.8 Hz, 1 H), 7.41 (d, J=2.6 Hz, 1 H), 7.31 (d, J=8.6 Hz, 1 H), 7.15 (d, J=1 .5 Hz, 1 H), 6.98 (d, J=8.8 Hz, 1 H), 6.89 (dd, J=1 .8, 8.6 Hz, 1 H). Example 98
2-Hvdroxy-5-(N-(2-phenyl-1 /y-indol-6-yl)sulfamoyl)benzamide
Figure imgf000172_0001
(a) 2-(2,4-Dinitrophenyl)-1 -phenylethanone
To a solution of 1 ,3-dinitrobenzene (3 g) and 2-chloro-1 -phenylethanone (3.31 g) in DMF (30 mL) at -10 °C was added DBU dropwise. The reaction mixture was allowed to warm to RT and was stirred for 2 hr. The reaction mixture was poured into water (50 mL) and extracted with EtOAc (2 x 80 mL). The combined EtOAc extracts were washed with saturated brine (30 mL), dried over sodium sulfate, and concentrated under reduced pressure to afford the crude product. The crude product was purified by silica gel column chromatography, eluting with 15-20% EtOAc/petroleum ether. The desired fractions were concentrated under reduced pressure to afford the titled compound (2.7 g). LCMS m/z 285.77 (M+H)+.
(b) 2-Phenyl-1 H-indol-6-amine
To a solution of 2-(2,4-dinitrophenyl)-1 -phenylethanone (1 g) in EtOH (15 mL) and water (15 mL) were added iron (1 .013 g) and ammonium chloride (0.934 g). The reaction mixture was heated to 70 °C and stirred for 16 hr. The reaction mixture was allowed to cool to RT and was filtered through Celite, which was washed with EtOAc (15 mL). The combined filtrates were poured into water (20 mL) and extracted with EtOAc (2 x 30 mL). The combined EtOAc extracts were washed with saturated brine (20 mL), dried over sodium sulfate and concentrated under reduced pressure to afford the crude product. The crude product was purified by silica gel column chromatography, eluting with 50-60% EtOAc/hexane to afford the titled compound (210 mg). LCMS m/z 209.18 (M+H)+.
(c) 2-Hydroxy-5-(N-(2-phenyl-1 H-indol-6-yl)sulfamoyl)benzamide
To a solution of 2-phenyl-1 /-/-indol-6-amine (212 mg) and pyridine (0.034 mL) in DCM (15 mL) at 0 °C was added 3-carbamoyl-4-hydroxybenzene-1 -sulfonyl chloride (lnt-1 , 200 mg) portionwise. The reaction mixture was allowed to warm to RT and was stirred for 16 hr. The reaction mixture was poured into water (20 mL) and extracted with DCM (2 x 30 mL). The combined DCM extracts were washed with saturated brine, dried over sodium sulfate and concentrated under reduced pressure to afford the crude product (250 mg). The crude product was purified by preparative reversed phase HPLC (Kromasil C-18, 21 x 250 mm) using a gradient of 10-45% acetonitrile in 10 mM ammonium bicarbonate. The desired fraction was lyophilized to afford the titled compound (145 mg). LCMS m/z 408.07 (M+H)+. 1H NMR (400MHz, DMSO-c/6) δ = 13.30 (s, 1 H), 1 1 .40 (s, 1 H), 9.86 (s, 1 H), 8.47 (br s, 1 H), 8.31 (d, J=2.2 Hz, 1 H), 7.95 (br s, 1 H), 7.82 - 7.74 (m, 2H), 7.68 (dd, J=2.2, 8.8 Hz, 1 H), 7.43 (t, J=7.8 Hz, 2H), 7.36 (d, J=8.3 Hz, 1 H), 7.31 - 7.24 (m, 1 H), 7.14 (s, 1 H), 6.99 (d, J=8.8 Hz, 1 H), 6.83 - 6.75 (m, 2H).
Example 99
2-Hvdroxy-5-(N-(4-methylthiophen-2-yl)sulfamoyl)benzamide
Figure imgf000173_0001
To a solution of 4-methylthiophen-2-amine (60 mg) in DCM (10 mL) was added pyridine (0.214 mL) and 3-carbamoyl-4-hydroxybenzene-1 -sulfonyl chloride (lnt-1 , 125 mg) and the reaction mixture was stirred at RT for 16 hr. The reaction mixture was diluted with water (10 mL) and extracted with DCM (3 x 20 mL). The combined DCM extracts were washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to afford the crude product (130 mg). The crude product was purified by preparative supercritical fluid chromatography (Chiralpak AS-H, 21 x 250 mm), eluting with 30% MeOH/C02. The desired fractions were concentrated under reduced pressure to afford the titled compound (68.8 mg). LCMS m/z 313.01 (M+H)+. Ή NMR (400MHz, DMSO- d8) δ = 13.47 (br s, 1 H), 10.26 (br s, 1 H), 8.74 (br s, 1 H), 8.26 (d, J = 2.4 Hz, 1 H), 7.87 (br s, 1 H), 7.65 (br d, J = 8.6 Hz, 1 H), 6.97 (br d, J = 6.8 Hz, 1 H), 6.63 (s, 1 H), 6.40 (s, 1 H), 2.05 (d, J = 1 .1 Hz, 3H).
Example 100
Methyl 6-(3-carbamoyl-4-hvdroxyphenylsulfonamido)-1 tf-indole-2-carboxylate
Figure imgf000174_0001
(a) 6-Nitroindoline-2-carboxylic acid
To a solution of indoline-2-carboxylic acid (5.0 g) in sulfuric acid (1 .361 mL) at -20 °C was added nitric acid (1 .141 mL). The reaction mixture was allowed to warm to -10 °C and was stirred for 4 hr. The reaction mixture was poured into crushed ice (100 g) and extracted with EtOAc (100 mL). The aqueous layer was neutralized with 20% NaOH (aq) to pH ~ 5 and was then extracted with EtOAc (2 x 200 mL). The combined EtOAc extracts were dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford the titled compound (2.0 g). LCMS m/z 209.01 (M+H)+.
(b) Methyl 6-nitroindoline-2-carboxylate
To a solution of 6-nitroindoline-2-carboxylic acid (2.0 g) in MeOH (20 mL) was added p- toluenesulfonic acid monohydrate (0.914 g). The reaction mixture was heated to 60 °C and stirred for 1 hr. The reaction mixture was concentrated under reduced pressure, diluted with EtOAc (50 mL) and extracted with saturated sodium bicarbonate (aq). The EtOAc layerwas dried over sodium sulfate, filtered and concentrated under reduced pressure to afford the titled compound (1 .0 g). LCMS m/z 223.01 (M+H)+.
(c) Methyl 6-nitro-1 H-indole-2-carboxylate
To a solution of methyl 6-nitroindoline-2-carboxylate (1 .0 g) in benzene (7 mL) and EtOAc (3 mL) was added DDQ (1 .13 g). The reaction mixture was heated to 80 °C and was stirred for 4 hr. The reaction mixture was allowed to cool to RT and was diluted with EtOAc (50 mL) and washed with saturated sodium bicarbonate (aq). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to afford the titled compound (700 mg). LCMS m/z 219.18 (M-H)".
(d) Methyl 6-amino-1 H-indole-2-carboxylate
To a solution of methyl 6-nitro-1 /-/-indole-2-carboxylate (700 mg) in EtOAc (20 mL) and water (20 mL) was added iron (888 mg) followed by ammonium chloride (680 mg). The reaction mixture was heated to 80 °C and was stirred for 16 hr. The reaction mixture was allowed to cool to RT and was filtered through Celite and the precipitate washed with EtOAc (50 mL) the combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure to afford the titled compound (350 mg), which was used without further purification. LCMS m/z 191 .14 (M+H)+. (e) Methyl 6-(3-carbamoyl-4-hydroxyphenylsulfonamido)-1 H-indole-2-carboxylate
To a solution of methyl 6-amino-1 H-indole-2-carboxylate (200 mg) in DCM (20 mL) was added pyridine (0.255 mL) followed by 3-carbamoyl-4-hydroxybenzene-1 -sulfonyl chloride (lnt-1 , 248 mg), and the reaction mixture was stirred at RT for 16 hr. The reaction mixture was diluted with water (10 mL) and the resulting solid was collected by filtration and dried under vacuum to afford the crude product (220 mg). The crude product was purified by preparative reversed phase HPLC (XBridge C18, 19 x 150 mm) using a gradient of 0-50% acetonitrile in 10 mM ammonium bicarbonate (aq). The desired fractions were lyophilized to afford the titled compound (109 mg). LCMS m/z 390.04 (M+H)+. NMR:1H NMR (400MHz, DMSO-c/e) δ = 13.33 (s, 1 H), 1 1 .74 (s, 1 H), 10.07 (s, 1 H), 8.48 (br s, 1 H), 8.32 (d, J=2.4 Hz, 1 H), 7.97 (br s, 1 H), 7.69 (dd, J=2.2, 8.8 Hz, 1 H), 7.50 (d, J=8.8 Hz, 1 H), 7.19 (s, 1 H), 7.04 (d, J=1 .3 Hz, 1 H), 6.99 (d, J=8.8 Hz, 1 H), 6.88 (dd, J=2.0, 8.6 Hz, 1 H), 3.83 (s, 3H).
Example 101
5-(N-(4-Bromo-1 H-indol-6-yl)sulfamoyl)-2-hvdroxybenzamide
Figure imgf000175_0001
To a solution of 4-bromo-1 /-/-indol-6-amine (200 mg) in DCM (20 mL) under nitrogen at RT was added pyridine (0.230 mL) followed by 3-carbamoyl-4-hydroxybenzene-1 -sulfonyl chloride (lnt-1 , 223 mg) and the reaction mixture was stirred for 16 hr. The reaction mixture was diluted with water (10 mL) and the resulting solid was collected by filtration and dried under vacuum to afford the crude product (250 mg). The crude product was purified by preparative reversed phase HPLC (Kromosil C18, 21 .2 x 250 mm) using a gradient of 10- 100% acetonitrile in 10 mM ammonium bicarbonate (aq). The desired fractions were concentrated under reduced pressure to afford the titled compound (81 mg). LCMS m/z 407.90 (M-H)-. 1H NMR (400MHz, DMSO-c/6) δ = 13.43 (br s, 1 H), 1 1 .21 (br s, 1 H), 10.15 (br s, 1 H), 8.53 (br s, 1 H), 8.34 (br s, 1 H), 7.98 (br s, 1 H), 7.76 (br d, J=7.9 Hz, 1 H), 7.33 - 7.15 (m, 2H), 7.04 - 6.93 (m, 2H), 6.61 (br s, 1 H). Example 102
2-Hvdroxy-5-(N-(7-methyl-1 /y-benzorcnimidazol-5-yl)sulfamoyl)benzamide
Figure imgf000176_0001
(a) tert-Butyl 6-((tert-butoxycarbonyl)amino)-4-chloro-1 H-benzo[d]imidazole-1 - carboxylate
To a solution of 4-chloro-1 H-benzo[d]imidazol-6-amine (Example 88(b), 1 g) in 1 .4-dioxane (20 mL) was added di-t-butyl-dicarbonate (8.31 mL). The reaction mixture was heated to 90 °C and stirred for 6 hr. The reaction mixture was allowed to cool to RT and was concentrated under reduced pressure to afford the crude product. The crude product was purified by silica gel column chromatography, eluting with 15% EtOAc/hexane to afford the titled compound (1 .4 g). LCMS m/z 368.27 (M+H)+.
(b) tert-Butyl 6-((tert-butoxycarbonyl)amino)-4-methyl-1 H-benzo[d]imidazole-1 - carboxylate compound with tert-butyl (4-methyl-1 H-benzo[d]imidazol-6- yl)carbamate
To a solution of tert-butyl 6-((tert-butoxycarbonyl)amino)-4-chloro-1 /-/-benzo[d]imidazole-1 - carboxylate (500 mg) in 1 .4-dioxane (5 mL) was added 2,4,6-trimethyl-1 ,3,5,2,4,6- trioxatriborinane (0.570 mL) and sodium tert-butoxide (392 mg). The reaction vessel was purged with nitrogen and then XPhos Pd G2 (107 mg) was added. The reaction vessel was flushed with nitrogen again, sealed, and heated to 120 °C and allowed to stir for 16 hr. The reaction mixture was allowed to cool to RT and was diluted with EtOAc (30 mL), filtered through Celite, and the filtrate concentrated under reduced pressure to afford the crude product (500 mg). LCMS of the crude product showed both the titled compound, m/z 348.33 (M+H) as well as the corresponding mono-Boc product, m/z 248.33 (M+H)+. The crude product was taken on to the next step without further purification.
(c) 4-Methyl-1 H-benzo[d]imidazol-6-amine
The crude product from the previous step (490 mg) was dissolved in DCM (5 mL) and cooled to 0 °C under nitrogen. Trifluoroacetic acid (0.635 mL) was added dropwise over 5 min. The reaction mixture was allowed to warm to RT and was stirred for 16 hr. The reaction mixture was concentrated under reduced pressure, treated with 5% (aq) sodium bicarbonate to raise the pH to 8-9, and then extracted with EtOAc (3 x 30 mL). The combined EtOAc extracts were washed with saturated brine (15 mL) and concentrated under reduced pressure to afford the titled compound (200 mg), which was used without further purification. LCMS m/z 148.1 (M+H)+.
(d) 2-Hydroxy-5-(N-(7-methyl-1 H-benzo[d]imidazol-5-yl)sulfamoyl)benzamide
To a suspension of 4-methyl-1 H-benzo[d]imidazol-6-amine (190 mg) in DCM (5 mL) under nitrogen at 0 °C was added 3-carbamoyl-4-hydroxybenzene-1 -sulfonyl chloride (lnt-1 , 300 mg) portionwise over 5 min. The reaction mixture was allowed to warm to RT and was stirred for 16 hr. The reaction mixture was concentrated under reduced pressure and water (10 mL) was added. The resulting solid was collected by filtration to afford the crude product (250 mg). The crude product was purified by preparative reversed phase HPLC (Kromasil C18, 21 x 150 mm), using a 10-35% gradient of acetonitrile in 10 mM ammonium acetate (aq). The desired fraction was lyophilized to afford the titled compound (34 mg). LCMS m/z 347.14 (M+H)+. 1H NMR (400MHz, DMSO-c/6) δ = 13.36 (br s, 1 H), 12.36 (br s, 1 H), 9.85 (s, 1 H), 8.49 (br s, 1 H), 8.30 (d, J=2.2 Hz, 1 H), 8.10 (s, 1 H), 7.97 (br s, 1 H), 7.69 (dd, J=2.2, 8.8 Hz, 1 H), 7.08 (s, 1 H), 6.99 (d, J=8.8 Hz, 1 H), 6.77 (s, 1 H), 2.40 (s, 3H).
Example 103
5-(N-(1 H-pyrazol-4-yl)sulfamoyl)-2-hvdroxybenzamide
Figure imgf000177_0001
A 40 mL reaction vial equipped with a stirbar was charged with a suspension of tert-butyl 4-amino-1 /-/-pyrazole-1 -carboxylate (0.466 g) in dichloromethane (DCM) (8.5 mL). The suspension was then treated with solid 3-carbamoyl-4-hydroxybenzene-1 -sulfonyl chloride (lnt-1 , 200 mg) portionwise, and the resulting mixture stirred overnight at room temperature. The mixture was then diluted up to an approximately 30 mL total volume with ethyl acetate and the resulting suspension filtered to collect the solids. The precipitate was found to contain the majority of the product and so the solid was taken up in ethyl acetate and treated with a 4N 1 ,4-dioxane solution of hydrochloric acid (5 mL). The resulting reaction mixture was warmed to 55 °C with stirring overnight. The reaction was cooled to room temperature and the resulting suspended solids collected by suction filtration. The cake was then washed with ethyl acetate, affording a dark purple solid. LCMS indicated the presence of some pyrazolyl amine still trapped in the solid and so the material was taken up in ~3 mL 0.1 % aqueous formic acid and sonicated. The resulting thick suspension was collected by suction filtration, the solid washed with ~3 mL 0.1 % aqueous formic acid and dried by suction to afford the title compound as a purple solid (180 mg). LCMS m/z 283.5 (M+H)+. 1H NMR (400 MHz, DMSO-c/6) δ ppm 7.04 (d, J=8.84 Hz, 1 H) 7.26 (br. s., 2 H) 7.68 (dd, J=8.72, 2.40 Hz, 1 H) 8.05 (br. s., 1 H) 8.23 (d, J=2.27 Hz, 1 H) 8.56 (br. s., 1 H) 9.52 (s, 1 H) 13.51 (br. s., 1 H).
Example 104
5-(N-(6-Fluoro-1 /y-indol-5-yl)sulfamoyl)-2-hvdroxybenzamide
Figure imgf000178_0001
(a) 4-Bromo-5-fluoro-2-iodoaniline
To a solution of 4-bromo-3-fluoroaniline (16 g) in acetic acid (30 mL) at 0 °C was slowly added NIS (18.94 g). The reaction mixture was allowed to warm to RT and was stirred for 90 min. The reaction mixture was poured into ice water and the resulting solid was collected by filtration and dried under vacuum to afford the titled compound (20 g), which was used without further purification. LCMS m/z 315.97 (M+H)+.
(b) 4-Bromo-5-fluoro-2-((trimethylsilyl)ethynyl)aniline
To a solution of 4-bromo-5-fluoro-2-iodoaniline (30 g),
bis(triphenylphosphine)palladium(ll) chloride (3.33 g) and copper(l) iodide (0.904 g) in triethylamine (400 mL) at 0 °C under nitrogen was slowly added ethynyltrimethylsilane (9.33 g). The reaction mixture was allowed to warm to RT and was stirred for 2 hr. The reaction mixture was filtered through Celite and the filtrate was washed with water followed by saturated brine, dried over sodium sulfate, and concentrated under reduced pressure to afford the crude product. The crude product was purified by silica gel column chromatography, eluting with 5% EtOAc/hexane to afford the titled compound (14 g). LCMS m/z 286.20 (M+H)+.
(c) 5-Bromo-6-fluoro-1 H-indole
To a solution of 4-bromo-5-fluoro-2-((trimethylsilyl)ethynyl)aniline (7 g) in DMF (120 mL) at 0 °C was added copper(l) iodide (9.32 g). The reaction mixture was heated to 1 15 °C and stirred for 7 hr. The reaction mixture was allowed to cool to RT and was diluted with water (300 mL) and extracted with EtOAc (2 x 600 mL). The combined EtOAc extracts were dried over sodium sulfate and concentrated under reduced pressure to afford the crude product. The crude product was purified by silica gel column chromatography, eluting with 10% EtOAc/hexane. The desired fractions were concentrated under reduced pressure to afford the titled compound (2.9 g). LCMS m/z 212.09 (M-H)". (d) 5-Bromo-6-fluoro-1 -(triisopropylsilyl)-l H-indole
LiHMDS (1 M in THF, 16.25 mL) was slowly added to a solution of 5-bromo-6-fluoro-1 /-/- indole (2.9 g) in THF (30 mL) at -78 °C. The reaction mixture was stirred at -78 °C for 20 min and then chlorotriisopropylsilane (2.59 mL) was added. The reaction mixture was allowed to warm to RT over 1 hr. The reaction mixture was quenched by the addition of saturated ammonium chloride (aq) (40 mL), diluted with water (80 mL) and extracted with EtOAc (3 x 200 ml). The combined EtOAc extracts were dried over sodium sulfate and concentrated under reduced pressure to afford the crude product. The crude product was purified by silica gel column chromatography, eluting with hexane. The desired fractions were concentrated under reduced pressure to afford the titled compound (3.5 g). LCMS m/z 370 (M+H)+.
(e) 6-Fluoro-N-(4-methoxybenzyl)-1 -(triisopropylsilyl)-l H-indol-5-amine
To a solution of 5-bromo-6-fluoro-1 -(triisopropylsilyl)-1 /-/-indole (1 .5 g) in toluene (15 mL) was added (4-methoxyphenyl)methanamine (0.833 g) followed by sodium tert-butoxide (1 .168 g). The reaction vessel was purged with argon and dicyclohexyl(2',4',6'-triisopropyl- 3,6-dimethoxy-[1 ,1 '-biphenyl]-2-yl)phosphine (0. 277 g) and Pd2(dba)3 (0.371 g) were then added. The reaction vessel was sealed and the reaction mixture was heated to 1 15 °C and stirred for 20 hr. The reaction mixture was allowed to cool to RT and was filtered through Celite. The filtrate was concentrated under reduced pressure to afford the crude product, which was purified by silica gel column chromatography, eluting with 4% EtOAc/hexane to afford the titled compound. LCMS m/z 427.3 (M+H)+.
(f) 6-Fluoro-1 -(triisopropylsilyl)-l H-indol-5-amine
To a solution of 6-fluoro-N-(4-methoxybenzyl)-1 -(triisopropylsilyl)-1 /-/-indol-5-amine (700 mg) in EtOAc (12 mL) at 0 °C under nitrogen was added 10% Pd/C (349 mg). The reaction mixture was stirred under a hydrogen balloon at RT for 16 hr. The reaction mixture was filtered through Celite and the filtrate concentrated under reduced pressure to afford the titled compound (380 mg), which was used without further purification. LCMS m/z 307.18 (M+H)+.
(a) 5-(N-(6-Fluoro-1 -(triisopropylsilyl)-l H-indol-5-yl)sulfamoyl)-2-hydroxybenzamide To a solution of 6-fluoro-1 -(triisopropylsilyl)-1 H-indol-5-amine (200 mg) in DCM (10 mL) was added pyridine (0.264 mL) followed by 3-carbamoyl-4-hydroxybenzene-1 -sulfonyl chloride (lnt-1 , 154 mg), and the reaction mixture was stirred at RT for 16 hr. The reaction mixture was diluted with water (10 mL) and extracted with DCM (3 x 20 mL). The combined DCM extracts were washed with saturated brine (25 mL), dried over sodium sulfated and concentrated under reduced pressure to afford the titled compound (210 mg), which was used without further purification. LCMS m/z 504.22 (M-H)~.
(g) 5-(N-(6-Fluoro-1 H-indol-5-yl)sulfamoyl)-2-hydroxybenzamide
To a solution of 5-(N-(6-fluoro-1 -(triisopropylsilyl)-1 /-/-indol-5-yl)sulfamoyl)-2- hydroxybenzamide (200 mg) in THF (5 mL) was added TBAF (1 M in THF, 1 .582 mL) at RT and the reaction mixture was stirred for 3 hr. The reaction mixture was diluted with water (29 mL) and extracted with EtOAc (3 x 40 mL). The combined EtOAc extracts were washed with saturated brine (50 mL), dried over sodium sulfate, and concentrated under reduced pressure to afford the crude product (190 mg). The crude product was purified by preparative reversed phase HPLC (XBridge C18, 19 x 150 mm) using a gradient of 10-45% acetonitrile in 10 mM ammonium acetate. The desired fractions were concentrated under reduced pressure to afford the titled compound (72 mg). LCMS m/z 350.05 (M+H)+. 1H NMR (400MHz, DMSO-c/6) δ = 13.47 (br s, 1 H), 1 1 .12 (br s, 1 H), 9.56 (s, 1 H), 8.50 (br s, 1 H), 8.21 (d, J = 2.0 Hz, 1 H), 7.94 (br s, 1 H), 7.65 (dd, J=2.2, 8.8 Hz, 1 H), 7.38 - 7.22 (m, 2H), 7.10 (d, J=10.7 Hz, 1 H), 7.01 (d, J=8.8 Hz, 1 H), 6.39 (br s, 1 H).
Example 105
2-Hvdroxy-5-(N-(2-(hvdroxymethyl)-1 /y-indol-6-yl)sulfamoyl)benzamide
Figure imgf000180_0001
To a suspension of LiAIH4 (73.1 mg) in THF (15 mL) at 0 °C was added methyl 6-(3- carbamoyl-4-hydroxyphenylsulfonamido)-1 /-/-indole-2-carboxylate (Example 100, 250 mg). The reaction mixture was allowed to warm to RT and was stirred for 2 hr. The reaction mixture was cooled to 0 °C diluted with saturated ammonium chloride (aq) and then extracted with EtOAc (2 x 50 mL). The combined EtOAc extracts were dried over sodium sulfate, filtered and concentrated under reduced pressure to afford the crude product (1 10 mg). The crude product was purified by preparative reversed phase HPLC (Kinetex Phenylhexyl, 150 x 30 mm) using a gradient of 5-30% acetonitrile in 10 mM ammonium bicarbonate (aq). The desired fractions were lyophilized to afford the titled compound (20 mg). LCMS m/z 360.06 (M-H)-. 1H NMR (400MHz, DMSO-c/6) δ = 13.31 (br s, 1 H), 10.88 (br s, 1 H), 9.70 (s, 1 H), 8.50 (br s, 1 H), 8.26 (d, J=2.2 Hz, 1 H), 7.93 (br s, 1 H), 7.63 (dd, J=2.2, 8.8 Hz, 1 H), 7.26 (d, J=8.3 Hz, 1 H), 7.06 (s, 1 H), 6.96 (d, J=8.8 Hz, 1 H), 6.70 (dd, J=1 .8, 8.6 Hz, 1 H), 6.15 (s, 1 H), 5.13 (br t, J=5.5 Hz, 1 H), 4.52 (d, J=5.0 Hz, 2H).
Example 106
5-(N-(3-Ethyl-1 /y-indol-6-yl)sulfamoyl)-4-(ethylamino)-2-hvdroxybenzamide
Figure imgf000181_0001
(a) 5-(N-(3-Ethyl-1 H-indol-6-yl)sulfamoyl)-4-fluoro-2-hydroxybenzamide
To a solution of 3-ethyl-1 H-indol-6-amine (Example 69 (b), 316 mg)in DCM (15 mL) at 0 °C under nitrogen was added pyridine (0.478 mL) followed by 5-carbamoyl-2-fluoro-4- hydroxybenzene-1 -sulfonyl chloride (lnt-2, 500 mg). The reaction mixture was allowed to warm to RT and was stirred for 16 hr. The reaction mixture was concentrated under reduced pressure to afford the crude product (600 mg), which was used without further purification. LCMS m/z 376.18 (M-H)-.
(b) 5-(N-(3-Ethyl-1 H-indol-6-yl)sulfamoyl)-4-(ethylamino)-2-hydroxybenzamide
5-(N-(3-Ethyl-1 /-/-indol-6-yl)sulfamoyl)-4-fluoro-2-hydroxybenzamide (600 mg) was suspended in ethanamine (2 M in THF, 3 mL) and the reaction vessel was sealed, heated to 120 °C and stirred for 16 hr. The reaction mixture was allowed to cool to RT and was concentrated under reduced pressure to afford the crude product (500 mg). The crude product was purified by preparative reversed phase HPLC (XBridge C18, 19 x 150 mm) using a gradient of 10-60% acetonitrile in 10 mM ammonium bicarbonate (aq). The desired fraction was lyophilized to afford the titled compound (191 mg). LCMS m/z 403.18 (M+H)+. 1H NMR (400MHz, DMSO-c/6) δ = 13.59 (br s, 1 H), 10.59 (s, 1 H), 9.78 (s, 1 H), 8.10 (s, 2H), 7.52 (br s, 1 H), 7.32 (d, J=8.6 Hz, 1 H), 7.06 - 6.97 (m, 2H), 6.73 (dd, J=1 .9, 8.4 Hz, 1 H), 6.06 - 6.02 (m, 1 H), 5.98 (s, 1 H), 3.16 (q, J=7.2 Hz, 2H), 2.61 (q, J=7.2 Hz, 2H), 1 .20 (t, J=7.5 Hz, 3H), 1 .09 (t, J=7.1 Hz, 3H).
Example 107
4-Fluoro-2-hvdroxy-5-(N-(4-isopropoxyphenyl)sulfamoyl)benzamide
Figure imgf000182_0001
To a solution of 5-carbamoyl-2-fluoro-4-hydroxybenzene-1 -sulfonyl chloride (lnt-2, 1 .4 g) in DCM (15 mL) at 0 °C was added pyridine (0.670 mL) followed by 4-isopropyxyaniline (0.696 mL). The reaction mixture was allowed to warm to RT and was stirred for 16 hr. The reaction mixture was poured into water (10 mL) and extracted with DCM (2 x 15 mL). The combined DCM extracts were washed with saturated brine (10 mL), dried over sodium sulfate and concentrated under reduced pressure to afford the crude product (900 mg). The crude product was purified by silica gel column chromatography, eluting with 30-40% EtOAc/petroleum ether to afford the titled compound (700 mg). LCMS m/z 369.09 (M+H)+. Ή NMR (400 MHz, DMSO-c/6) δ ppm 1 .19 (d, J=5.92 Hz, 6 H) 4.36 - 4.56 (m, 1 H) 6.58 - 6.84 (m, 2 H) 6.84 - 7.10 (m, 3 H) 8.06 (br. s., 1 H) 8.31 (d, J=8.1 1 Hz, 1 H) 8.62 (br. s., 1 H) 10.06 (s, 1 H) 14.06 (br. s., 1 H).
Example 108
4-((2-Chlorobenzyl)amino)-2-hydroxy-5-(N-(4- isopropoxyphenvDsulfamovDbenzamide
Figure imgf000182_0002
To a solution of (2-chlorophenyl)methanamine (0.235 mL) in toluene (10 mL) was added NaH (32.6 mg) followed by 4-fluoro-2-hydroxy-5-(N-(4- isopropoxyphenyl)sulfamoyl)benzamide (Example 107, 200 mg). The reaction vessel was sealed and the reaction mixture was heated to 120 °C and stirred for 48 hr. The reaction mixture was allowed to cool to RT and was poured into water (10 mL) and extracted with EtOAc (2 x 20 mL). The combined EtOAc extracts were washed with saturated brine (10 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to afford the crude product (250 mg). The crude product was purified by preparative reversed phase HPLC (Xterra RP18, 19 x 250 mm) using a gradient of 10-55% acetonitrile in 0.1 % formic acid (aq). The desired fraction was lyophilized to afford the titled compound (70 mg). LCMS m/z 490.18 (M+H)+. Ή NMR (400MHz, DMSO-c/6) δ = 13.58 (br s, 1 H), 9.84 (br s, 1 H), 8.15 (s, 2H), 7.68 - 7.44 (m, 2H), 7.34 - 7.15 (m, 3H), 7.05 - 6.94 (m, 2H), 6.84 - 6.73 (m, 3H), 5.80 (s, 1 H), 4.59 - 4.38 (m, 3H), 1 .20 (d, J=5.9 Hz, 6H).
Example 109
Methyl 6-(3-carbamoyl-4-hvdroxyphenylsulfonamido)-1 tf-indole-4-carboxylate
Figure imgf000183_0001
(a) Methyl 2-methyl-3,5-dinitrobenzoate
To a solution of 2-methyl-3,5-dinitrobenzoic acid (10 g) in MeOH (200 mL) at 0 °C under nitrogen was added SOCI2 (9.68 mL) dropwise. The reaction mixture was heated to 75 °C and stirred for 16 hr. The reaction mixture was allowed to cool to RT and was concentrated under reduced pressure, diluted with water (150 mL) and extracted with EtOAc (3 x 100 mL). The combined EtOAc extracts were washed with saturated sodium bicarbonate (aq) (2 x 150 mL) and saturated brine (100 mL), and were dried over sodium sulfated, filtered and concentrated under reduced pressure to afford the titled compound (10.5 g). LCMS m/z 238.85 (M+H)+.
(b) (E)-Methyl 2-(2-(dimethylamino)vinyl)-3,5-dinitrobenzoate
To a solution of methyl 2-methyl-3,5-dinitrobenzoate (1 1 g) in DMF (2 mL) was added 1 ,1 - dimethoxy-N,N-dimethylmethanamine (12.17 mL) and the reaction mixture was heated to 75 °C and stirred for 1 hr. The reaction mixture was allowed to cool to RT and poured into ice water (500 mL). The resulting solid was collected by filtration, washed with water (3 x 150 mL) followed by n-pentane (2 x 150 ml), and dried under vacuum to afford the titled compound (1 1 .5 g) Ή NMR (400 MHz, DMSO-c/6) L ppm 2.99 (s, 6 H) 3.86 (s, 3 H) 5.69 (d, J=12.94 Hz, 1 H) 6.95 (d, J=12.94 Hz, 1 H) 8.41 (d, J=2.63 Hz, 1 H) 8.59 (d, J=2.41 Hz, 1 H). (c) Methyl 6-amino-1 H-indole-4-carboxylate
To a solution of (E)-methyl 2-(2-(dimethylamino)vinyl)-3,5-dinitrobenzoate (1 1 .5 g) in MeOH (15 ml_) under nitrogen was added 10% Pd/C (1 .66 g), and the reaction mixture was stirred under a hydrogen balloon for 48 hr. The reaction mixture was filtered through Celite and the precipitate washed with MeOH (3 x 5 ml_). The combined filtrates were concentrated under reduced pressure. The resulting solid was washed with n-pentane (2 x 10 ml_) and dried under vacuum to afford the crude product. The crude product was purified by silica gel flash chromatography, eluting with 30% EtOAc/petroleum ether. The desired fraction was concentrated under reduced pressure and the resulting solid was triturated with DCM (5 ml_) and n-pentane (10 ml_) and dried under vacuum to afford the titled compound (200 mg). LCMS m/z 191 .0 (M+H)+.
(d) Methyl 6-(3-carbamoyl-4-hydroxyphenylsulfonamido)-1 H-indole-4-carboxylate
To a solution of methyl 6-amino-1 /-/-indole-4-carboxylate (174 mg) and pyridine (0.247 ml_) in DCM (15 ml_) at 0 °C under nitrogen was added 3-carbamoyl-4-hydroxybenzene-1 - sulfonyl chloride (lnt-1 , 240 mg). The reaction mixture was allowed to warm to RT and was stirred for 16 hr. The reaction mixture was concentrated under reduced pressure, water (15 ml_) was added and the reaction mixture was stirred for 30 min. The resulting solid was collected by filtration, washed with water (2 x 5 ml_), diethyl ether (5 ml_) and 10% acetonitrile/water (3 ml_) and dried under vacuum to afford the titled compound (180 mg). LCMS m/z 388.06 (M-H)". Ή NMR (400MHz, DMSO-c/6) δ = 13.35 (br s, 1 H), 1 1 .33 (s, 1 H), 9.99 (s, 1 H), 8.46 (br s, 1 H), 8.29 (s, 1 H), 7.97 (br s, 1 H), 7.66 (d, J=8.1 Hz, 1 H), 7.57 - 7.37 (m, 3H), 6.99 (d, J=7.7 Hz, 1 H), 6.82 (s, 1 H), 3.86 (s, 3H).
Example 110
2-Hvdroxy-4-((2-hvdroxyethyl)amino)-5-(N-(4- isopropoxyphenvDsulfamovDbenzamide
Figure imgf000184_0001
4-Fluoro-2-hydroxy-5-(N-(4-isopropoxyphenyl)sulfamoyl)benzamide (Example 107, 500 mg) and 2-aminoethanol (10 ml_) were heated to 100 °C in a sealed reaction vessel and were stirred for 16 hr. The reaction mixture was allowed to cool to RT and was concentrated under reduced pressure to afford the crude product (500 mg). The crude product was purified by preparative reversed phase HPLC (Kromasil C18, 21 x 150 mm) using a gradient of 10-50% acetonitrile in 10 mM ammonium bicarbonate (aq). The desired fraction was lyophilized to afford the titled compound (179 mg). LCMS m/z 408.18 (M-H)". 1H NMR (400MHz, DMSO-c/e) δ = 13.71 (br s, 1 H), 9.64 (br s, 1 H), 8.25 (br s, 1 H), 8.05 (s, 1 H), 7.50 (br s, 1 H), 7.02 - 6.83 (m, 2H), 6.80 - 6.59 (m, 2H), 6.29 (br s, 1 H), 6.03 (br s, 1 H), 4.80 (br s, 1 H), 4.53 - 4.36 (m, 1 H), 3.57 (br s, 2H), 3.17 (q, J=5.3 Hz, 2H), 1 .18 (d, J=6.1 Hz, 6H).
Example 111
5-(N-(2-Ethyl-1 tf-indol-6-yl)sulfamoyl)-4-(ethylamino)-2-hvdroxybenzamide
Figure imgf000185_0001
(a) 5-(N-(2-Ethyl-1 H-indol-6-yl)sulfamoyl)-4-fluoro-2-hydroxybenzamide
To a solution of 2-ethyl-1 /-/-indol-6-amine (Example 75 (b), 250 mg) in DCM (10 mL) was added pyridine (0.379 mL) followed by 5-carbamoyl-2-fluoro-4-hydroxybenzene-1 -sulfonyl chloride (lnt-2, 396 mg), and the reaction mixture was stirred at RT for 16 hr. The reaction mixture was diluted with water (50 mL) and extracted with DCM (2 x 100 mL). The combined DCM extracts were washed with saturated brine (50 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford the titled compound (400 mg), which was used without further purification. LCMS m/z 376.04 (M-H)".
(b) 5-(N-(2-Ethyl-1 H-indol-6-yl)sulfamoyl)-4-(ethylamino)-2-hydroxybenzamide
5-(N-(2-Ethyl-1 /-/-indol-6-yl)sulfamoyl)-4-fluoro-2-hydroxybenzamide (400 mg) and ethanamine (2 M in THF, 10 mL) were heated to 100 °C in a sealed reaction vessel and were stirred for 16 hr. The reaction mixture was allowed to cool to RT and was concentrated under reduced pressure to afford the crude product. The crude product was purified by preparative reversed phase HPLC (Kromasil C18, 21 x 250 mm) using a gradient of 65- 100% acetonitrile in 0.1 % formic acid (aq). The desired fraction was lyophilized to afford the titled compound (66.9 mg). LCMS m/z 403.18 (M+H)+. Ή NMR (400MHz, DMSO-c/6) δ = 13.59 (br s, 1 H), 10.77 (br s, 1 H), 9.70 (br s, 1 H), 8.07 (br s, 2H), 7.51 (br s, 1 H), 7.21 (br d, J=8.1 Hz, 1 H), 6.95 (br s, 1 H), 6.68 (br d, J=7.7 Hz, 1 H), 6.15 - 5.88 (m, 3H), 3.19 - 2.93 (m, 2H), 2.66 (br d, J=7.0 Hz, 2H), 1 .22 (br t, J=7.3 Hz, 3H), 1 .09 (br t, J=6.9 Hz, 3H). Example 112
4-((3-Chlorobenzyl)amino)-2-hydroxy-5-(N-(4- isopropoxyphenvDsulfamovDbenzamide
Figure imgf000186_0001
To a solution of (3-chlorophenyl)methanamine (231 mg) in toluene (10 mL) was added NaH (32.6 mg) followed by 4-fluoro-2-hydroxy-5-(N-(4-isopropoxyphenyl)sulfamoyl)benzamide (Example 107, 200 mg). The reaction vessel was sealed and the reaction mixture was stirred at 120 °C for 48 hr. The reaction mixture was allowed to cool to RT and was then poured into water (10 mL) and extracted with EtOAc (2 x 20 mL). The combined EtOAc extracts were washed with saturated brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to afford the crude product (200 mg). The crude product was purified by preparative reversed phase HPLC (Sunfire C18, 19 x 150 mm) using a gradient of 30-70% acetonitrile in 0.1 % formic acid (aq). The desired fraction was lyophilized to afford the titled compound (80 mg). LCMS m/z 490.15 (M+H)+. 1H NMR (400MHz, DMSO-c/e) δ = 13.58 (br s, 1 H), 9.84 (br s, 1 H), 8.79 - 8.31 (m, 1 H), 8.12 (s, 1 H), 7.68 - 7.44 (m, 2H), 7.34 - 7.15 (m, 3H), 7.05 - 6.94 (m, 2H), 6.84 - 6.73 (m, 3H), 5.80 (s, 1 H), 4.59 - 4.38 (m, 3H), 1 .20 (d, J=5.9 Hz, 6H).
Example 113
4-((2-Aminoethyl)amino)-2-hydroxy-5-(N-(4- isopropoxyphenvDsulfamovDbenzamide, Formic acid salt
Figure imgf000186_0002
4-Fluoro-2-hydroxy-5-(N-(4-isopropoxyphenyl)sulfamoyl)benzamide (Example 107, 500 mg) and ethane diamine (10 mL) were heated to 100 °C in a sealed reaction vessel and were stirred for 16 hr. The reaction mixture was allowed to cool to RT and was concentrated under reduced pressure to afford the crude product (500 mg). The crude product was purified by preparative reversed phase HPLC (Sunfire C18, 30 x 250 mm) using a gradient of 10-40% acetonitrile in 0.1 % formic acid (aq). The desired fraction was lyophilized to afford the titled compound (159 mg). LCMS m/z 409.23 (M+H)+. Ή NMR (400MHz, DMSO- de) δ = 8.58 (br s, 1 H), 8.37 (br s, 1 H), 8.05 (s, 1 H), 7.34 (br s, 1 H), 7.01 - 6.86 (m, 2H), 6.79 - 6.67 (m, 2H), 6.19 (br s, 1 H), 6.12 (s, 1 H), 4.54 - 4.42 (m, 1 H), 3.31 (br d, J=3.5 Hz, 2H), 2.90 (br t, J=6.2 Hz, 2H), 1 .18 (d, J=6.1 Hz, 6H).
Example 114
(S)-2-Hvdroxy-5-(N-(4-isopropoxyphenyl)sulfamoyl)-4-((1 - phenylethyl)amino)benzamide
Figure imgf000187_0001
To a solution of (S)-1 -phenylethanamine (197 mg) in toluene (10 mL) was added NaH (32.6 mg) followed by 4-fluoro-2-hydroxy-5-(N-(4-isopropoxyphenyl)sulfamoyl)benzamide (Example 107, 200 mg). The reaction vessel was sealed and the reaction mixture was stirred at 120 °C for 48 hr. The reaction mixture was allowed to cool to RT and was then poured into water (10 mL) and extracted with EtOAc (2 x 20 mL). The combined EtOAc extracts were washed with saturated brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to afford the crude product (150 mg). The crude product was purified by preparative reversed phase HPLC (XBridge C18, 19 x 150 mm) using a gradient of 30-70% acetonitrile in 10 mM ammonium bicarbonate (aq). The desired fraction was lyophilized to afford the titled compound (34 mg). LCMS m/z 470.24 (M+H)+. Ή NMR (400 MHz, DMSO-c/6) δ ppm 1 .19 (dd, J=5.92, 2.41 Hz, 6 H) 1 .45 (d, J=6.58 Hz, 3 H) 4.42 - 4.53 (m, 1 H) 4.53 - 4.65 (m, 1 H) 5.75 (s, 1 H) 6.47 (d, J=5.48 Hz, 1 H) 6.75 - 6.84 (m, 2 H) 6.97 - 7.05 (m, 2 H) 7.16 - 7.34 (m, 5 H) 7.38 - 7.63 (m, 1 H) 8.12 (s, 1 H) 8.29 (br. s., 1 H) 10.02 (br. s., 1 H) 13.57 (br. s., 1 H). Example 115
4-(Benzylamino)-5-(N-(3-ethyl-1 /y-indol-6-yl)sulfamoyl)-2-hvdroxybenzamide
Figure imgf000188_0001
(a) 5-(N-(3-Ethyl-1 H-indol-6-yl)sulfamoyl)-4-fluoro-2-hydroxybenzamide
To a solution of 5-carbamoyl-2-fluoro-4-hydroxybenzene-1 -sulfonyl chloride (lnt-2, 500 mg) in DCM (15 ml_) at 0 °C under nitrogen was added pyridine (0.399 ml_) followed by 3-ethyl- 1 /-/-indol-6-amine (Example 69 (b), 316 mg). The reaction mixture was allowed to warm to RT and was stirred for 16 hr. The reaction mixture was concentrated under reduced pressure to afford the titled compound (700 mg), which was used without further purification. LCMS m/z 378.21 (M+H)+.
(b) 4-(Benzylamino)-5-(N-(3-ethyl-1 H-indol-6-yl)sulfamoyl)-2-hydroxybenzamide
To a solution of 5-(N-(3-ethyl-1 /-/-indol-6-yl)sulfamoyl)-4-fluoro-2-hydroxybenzamide (600 mg) in EtOH (15 ml_) was added benzylamine (3 ml_). The reaction vessel was sealed and the reaction mixture was heated to 100 °C and stirred for 16 hr. The reaction mixture was allowed to cool to RT and was concentrated under reduced pressure to afford the crude product (500 mg). The crude product was purified by preparative reversed phase HPLC (XBridge C18, 19 x 150 mm) using a gradient of 10-60% acetonitrile in 10 mM ammonium bicarbonate (aq). The desired fraction was lyophilized to afford the titled compound (98 mg). LCMS m/z 463.24 (M-H)". 1H NMR (400 MHz, DMSO-c/6) δ ppm 1 .21 (t, J=7.56 Hz, 3 H) 2.63 (q, J=7.75 Hz, 2 H) 4.42 (d, J=5.92 Hz, 2 H) 5.86 (s, 1 H) 6.70 - 6.91 (m, 2 H) 7.01 (s, 1 H) 7.09 (d, J=1 .53 Hz, 1 H) 7.17 - 7.30 (m, 4 H) 7.34 (d, J=8.33 Hz, 1 H) 8.16 (s, 2 H) 9.89 (s, 1 H) 10.61 (s, 1 H) 13.50 (s, 1 H).
Example 116
5-(N-(1 H-Benzord1imidazol-6-yl)sulfamoyl)-3-bromo-2-hvdroxybenzamide
Figure imgf000189_0001
3-Bromo-5-carbamoyl-4-hydroxybenzene-1 -sulfonyl chloride (lnt-3, 290 mg) was added to a stirred suspension of 1 H-benzo[d]imidazol-6-amine (398 mg) in dichloromethane (DCM) (10 ml_), the suspension sonicated briefly, and the resulting mixture stirred overnight at room temperature. The reaction mixture was diluted up to ~40 ml_ total volume with DCM and filtered to isolate the precipitate from the solvent. The desired compound was found to be almost entirely in the precipitate, and the filtrate was discarded. The precipitate was then taken up in a minimum amount of ethanol for injection onto a 30 gram SNAP Ultra C-18 silica cartridge for purification, eluting with a gradient of 0-60% ethanol in 0.1 % aq. formic acid 17.5 CV. Fractions containing the desired material were then pooled and concentrated to a residue which was subsequently triturated with ethanol to afford the titled compound as a rust-brown solid (49 mg). LCMS m/z 41 1 .2, 413.3 (M+H, bromide). 1H NMR (400 MHz, DMSO-c/e) δ ppm 6.97 (dd, J=8.62, 2.03 Hz, 1 H) 7.31 (dd, J=2.03, 0.51 Hz, 1 H) 7.49 (dd, J=8.62, 0.51 Hz, 1 H) 8.00 (d, J=2.28 Hz, 1 H) 8.13 (s, 1 H) 8.19 - 8.28 (m, 2 H) 8.30 (s, 1 H) 9.13 (br. s., 1 H) 10.02 (s, 1 H) 12.90 (br. s., 1 H).
Example 117
5-(N-(1 H-lndol-5-yl)sulfamoyl)-2-hvdroxy-3-methylbenzamide
Figure imgf000189_0002
To a solution of 1 H-indol-5-amine (265 mg) in DCM (5 ml_) at 0 °C was added pyridine (0.486 ml_) followed by 3-carbamoyl-4-hydroxy-5-methylbenzene-1 -sulfonyl chloride (lnt-4, 500 mg). The reaction mixture was allowed to warm to RT and was stirred overnight. The reaction mixture was concentrated under reduced pressure, poured into ice water (10 mL), and the water layer decanted from the resulting solid to afford the crude product (200 mg). The crude product was purified by preparative reversed phase HPLC (Kromasil C18, 25 x 250 mm) using a gradient of 10-50% acetonitrile in 10 mM ammonium bicarbonate (aq). The desired fraction was concentrated under reduced pressure and the resulting solid was collected by filtration, washed with water, and dried under vacuum to afford the titled compound (133.8 mg). LCMS m/z 346.00 (M+H)+. Ή NMR (400 MHz, DMSO-c/6) δ ppm 2.13 (s, 3 H) 6.32 (t, J=2.08 Hz, 1 H) 6.80 (dd, J=8.66, 2.08 Hz, 1 H) 7.16 - 7.35 (m, 3 H) 7.64 (d, J=1 .32 Hz, 1 H) 8.04 (br. s., 1 H) 8.1 1 (d, J=1 .97 Hz, 1 H) 8.71 (br. s., 1 H) 9.57 (s, 1 H) 1 1 .00 (br. s., 1 H) 14.28 (s, 1 H).
Example 118
5-(N-(1 H-Benzord1imidazol-5-yl)sulfamoyl)-2-hvdroxy-3-methylbenzamide.
Trifluoroacetate
Figure imgf000190_0001
To a solution of 1 H-benzo[d]imidazol-5-amine (400 mg) in DCM (10 mL) at 0 °C was added 3-carbamoyl-4-hydroxy-5-methylbenzene-1 -sulfonyl chloride (lnt-4, 500 mg). The reaction mixture was allowed to warm to RT and was stirred for 16 hr. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2 x 50 mL). The combined EtOAc extracts were washed with saturated brine (50 mL), dried over sodium sulfate and concentrated under reduced pressure to afford the crude product (500 mg). The crude product was purified by preparative reversed phase HPLC (Sunfire C18, 19 x 150 mm) using a gradient of 10-30% acetonitrile in 0.1 % TFA (aq). The desired fraction was concentrated under reduced pressure and the resulting solid was collected by filtration, washed with water (10 mL) and dried under vacuum to afford the titled compound (103.8 mg). LCMS 347.05 (M+H)+. 1H NMR (400 MHz, DMSO-c/6) δ ppm 2.14 (s, 3 H) 7.22 (dd, J=8.77, 1 .97 Hz, 1 H) 7.44 (d, J=1 .75 Hz, 1 H) 7.54 - 7.78 (m, 2 H) 8.12 (br. s., 1 H) 8.21 (d, J=1 .97 Hz, 1 H) 8.77 (br. s., 1 H) 9.06 (s, 1 H) 10.28 (s, 1 H) 14.33 (br. s., 1 H). Example 119
2-Hvdroxy-5-(N-(4-isopropoxyphenyl)sulfamoyl)-3-methylbenzamide
Figure imgf000191_0001
To a solution of 4-isopropoxyaniline (151 mg) in DCM (5 mL) at 0 °C was added pyridine (0.243 mL) followed by 3-carbamoyl-4-hydroxy-5-methylbenzene-1 -sulfonyl chloride (lnt-4, 250 mg). The reaction mixture was allowed to warm to RT and was stirred for 16 hr. The reaction mixture was diluted with water (30 mL) and extracted with DCM ( 2 x 50 mL). The combined DCM extracts were washed with saturated brine (25 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to afford the crude product. The crude product was washed with diethyl ether (2 x 10 mL) and dried under vacuum to afford the titled compound (212 mg). LCMS m/z 365.09 (M+H)+. Ή NMR (400MHz, DMSO-c/6) δ = 14.33 (br s, 1 H), 9.63 (s, 1 H), 8.74 (br s, 1 H), 8.10 (d, J = 2.2 Hz, 2H), 7.60 (d, J = 1 .3 Hz, 1 H), 6.98 - 6.91 (m, 2H), 6.80 - 6.74 (m, 2H), 4.47 (td, J=6.0, 12.1 Hz, 1 H), 2.15 (s, 3H), 1 .19 (d, J = 5.9 Hz, 6H).
Example 120
5-(N-(1 H-lndazol-6-yl)sulfamoyl)-2-hvdroxy-3-methylbenzamide
Figure imgf000191_0002
To a solution of 1 H-indazol-6-amine (133 mg) in DCM (5 mL) at 0 °C was added pyridine (0.243 mL) followed by 3-carbamoyl-4-hydroxy-5-methylbenzene-1 -sulfonyl chloride (Int- 4, 250 mg). The reaction mixture was allowed to warm to RT and was stirred for 16 hr. The reaction mixture was diluted with water (30 ml_) and extracted with DCM (2 x 50 ml_). The combined DCM extracts were washed with saturated brine (25 ml_), dried over sodium sulfate, filtered and concentrated under reduced pressure to afford the crude product (300 mg). The crude product was purified by preparative reversed phase HPLC (XBridge C18, 4.6 X 50 mm) using a gradient of 5-15% acetonitrile in 5 mM ammonium bicarbonate (aq). The desired fraction was concentrated under reduced pressure and the resulting solid was collected by filtration, washed with water (10 ml_), and dried under vacuum to afford the titled compound (87.8 mg). LCMS m/z 347.06 (M+H)+. Ή NMR (400MHz, DMSO-c/6) δ = 14.32 (s, 1 H), 12.80 (s, 1 H), 10.17 (s, 1 H), 8.79 (br s, 1 H), 8.23 (d, J = 2.0 Hz, 1 H), 8.1 1 (br s, 1 H), 7.93 (s, 1 H), 7.68 (d, J = 1 .3 Hz, 1 H), 7.60 (d, J = 8.8 Hz, 1 H), 7.20 (s, 1 H), 6.92 (dd, J = 1 .8, 8.8 Hz, 1 H), 2.13 (s, 3H).
Example 121
5-(N-(1 H-indol-6-yl)sulfamoyl)-2-hvdroxy-3-methylbenzamide
Figure imgf000192_0001
To a solution of 1 H-indol-6-amine (132 mg) in DCM (5 ml_) at 0 °C was added pyridine (0.243 ml_) followed by 3-carbamoyl-4-hydroxy-5-methylbenzene-1 -sulfonyl chloride (Int- 4, 250 mg). The reaction mixture was allowed to warm to RT and was stirred for 16 hr. The reaction mixture was diluted with water (30 ml_) and extracted with DCM (2 x 50 ml_). The combined DCM extracts were washed with saturated brine (25 ml_), dried over sodium sulfate, filtered and concentrated under reduced pressure to afford the crude product. The crude product was washed with 10% MeOH/DCM (2 x 10 ml_) and dried under vacuum to afford the titled compound (144 mg). LCMS m/z 346.09 (M+H)+. Ή NMR (400MHz, DMSO- d6) δ = 14.32 (s, 1 H), 10.94 (br s, 1 H), 9.71 (s, 1 H), 8.78 (br s, 1 H), 8.17 (s, 1 H), 8.02 (br s, 1 H), 7.64 (s, 1 H), 7.35 (d, J = 8.3 Hz, 1 H), 7.23 (t, J = 2.6 Hz, 1 H), 7.13 (s, 1 H), 6.77 (dd, J = 1 .9, 8.4 Hz, 1 H), 6.31 (br s, 1 H), 2.12 (s, 3H). Example 122
2-Hvdroxy-3-methyl-5-(N-(2-methyl-1 /y-indol-6-yl)sulfamoyl)benzamide
Figure imgf000193_0001
To a solution of 2-methyl-1 /-/-indol-6-amine (76 mg) in DCM (5 mL) at 0 °C was added pyridine (0.126 mL) followed by 3-carbamoyl-4-hydroxy-5-methylbenzene-1 -sulfonyl chloride (lnt-4, 130 mg). The reaction mixture was allowed to warm to RT and was stirred for 16 hr. The reaction mixture was diluted with water (30 mL) and extracted with DCM (2 x 50 mL). The combined DCM extracts were washed with saturated brine (25 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to afford the crude product. The crude product was washed with diethyl ether (2 x 10 mL) and dried under vacuum to afford the titled compound (57.7 mg). LCMS 360.09 (M+H)+. Ή NMR (400MHz, DMSO-c/e) δ = 14.26 (s, 1 H), 10.75 (s, 1 H), 9.60 (s, 1 H), 8.71 (br s, 1 H), 8.13 - 8.01 (m, 2H), 7.64 (s, 1 H), 7.20 (d, J = 8.3 Hz, 1 H), 6.97 (s, 1 H), 6.69 (dd, J = 1 .8, 8.3 Hz, 1 H), 5.99 (s, 1 H), 2.30 (s, 3H), 2.13 (s, 3H).
Example 123
2-Hvdroxy-3-methyl-5-(N-(3-methyl-1 tf-indol-6-yl)sulfamoyl)benzamide
Figure imgf000193_0002
To a stirred solution of 3-methyl-1 H-indol-6-amine (371 mg) in DCM (15 mL) at 0 °C under nitrogen was added pyridine (0.194 mL) followed by 3-carbamoyl-4-hydroxy-5- methylbenzene-1 -sulfonyl chloride (lnt-4, 200 mg). The reaction mixture was allowed to warm to RT and was stirred for 16 hr. The reaction mixture was concentrated under reduced pressure to afford the crude product (500 mg). The crude product was purified by preparative reversed phase HPLC (Kinetex Phenylhexyl, 30 x 150 mm) using 20% acetonitrile in 10 mM ammonium formate (aq). The desired fraction was lyophilized to afford the titled compound (90 mg). LCMS m/z 360.13 (M+H)+. Ή NMR (400 MHz, DMSO-c/6) δ ppm: 14.26 (br s, 1 H), 10.57 (s, 1 H), 9.68 (br s, 1 H), 8.79 (br s, 1 H), 8.12 (d, J=1 .97 Hz, 1 H), 8.01 (br s, 1 H), 7.64 (s, 1 H)„ 7.28 (d, J=8.33 Hz, 1 H), 7.05 (d, J=1 .53 Hz, 1 H), 6.99 (d, J=0.88 Hz, 1 H), 6.76 (dd, J=8.33, 1 .97 Hz, 1 H), 2.1 1 - 2.20 (m, 6 H).
Example 124
5-(N-(2-Ethyl-1 tf-benzord1imidazol-5-yl)sulfamoyl)-2-hvdroxy-3-methylbenzamide
Figure imgf000194_0001
To a stirred solution of 2-ethyl-1 H-benzo[d]imidazol-5-amine (194 mg) in DCM (10 mL) at 0 °C was added pyridine (0.292 mL) followed by 3-carbamoyl-4-hydroxy-5-methylbenzene- 1 -sulfonyl chloride (lnt-4, 300 mg). The reaction mixture was allowed to warm to RT and was stirred for 16 hr. The reaction mixture was concentrated under reduced pressure to afford the crude product (500 mg). The crude product was purified by preparative reversed phase HPLC (Kromasil C18, 21 x 250 mm) using 20% acetonitrile in 10 mM ammonium bicarbonate (aq). The desired fraction was concentrated under reduced pressure to afford the titled compound (70 mg). LCMS m/z 374.9 (M+H)+. Ή NMR (400MHz, DMSO-c/6) δ = 14.27 (br s, 1 H), 1 1 .99 (br s, 1 H), 9.68 (br s, 1 H), 8.99 - 8.76 (m, 1 H), 8.10 (d, J = 1 .8 Hz, 1 H), 7.92 (br d, J = 2.4 Hz, 1 H), 7.60 (br s, 1 H), 7.28 (br s, 1 H), 7.12 (br s, 1 H), 6.85 (dd, J = 2.0, 8.6 Hz, 1 H), 2.75 (q, J = 7.7 Hz, 2H), 2.1 1 (s, 3H), 1 .26 (t, J=7.6 Hz, 3H).
Example 125
5-(N-(3-Ethyl-1 tf-indol-6-yl)sulfamoyl)-2-hvdroxy-3-methylbenzamide
Figure imgf000194_0002
To a stirred solution of 3-ethyl-1 /-/-indol-6-amine (Example 69 (b), 244 mg) in DCM (15 mL) at 0 °C under nitrogen was added pyridine (0.194 mL) followed by 3-carbamoyl-4-hydroxy- 5-methylbenzene-1 -sulfonyl chloride (lnt-4, 200 mg). The reaction mixture was allowed to warm to RT and was stirred for 16 hr. The reaction mixture was concentrated under reduced pressure to afford the crude product (240 mg). The crude product was purified by preparative reversed phase HPLC (Kinetex C8, 30 x150 mm), eluting with a gradient of 10- 45% acetonitrile in 10 mM ammonium bicarbonate (aq). The desired fraction was lyophilized to afford the titled compound (50 mg). LCMS m/z 372.15 (M-H)-. Ή NMR (400MHz, DMSO-c/e) δ = 14.27 (s, 1 H), 10.59 (s, 1 H), 9.70 (s, 1 H), 8.72 (br s, 1 H), 8.13 (d, J=2.2 Hz, 1 H), 8.06 (br s, 1 H), 7.66 (d, J=1 .3 Hz, 1 H), 7.32 (d, J=8.6 Hz, 1 H), 7.05 (d, J=1 .8 Hz, 1 H), 7.02 - 6.97 (m, 1 H), 6.75 (dd, J=1 .9, 8.4 Hz, 1 H), 2.66 - 2.54 (m, 2H), 2.13 (s, 3H), 1 .25 - 1 .13 (m, 3H).
Example 126
5-(N-(2-Ethyl-1 /y-indol-6-yl)sulfamoyl)-2-hvdroxy-3-methylbenzamide
Figure imgf000195_0001
To a solution of 2-ethyl-1 /-/-indol-6-amine (Example 75 (b), 128 mg) in DCM (10 mL) was added pyridine (0.194 mL) followed by 3-carbamoyl-4-hydroxy-5-methylbenzene-1 -sulfonyl chloride (lnt-4, 200 mg), and the reaction mixture was stirred at RT for 16 hr. The reaction mixture was diluted with water (20 mL) and extracted with DCM (2 x 50 mL). The combined DCM extracts were washed with saturated brine (25 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford the crude product (300 mg). The crude product was purified by preparative reversed phase HPLC (Kinetex Phenylhexyl, 19 x 250 mm) using 40% acetonitrile in 0.1 % TFA (aq). The desired fraction was concentrated under reduced pressure to afford the titled compound (25.6 mg). LCMS m/z 372.04(M-H)". 1H NMR (400MHz, DMSO-c/6) δ = 14.25 (br s, 1 H), 10.77 (br s, 1 H), 9.58 (br s, 1 H), 9.00 - 8.68 (m, 1 H), 8.12 (br s, 2H), 8.04 - 7.82 (m, 1 H), 7.61 (br s, 1 H), 7.21 (br d, J=8.6 Hz, 1 H), 6.99 (br s, 1 H), 6.70 (br d, J=7.7 Hz, 1 H), 6.01 (br s, 1 H), 2.66 (br d, J=7.5 Hz, 2H), 2.1 1 (br s, 2H), 1 .22 (br t, J=7.5 Hz, 3H). Example 127
5-(N-(4-(Ethylamino)phenyl)sulfamoyl)-2-hvdroxy-3-methylbenzamide
Figure imgf000196_0001
(a) N-Ethyl-4-nitroaniline
1 -Fluoro-4-nitrobenzene (2 g) and ethylamine (9.13 g) were placed in a sealed reaction vessel and stirred at 100 °C for 16 hr. The reaction mixture was allowed to cool to RT and was concentrated under reduced pressure to afford the titled compound (2 g), which was used without further purification. LCMS m/z 167.01 (M+H)+.
(b) tert-Butyl ethyl(4-nitrophenyl)carbamate
To a solution of N-ethyl-4-nitroaniline (2 g) in acetonitrile (30 mL) was added di-t-butyl dicarbonate (8.38 mL), followed by TEA (10.06 mL) and DMAP (0.294 g). The reaction mixture was heated to 90 °C and stirred for 16 hr. The reaction mixture was allowed to cool to RT and was concentrated under reduced pressure to afford the crude product. The crude product was purified by silica gel column chromatography, eluting with 5% EtOAc/hexane to afford the titled compound (3 g). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1 .22 (t, J=7.02 Hz, 3 H) 1 .48 (s, 9 H) 3.77 (q, J=7.16 Hz, 2 H) 7.29 - 7.52 (m, 2 H) 8.10 - 8.27 (m, 2 H).
(c) tert-Butyl (4-aminophenyl)(ethyl)carbamate
To a solution of tert-butyl ethyl(4-nitrophenyl)carbamate (3 g) in EtOH (30 mL) was added 10% Pd/C (0.3 g). The reaction mixture was stirred under a hydrogen atmosphere (balloon pressure) at RT for 16 hr. The reaction mixture was filtered through Celite and the precipitate washed with MeOH (2 x 10 mL). The combined filtrates were concentrated under reduced pressure to afford the titled compound (2.5 g), which was used without further purification. LCMS m/z 237.18 (M+H)+.
(d) tert-Butyl (4-(3-carbamoyl-4-hydroxy-5- methylphenylsulfonamido)phenyl)(ethyl)carbamate
To a solution of tert-butyl (4-aminophenyl)(ethyl)carbamate (284 mg) and pyridine (0.486 mL) in DCM (5 mL) under nitrogen at 0 °C was added 3-carbamoyl-4-hydroxy-5- methylbenzene-1 -sulfonyl chloride (lnt-4, 300 mg) portionwise over 10 min. The reaction mixture was allowed to warm to RT and was stirred for 16 hr. The reaction mixture was concentrated under reduced pressure and the crude product was purified by silica gel column chromatography, eluting with 50% EtOAc/hexane, to afford the titled compound (400 mg). LCMS 349.9 m/z (M+H-Boc).
(e) 5-(N-(4-(Ethylamino)phenyl)sulfamoyl)-2-hydroxy-3-methylbenzamide
To a solution of tert-butyl (4-(3-carbamoyl-4-hydroxy-5- methylphenylsulfonamido)phenyl)(ethyl)-carbamate (400 mg) in DCM (15 mL) under nitrogen at 0 °C was added TFA (0.686 mL) dropwise over 5 min. The reaction mixture was allowed to warm to RT and was stirred for 16 hr. The reaction mixture was concentrated under reduced pressure to afford the crude product (600 mg). The crude product was purified by preparative reversed phase HPLC (Kinetex Phenylhexyl, 30 x 150 mm) using a gradient of 10-60% acetonitrile in 10 mM ammonium acetate (aq). The desired fraction was lyophilized to afford the titled compound (20 mg). LCMS m/z 350.09 (M+H)+. 1 HNMR: (400MHz, DMSO-c/e) δ = 14.28 (br s, 1 H), 9.21 (br s, 1 H), 8.71 (br s, 1 H), 8.04 (br d, J=1 .8 Hz, 2H), 7.56 (br s, 1 H), 6.77 - 6.71 (m, 2H), 6.42 - 6.33 (m, 2H), 5.37 (br s, 1 H), 2.97 - 2.87 (m, 2H), 2.13 (s, 3H), 1 .09 (t, J=7.0 Hz, 3H).
Example 128
5-(N-(1 H-Benzord1imidazol-5-yl)sulfamoyl)-2-hvdroxy-3-isopropylbenzamide
Figure imgf000197_0001
A 20 mL reaction vial equipped with a stirbar was charged with 1 H-benzo[d]imidazol-5- amine (144 mg). The solid was taken up in dichloromethane (DCM) (1 .8 mL) and sonicated into solution. The mixture was then treated with a solution of 3-carbamoyl-4-hydroxy-5- isopropylbenzene-1 -sulfonyl chloride (lnt-6, 100 mg) in dichloromethane (DCM) (1 .8 mL) and the resulting reaction mixture stirred overnight at room temperature. The reaction mixture was then diluted to approximately 20 mL total volume with ethyl acetate. The resulting suspension was filtered and the EtOAc filtrate dried over sodium sulfate, filtered, and concentrated to afford the crude product. The crude product was taken up in a small amount of dichloromethane and injected onto a 10 gram SNAP Ultra silica cartridge for purification (EtOAc into heptane, 30-100% over 20 CV+15 CV at 100%, desired elutes at 100% EtOAc). Fractions containing the desired material were pooled and concentrated to afford the titled compound as an off white solid (55 mg). LCMS m/z 375.3 (M+H)+. 1H NMR (400 MHz, DMSO-c/e) δ ppm 1 .01 (d, J=6.82 Hz, 6 H) 3.15 (spt, J=6.86 Hz, 1 H) 6.95 (dd, J=8.59, 2.02 Hz, 1 H) 7.26 (br. s., 1 H) 7.43 (d, J=7.58 Hz, 1 H) 7.55 (d, J=2.02 Hz, 1 H) 8.02 - 8.20 (m, 3 H) 8.81 (br. s., 1 H) 9.86 (s, 1 H) 12.35 (br. s., 1 H) 14.52 (br. s., 1 H).
Example 129
5-(N-(1 H-lndazol-6-yl)sulfamoyl)-2-hvdroxy-3-isopropylbenzamide
Figure imgf000198_0001
The title compound was prepared as in Example 128, using lnt-6 (100 mg) and 1 H-indazol- 6-amine (144 mg) to afford the titled compound as an off-white solid (99 mg). LCMS m/z 375.3 (M+H)+. 1H NMR (400 MHz, DMSO-c/6) δ ppm 1 .01 (d, J=6.82 Hz, 6 H) 3.14 (spt, J=6.86 Hz, 1 H) 6.93 (dd, J=8.84, 1 .77 Hz, 1 H) 7.19 - 7.26 (m, 1 H) 7.57 - 7.64 (m, 2 H) 7.94 (s, 1 H) 8.16 (br. s., 1 H) 8.22 (d, J=2.27 Hz, 1 H) 8.85 (br. s., 1 H) 10.16 (s, 1 H) 12.88 (s, 1 H) 14.54 (s, 1 H).
Example 130
5-(N-(1 H-indazol-6-yl)sulfamoyl)-3-ethyl-2-hvdroxybenzamide
Figure imgf000198_0002
A 20 mL reaction vial equipped with a stirbar was charged with 1 H-indazol-6-amine (303 mg). The solid was taken up in dichloromethane (DCM) (3.8 mL), the suspension treated with a suspension of 3-carbamoyl-5-ethyl-4-hydroxybenzene-1 -sulfonyl chloride (lnt-7, 200 mg) in dichloromethane (DCM) (3.8 mL), and the resulting reaction mixture stirred overnight at room temperature. The reaction was then diluted up to 20 mL with ethyl acetate and the resulting suspension filtered and the filtrate dried over sodium sulfate, filtered, and concentrated to a residue. The residue was then taken up in a minimum amount of ethyl acetate for injection onto a 25 gram SNAP Ultra silica cartridge for purification (EtOH into EtOAc, 0-55% over 15CV [elutes in the 100% EtOAc equilibration zone]). Fractions containing the desired material were pooled and concentrated to afford the title compound as an off-white solid (145 mg). LCMS m/z 361 .3 (M+H)+. Ή NMR (400 MHz, DMSO-c/6) δ ppm 1 .02 (t, J=7.58 Hz, 3 H) 2.52 (q, J=7.58 Hz, 2 H) 6.92 (dd, J=8.59, 1 .77 Hz, 1 H) 7.17 - 7.25 (m, 1 H) 7.56 - 7.65 (m, 2 H) 7.94 (t, J=1 .26 Hz, 1 H) 8.15 (br. s., 1 H) 8.23 (d, J=2.27 Hz, 1 H) 8.83 (br. s., 1 H) 10.19 (s, 1 H) 12.85 (s, 1 H) 14.43 (s, 1 H).
Example 131
5-(N-(1 H-benzord1imidazol-6-yl)sulfamoyl)-3-ethyl-2-hvdroxybenzamide
Figure imgf000199_0001
The title compound was prepared as in Example 129 using lnt-7 (200 mg) and 1 H- benzo[d]imidazol-6-amine (303 mg) to afford an off-white solid (37 mg). LCMS m/z 361 .3 (M+H)+. Ή NMR (400 MHz, DMSO-c/6) δ ppm 1 .02 (t, J=7.58 Hz, 3 H) 2.51 (q, J=7.58 Hz, 2 H) 6.94 (dd, J=8.59, 2.02 Hz, 1 H) 7.26 (s, 1 H) 7.43 (d, J=8.34 Hz, 1 H) 7.58 (d, J=2.02 Hz, 1 H) 8.03 - 8.19 (m, 3 H) 8.79 (br. s., 1 H) 9.86 (s, 1 H) 12.35 (br. s., 1 H) 14.41 (br. s., 1 H).
Example 132
5-(N-(1 H-lndol-5-yl)sulfamoyl)-3-chloro-2-hvdroxybenzamide
Figure imgf000200_0001
To a solution of 1 H-indol-5-amine (147 mg) and pyridine (0.499 mL) in DCM (5 mL) under nitrogen at 0 °C was added 3-carbamoyl-5-chloro-4-hydroxybenzene-1 -sulfonyl chloride (300 mg) portionwise over 15 min and the reaction mixture was allowed to warm to RT and stirred for 16 hr. The reaction mixture was concentrated under reduced pressure and diluted with water (15 mL). The resulting solid was isolation by filtration to afford the crude product (300 mg), which was purified by silica gel column chromatography, using 5% MeOH/DCM to obtain the titled compound (70 mg). LCMS m/z 364.1 1 (M-H)". Ή NMR (400 MHz, DMSO-c/e) δ ppm 3.32 (br. s., 1 H) 6.35 (t, J=2.08 Hz, 1 H) 6.79 (dd, J=8.55, 1 .97 Hz, 1 H) 7.16 - 7.37 (m, 3 H) 7.88 (d, J=2.19 Hz, 1 H) 8.07 - 8.28 (m, 1 H) 8.31 (br. s., 1 H) 8.93 (br. s., 1 H) 9.72 (s, 1 H) 1 1 .05 (br. s., 1 H) 14.95 (br. s., 1 H).
Example 133
5-(N-(1 H-Benzord1imidazol-5-yl)sulfamoyl)-3-chloro-2-hvdroxybenzamide
Figure imgf000200_0002
A suspension of 1 H-benzo[d]imidazol-5-amine (345 mg) and 3-carbamoyl-5-chloro-4- hydroxybenzene-1 -sulfonyl chloride (lnt-5, 700 mg) in DCM (5 mL) under nitrogen was stirred for 16 hr. The reaction mixture was concentrated under reduced pressure and then water was added and the reaction mixture was stirred for 2 hr. The resulting solid was collected by filtration, and was washed with water (2 x 2 mL) followed by n=pentane (2 x 2 mL), and dried under high vacuum to afford the crude product (900 mg). The crude product was purified by preparative reversed phase HPLC (XBridge C18, 19 x 150 mm) using a 10- 55% gradient of acetonitrile in ammonium bicarbonate (aq). The desired fractions were combined and lyophilized to afford the titled compound (155 mg). LCMS m/z 366.99 (M+H)+. Ή NMR after D20 exchange(400 MHz, DMSO-c/6) δ ppm 6.97 (dd, J=8.55, 1 .97 Hz, 1 H) 7.33 (d, J=1 .75 Hz, 1 H) 7.47 (d, J=8.77 Hz, 1 H) 7.62 (d, J=2.41 Hz, 1 H) 8.06 - 8.30 (m, 2 H).
Example 134
3-Chloro-2-hvdroxy-5-(N-(3-methyl-1 /y-indol-6-yl)sulfamoyl)benzamide
Figure imgf000201_0001
To a solution of 3-methyl-1 /-/-indol-6-amine (515 mg) in DCM (15 mL) at 0 °C under nitrogen was added pyridine (0.270 mL) followed by 3-carbamoyl-5-chloro-4-hydroxybenzene-1 - sulfonyl chloride (lnt-5, 300 mg). The reaction mixture was allowed to warm to RT and was stirred for 16 hr. The reaction mixture was concentrated under reduced pressure to afford the crude product (550 mg). The crude product was purified by preparative reversed phase HPLC (Kromasil C18, 21 x 250 mm) using 45% acetonitrile in 0.1 % TFA (aq). The desired fraction was lyophilized to afford the titled compound (135 mg). LCMS m/z 380.03 (M+H)+. Ή NMR (400 MHz, DMSO-c/6) δ ppm 14.94 (br s, 1 H), 10.63 (br s, 1 H), 9.82 (s, 1 H), 8.96 (br s, 1 H), 8.22 - 8.36 (m, 2 H), 7.90 (d, J=1 .97 Hz, 1 H), 7.32 (d, J=8.55 Hz, 1 H), 7.01 - 7.08 (m, 2 H), 6.76 (dd, J=8.33, 1 .75 Hz, 1 H), 2.18 (s, 3 H). Example 135
3-Chloro-2-hvdroxy-5-(N-(4-isopropoxyphenyl)sulfamoyl)benzamide
Figure imgf000202_0001
To a solution of 4-isopropoxyaniline (168 mg) and pyridine (0.449 mL) in DCM (5 mL at 0 °C under nitrogen was added 3-carbamoyl-5-chloro-4-hydroxybenzene-1 -sulfonyl chloride (lnt-5, 300 mg) portionwise over 10 min. The reaction mixture was allowed to warm to RT and was stirred for 16 hr. The reaction mixture was concentrated under reduced pressure and then treated with 0.5 N HCI (aq, 915 mL). The resulting solid was collected by filtration, washed with water (2 x 15 mL), diethyl ether (2 x 15 mL) and n-pentane (2 x 1 mL) and dried to afford the titled compound (235 mg). LCMS m/z 385.1 (M+H)+. NMR: Ή NMR (400 MHz, DMSO-c/e) δ ppm 15.00 (br s, 1 H), 9.76 (s, 1 H), 8.96 (br s, 1 H), 8.36 (br s, 1 H), 8.21 (d, J=2.19 Hz, 1 H), 7.82 (d, J=1 .97 Hz, 1 H), 6.88 - 7.03 (m, 2 H), 6.70 - 6.88 (m, 2 H), 4.49 (m, 1 H), 1 .20 (d, J=6.14 Hz, 6 H).
Example 136
3-Chloro-5-(N-(2-ethyl-1 /y-benzorcnimidazol-5-yl)sulfamoyl)-2-hvdroxybenzamide
Figure imgf000202_0002
(a) 2-Ethyl-6-nitro-1 H-benzo[d]imidazole
4-Nitrobenzene-1 ,2-diamine (5 g) was added to propionic acid (30 ml_) and the reaction mixture was stirred at 150 °C for 24 hr. The reaction mixture was allowed to cool to RT and was concentrated under reduced pressure to afford the crude product as a solid. Water (30 ml_) was added to the crude product, which was then treated with 1 N NaOH (aq) to raise the pH to 8. The resulting precipitate was collected by filtration, washed with water (3 x 15 ml_) and dried under vacuum to afford the titled compound (4.5 g). LCMS m/z 192.06 (M+H)+.
(b) 2-Ethyl-1 H-benzo[d]imidazol-6-amine To a solution of 2-ethyl-6-nitro-1 /-/-benzo[d]imidazole (1 g) in MeOH (20 ml_) was added 10% Pd/C (0.15 g) and the reaction mixture was stirred under a hydrogen atmosphere (balloon) for 16 hr. The reaction mixture was filtered through Celite and the precipitate washed with MeOH. The combined filtrates were concentrated under reduced pressure to afford the titled compound (700 mg). LCMS m/z 162.1 (M+H)+.
(c) 3-Chloro-5-(N-(2-ethyl-1 H-benzo[d]imidazol-5-yl)sulfamoyl)-2-hydroxybenzamide
To a solution of 2-ethyl-1 H-benzo[d]imidazol-6-amine (179 mg) and pyridine (0.449 ml_) in DCM (5 ml_) at 0 °C under nitrogen was added 3-carbamoyl-5-chloro-4-hydroxybenzene- 1 -sulfonyl chloride (lnt-5, 300 mg) portionwise over 15 min. The reaction mixture was allowed to warm to RT and was stirred for 16 hr. The reaction mixture was concentrated under reduced pressure and water (15 ml_) was added. The resulting solid was collected by filtration to afford the crude product (300 mg). The crude product was purified by preparative reversed phase HPLC (Durashell C18, 21 x 150 mm) using a gradient of 10- 40% acetonitrile in 10 mM ammonium bicarbonate (aq). The desired fraction was lyophilized to afford the titled compound (168 mg). LCMS m/z 395.08 (M+H)+. 1H NMR (400MHz, DMSO-c/e) δ = 13.6 (br s, 2H), 9.89 (s, 1 H), 9.31 (br s, 1 H), 8.20 (d, J=2.2 Hz, 1 H), 8.01 (br s, 1 H), 7.80 (d, J=2.2 Hz, 1 H), 7.38 (d, J=8.6 Hz, 1 H), 7.21 (d, J=1 .8 Hz, 1 H), 6.93 (dd, J=2.1 , 8.7 Hz, 1 H), 2.82 (q, J=7.6 Hz, 2H), 1 .29 (t, J=7.7 Hz, 3H).
Example 137
5-(N-(1 H-lndazol-6-yl)sulfamoyl)-3-chloro-2-hvdroxybenzamide
Figure imgf000204_0001
To a solution of 1 H-indazol-6-amine (148 mg) and pyridine (0.449 mL) in DCM (10 mL) at 0 °C under nitrogen was added 3-carbamoyl-5-chloro-4-hydroxybenzene-1 -sulfonyl chloride (lnt-5, 300 mg) portionwise over 15 min. The reaction mixture was allowed to warm to RT and was stirred for 16 hr. The reaction mixture was concentrated under reduced pressure and water (15 mL) was added. The resulting solid was collected by filtration to afford the crude product (300 mg). The crude product was purified by preparative reversed phase HPLC (Kromasil Phenylhexyl, 25- 250 mm) using a gradient of 10-45% acetonitrile in 10 mM ammonium bicarbonate (aq). The desired fraction was lyophilized to afford the titled compound (104 mg). LCMS m/z 367.04 (M+H)+. Ή NMR (400MHz, DMSO-c/6) δ = 14.98 (br s, 1 H), 12.86 (br s, 1 H), 10.27 (s, 1 H), 9.1 (br s, 1 H), 8.34 (d, J=2.0 Hz, 2H), 8.06 - 7.82 (m, 2H), 7.64 (d, J=8.8 Hz, 1 H), 7.23 (s, 1 H), 6.92 (dd, J=1 .8, 8.6 Hz, 1 H).
Example 138
3-Chloro-2-hvdroxy-5- N-(2-methyl-1 tf-indol-6-yl)sulfamoyl)benzamide
Figure imgf000204_0002
To a suspension of 2-methyl-1 /-/-indol-6-amine (97 mg) in DCM (15 mL) at 0 °C under nitrogen was added 3-carbamoyl-5-chloro-4-hydroxybenzene-1 -sulfonyl chloride (lnt-5, 200 mg) portionwise. The reaction mixture was allowed to warm to RT and was stirred for 16 hr. The reaction mixture was concentrated under reduced pressure and the resulting solid was triturated with water (3 x 15 mL). The solid was collected by filtration and washed with diethyl ether (3 x 15 mL) and n-pentane (3 x 15 mL) and dried to afford the titled compound. The crude product was purified by preparative reversed phase HPLC (Kromasil Phenylhexyl, 25 x 250 mm) using a gradient of 10-40% acetonitrile in 10 mM ammonium bicarbonate (aq). The desired fraction was concentrated under reduced pressure and the resulting solid was collected by filtration. The solid was washed with water (3 x 5 mL) and n-pentane (3 x 5 mL) and dried under vacuum to afford the titled compound (68.3 mg). LCMS m/z 380.03 (M+H)+. Ή NMR (DMSO-c/6) δ: 14.94 (br s, 1 H), 10.80 (s, 1 H), 9.73 (s, 1 H), 8.95 (br s, 1 H), 8.24-8.39 (bs, 1 H), 8.21 (d, J=2.0 Hz, 1 H), 7.88 (d, J=2.2 Hz, 1 H), 7.23 (d, J=8.3 Hz, 1 H), 6.97 (s, 1 H), 6.69 (dd, J=8.4, 1 .9 Hz, 1 H), 6.01 (s, 1 H), 2.31 (s, 3H).
Example 139
5-(N-(1 H-lndol-6-yl)sulfamoyl)-3-chloro-2-hvdroxybenzamide
Figure imgf000205_0001
To a solution of 1 H-indol-6-amine (147 mg) and pyridine (0.449 mL) in DCM (5 mL) at 0 °C under nitrogen was added 3-carbamoyl-5-chloro-4-hydroxybenzene-1 -sulfonyl chloride (lnt-5, 300 mg) portionwise over 15 min. The reaction mixture was allowed to warm to RT and was stirred for 16 hr. The reaction mixture was concentrated under reduced pressure and water (15 mL) was added. The resulting solid was collected by filtration to afford the crude product (200 mg). The crude product was purified by preparative reversed phase HPLC (XTerra C18, 21 x 250 mm) using a gradient of 10-60% acetonitrile in 10 mM ammonium bicarbonate (aq). The desired fraction was lyophilized to afford the titled compound (60 mg). LCMS m/z 366.03 (M+H)+. Ή NMR (400MHz, DMSO-c/6) δ = 14.95 (br s, 1 H), 10.98 (br s, 1 H), 9.84 (s, 1 H), 8.97 (br s, 1 H), 8.30 (br s, 1 H), 8.24 (d, J=2.2 Hz, 1 H), 7.89 (d, J=1 .8 Hz, 1 H), 7.39 (d, J=8.6 Hz, 1 H), 7.27 (t, J=2.7 Hz, 1 H), 7.13 (s, 1 H), 6.77 (dd, J=1 .9, 8.4 Hz, 1 H), 6.33 (t, J=2.0 Hz, 1 H). Example 140
3-Chloro-5-(N-(4-(ethylamino)phenyl)sulfamoyl)-2-hvdroxybenzamide
Figure imgf000206_0001
(a) tert-Butyl (4-(3-carbamoyl-5-chloro-4- hydroxyphenylsulfonamido)phenyl)(ethyl)carbamate
To a solution of tert-butyl (4-aminophenyl)(ethyl)carbamate (Example 127 (c), 437 mg) and pyridine (0.749 ml_) in DCM (5 ml_) at O °C under nitrogen was added 3-carbamoyl-5-chloro- 4-hydroxybenzene-1 -sulfonyl chloride (lnt-5, 300 mg) portionwise over 10 min. The reaction mixture was allowed to warm to RT and was stirred for 16 hr. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography, eluting with 50% EtOAc/hexane to afford the titled compound (450 mg). LCMS m/z 470.1 (M+H)+.
(b) 3-Chloro-5-(N-(4-(ethylamino)phenyl)sulfamoyl)-2-hydroxybenzamide
To a solution of tert-butyl (4-(3-carbamoyl-5-chloro-4- hydroxyphenylsulfonamido)phenyl)(ethyl)-carbamate (430 mg) in DCM (15 ml_) at 0 °C under nitrogen was added TFA (0.705 ml_) dropwise over 5 min. The reaction mixture was allowed to warm to RT and was stirred for 16 hr. The reaction mixture was concentrated under reduced pressure to afford the crude product (550 mg). The crude product was purified by preparative reversed phase HPLC (Durashell C18, 21 x 150 mm) using a gradient of 10-45% acetonitrile in 10 mM ammonium bicarbonate (aq). The desired fraction was lyophilized to afford the titled compound (213 mg). LCMS m/z 370.06 (M+H)+. Ή NMR (400MHz, DMSO-c/6) δ = 14.99 (br s, 1 H), 9.40 (s, 1 H), 8.98 (br s, 1 H), 8.31 (br s, 1 H), 8.17 (d, J=2.0 Hz, 1 H), 7.80 (d, J=2.2 Hz, 1 H), 6.78 - 6.72 (m, 2H), 6.42 (d, J=8.8 Hz, 2H), 5.50 (br s, 1 H), 2.94 (q, J=7.2 Hz, 2H), 1 .10 (t, J=7.1 Hz, 3H). Example 141
3-Chloro-5-(N-(3-ethyl-1 /y-indol-6-yl)sulfamoyl)-2-hvdroxybenzamide
Figure imgf000207_0001
To a solution of 3-ethyl-1 H-indol-6-amine (Example 69 (b), 248 mg) in DCM (10 mL) at 0 °C under nitrogen was added pyridine (0.198 mL) followed by 3-carbamoyl-5-chloro-4- hydroxybenzene-1 -sulfonyl chloride (lnt-5, 220 mg). The reaction mixture was allowed to warm to RT and was stirred for 16 hr under nitrogen. The reaction mixture was concentrated under reduced pressure to afford the crude product (340 mg). The crude product was purified by preparative reversed phase HPLC (XBridge C18, 19 x 150 mm) using 50% acetonitrile in 10 mM ammonium bicarbonate (aq). The desired fraction was lyophilized to afford the titled compound (60 mg). LCMS m/z 394.14 (M+H)+. Ή NMR (400MHz, DMSO- d8) δ = 14.94 (br s, 1 H), 10.65 (s, 1 H), 9.83 (s, 1 H), 8.95 (br s, 1 H), 8.24 (d, J=2.0 Hz, 2H), 7.91 (d, J=2.2 Hz, 1 H), 7.35 (d, J=8.6 Hz, 1 H), 7.09 - 7.00 (m, 2H), 6.75 (dd, J=1 .9, 8.4 Hz, 1 H), 2.62 (q, J=7.2 Hz, 2H), 1 .26 - 1 .19 (m, 3H).
Example 142
3-Chloro-5-(N-(2-ethyl-1 tf-indol-6-yl)sulfamoyl)-2-hvdroxybenzamide
Figure imgf000207_0002
To a solution of 2-ethyl-1 /-/-indol-6-amine (Example 75 (b), 1 19 mg) in DCM (10 mL) was added pyridine (0.180 mL) followed by 3-carbamoyl-5-chloro-4-hydroxybenzene-1 -sulfonyl chloride (lnt-5, 200 mg). The reaction mixture was stirred at RT for 16 hr. The reaction mixture was diluted with water (20 mL) and extracted with DCM (2 x 50 mL). The combined DCM extracts were washed with saturated brine (25 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to afford the crude product (300 mg). The crude product was purified by preparative reversed phase HPLC (Kromosil Phenyl, 25 x 250 mm), eluting with 48% acetonitrile in 0.1 % TFA (aq). The desired fraction was concentrated under reduced pressure to afford the titled compound (25.6 mg). LCMS m/z 394.07 (M+H)+. 1H NMR (400MHz, DMOS-c/6) δ = 14.94 (br s, 1 H), 10.82 (br s, 1 H), 9.75 (s, 1 H), 8.94 (br s, 1 H), 8.40 - 8.12 (m, 2H), 7.89 (s, 1 H), 7.25 (d, J=8.3 Hz, 1 H), 6.99 (s, 1 H), 6.70 (dd, J=1 .8, 8.3 Hz, 1 H), 6.04 (s, 1 H), 2.67 (q, J=7.5 Hz, 2H), 1 .23 (t, J=7.6 Hz, 3H).
Example 143
Methyl 6-(3-carbamoyl-5-chloro-4-hvdroxyphenylsulfonamido)-1 tf-indole-2- carboxylate
Figure imgf000208_0001
To a solution of methyl 6-amino-1 /-/-indole-2-carboxylate (180 mg) in DCM (20 mL)was added pyridine (0.230 mL) followed by 3-carbamoyl-5-chloro-4-hydroxybenzene-1 -sulfonyl chloride (lnt-5, 256 mg). The reaction mixture was allowed to stir at RT for 16 hr. The reaction mixture was diluted with water (10 mL) and the resulting solid was collected by filtration and dried under vacuum to afford the crude product (270 mg). The crude product was purified by preparative reversed phase HPLC (Sunfire C18, 30 x 250 mm), eluting with a gradient of 10-30% acetonitrile in 10 mM ammonium bicarbonate (aq). The desired fractions were concentrated under reduced pressure to afford the titled compound (109 mg). LCMS m/z 422.00 (M-H)-. 1H NMR (400MHz, DMSO-c/6) δ = 14.97 (br s, 1 H), 1 1 .77 (br s, 1 H), 10.10 (s, 1 H), 8.99 (br s, 1 H), 8.38 - 8.25 (m, 2H), 7.90 (d, J=1 .5 Hz, 1 H), 7.53 (d, J=8.8 Hz, 1 H), 7.18 (s, 1 H), 7.06 (d, J=1 .3 Hz, 1 H), 6.90 (dd, J=1 .8, 8.6 Hz, 1 H), 3.84 (s, 3H). Example 144
5-(N-(4-Bromo-1 /y-indol-6-yl)sulfamoyl)-3-chloro-2-hvdroxybenzamide
Figure imgf000209_0001
To a solution of 4-bromo-1 /-/-indol-6-amine (180 mg) in DCM (20 mL) under nitrogen was added pyridine (0.207 mL) followed by 3-carbamoyl-5-chloro-4-hydroxybenzene-1 -sulfonyl chloride (lnt-5, 230 mg), and the reaction mixture was stirred at RT for 16 hr. The reaction mixture was diluted with water (10 mL) and the resulting solid was collected by filtration and dried under vacuum to afford the crude product (170 mg). The crude product was purified by preparative reversed phase HPLC (Kinetex Phenylhexyl, 30 x 150 mm) using a gradient of 10-45% acetonitrile in 10 mM ammonium bicarbonate. The desired fractions were lyophilized to afford the titled compound (98 mg). LCMS m/z 444.18 (M+H)+. Ή NMR (400MHz, DMSO-c/e) δ = 1 1 .16 (br s, 1 H), 10.49 (br s, 1 H), 9.76 (br s, 1 H), 8.13 (br s, 1 H), 7.54 (br s, 1 H), 7.24 - 7.18 (m, 2H), 7.10 - 6.97 (m, 4H), 6.72 (br s, 1 H).
Example 145
Methyl 6-(3-carbamoyl-5-chloro-4-hvdroxyphenylsulfonamido)-1 tf-indole-4- carboxylate
Figure imgf000209_0002
To a solution of methyl 6-amino-1 /-/-indole-4-carboxylate (Example 109 (c), 127 mg) and pyridine (0.180 mL) in DCM (15 mL) at 0 °C under nitrogen was added 3-carbamoyl-5- chloro-4-hydroxybenzene-1 -sulfonyl chloride (lnt-5, 200 mg). The reaction mixture was allowed to warm to RT and was stirred for 16 hr. The reaction mixture was concentrated under reduced pressure and then triturated with water (1 5 mL). The resulting solid was collected by filtration , washed with water (2 x 5 mL), diethyl ether (5 mL) and 10% acetonitrile/water (3 mL) , and dried under vacuum to afford the titled compound (1 82.7 mg). LCMS m/z 421 .98 (M-H)". Ή NMR (400MHz, DMSO-c/6) δ = 15.5-14.4 (bs, 1 H), 1 1 .36 (s, 1 H), 10.02 (s, 1 H), 8.93 (br s, 1 H), 8.33 (bs, 1 H), 8.22 (d, J=2.0 Hz, 1 H), 7.91 (d, J=2.0 Hz, 1 H), 7.54 - 7.45 (m, 2H), 7.40 (s, 1 H), 6.84 ( s, 1 H), 3.86 (s, 3H).
Example 146
3-Chloro-2-hvdroxy-5-(N-(2-(hvdroxymethyl)-1 /y-indol-6-yl)sulfamoyl)benzamide
Figure imgf000210_0001
To a suspension of LAH (81 mg) in THF (20 mL) at 0 °C was added methyl 6-(3-carbamoyl- 5-chloro-4-hydroxyphenylsulfonamido)-1 /-/-indole-2-carboxylate (Example 145, 300 mg). The reaction mixture was allowed to warm to RT and was stirred for 3 hr. The reaction mixture was diluted with ice water (10 mL) and saturated NH4CI (20 mL) at 0 °C and then extracted with EtOAc (2 x 1 00 mL). The combined EtOAc extracts were dried over sodium sulfate, filtered and concentrated under reduced pressure to afford the crude product (170 mg). The crude product was purified by preparative reversed phase HPLC (Sunfire C18, 30 x 250 mm) using a 20-50% gradient of acetonitrile in 0.1 % formic acid (aq). The desired fractions were lyophilized to afford the titled compound (25 mg). LCMS m/z 394.04(M-H)~. Ή NMR (400MHz, DMSO-c/6) δ = 14.94 (br s, 1 H), 10.92 (s, 1 H), 9.76 (s, 1 H), 8.99 (br s, 1 H), 8.21 (d, J=2.2 Hz, 2H), 7.86 (s, 1 H), 7.30 (d, J=8.3 Hz, 1 H), 7.07 - 7.04 (m, 1 H), 6.71 (dd, J=2.0, 8.6 Hz, 1 H), 6.17 (d, J=1 .1 Hz, 1 H), 5.1 5 (br s, 1 H), 4.53 (s, 2H).
Example 147
Methyl 6-(3-carbamoyl-5-chloro-4-hvdroxyphenylsulfonamido)-1 tf-indole-3- carboxylate
Figure imgf000211_0001
To a solution of methyl 6-amino-1 /-/-indole-3-carboxylate (150 mg) in DCM (10 mL) at 0 °C was added pyridine (0.191 mL) followed by3-carbamoyl-5-chloro-4-hydroxybenzene-1 - sulfonyl chloride (lnt-5,, 213 mg). The reaction mixture was allowed to warm to RT and was stirred for 16 hr. The reaction mixture was diluted with water (30 mL) and extracted with DCM (2 x 50 mL). The combined DCM extracts were washed with saturated brine (50 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to afford the crude product (500 mg). The crude product was purified by preparative reversed phase HPLC (Kromasil C18, 21 x 250 mm) using a gradient of 10-50% acetonitrile in 10 mM ammonium bicarbonate (aq). The desired fraction was concentrated under reduced pressure to afford the titled compound (1 17.3 mg). LCMS m/z 422.0 (M-H)~. 1H NMR (400MHz, DMSO-c/e) δ = 14.96 (br s, 1 H), 1 1 .78 (br s, 1 H), 9.71 (br s, 2H), 8.13 (br s, 1 H), 7.95 (d, J=2.7 Hz, 1 H), 7.78 (d, J=8.6 Hz, 1 H), 7.58 (br s, 1 H), 7.26 - 6.93 (m, 4H), 3.76 (s, 3H).
Example 148
3-Chloro-5-(N-(3-chloro-1 tf-indol-6-yl)sulfamoyl)-2-hvdroxybenzamide
Figure imgf000211_0002
To a solution of 3-chloro-1 /-/-indol-6-amine (150 mg) in DCM (10 mL) at 0 °C was added pyridine (0.218 mL) followed by 3-carbamoyl-5-chloro-4-hydroxybenzene-1 -sulfonyl chloride (lnt-5, 213 mg). The reaction mixture was allowed to warm to RT and was stirred for 16 hr. The reaction mixture was diluted with water (30 mL) and extracted with DCM (2 x 50 mL). The combined DCM extracts were washed with saturated brine (50 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to afford the crude product (500 mg). The crude product was purified by preparative reversed phase HPLC (Kromasil C18, 21 x 250 mm) using a gradient of 10-40% acetonitrile in 10 mM ammonium bicarbonate (aq). The desired fraction was concentrated under reduced pressure to afford the titled compound (124.3 mg). LCMS m/z 398.07 (M-H)". Ή NMR (400MHz, DMSO-c/6) δ = 14.96 (br s, 1 H), 1 1 .21 (br s, 1 H), 9.78 (br s, 2H), 8.16 (br s, 1 H), 7.66 (br s, 1 H), 7.39 (d, J=2.7 Hz, 1 H), 7.31 (d, J=8.6 Hz, 1 H), 7.23 - 6.92 (m, 3H), 6.89 (dd, J=1 .7, 8.6 Hz, 1 H).
Example 149
Chloro-2-hvdroxy-5-(N-(2-oxoindolin-6-yl)sulfamoyl)benzamide
Figure imgf000212_0001
To a solution of 6-aminoindan-2-one (165 mg) in DCM (15 mL) at 0 °C under nitrogen was added 3-carbamoyl-5-chloro-4-hydroxybenzene-1 -sulfonyl chloride (lnt-5, 300 mg). The reaction mixture was allowed to warm to RT and was stirred for 16 hr. The reaction mixture was concentrated under reduced pressure to afford the crude product (300 mg). The crude product was purified by reversed phase HPLC (Kinetex C8, 30 x 150 mm) using a gradient of 10-45% acetonitrile in 10 mM ammonium bicarbonate (aq). The desired fraction was lyophilized to afford the titled compound (101 mg). LCMS m/z 380.0 (M-H)". 1H NMR (400MHz, DMSO-c/e) δ = 15.21 - 14.85 (m, 1 H), 10.27 (s, 1 H), 10.06 (s, 1 H), 9.22 - 8.97 (m, 1 H), 8.29 (d, J=2.0 Hz, 2H), 7.88 (d, J=1 .5 Hz, 1 H), 7.05 (d, J=7.9 Hz, 1 H), 6.68 (dd, J=1 .9, 8.0 Hz, 1 H), 6.60 (d, J=1 .8 Hz, 1 H), 3.35 (s, 2H).
Example 150
3-Chloro-5-(N-(3-ethyl-1 /y-indazol-6-yl)sulfamoyl)-2-hvdroxybenzamide
Figure imgf000213_0001
(a) 3-lodo-6-nitro-1 H-indazole
To a solution of 6-nitro-1 /-/-indazole (5 g) and potassium carbonate (8.47 g) in DMF (60 mL) was added a solution of iodine (13.46 g) in DMF (60 mL) dropwise over 15 min, and the reaction mixture was stirred at RT for 3 hr. The reaction mixture was quenched by the addition of saturated sodium thiosulfate (aq) (120 mL) and then diluted with water (150 mL). The resulting solid was collected by filtration and dried under vacuum to afford the titled compound (6.2 g). LCMS m/z 288.14 (M-H)".
(b) 6-Nitro-3-vinyl-1 H-indazole
A degassed mixture of 3-iodo-6-nitro-1 /-/-indazole (500 mg) 2,4,6-trivinyl-1 ,3,5,2,4,6- trioxatriborinane pyridine (1 :1) complex (416 mg), sodium carbonate (367 mg) and bis(diphenyl phosphino)ferrocene palladium dichloride (127 mg) in 1 ,4-dioxane (9 mL) and water (3 mL) was heated at 100 °C for 16 hr. The reaction mixture was allowed to cool to RT and was filtered through Celite. The filtrate was diluted with water (20 mL) and extracted with EtOAc (3 x 40 mL). The combined EtOAc extracts were washed with saturated brine (50 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to afford the titled compound (260 mg), which was used without further purification. LCMS m/z 190.08 (M+H)+.
(c) 3-Ethyl-1 H-indazol-6-amine
To a solution of 6-nitro-3-vinyl-1 /-/-indazole (300 mg) in MeOH (10 mL) was added 10% Pd/C (338 mg) at RT, and the reaction mixture was stirred under a hydrogen atmosphere (balloon) for 16 hr. The reaction mixture was filtered through Celite and the filtrate concentrated under reduced pressure to afford the titled compound (300 mg), which was used without further purification. LCMS m/z 161 .91 (M+H)+.
(d) 3-Chloro-5-(N-(3-ethyl-1 H-indazol-6-yl)sulfamoyl)-2-hydroxybenzamide
To a solution of 3-ethyl-1 /-/-indazol-6-amine (134 mg) and pyridine (0.225 mL) in DCM (15 mL) at 0 °C under nitrogen was added 3-carbamoyl-5-chloro-4-hydroxybenzene-1 -sulfonyl chloride (lnt-5, 250 mg). The reaction mixture was allowed to warm to RT and was stirred for 16 hr. The reaction mixture was diluted with water (15 mL) and extracted with DCM (3 x 30 mL). The combined DCM extracts were washed with saturated brine (50 mL), dried over sodium sulfate and concentrated under reduced pressure to afford the crude product (200 mg). The crude product was purified by preparative reversed phase HPLC (Kinetex C8, 30 x 150 mm) using a gradient of 35-45% acetonitrile in 0.1 % formic acid (aq). The desired fractions were concentrated under reduced pressure to afford the titled compound (69 mg). LCMS m/z 395.04 (M+H)+. 1H NMR (400MHz, DMSO-c/e) δ = 15.00 (br s, 1 H), 12.41 (s, 1 H), 10.21 (s, 1 H), 9.05 (br s, 1 H), 8.32 (d, J = 2.2 Hz, 2H), 7.90 (s, 1 H), 7.59 (d, J = 8.6 Hz, 1 H), 7.16 - 7.13 (m, 1 H), 6.88 - 6.83 (m, 1 H), 2.83 (q, J = 7.6 Hz, 2H), 1 .25 (t, J = 7.6 Hz, 3H).
Example 151
3-Chloro-2-hvdroxy-5-(N-(1 -methyl-1 /y-indol-5-yl)sulfamoyl)benzamide
Figure imgf000214_0001
To a solution of 1 -methyl-1 /-/-indol-5-amine (135 mg) and pyridine (0.374 ml_) in DCM (10 ml_) at 0 °C under nitrogen was added 3-carbamoyl-5-chloro-4-hydroxybenzene-1 -sulfonyl chloride (lnt-5, 250 mg) portionwise over 15 min. The reaction mixture was allowed to warm to RT and was stirred for 16 hr. The reaction mixture was concentrated under reduced pressure and water (10 ml_) was added to the residue, which was stirred for 15 min. The resulting solid was collected by filtration to afford the crude product (350 mg). The crude product was purified by reversed phase HPLC (Kromasil C18, 21 x 250 mm) using a gradient of 10-40% acetonitrile in 10 mM ammonium bicarbonate. The desired fractions were concentrated under reduced pressure , and the resulting solid was collected by filtration and air-dried to afford the titled compound (70 mg). LMCS 378.02 (M-H)". 1H NMR (400MHz, DMSO-de) δ = 14.95 (br s, 1 H), 9.53 (br s, 2H), 8.12 (br s, 1 H), 7.67 (br s, 2H), 7.34 - 7.20 (m, 3H), 7.08 (br m, 1 H), 6.87 (dd, J=2.0, 8.8 Hz, 1 H), 6.32 (d, J=2.9 Hz, 1 H), 3.71 (s, 3H). Example 152
5-(N-(1 H-Benzord1imidazol-6-yl)sulfamoyl)-3-fluoro-2-hvdroxybenzamide
Figure imgf000215_0001
(a) 3-Fluoro-2-hydroxybenzamide
A 20 mL reaction vial equipped with a stirbar and needle-vented septum cap was charged with 3-fluoro-2-hydroxybenzoic acid (0.568 g) and 1 ,1 '-carbonyldiimidazole (1 .180 g). The solid materials were taken up in Ν,Ν-dimethylformamide (DMF) (2.65 mL) and treated with cone, aqueous ammonia (2.62 mL). After the foaming had subsided, the resulting mixture was stirred 30 minutes at room temperature. The mixture was then transferred to a 100 mL conical flask and diluted with water to approximately 30 mL total volume and then treated with glacial acetic acid until the pH was approximately 6-7. The aqueous mixture/suspension was then extracted with ethyl acetate twice, the organics pooled, dried over sodium sulfate, filtered, and concentrated to a residue. The residue was then triturated with dichloromethane to afford the titled compound as a brilliant yellow solid (216 mg). LCMS m/z 156.0 (M+H)+. Ή NMR (400 MHz, DMSO-c/6) δ ppm 6.85 (td, J=8.08, 4.80 Hz, 1 H) 7.39 (ddd, J=1 1 .12, 8.08, 1 .52 Hz, 1 H) 7.68 (dt, J=8.21 , 1 .33 Hz, 1 H) 8.14 (br. s., 1 H) 8.56 (br. s., 1 H) 13.47 (br. s., 1 H).
(b) 5-(N-(1 H-Benzo[d]imidazol-6-yl)sulfamoyl)-3-fluoro-2-hydroxybenzamide
A 20 mL reaction vial equipped with a stirbar and vented septum cap was charged with 3- fluoro-2-hydroxybenzamide (215 mg). The solid material was taken up in chlorosulfonic acid (0.650 mL) and the resulting reaction mixture warmed to 55 °C with stirring, overnight. The mixture was then cooled to room temperature and added dropwise to approximately 50 mL of water-saturated crushed ice. The afforded suspension was stirred for 1 hour and the resulting precipitate collected by suction filtration and carried on to the next step without further characterization or purification.
The isolated solid was added to a stirred suspension of 1 H-benzo[d]imidazol-6-amine (554 mg, 4.16 mmol) in dichloromethane (DCM) (13 mL), the suspension sonicated briefly, and the resulting mixture stirred 4 days at room temperature. The reaction mixture was then diluted up to ~30 mL total volume with EtOAc and filtered, and the collected solid material then taken up in ethanol and sonicated to a fine suspension. The suspension was filtered and the filtrate concentrated to a residue, redissolved in approximately 1 mL ethanol, and injected onto a 30 gram SNAP Ultra C-18 silica cartridge for purification, eluting with a 0- 70% gradient of EtOH in 0.1 % aq. formic acid over 17.5 CV. Fractions containing the desired material were pooled and concentrated to a residue and triturated with ethyl acetate to afford the titled compound as a brick-red solid (224 mg). LCMS m/z 351 .2 (M+H)+. 1H NMR (400 MHz, DMSO-c/6) δ ppm 6.96 (dd, J=8.72, 2.15 Hz, 1 H) 7.30 (d, J=2.02 Hz, 1 H) 7.47 (d, J=8.59 Hz, 1 H) 7.63 (dd, J=10.23, 2.15 Hz, 1 H) 8.1 1 (dd, J=2.02, 1 .01 Hz, 1 H) 8.13 - 8.22 (m, 1 H) 8.25 (s, 1 H) 8.87 (br. s., 1 H) 10.03 (s, 1 H) 13.25 (br. s., 2 H).
Example 153
5-(N-(1 H-benzord1imidazol-6-yl)sulfamoyl)-2-hvdroxy-3-(trifluoromethyl)benzamide
Figure imgf000216_0001
3-Carbamoyl-4-hydroxy-5-(trifluoromethyl)benzene-1 -sulfonyl chloride(lnt-8, 250 mg) was added to a stirred suspension of 1 H-benzo[d]imidazol-6-amine (419 mg) in dichloromethane (DCM) (10 mL), the suspension sonicated briefly, and the resulting mixture stirred overnight at room temperature. The reaction mixture was then diluted up to 40 mL total volume and the precipitate collected by suction filtration. The precipitate was then taken up in a minimum amount of ethanol for injection onto a 30 gram SNAP Ultra C- 18 silica cartridge for purification eluting with a 0-75% gradient of ethanol in 0.1 % aq. formic acid over 17.5 CV. Fractions containing the desired material were then pooled and concentrated to a residue which was triturated with 0.1 % aqueous formic acid to afford the titled compound as a light purple solid (193 mg). LCMS m/z 401 .5 (M+H)+. 1H NMR (400 MHz, DMSO-c/e) δ ppm 7.02 (dd, J=8.84, 2.02 Hz, 1 H) 7.34 (dd, J=2.02, 0.51 Hz, 1 H) 7.53 (dd, J=8.59, 0.51 Hz, 1 H) 7.94 (d, J=2.02 Hz, 1 H) 8.10 (br. s., 1 H) 8.45 (d, J=2.27 Hz, 1 H) 8.50 (s, 1 H) 9.44 (br. s., 1 H) 10.10 (s, 1 H) 14.04 (br. s., 2 H).
Example 154
5-(N-(1 H-lndol-6-yl)sulfamoyl)-2-hvdroxyisophthalamide
Figure imgf000217_0001
(a) 2-Methoxyisophthalamide
2-Methoxyisophthalic acid (2 g) was taken up in anhydrous DCM (34.0 mL) in a 20 mL vial. Oxalyl chloride (1 .79 mL) and DMF (0.079 mL) were added, and the reaction mixture was stirred at room temperature. After 1 h, 35 min, a solution of 7 M ammonia in MeOH (7 mL) was carefully added, and stirring was allowed to continue at room temperature. A white precipitate immediately formed. After another 20 min, the reaction was concentrated under reduced pressure. The precipitate was rinsed with MeOH and allowed to aspirate dry overnight to afford the titled compound ( 3.277 g), which was used without further purification. LCMS m/z 195.1 (M+H)+.
(b) 2-Hydroxyisophthalamide
A solution of 1 M BBr3 in DCM (13 mL) was added to a suspension of 2- methoxyisophthalamide (1 g) in anhydrous DCM (20 mL) under nitrogen at 0 °C. The ice bath was removed and stirring was continued at room temperature. After 165 min, saturated NaHC03 (30 mL) was added slowly. The reaction mixture was then acidified with 2 M HCI (aq) and the resulting solid was collected by filtration. The collected solids were triturated twice with pH 5 acetate buffer and dried under vacuum overnight to afford the titled compound ( 334 mg). LCMS m/z 181 .1 (M+H)+.
(c) 3,5-Dicarbamoyl-4-hydroxybenzene-1 -sulfonyl chloride
2-Hydroxyisophthalamide (228 mg) was taken up in chlorosulfonic acid (2 m). An air condenser was attached, and the reaction was heated to 50 °C. After 3.5 h, the reaction was added to 10 mL of ice, and the resulting white precipitate was collected by filtration, washed with water (3 x 2 mL), and dried under suction filtration overnight to afford the titled compound (221 mg), which was used without further purification. LCMS m/z 278.9 (M+H)+.
(d) 5-(N-(1 H-lndol-6-yl)sulfamoyl)-2-hydroxyisophthalamide
3,5-Dicarbamoyl-4-hydroxybenzene-1 -sulfonyl chloride (105 mg) and 1 H-indol-6-amine (49.8 mg) were taken up in anhydrous pyridine (1 .5 mL). DMAP (4.60 mg, 0.038 mmol) was added, and the reaction mixture was stirred at room temperature. After 3 h, the reaction mixture was concentrated under reduced pressure at 70 °C. The residue was taken up in 2 M HCI (3.5 mL) and EtOAc (2 mL). The layers were separated, and the aqueous layer was extracted with EtOAc (3 x 2 mL). The combined organic layers were concentrated under a stream of nitrogen at 50 °C. The residue was then taken up in DMSO (1 ml_) and purified by preparative reversed phase HPLC to afford the titled compound ( 1 .66 mg). LCMS m/z 375.1 (M+H)+. 1H NMR (400MHz, METHANOL-d4) δ = 8.41 (s, 2H), 7.37 (d, J=8.3 Hz, 1 H), 7.16 (d, J=2.8 Hz, 2H), 6.69 (dd, J=1 .9, 8.5 Hz, 1 H), 6.35 (d, J=2.5 Hz, 1 H).
Example 155
2-Hvdroxy-5-(N-(4-isopropoxyphenyl)sulfamoyl)-4-(methylamino)benzamide
Figure imgf000218_0001
A solution of 4-fluoro-2-hydroxy-5-(N-(4-isopropoxyphenyl)sulfamoyl)benzamide (Example 107, 200 mg) in methylamine (2 M in MeOH, 5 mL) was stirred at 100 °C for 16 hr in a sealed reaction vessel. The reaction mixture was allowed to cool to RT and was concentrated under reduced pressure to afford the crude product (150 mg). The crude product was purified by preparative reversed phase HPLC (XBridge C18, 19 x 50 mm) using a gradient of 5-50% acetonitrile in 10 mM ammonium bicarbonate (aq). The desired fraction was lyophilized to afford the titled compound (45 mg). LCMS m/z 380.14 (M+H)+. Ή NMR (400MHz, DMSO-c/6) δ = 13.76 (br s, 1 H), 9.68 (br s, 1 H), 8.25 (br s, 1 H), 8.05 (s, 1 H), 7.49 (br s, 1 H), 6.95 - 6.84 (m, 2H), 6.79 - 6.69 (m, 2H), 6.15 (br s, 1 H), 5.98 (s, 1 H), 4.46 (td, J=6.0, 12.1 Hz, 1 H), 2.79 (d, J=4.8 Hz, 3H), 1 .18 (d, J=5.9 Hz, 6H).
Example 156
4-(Ethylamino)-2-hvdroxy-5-(N-(4-isopropoxyphenyl)sulfamoyl)benzamide
Figure imgf000218_0002
A solution of 4-fluoro-2-hydroxy-5-(N-(4-isopropoxyphenyl)sulfamoyl)benzamide (Example 107, 300 mg) in ethylamine (2 M in EtOH, 5 mL) was stirred at 100 °C for 16 hr in a sealed reaction vessel. The reaction mixture was allowed to cool to RT and then was concentrated under reduced pressure to afford the crude product (250 mg). The crude product was purified by preparative reversed phase HPLC (Kinetex Phenylhexyl, 30 x 150 mm) using a gradient of 10-50% acetonitrile in 10 mM ammonium bicarbonate (aq). The desired fraction was lyophilized to afford the titled compound (184 mg). LCMS m/z 394.22 (M+H)+. 1H NMR (400MHz, DMSO-c/e) δ = 13.70 (br s, 1 H), 9.75 (br s, 1 H), 8.10 - 8.04 (m, 1 H), 8.38 - 8.02 (m, 1 H), 7.54 (br s, 1 H), 6.96 - 6.89 (m, 2H), 6.79 - 6.74 (m, 2H), 6.06 - 5.99 (m, 2H), 4.47 (td, J=6.0, 12.1 Hz, 1 H), 3.17 - 3.09 (m, 2H), 1 .19 (d, J=6.1 Hz, 6H), 1 .13 (t, J=7.1 Hz, 3H). Example 157
Figure imgf000219_0001
A solution of 4-fluoro-2-hydroxy-5-(N-(4-isopropoxyphenyl)sulfamoyl)benzamide (Example 107, 300 mg) and benzylamine (0.445 ml_) in toluene (10 ml_) was stirred at 100 °C in a sealed reaction vessel for 16 hr. The reaction mixture was allowed to cool to RT and was concentrated under reduced pressure to afford the crude product (250 mg). The crude product was purified by preparative reversed phase HPLC (Kromasil C18, 21 x 250 mm) using a gradient of 10-60% acetonitrile in ammonium bicarbonate (aq). The desired fraction was lyophilized to afford the titled compound (50 mg). LCMS m/z 456.20 (M+H)+. 1H NMR (DMSO-c/e) δ: 8.1 1 (s, 1 H), 7.20-7.34 (m, 5H), 6.94-7.02 (m, 2H), 6.77 (d, J=9.0 Hz, 3H), 5.87 (br s, 1 H), 4.39-4.51 (m, 3H), 1 .19 (d, J=6.1 Hz, 5H).
Example 158
2-hvdroxy-5-(A/-(4-isopropoxyphenyl)sulfamoyl)-4-((pyridin-4- ylmethyl)amino)benzamide
Figure imgf000219_0002
A 5 mL microwave reaction vial equipped with a stirbar was charged with 4-fluoro-2- hydroxy-5-(N-(4-isopropoxyphenyl)sulfamoyl)benzamide (Example 107, 0.200 g) and pyridin-4-ylmethanamine (0.165 mL). The solids were then taken up in 1 -butanol (2.5 mL) and the mixture sealed in the vial. The mixture was subjected to microwave irradiation at 1 10 °C with stirring for 2 h. The mixture was then cooled to room temperature and concentrated to a residue. The residue was taken up in a minimum amount of DMSO and purified by reverse phase silica gel using a 25 gram RediSep Gold C18Aq reverse phase silica cartridge (10-90% MeCN in 0.2M aq ammonium acetate). Fractions containing the desired material were pooled and concentrated to remove the majority of the acetonitrile and the resulting suspension was then suction filtered to afford the title compound as an off white solid (109 mg). LCMS m/z 457.3 (M+H)+. Ή NMR (400 MHz, DMSO-c/6) δ ppm 1 .20 (d, J=6.08 Hz, 6 H) 4.42 - 4.66 (m, 3 H) 5.84 (s, 1 H) 6.73 - 6.84 (m, 2 H) 6.87 (t, J=6.08 Hz, 1 H) 6.95 - 7.06 (m, 2 H) 7.19 - 7.32 (m, 2 H) 7.64 (br. s., 1 H) 8.16 (s, 1 H) 8.31 (br. s., 1 H) 8.41 - 8.55 (m, 2 H) 9.95 (s, 1 H) 13.69 (s, 1 H).
Example 159
4-(((1 /y-pyrazol-3-yl)methyl)amino)-2-hvdroxy-5-(A/-(4-isopropoxyphenyl)sulfamoyl)- benzamide
Figure imgf000220_0001
A 5 mL microwave reaction vial equipped with a stirbar was charged with 4-fluoro-2- hydroxy-5-(N-(4-isopropoxyphenyl)sulfamoyl)benzamide (Example 107, 0.250 gl) and (1 H-pyrazol-3-yl)methanamine (0.198 g). The solids were taken up in 1 -butanol (3.4 mL) and the resulting reaction mixture was subjected to microwave irradiation at 1 10 °C with stirring on high absorption setting for 2 sessions of 2 h each for a total of 4 h reaction time. The reaction mixture was resubjected to microwave irradiation at 140 °C with stirring for an additional 2 sessions of 2 h and 8 h (14 h total microwave reaction time). The mixture was then cooled to room temperature, diluted with ethanol to ~20 mL total volume, filtered, and concentrated to a residue. The residue was taken up in a minimum amount of DMSO for purification by reverse phase silica gel using a 30 gram RediSep Gold C18 reverse phase silica cartridge (0-90% acetonitrile in 0.2M aq ammonium acetate). Fractions containing the desired material were pooled and then concentrated to remove the acetonitrile. The aqueous layer was acidified to ~pH 4.5 by addition of 1 N aq hydrochloric acid. The mixture was extracted twice with ethyl acetate and the organic layers were pooled, dried over sodium sulfate, filtered, and concentrated to dryness. The solid mass was triturated with diethyl ether to afford the title compound as an off-white solid (52 mg. LCMS m/z 446.3 (M+H)+. 1H NMR (400 MHz, DMSO-c/6) δ ppm 1 .13 - 1 .23 (m, 6 H) 4.38 (d, J=5.58 Hz, 2 H) 4.47 (spt, J=6.04 Hz, 1 H) 6.13 (s, 1 H) 6.16 (d, J=2.03 Hz, 1 H) 6.63 - 6.81 (m, 3 H) 6.89 - 7.01 (m, 2 H) 7.62 (br. s., 2 H) 8.06 (s, 1 H) 8.27 (br. s., 1 H) 9.81 (br. s., 1 H) 12.52 (br. s., 1 H) 13.74 (br. s., 1 H).
Example 160
2-hvdroxy-5-(A/-(4-isopropoxyphenyl)sulfamoyl)-4-((isoxazol-5- ylmethyl)amino)benzamide
Figure imgf000221_0001
A 5 mL microwave reaction vial equipped with a stirbar was charged with 4-fluoro-2- hydroxy-5-(N-(4-isopropoxyphenyl)sulfamoyl)benzamide (Example 107, 0.250 g) and isoxazol-3-ylmethanamine (0.200 g). The solids were taken up in 1 -butanol (3.4 mL) and the resulting reaction mixture was subjected to microwave irradiation at 1 10 °C with stirring on high absorption setting for 2 sessions of 2 h for a total of 4 h reaction time. The mixture was then cooled to room temperature, diluted with ethyl acetate to 30 mL total volume, and washed twice with 1 N aq hydrochloric acid. The organic layer was dried over sodium sulfate, filtered, and concentrated to a residue. The residue was triturated with diethyl ether and the filtrate concentrated to a residue. The residue was then taken up in a minimum amount of DMSO (~1 .25 mL) and purified by reverse phase silica gel using a 30 gram RediSep Gold C18 reverse phase silica cartridge (10-90% acetonitrile in 0.2M aq ammonium acetate). The fraction containing the desired material was concentrated to remove the acetonitrile. The resulting suspension was suction filtered to afford the title compound as a white solid (1 1 1 mg). LCMS m/z 447.2 (M+H)+. Ή NMR (400 MHz, DMSO- de) δ ppm 1 .18 (d, J=6.08 Hz, 6 H) 4.46 (spt, J=6.00 Hz, 1 H) 4.55 (d, J=6.08 Hz, 2 H) 6.09 (s, 1 H) 6.47 (d, J=1 .77 Hz, 1 H) 6.69 - 6.75 (m, 2 H) 6.75 - 6.81 (m, 1 H) 6.90 - 6.97 (m, 2 H) 7.64 (br. s., 1 H) 8.08 (s, 1 H) 8.29 (br. s., 1 H) 8.86 (d, J=1 .52 Hz, 1 H) 9.83 (s, 1 H) 13.76 (s, 1 H). Example 161
2-hvdroxy-5-(A/-(4-isopropoxyphenyl)sulfamoyl)-4-((thiophen-2-ylmethyl)amino)- benzamide
Figure imgf000222_0001
A 5 mL microwave reaction vial equipped with a stirbar was charged with a suspension of 4-fluoro-2-hydroxy-5-(N-(4-isopropoxyphenyl)sulfamoyl)benzamide (Example 107, 0.156 g) in 1 -butanol (3.75 mL). The suspension was then treated in one quick portion with a solution of thiophen-2-ylmethanamine (0.138 g) in 1 -butanol (0.75 mL) and the resulting mixture sealed in the vial and subjected to microwave irradiation at 120 °C with stirring for 1 h. The mixture was then cooled to room temperature, transferred to a 40 mL reaction vial and concentrated to a solid. The solid was taken up in ethanol (~1 -2 mL) and sonicated, affording a fine suspension. The crude solid (130 mg) was isolated by suction filtration and then taken up in 5 mL of Dl water and treated with sufficient cone, aq ammonium hydroxide to dissolve the solid. The solution was acidified to ~pH 3-4 by addition of 6N aq hydrochloric acid. The afforded suspension was collected by suction filtration to afford a bright white solid (106 mg). LCMS m/z 462.2 (M+H)+. Ή NMR (400 MHz, DMSO-c/6) δ ppm 1 .19 (d, J=5.83 Hz, 6 H) 4.48 (spt, J=6.00 Hz, 1 H) 4.64 (d, J=5.83 Hz, 2 H) 6.1 1 (s, 1 H) 6.72 - 6.78 (m, 2 H) 6.79 (t, J=5.96 Hz, 1 H) 6.93 - 7.01 (m, 3 H) 7.04 (dd, J=3.55, 1 .27 Hz, 1 H) 7.41 (dd, J=5.07, 1 .27 Hz, 1 H) 7.63 (br. s., 1 H) 8.12 (s, 1 H) 8.30 (br. s., 1 H) 9.88 (s, 1 H) 13.73 (s, 1 H).
Example 162
2-hvdroxy-4-((2-hvdroxybenzyl)amino)-5-(N-(4- isopropoxyphenvDsulfamovDbenzamide
Figure imgf000222_0002
4-Fluoro-2-hydroxy-5-(N-(4-isopropoxyphenyl)sulfamoyl)benzamide (Example 107, 200 mg, 0.543 mmol) and 2-(aminomethyl)phenol (201 mg, 1 .629 mmol) were suspended in 1 - butanol (3 mL) in a microwave vial and stirred for 2 h in a microwave reactor at 1 10 °C. Analysis by LCMS indicated that the reaction had gone substantially to completion. The reaction mixture was diluted with EtOAc (20 ml_) and extracted with 1 N aq HCI (3 x 20 ml_) and saturated brine (20 ml_), dried over sodium sulfate, and evaporated to dryness to afford the crude product (315 mg) as an off-white solid. The crude product was dissolved in 1 .4 mL DMSO and purified by reversed phase flash chromtography (ISCO CombiFlash, 30 g RediSep Gold C18) using an eluent of 10-90% acetonitrile in 0.2 mM aq ammonium acetate. The desired fraction was concentrated under reduced pressure to remove the acetonitrile. The resulting precipitate was collected by filtration, washed with water and air- dried to afford 2-hydroxy-4-((2-hydroxybenzyl)amino)-5-(N-(4-isopropoxyphenyl)- sulfamoyl)benzamide (72.7 mg, 0.154 mmol, 28% yield) as an off-white powder. LCMS m/z 472.3 (M+H)+. 1H NMR (400 MHz, DMSO-c/6) δ ppm 1 .19 (d, J=6.08 Hz, 6 H) 4.33 (d, J=5.58 Hz, 2 H) 4.48 (dt, J=12.10, 5.99 Hz, 1 H) 5.93 (s, 1 H) 6.66 - 6.86 (m, 5 H) 6.94 - 7.02 (m, 2 H) 7.03 - 7.10 (m, 2 H) 7.57 (br. s., 1 H) 8.1 1 (s, 1 H) 8.27 (br. s., 1 H) 9.75 (br. s., 1 H) 9.89 (br. s., 1 H) 13.67 (br. s., 1 H).
Example 163
2-hvdroxy-4-((3-hvdroxybenzyl)amino)-5-(N-(4- isopropoxyphenvDsulfamovDbenzamide
Figure imgf000223_0001
4-Fluoro-2-hydroxy-5-(N-(4-isopropoxyphenyl)sulfamoyl)benzamide (Example 107, 200 mg, 0.543 mmol) and 3-(aminomethyl)phenol (201 mg, 1 .629 mmol) were suspended in 1 - butanol (3 mL) in a microwave vial. The reaction mixture was stirred at 1 10 °C in a microwave reactor for 2 h. Analysis by LCMS indicated that the reaction had substantially gone to completion. The reaction mixture was diluted with EtOAc (20 mL) and washed with 1 N aq HCI (3 x 20 mL) and saturated brine (20 mL), dried over sodium sulfate, evaporated to dryness and dried under vacuum to afford the crude product (301 .5 mg) as a dark yellow oil. The crude product was dissolved in 1 .5 mL DMSO and purified by reversed phase flash chromtography (ISCO CombiFlash, 30 g RediSep Gold C18) using an eluent of 10-90% acetonitrile in 0.2 mM aq ammonium acetate. The desired fraction was concentrated under reduced pressure to remove the acetonitrile, which resulted in the product oiling out in the residual aqueous eluant. This was allowed to stand at RT overnight, and the oil solidified. The solid was broken up, collected by filtration, washed with water and air-dried to afford 2-hydroxy-4-((3-hydroxybenzyl)amino)-5-(N-(4-isopropoxyphenyl)sulfamoyl)benzamide (1 12.8 mg, 0.239 mmol, 44% yield), as on off-white solid. LCMS: m/z 472.3 (M+H)+. Ή NMR (400 MHz, DMSO-c/6) δ ppm 1 .19 (d, J=6.08 Hz, 6 H) 4.36 (d, J=5.83 Hz, 2 H) 4.48 (dt, J=1 1 .98, 6.05 Hz, 1 H) 5.91 (s, 1 H) 6.62 - 6.80 (m, 6 H) 6.88 - 7.01 (m, 2 H) 7.09 (t, J=7.86 Hz, 1 H) 7.59 (br. s., 1 H) 8.1 1 (s, 1 H) 8.27 (br. s., 1 H) 9.41 (s, 1 H) 9.91 (s, 1 H) 13.69 (s, 1 H).
Example 164
4-(((4H-1.2.4-triazol-3-yl)methyl)amino)-2-hvdroxy-5-(N-(4- isopropoxyphenvDsulfamovDbenzamide
Figure imgf000224_0001
To a solution of 4-fluoro-2-hydroxy-5-(N-(4-isopropoxyphenyl)sulfamoyl)benzamide (Example 107, 85 mg, 0.231 mmol) in n-butanol (2 ml_) in a microwave viol was added DIEA (0.040 ml_, 0.231 mmol) followed by (4H-1 ,2,4-triazol-3-yl)methanamine (67.9 mg, 0.692 mmol). The microwave reaction vessel was sealed and the mixture was subjected to 150 °C for 1 h in the microwave. The reaction mixture was allowed to cool to RT and was quenched with saturated aq ammonium chloride and extracted with ethyl acetate. The combined organic layers were dried and concentrated. The residue was purified by reverse phase flash chromatography using an eluent of 0-100% acetonitrile in water. The desired fractions were lyophilized to afford the title compound (38 mg, 37% yield) as white solid. LCMS m/z 447.1 (M+H)+. 1H NMR (400MHz, DMSO-c/6) δ 1 .12 - 1 .25 (m, 7 H) 4.39 - 4.53 (m, 3 H) 6.20 (s, 1 H) 6.70 - 6.77 (m, 2 H) 6.81 (t, J=5.62 Hz, 1 H) 6.97 (d, J=8.80 Hz, 2 H) 7.50 - 7.65 (m, 1 H) 8.04 (s, 1 H) 8.20 - 8.38 (m, 1 H) 9.62 - 9.80 (m, 1 H) 13.57 - 14.08 (m, 2 H).
Example 165
2-hvdroxy-4-((3-hvdroxypropyl)amino)-5-(N-(4- isopropoxyphenvDsulfamovDbenzamide
Figure imgf000224_0002
Following the procedure described in example 164 but using 3-aminopropan-1 -ol (52.0 mg, 0.692 mmol) and then purification by preparative reverse phase HPLC (20-60% acetonitrile in water with 0.1 % TFA) afforded the title compound as a white solid (96 mg, 98% yield). LCMS m/z 424.2 (M+H)+. Ή NMR (400MHz, DMSO-c/6) δ 1 .19 (d, J=6.1 1 Hz, 6 H) 1 .69 (quin, J=6.42 Hz, 2 H) 3.19 (q, J=6.60 Hz, 2 H) 3.49 (t, J=6.1 1 Hz, 3 H) 4.47 (dt, =12.04, 6.08 Hz, 1 H) 6.05 (s, 1 H) 6.16 (t, J=5.26 Hz, 1 H) 6.71 - 6.79 (m, 2 H) 6.86 - 6.99 (m, 2 H) 7.48 - 7.63 (m, 1 H) 8.07 (s, 1 H) 8.14 - 8.35 (m, 1 H) 9.77 (s, 1 H) 13.66 - 13.78 (m, 1 H). Example 166
2-hvdroxy-4-((1 -hvdroxypropan-2-yl)amino)-5-(N-(4- isopropoxyphenvDsulfamovDbenzamide
Figure imgf000225_0001
To a solution of 4-fluoro-2-hydroxy-5-(N-(4-isopropoxyphenyl)sulfamoyl)benzamide (Example 107, 80 mg, 0.217 mmol) in n-butanol (2 mL) in a microwave viol was added DIEA (0.038 mL, 0.217 mmol) followed by 2-aminopropan-1 -ol (0.034 mL, 0.652 mmol). The microwave reaction vessel was sealed and the mixture was subjected to 150 °C for 1 h in the microwave. The reaction mixture was allowed to cool to RT and was quenched with saturated aq ammonium chloride and extracted with ethyl acetate. The combined organic layers were dried and concentrated. The residue was purified by flash chromatography using an eluent of ethyl acetate in hexanes. The desired fractions were lyophilized to afford the title compound (34 mg, 37% yield). LCMS m/z 424.2 (M+H)+. 1 H NMR (400 MHz, DMSO-c/6) δ ppm 1 .09 (d, J=6.36 Hz, 3 H) 1 .16 - 1 .23 (m, 6 H) 3.30 - 3.45 (m, 3 H) 3.52 (dt, J=12.23, 6.1 1 Hz, 1 H) 4.48 (dt,J=12.10, 5.93 Hz, 1 H) 6.04 - 6.15 (m, 2 H) 6.70 - 6.81 (m, 2 H) 6.86 - 7.01 (m, 2 H) 7.48 - 7.67 (m, 1 H) 8.07 (s, 1 H) 8.15 - 8.29 (m, 1 H) 9.73 (s, 1 H) 13.60 - 13.78 (m, 1 H).
Example 167
6-(3-carbamoyl-5-chloro-4-hvdroxyphenylsulfonamido)-1 Hindole-3-carboxamide
Figure imgf000225_0002
(a) 6-amino-1 H-indole-3-carboxamide
To a stirred solution of 6-nitro-1 H-indole-3-carboxamide (400 mg) in ethanol (10 mL) and water (10 mL) were added ammonium chloride (521 mg) and iron (544 mg) at room temperature. The reaction mixture was refluxed at 80°C for 2 h. After completion of reaction, the reaction mixture was filtered through celite and filtrate was extracted with EtOAc (2 x 20 mL) and washed with brine (25 mL). The combined organic layers were dried over anhydrous Na2S04, filtered, and concentrated to afford crude 6-amino-1 H- indole-3-carboxamide (200 mg) as a brown solid. This was carried directly on to the next step.
(b) 6-(3-carbamoyl-5-chloro-4-hydroxyphenylsulfonamido)-1 Hindole-3-carboxamide
To a stirred solution of 6-amino-1 H-indole-3-carboxamide (200 mg) in dichloromethane (DCM) (10 mL) were added pyridine (0.277 mL) and 3-carbamoyl-5-chloro-4- hydroxybenzene-1 -sulfonyl chloride (lnt-5, 308 mg) at room temperature. The reaction mixture was stirred for 16 h under nitrogen. The reaction mixture was diluted with water (30 mL) and extracted with DCM (2 x 50 mL). The combined organic layers were washed with brine solution (50 mL). The organic layer was separated, dried over anhydrous Na2S04, filtered, and concentrated. The crude product was purified by prep-HPLC (Kinetix C8) with an eluent of 3-17% acetonitrile to water with 0.1 % HCOOH and the main fraction (200 mL) was lyophilized to afford 6-(3-carbamoyl-5-chloro-4-hydroxyphenylsulfonamido)- 1 H-indole-3-carboxamide (28.7 mg) as a brown solid. LCMS m/z 407.06 (M-H)-; 1H NMR (400 MHz, DMSO-c/e) δ ppm 14.96 (br s, 1 H), 1 1 .39 (br d, J=2.2 Hz, 1 H), 9.92 (s,1 H), 9.19 - 8.90 (m, 1 H), 8.19 - 8.1 .9 (m, 1 H), 8.25 (d, J= 2.2 Hz, 1 H), 8.04 - 7.76 (m, 3H), 7.36 - 7.18 (m, 1 H), 7.13 (d, J=1 .8 Hz, 1 H), 6.89 (dd, J=1 .9, 8.7 Hz, 1 H), 6.68 - 6.80 (m, 1 H).
Example 168
3-chloro-2-hvdroxy-5-(N-(3-methyl-1 H-indazol-6-yl)sulfamoyl)benzamide
Figure imgf000226_0001
To a solution of 3-methyl-1 H-indazol-6-amine (0.100 mL) and pyridine (0.180 mL) in dichloromethane (DCM) (15 mL) stirred under nitrogen at 0 °C was added 3-carbamoyl-5- chloro-4-hydroxybenzene-1 -sulfonyl chloride (lnt-5, 200 mg). The reaction mixture was warmed to 25 °C for 16 h. The reaction mixture was then concentrated. The crude solids were triturated with water (3 x 15 mL) and filtered. The solids were washed with diethyl ether (3 x 20 mL) and n-pentane (3 x 15 mL). The crude product was purified by prep- HPLC (Durashell phenyl) using an eluent of 10% acetonitrile to 10 mM aq ammonium bicarbonate. The main fraction (200 mL) was lyophilized to afford an off-white solid. The solid was washed with water (2 x 3 mL) and dried under high vacuum to obtain 3-chloro-2- hydroxy-5-(N-(3-methyl-1 H-indazol-6-yl)sulfamoyl)benzamide (36.8 mg) as an off-white solid. LCMS m/z 381 .04 (M+H)+; 1H NMR (400 MHz, DMSO-c/6) δ ppm 15.10 - 14.88 (m, 1 H), 12.42 (bs, 1 H), 10.22 (s, 1 H), 9.01 (bs, 1 H), 8.42 - 8.32 (m, 1 H), 8.32 (d, J=2.0 Hz, 1 H), 7.91 (d, J=1 .8 Hz, 1 H), 7.56 (d, J=8.6 Hz, 1 H), 7.14 (d,J=1 .3 Hz, 1 H), 6.87 (dd, J=1 .8, 8.8 Hz, 1 H), 2.40 (s, 3H).
Example 169
3-chloro-2-hvdroxy-5-(N-(2-phenyl-1 H-indol-6-yl)sulfamoyl)benzamide
Figure imgf000227_0001
To a solution of 2-phenyl-1 H-indol-6-amine (245 mg) and pyridine (0.374 mL) in dichloromethane (DCM) (10 mL) stirred under nitrogen at 0 °C was added 3-carbamoyl-5- chloro-4-hydroxybenzene-1 -sulfonyl chloride (lnt-5, 250 mg) portion wise over 5 min. The reaction mixture was stirred at 25 °C for 16 h. The reaction mixture was then concentrated under reduced pressure. Water (10 mL) was added to the reaction mixture, which was then stirred for 15 min. The resultant precipitate was filtered to afford crude product. The crude product was purified by prep-HPLC (KINETIX C8) using an eluent of 3-17% acetonitrile to 10 mM aq ammonium bicarbonate and the main fraction was concentrated to 10-15 mL. The precipitate was filtered and air-dried to obtain 3-chloro-2-hydroxy-5-(N-(2-phenyl-1 H- indol-6-yl)sulfamoyl)benzamide (99 mg) as a yellow solid. LCMS m/z 440.03 (M-H)~; 1H NMR (400 MHz, DMSO-c/6) δ ppm 14.95 (br s, 1 H), 1 1 .44 (s, 1 H), 9.91 (s, 1 H), 8.97 (br s, 1 H), 8.32 (br s, 1 H), 8.26 (d, J=2.2 Hz, 1 H), 8.02 - 7.85 (m, 1 H), 7.85 - 7.73 (m, 2H), 7.52 - 7.35 (m, 3H), 7.35 - 7.22 (m, 1 H), 7.13 (s, 1 H), 6.93 - 6.74 (m, 2H).
Example 170
3-chloro-2-hvdroxy-5-(N-(4-(hvdroxymethyl)-1 H-indol-6-yl)sulfamoyl)benzamide
Figure imgf000227_0002
To a solution of (6-amino-1 H-indol-4-yl)methanol (0.165 ml_) and pyridine (0.270 ml_) in dichloromethane (DCM) (15 ml_) stirred under nitrogen at 0 °C was added 3-carbamoyl-5- chloro-4-hydroxybenzene-1 -sulfonyl chloride (Int 5, 300 mg) and the reaction mixture was allowed to stirred at 25 °C for 16 h. The reaction mixture was then concentrated. The crude residue was triturated with water (3 x 15 ml_), filtered, washed with diethyl ether (3 x 20 ml_) and n-pentane (3 x 15 ml_), and dried under vacuum to afford a brown solid. The crude product was purified by prep-HPLC (Kinetix Phenyl Hexyl) using an eluent of 10-36% acetonitrile to 10 mM aq ammonium acetate and the product fractions were lyophilized to obtain 3-chloro-2-hydroxy-5-(N-(4-(hydroxymethyl)-1 H-indol-6-yl)sulfamoyl)benzamide (38 mg) as an off-white solid. LCMS m/z 394.01 (M-H)-; 1H NMR (400 MHz, DMSO-cfe) δ ppm 15.07-14.81 (br s, 1 H), 10.96 (s, 1 H), 9.84 (s, 1 H), 9.05-8.88 (br s, 1 H), 8.40-8.27 (br s, 1 H), 8.26 (d, J=2.0 Hz, 1 H), 7.92 (d, J=2.0 Hz, 1 H), 7.25-7.20 (t, 1 H), 7.01 (s, 1 H), 6.89- 6.82 (m, 1 H), 6.39 (t, J=2.1 Hz, 1 H), 5.18-4.99 (br s, 1 H), 4.65 (s, 2H). Example 171
6-(3-carbamoyl-5-chloro-4-hvdroxyphenylsulfonamido)-1 H-indole-2-carboxamide
Figure imgf000228_0001
(a) 6-amino-1 H-indole-2-carboxamide
To a stirred solution of 6-nitro-1 H-indole-2-carboxamide (500 mg) in ethyl acetate (20 ml_) and water (20 ml_) were added ammonium chloride (521 mg) and iron (680 mg) at room temperature. The reaction mixture was stirred for 16 h at 80 °C. The reaction mixture was filtered through a pad of celite and then washed with ethyl acetate (100 ml_). The filtrate was dried over anhydrous Na2S04, filtered and concentrated to afford crude 6-amino-1 H- indole-2-carboxamide (270 mg) as a black solid. This was carried directly on to the next step.
(b) 6-(3-carbamoyl-5-chloro-4-hydroxyphenylsulfonamido)-1 H-indole-2-carboxamide
To a stirred solution of 6-amino-1 H-indole-2-carboxamide (200 mg) in dichloromethane (DCM) (20 ml_) were added pyridine (0.277 ml_) and 3-carbamoyl-5-chloro-4- hydroxybenzene-1 -sulfonyl chloride (Int 5, 308 mg) at room temperature. The reaction mixture was stirred for 16 h. The reaction mixture was then diluted with water (10 ml_). The solids were filtered under vacuum to afford crude product. The crude product was purified by prep-HPLC (Kromosil Phenyl) using an eluent of 15% acetonitrile to 10 mM aq ammonium acetate with 0.1 % ammonia and the product fractions were lyophilized to afford impure product. This was purified by prep-HPLC (Kromasil C18) using an eluent of 10- 40% acetonitrile to 10 mM aq ammonium bicarbonate and the product fractions were lyophilized to afford 6-(3-carbamoyl-5-chloro-4-hydroxyphenylsulfonamido)-1 H-indole-2- carboxamide (36 mg) as an off-white solid. LCMS m/z 406.92 (M-H)-; 1H NMR (400 MHz, DMSO-c/e) δ ppm 1 1 .36 (s, 1 H), 9.64 (br s, 1 H), 8.13 (br s, 1 H), 7.57 (br s, 1 H), 7.38-7.48 (m, 1 H), 7.41 (d, J=8.6 Hz, 1 H), 6.84-7.35 (m, 6H), 6.81 (dd, J=8.7, 1 .9 Hz, 1 H).
Example 172
3-chloro-5-(N-(1 ,2-dimethyl-1 H-indol-5-yl)sulfamoyl)-2-hvdroxybenzamide
Figure imgf000229_0001
To a solution of 1 ,2-dimethyl-1 H-indol-5-amine (0.182 mL) and pyridine (0.225 mL) in dichloromethane (DCM) (15 mL) stirred under nitrogen at room temperature was added 3- carbamoyl-5-chloro-4-hydroxybenzene-1 -sulfonyl chloride (Int 5, 250 mg). The reaction mixture was stirred for 16 h. The reaction mixture was then concentrated and the residue diluted with water (10 mL). The solids were collected by filtration afford crude product. The crude product was purified by prep-HPLC (XBridge C-18) using an eluent of 10-40% acetonitrile to 10 mM aq ammonium bicarbonate and the product fractions were concentrated to afford 3-chloro-5-(N-(1 ,2-dimethyl-1 H-indol-5-yl)sulfamoyl)-2- hydroxybenzamide (72 mg) as a pale pink solid. LCMS m/z 394.1 1 (M+H)+; 1H NMR (400 MHz, DMSO-c/e) δ ppm 14.95 (br s, 1 H), 9.51 (br s, 1 H), 8.13 (br s, 1 H), 7.72 (br s, 1 H), 7.20 (d, J = 8.56 Hz, 1 H), 7.12 (d, J = 1 .96 Hz, 1 H), 6.93-7.09 (m, 2H), 6.76 (dd, J = 2.08, 8.68 Hz, 1 H), 6.1 1 (s, 1 H), 3.58 (s, 3H), 2.34 (d, J = 0.73 Hz, 3H).
Example 173
3-chloro-5-(N-(2-ethyl-2H-indazol-6-yl)sulfamoyl)-2-hvdroxybenzamide
Figure imgf000229_0002
To a stirred solution of 2-ethyl-2H-indazol-6-amine (358 mg) in dichloromethane (DCM) (20 mL) were added pyridine (0.225 mL) and 3-carbamoyl-5-chloro-4-hydroxybenzene-1 - sulfonyl chloride (Int 5, 500 mg) at 0 °C and stirred to room temperature for 16 h. The reaction mixture was then poured into water (20 mL). The solids were filtered and dried under vacuum to afford crude product. The crude product was purified by prep-HPLC (kromasil C18) using an eluent of 10-60% acetonitrile to water with 0.2% formic acid and the product fractions were lyophilized to afford 3-chloro-5-(N-(2-ethyl-2H-indazol-6- yl)sulfamoyl)-2-hydroxybenzamide (225 mg) as an off-white solid. LCMS m/z 395.08 (M+H)+; Ή NMR (400 MHz, DMSO-c/6) δ ppm 15.04 (br. s., 1 H), 10.16 (s, 1 H), 9.06 (br. s., 1 H), 8.38 (d, J=2.19 Hz, 2 H), 8.30 (s, 1 H), 7.97 (d, J=2.19 Hz, 1 H), 7.60 (d, J=8.77 Hz, 1 H), 7.29 (s, 1 H), 6.85 (dd, J=8.88, 1 .86 Hz, 1 H), 4.40 (q, J=7.38 Hz, 2 H), 1 .49 (t, J=7.34 Hz, 3 H).
Example 174
3-chloro-2-hvdroxy-5-(N-(3-phenyl-1 H-indol-6-yl)sulfamoyl)benzamide
Figure imgf000230_0001
(a) 3-phenyl-1 H-indol-6-amine
To a stirred solution of 6-nitro-3-phenyl-1 H-indole (200 mg) in ethanol (10 mL) and water (10 mL) were added iron (234 mg) and ammonium chloride (225 mg) at room temperature then heated to 80 °C for 2 h. The reaction mixture was filtered through celite and filtrate was extracted with EtOAc (2 x 30 mL) and washed with a brine solution (30 mL). The organic layer was separated, dried over anhydrous Na2S04 and concentrated to afford 3- phenyl-1 H-indol-6-amine (200 mg) as a brown solid. LCMS m/z 209.08 (M+H)+.
(b) 3-chloro-2-hvdroxy-5-(N-(3-phenyl-1 H-indol-6-yl)sulfamoyl)benzamide
To a stirred solution of 3-phenyl-1 H-indol-6-amine (200 mg) in dichloromethane (DCM) (10 mL) were added pyridine (0.233 mL) and 3-carbamoyl-5-chloro-4-hydroxybenzene-1 - sulfonyl chloride (Int 5, 259 mg) at room temperature. After 16 h, the reaction mixture was diluted with water (30 mL) and extracted with DCM (2 x 50 mL). The combined organic layers were washed with a brine solution (50 mL). The organic layer was separated, dried over anhydrous Na2S04, filtered and concentrated to afford crude product. The crude product was purified by prep-HPLC (KINETEX C-18) using an eluent of 10-30% acetonitrile to 10 mM aq ammonium bicarbonate (adjusted to pH 9.0) and the product fractions were concentrated to afford 3-chloro-2-hydroxy-5-(N-(3-phenyl-1 H-indol-6- yl)sulfamoyl)benzamide (71 mg) as an off-white solid. LCMS m/z 440.15 (M-H)-; 1H NMR (400 MHz, DMSO-c/e) δ ppm 14.97 (br s, 1 H), 1 1 .25 (br s, 1 H), 9.95 (s, 1 H), 8.98 (br s, 1 H), 8.47 - 8.17 (m, 2H), 7.92 (d, J=1 .7 Hz, 1 H), 7.72 (d, J=8.6 Hz, 1 H), 7.68 - 7.48 (m, 3H), 7.39 (t, J=7.7 Hz, 2H), 7.26 - 7.10 (m, 2H), 6.88 (dd, J=1 .8, 8.7 Hz,1 H).
Example 175
3-chloro-2-hvdroxy-5-(N-(4-methyl-1 H-indol-6-yl)sulfamoyl)benzamide
Figure imgf000231_0001
To a stirred solution of 4-methyl-1 H-indol-6-amine (75 mg) in dichloromethane (DCM) (20 ml_) stirred under nitrogen at room temperature were added pyridine (0.124 ml_) and 3- carbamoyl-5-chloro-4-hydroxybenzene-1 -sulfonyl chloride (Int 5, 139 mg) at room temperature. The reaction mixture was stirred for 16 h. The reaction mixture was diluted with water (10 ml_). The solids were filtered and dried under vacuum to afford crude product. The crude product was purified by prep-HPLC (Kinetex C8) using an eluent of 10- 50% acetonitrile to water with 0.1 % formic acid and the product fractions were lyophilized to afford 3-chloro-2-hydroxy-5-(N-(4-methyl-1 H-indol-6-yl)sulfamoyl)benzamide (9 mg) as an off-white solid. LCMS m/z 378.15 (M-H)-; Ή NMR (400 MHz, DMSO-c/6) δ ppm 15.01 (s, 1 H), 10.92 (br s, 1 H), 9.64 (br s, 2H), 8.15 (br s, 1 H), 7.89 (br s, 2H), 7.19 (br s, 1 H), 6.96 (s, 1 H), 6.59 (s, 1 H), 6.32 (br s, 1 H), 2.35 (s, 3H).
Example 176
3-chloro-5-(N-(2-(dimethylamino)-1 Hbenzord1imidazol-6-yl)sulfamoyl)-2- hydroxybenzamide
Figure imgf000231_0002
(a) N,N-dimethyl-5-nitro-1 H-benzo[d]imidazol-2-amine
Dimethylamine (2M in THF, 15 ml_) was added to a sealable tube containing 2-chloro-5- nitro-1 H-benzo[d]imidazole (1 g, Example 181 (a)). The reaction flask was sealed and heated at 80 °C for 16 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to afford the crude title product as a black tar (800 mg). This was used directly without purification. LCMS m/z 207.16 (M+H)+.
(b) N2,N2-dimethyl-1 H-benzo[d]imidazole-2,6-diamine
To a solution of N,N-dimethyl-5-nitro-1 H-benzo[d]imidazol-2-amine (800 mg) in ethanol (15 mL) and water (5 mL) was added ammonium chloride (1038 mg) followed by iron (1083 mg). The reaction mixture was heated at 85 °C for 3 h and then cooled to room temperature, filtered through a pad of Celite, and washed with ethyl acetate (15 mL). The filtrate was concentrated in vacuo to afford the crude title product as a black tar (700 mg), which was used directly without purification. LCMS m/z 177.1 (M+H)+.
(c) 3-chloro-5-(N-(2-(dimethylamino)-1 Hbenzo[d]imidazol-6-yl)sulfamoyl)-2- hydroxybenzamide
Pyridine (0.225 mL) and N2,N2-dimethyl-1 H-benzo[d]imidazole-2,6-diamine (196 mg) were added to a stirred solution of 3-carbamoyl-5-chloro-4-hydroxybenzene-1 -sulfonyl chloride (Int 5, 300 mg) in dichloromethane (DCM) (15 mL) at 0 °C. The reaction mixture was warmed to room temperature and stirred for 16 h. The reaction mixture was then concentrated, diluted with ice water (20 mL), and extracted with DCM (25 mL). The separated organic layer was dried over anhydrous sodium sulphate, filtered, and concentrated to afford crude product. The crude product was purified by prep-HPLC (Sunfire C-18) using an eluent of 15% acetonitrile to 10 mM aq ammonium acetate and the product fractions were lyophilized to afford 3-chloro-5-(N-(2-(dimethylamino)- 1 Hbenzo[d]imidazol-6-yl)sulfamoyl)-2-hydroxybenzamide (75 mg) as a grey solid. LCMS m/z 410.1 (M+H)+; Ή NMR (400 MHz, DMSO-c/6) δ ppm 12.13-13.50 (m, 2H), 9.96 (br s, 1 H), 9.68 (br s, 1 H), 8.1 1 (d, J=2.19 Hz, 1 H), 7.59 (br s, 1 H), 7.30-7.44 (m, 1 H), 7.14 (d, J=8.55 Hz, 1 H), 7.03 (d, J=1 .75 Hz, 1 H), 6.84 (dd, J=1 .75, 8.55 Hz, 1 H), 3.08 (s, 6H).
Example 177
5-(N-(1 H-benzordiri ,2,31triazol-6-yl)sulfamoyl)-3-chloro-2-hvdroxybenzamide
Figure imgf000232_0001
To a solution of 1 H-benzo[d][1 ,2,3]triazol-6-amine (0.091 mL) and pyridine (0.180 mL) in dichloromethane (DCM) (15 mL) stirred under nitrogen at 0 °C was added 3-carbamoyl-5- chloro-4-hydroxybenzene-1 -sulfonyl chloride (Int 5, 200 mg) and the reaction mixture was allowed to stirred at 25 °C for 16 h. The reaction mixture was then concentrated and the residue was triturated with water (3 x 15 mL), filtered, washed with diethyl ether (3 x 20 mL) and n-pentane (3 x 15 mL), and dried under high vacuum to afford crude product. The crude product was purified by prep-HPLC (Xbridge C-18) using an eluent of 10-45% acetonitrile to water with 0.1 % formic acid and the product fractions were lyophilized to obtain 5-(N-(1 H-benzo[d][1 ,2,3]triazol-6-yl)sulfamoyl)-3-chloro-2-hydroxybenzamide (25.7 mg) as a pale pink solid. LCMS m/z 367.98 (M+H)+; Ή NMR (400 MHz, DMSO-c/6) δ ppm 15.77-15.33 (m, 1 H), 15.05 (br s, 1 H), 10.59-10.14 (m, 1 H), 9.16 (br s, 1 H), 8.44-8.00 (m, 2H), 7.99-7.33 (m, 3H), 7.18 (d, J=14.51 Hz, 1 H).
Example 178
6-(3-carbamoyl-5-chloro-4-hvdroxyphenylsulfonamido)-1 H-indole-4-carboxamide
Figure imgf000233_0001
(a) 6-amino-1 H-indole-4-carboxamide
A solution of methyl 6-amino-1 H-indole-4-carboxylate (300 mg) in 7 M ammonia in methanol (18 ml) was stirred in a sealed tube at 80 °C for 32 h. The reaction mixture was transferred to a steel bomb and heated at 120 °C for 32 h. The reaction mixture was then cooled to room temperature and concentrated. The solids were washed with MeOH (3 x 15 mL). The combined filtrate was concentrated under reduced pressure to obtain 6-amino- 1 H-indole-4-carboxamide (300 mg) as a brown solid. LCMS m/z 177.1 (M+H)+.
(b) 6-(3-carbamoyl-5-chloro-4-hydroxyphenylsulfonamido)-1 H-indole-4-carboxamide To a solution of 6-amino-1 H-indole-4-carboxamide (175 mg) and pyridine (0.270 mL) in dichloromethane (DCM) (15 mL) stirred under nitrogen at 0 °C was added 3-carbamoyl-5- chloro-4-hydroxybenzene-1 -sulfonyl chloride (Int 5, 300 mg). The reaction mixture was warmed to 25 °C for 16 h. The reaction mixture was then concentrated. The crude product was triturated with water (3 x 15 mL), filtered, washed with diethyl ether (3 x 20 mL) and n- pentane (3 x 15 mL), and dried under vacuum to afford crude product. The crude product was purified by prep-HPLC (Kinetex C8) using an eluent of 10-50% acetonitrile in water with 0.1 % formic acid and the product fractions were lyophilized to obtain 6-(3-carbamoyl- 5-chloro-4-hydroxyphenylsulfonamido)-1 H-indole-4-carboxamide (41 .2 mg) as a pale brown solid. LCMS m/z 406.83 (M-H)-; Ή NMR (400 MHz, DMSO-c/6) δ ppm 15.09- 14.87 (m, 1 H), 1 1 .16 (br s, 1 H), 9.92 (br s, 1 H), 9.1 1 -8.91 (m, 1 H), 8.23 (d, J=2.19 Hz, 2H), 7.90 (br s, 1 H), 7.54 (br s, 1 H), 7.36 (t, J=2.74 Hz, 1 H), 7.27 (d, J=1 .75 Hz, 2H), 7.18 (s, 1 H), 6.70 (t, J=2.19 Hz, 1 H). Example 179
3-chloro-2-hvdroxy-5-(N-(2-isopropyl-1 H-indol-6-yl)sulfamoyl)benzamide
Figure imgf000234_0001
(a) 1 -(2,4-dinitrophenyl)-3-methylbutan-2-one
To a stirred solution of 1 ,3-dinitrobenzene (1 g) and 3-methylbutan-2-one (10 mL) was added KMn04 (0.940 g) and tetrabutylammonium fluoride trihydrate (9.38 g). The reaction mixture was stirred at room temperature for 16 h under argon. The reaction mixture was then diluted with water (20 mL) and extracted with ethyl acetate (50 mL). The separated organic layer was dried over anhydrous sodium sulphate, filtered, and concentrated to afford 1 -(2,4-dinitrophenyl)-3-methylbutan-2-one (850 mg) as a yellow solid. LCMS m/z 253.06 (M+H)+.
(b) 2-isopropyl-1 H-indol-6-amine
Pd/C (359 mg) was added to a stirred solution of 1 -(2,4-dinitrophenyl)-3-methylbutan-2-one (850 mg) in methanol (10 mL) and ammonium formate (638 mg) at room temperature. The reaction mixture was heated to 60 °C in sealed tube for 16 h. The reaction mixture was filtered through a pad of celite and the filtrate was concentrated to afford 2-isopropyl-1 H- indol-6-amine (500 mg) as a black solid. LCMS m/z 175.2 (M+H)+.
(c) 3-chloro-2-hydroxy-5-(N-(2-isopropyl-1 H-indol-6-yl)sulfamoyl)benzamide
Pyridine (0.225 mL) was added to a stirred solution of 3-carbamoyl-5-chloro-4- hydroxybenzene-1 -sulfonyl chloride (Int 5, 300 mg) in dichloromethane (DCM) (15 mL) at 0°C. 2-lsopropyl-1 H-indol-6-amine (194 mg) was added to the reaction mixture, which was then allowed to warm to room temperature. After 16 h, the reaction mixture was concentrated. The reaction mixture was diluted with ice water (20 mL) and extracted with DCM (25 mL). The separated organic layer was dried over anhydrous sodium sulphate, filtered, and concentrated to afford crude product. The crude product was purified by prep- HPLC (Kinetex C18) using an eluent of 10-55% acetonitrile to 10 mM aq ammonium acetate (pH 9) and the product fractions were lyophilized to afford 3-chloro-2-hydroxy-5-(N-(2- isopropyl-1 H-indol-6-yl)sulfamoyl)benzamide (25 mg) as a grey solid. LCMS m/z 406.03 (M-H)-; Ή NMR (400 MHz, DMSO-c/6) δ ppm 14.94 (br s, 1 H), 10.81 (s, 1 H), 9.77 (s, 1 H), 8.94 (br s, 1 H), 8.28-8.42 (m, 1 H), 8.22 (d, J=1 .97 Hz, 1 H), 7.90 (d, J=1 .75 Hz, 1 H), 7.25 (d, J=8.33 Hz, 1 H), 7.00 (s, 1 H), 6.70 (dd, J=1 .75, 8.33 Hz, 1 H), 5.97-6.09 (m, 1 H), 2.97 (td, J=6.74, 13.70 Hz, 1 H), 1 .25 (d, J=6.80 Hz, 6H). Example 180
3-chloro-5-(N-(1 -ethyl-1 H-indol-5-yl)sulfamoyl)-2-hvdroxybenzamide
Figure imgf000235_0001
To a solution of 1 -ethyl-1 H-indol-5-amine (0.136 mL) and pyridine (0.225 mL) in dichloromethane (DCM) (15 mL) stirred under nitrogen at room temperature was added 3- carbamoyl-5-chloro-4-hydroxybenzene-1 -sulfonyl chloride (Int 5, 250 mg). The reaction mixture was stirred for 16 h. The reaction mixture was then concentrated and diluted with water (10 mL). The solids were collected by filtration to afford crude product. The crude product was purified by prep-HPLC (Kromasil) using an eluent of 10-50% acetonitrile to 10 mM aq ammonium bicarbonate and the product fractions were concentrated to afford 3- chloro-5-(N-(1 -ethyl-1 H-indol-5-yl)sulfamoyl)-2-hydroxybenzamide (74 mg) as an off-white solid. LCMS m/z 394.04 (M+H)+; 1H NMR (400 MHz, DMSO-c/6) δ ppm 14.97 (br s, 1 H), 9.75 (s, 1 H), 8.95 (br s, 1 H), 8.17-8.34 (m, 2H), 7.88 (s, 1 H), 7.31 -7.39 (m, 2H), 7.27 (d, J = 1 .97 Hz, 1 H), 6.83 (dd, J = 1 .97, 8.77 Hz, 1 H), 6.35 (d, J = 3.29 Hz, 1 H), 4.13 (q, J = 7.23 Hz, 2H), 1 .31 (t, J = 7.23 Hz, 3H).
Example 181
3-chloro-2-hvdroxy-5-(N-(2-(methylamino)-1 H-benzord1imidazol-6- vDsulfamovDbenzamide
Figure imgf000235_0002
(a) 2-chloro-5-nitro-1 H-benzo[d]imidazole
To a solution of 2-chloro-1 H-benzo[d]imidazole (10 g) in sulfuric acid (62.9 mL) at 0 °C was slowly added dropwise nitric acid (17.57 mL). After 1 h, the reaction mixture was poured into ice water (100 mL). A yellow solid precipitated and was filtered and dried in vacuo to afford the title product (6.5 g). This was used directly in the next step. (b) N-methyl-5-nitro-1 H-benzo[d]imidazol-2-amine
Methanamine (2M in THF, 15 mL) was added to a sealable tube containing 2-chloro-5-nitro- 1 H-benzo[d]imidazole (1 g). The reaction flask was sealed and stirred at 80 °C for 16 h. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was washed with diethyl ether (15 mL) and dried in vacuo to afford the crude title product as a black tar (600 mg), which was used directly without purification. LCMS m/z 193.06 (M+H)+.
(c) N2-methyl-1 H-benzo[d]imidazole-2,6-diamine
To a solution of N-methyl-5-nitro-1 H-benzo[d]imidazol-2-amine (600 mg) in ethanol (15 mL) and water (5 mL) was added ammonium chloride (835 mg) followed by iron (872 mg). The reaction mixture was heated at 85 °C for 3 h. The reaction mixture was then cooled to room temperature and filtered through a pad of Celite which was washed with ethyl acetate (15 mL). The filtrate was concentrated in vacuo to afford the crude title product as a black tar (400 mg), which was used directly without purification.
(d) 3-chloro-2-hydroxy-5-(N-(2-(methylamino)-1 H-benzo[d]imidazol-6- yl)sulfamoyl)benzamide
Pyridine (0.225 mL) was added to a stirred solution of 3-carbamoyl-5-chloro-4- hydroxybenzene-1 -sulfonyl chloride (Int 5, 300 mg) in dichloromethane (DCM) (15 mL) at 0 °C. N2-methyl-1 H-benzo[d]imidazole-2,6-diamine (180 mg) was added to the reaction mixture, which was then warmed to room temperature. After 6 h, the reaction mixture was concentrated. The crude product was purified by silica gel flash chromatography using an eluent of 50% EtOAc in hexanes. The pure fractions were concentrated. The impure product was purified by prep-HPLC (Xbridge C18) using an eluent of 10-50% acetonitrile to 10 mM aq ammonium bicarbonate and the product fractions were lyophilized to afford 3- chloro-2-hydroxy-5-(N-(2-(methylamino)-1 H-benzo[d]imidazol-6-yl)sulfamoyl)benzamide (22 mg) as an off-white solid. LCMS m/z 396.14 (M+H)+; Ή NMR (400 MHz, DMSO-c/6) δ ppm 10.65 (s, 1 H), 10.22 (s, 1 H), 9.02-9.24 (m, 1 H), 8.32 (d, J=7.82 Hz, 2H), 7.34 (d, J=8.31 Hz, 1 H), 6.97-7.1 1 (m, 2H), 6.78 (dd, J=1 .96, 8.56 Hz, 1 H), 2.61 (dd, J=0.73, 7.58 Hz, 2H), 1 .20 (t, J=7.46 Hz, 3H).
Example 182
3-chloro-5-(N-(2,3-dimethyl-1 H-indol-6-yl)sulfamoyl)-2-hvdroxybenzamide
Figure imgf000236_0001
(a) 3-(2,4-dinitrophenyl)butan-2-one
Following the procedure of Example 195(a), the title product was also isolated as a yellow solid (10 g).
(b) 2,3-dimethyl-1 H-indol-6-amine
To a solution of 3-(2,4-dinitrophenyl)butan-2-one (1 g) in ethanol (10 ml_) and water (5 ml_) was added ammonium chloride (1 .572 g) and iron (1 .641 g). The reaction mixture was stirred at 80 °C for 16 h. The reaction mixture was then cooled to room temperature and filtered through a bed of Celite. The filtrate was extracted with ethyl acetate (2 x 30 ml_) and the combined organic layers were washed with brine (30 ml_), dried over sodium sulfate, filtered, and concentrated in vacuo to afford the crude title product as a brown solid (500 mg). This was used directly without purification. LCMS m/z 161 .1 1 (M+H)+.
(c) 3-chloro-5-(N-(2,3-dimethyl-1 H-indol-6-yl)sulfamoyl)-2-hydroxybenzamide
To a stirred solution of 2,3-dimethyl-1 H-indol-6-amine (250 mg) in dichloromethane (DCM) (10 ml_) at room temperature were added pyridine (0.379 ml_) and 3-carbamoyl-5-chloro- 4-hydroxybenzene-1 -sulfonyl chloride (Int 5, 421 mg). After 16 h, the reaction mixture was diluted with water (30 ml_) and extracted with DCM (2 x 50 ml_). The combined organic layers were washed with brine solution (50 ml_). The organic layer was separated, dried over anhydrous Na2S04, filtered and concentrated. The crude product was purified by prep-HPLC (XBRIDGE C-18) using an eluent of 25-60% acetonitrile to water with 0.1 % formic acid and the product fractions were lyophilized to afford 3-chloro-5-(N-(2,3-dimethyl- 1 H-indol-6-yl)sulfamoyl)-2-hydroxybenzamide (55 mg) as an off-white solid. LCMS m/z 392.1 (M-H)-; Ή NMR (400 MHz, DMSO-c/6) δ ppm 14.93 (br s, 1 H), 10.55 (s, 1 H), 9.71 (s, 1 H), 8.95 (br s, 1 H), 8.31 (br s, 1 H), 8.20 (d, J=2.0 Hz, 1 H), 7.88 (d, J=1 .8 Hz, 1 H), 7.19 (d, J=8.3 Hz, 1 H), 6.93 (d, J=1 .8 Hz, 1 H), 6.69 (dd, J=1 .9, 8.4 Hz, 1 H), 2.24 (s, 3H), 2.07 (s, 3H).
Example 183
3-chloro-5-(N-(1 ,3-dimethyl-1 Hindol-5-yl)sulfamoyl)-2-hvdroxybenzamide
Figure imgf000237_0001
(a) 1 -methyl-5-nitro-1 H-indole-3-carbaldehyde
To a solution of 5-nitro-1 H-indole-3-carbaldehyde (800 mg) in N,N-dimethylformamide (10 ml_) was added potassium carbonate (1744 mg) and methyl iodide (0.316 ml_). The reaction mixture was heated at 60 °C for 24 h. The reaction mixture was then poured into ice water (30 mL). The resulting precipitate was filtered and dried under vacuum to afford the title product as a yellow solid (700 mg). LCMS m/z 205.15 (M+H)+.
(b) 1 ,3-dimethyl-1 H-indol-5-amine
To a solution of 1 -methyl-5-nitro-1 H-indole-3-carbaldehyde (250 mg) in ethanol (10 mL) was added 10% Pd/C (250 mg). The reaction mixture was stirred under a hydrogen balloon for 3 h at room temperature. The reaction mixture was then filtered through a bed of Celite and washed with ethyl acetate (10 mL). The filtrate was concentrated in vacuo to afford the crude title product as a tan solid (120 mg). The crude product was used directly in the next step. LCMS m/z 160.91 (M+H)+.
(c) 3-chloro-5-(N-(1 ,3-dimethyl-1 Hindol-5-yl)sulfamoyl)-2-hydroxybenzamide
To a stirred solution of 1 ,3-dimethyl-1 H-indol-5-amine (107 mg) in dichloromethane (DCM) (15 mL) at 0 °C were added pyridine (0.067 mL) and 3-carbamoyl-5-chloro-4- hydroxybenzene-1 -sulfonyl chloride (Int 5, 150 mg). The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was then poured into water (10 mL). The solids were filtered and dried under vacuum to afford crude product. The crude product was purified by prep-HPLC (Kinetex C18) using an eluent of 25-60% acetonitrile to water with 0.1 % formic acid and the product fractions were lyophilized to afford 3-chloro-5-(N- (1 ,3-dimethyl-1 Hindol-5-yl)sulfamoyl)-2-hydroxybenzamide (53 mg) as an off-white solid. LCMS m/z 392.18 (M-H)"; 1H NMR (400 MHz, DMSO-c/6) δ ppm 15.00 (br. s., 1 H), 12.71 (br. s., 1 H), 9.70 (br. s., 1 H), 9.04 (br. s., 1 H), 8.23 (br. s., 1 H), 7.88 (br. s., 1 H), 7.15 - 7.42 (m, 2 H), 7.08 (s, 1 H), 6.85 (dd, J=8.60, 1 .88 Hz, 1 H), 3.68 (s, 3 H), 2.18 (s, 3 H).
Example 184
3-chloro-5-(N-(4-chloro-1 H-indol-6-yl)sulfamoyl)-2-hvdroxybenzamide
Figure imgf000238_0001
To a solution of 4-chloro-1 H-indol-6-amine (1 1 1 mg) and pyridine (0.180 mL) in dichloromethane (DCM) (15 mL) stirred under nitrogen at 0 °C was added 3-carbamoyl-5- chloro-4-hydroxybenzene-1 -sulfonyl chloride (Int 5, 200 mg). The reaction mixture was warmed to 25 °C for 16 h. The reaction mixture was then concentrated and triturated with water (3 x 15 mL). The solids were filtered on a buchner funnel, washed with diethyl ether (3 x 20 mL) and n-pentane (3 x 15 mL), and dried under vacuum to afford crude product. The crude product was purified by prep-HPLC (Kromasil C18) using an eluent of 10-45% acetonitrile to 10 mM aq ammonium bicarbonate and the product fractions were lyophilized to afford 3-chloro-5-(N-(4-chloro-1 H-indol-6-yl)sulfamoyl)-2-hydroxybenzamide (25.3 mg) as an off-white solid. LCMS m/z 400.1 (M+H)+; Ή NMR (400 MHz, DMSO-c/6) δ ppm 14.95 (br s, 1 H), 1 1 .28 (br s, 1 H), 9.83 (br s, 1 H), 8.16 (br s, 1 H), 7.93-7.62 (m, 2H), 7.32 (t, J=2.63 Hz, 1 H), 7.18- 6.89 (m, 2H), 6.83 (d, J=1 .53 Hz, 1 H), 6.32 (t, J=2.08 Hz, 1 H).
Example 185
3-chloro-5-(N-(2-(ethylamino)-1 H-benzorcnimidazol-6-yl)sulfamoyl)-2- hydroxybenzamide
Figure imgf000239_0001
To a stirred solution of 3-carbamoyl-5-chloro-4-hydroxybenzene-1 -sulfonyl chloride (Int 5, 300 mg) in dichloromethane (DCM) (15 mL) at 0 °C was added pyridine (0.225 mL) and N2- ethyl-1 H-benzo[d]imidazole-2,6-diamine (196 mg; this can be prepared in a similar manner as Example 181 (c)). The reaction mixture was warmed to room temperature. After 16 hr, the reaction mixture was concentrated, diluted with ice water (20 mL), and extracted with DCM (25 mL). The separated organic layer was dried over anhydrous sodium sulphate, filtered, and concentrated. The crude product was purified by prep-HPLC (Kromasil C18) using an eluent of 10-25% acetonitrile to 10 mM aq ammonium bicarbonate and the product fractions were lyophilized to afford impure product. The impure product was purified by prep-HPLC (Kromasil C18) using an eluent of 10-25% acetonitrile to 10 mM aq ammonium bicarbonate and the product fractions were lyophilized to afford 3-chloro-5-(N-(2- (ethylamino)-1 H-benzo[d]imidazol-6-yl)sulfamoyl)-2-hydroxybenzamide (25 mg) as an off- white solid. LCMS m/z 410.22 (M+H)+; Ή NMR (400 MHz, DMSO-c/6) δ ppm 12.36 (br s, 2H), 10.28 (br s, 1 H), 9.65 (br s, 1 H), 8.27 (br s, 1 H), 8.07 (d, J=2.63 Hz, 1 H), 7.50 (br s, 1 H), 6.96-7.25 (m, 3H), 6.85 (dd, J=1 .75, 8.55 Hz, 1 H), 3.32 (br s, 2H), 1 .18 (t, J=7.23 Hz, 3H).
Example 186
3-chloro-2-hvdroxy^-(N-(1 -methyl-1 Hbenzord1imidazol-5-yl)sulfamoyl)benzamide
Figure imgf000240_0001
(a) 1 -methyl-1 H-benzo[d]imidazol-5-amine
To a suspension of NaH (0.883 g) in Ν,Ν-dimethylformamide (DMF) (20 mL) at 0 °C was added 6-nitro-1 H-benzo[d]imidazole (2 g) and methyl iodide (2.3 mL). The reaction mixture was warmed to room temperature for 2 h . The reaction mixture was then poured into ice/water (30 mL). The solid were filtered and dried under reduced pressure to afford a mixture of 1 -methyl-6-nitro-1 H-benzo[d]imidazole and 1 -methyl-5-nitro-1 H- benzo[d]imidazole (1 g) as a yellow solid. LCMS m/z 178.12 (M+H)+.
To a suspension of Pd/C (0.601 g, 0.564 mmol) in methanol (20 mL) at room temperature was added the mixture of 1 -methyl-6-nitro-1 H-benzo[d]imidazole and 1 -methyl-5-nitro-1 H- benzo[d]imidazole (1 g). The reaction was placed under hydrogen (1 atm) for 16 h. The reaction mixture was then filtered through a pad of celite and was concentrated to afford a mixture of 1 -methyl-1 Hbenzo[d]imidazol-6-amine and 1 -methyl-1 H-benzo[d]imidazol-5- amine (500 mg) as a brown solid. LCMS m/z 148.0 (M+H)+.
(b) 3-chloro-2-hydroxy-5-(N-(1 -methyl-1 Hbenzo[d]imidazol-5- yl)sulfamoyl)benzamide
To a stirred solution of a mixture of 1 -methyl-1 H-benzo[d]imidazol-5-amine and 1 -methyl- 1 H-benzo[d]imidazol-6-amine (500 mg) in dichloromethane (DCM) (20 mL) at room temperature were added pyridine (0.824 mL) and 3-carbamoyl-5-chloro-4- hydroxybenzene-1 -sulfonyl chloride (Int 5, 918 mg). After 16 h, the reaction mixture was diluted with water (30 mL) and extracted with DCM (2 x 50 mL). The combined organic layers were washed with brine solution (50 mL). The organic layer was dried over anhydrous Na2S04, filtered and concentrated. The crude product was purified by prep- HPLC (XBridge C18) using an eluent of 10-25% acetonitrile to 10 mM aq ammonium bicarbonate (adjusted to pH 9 with NH4OH) and the product fractions were lyophilized to afford 3-chloro-2-hydroxy-5-(N-(1 -methyl-1 Hbenzo[d]imidazol-5-yl)sulfamoyl)benzamide (87 mg) as an off-white solid. LCMS m/z 381 .32 (M+H)+; Ή NMR (400 MHz, DMSO-c/6) δ ppm 15.05 - 13.84 (m, 1 H), 9.86 (br s, 1 H), 9.69 (br s, 1 H), 8.12 (br s, 2H), 7.63 (br s, 1 H), 7.54 - 7.28 (m, 3H), 7.02 (d, J=8.6 Hz, 1 H), 3.76 (s, 3H). Example 187
5-(N-(2-acetamido-1 Hbenzord1imidazol-6-yl)sulfamoyl)-3-chloro-2- hydroxybenzamide
Figure imgf000241_0001
(a) N-(6-nitro-1 H-benzo[d]imidazol-2-yl)acetamide
DIPEA (2.451 mL) was added to a solution of 6-nitro-1 Hbenzo[d]imidazol-2-amine (1 g) in dichloromethane (DCM) (10 mL) at 0 °C. Acetyl chloride (0.399 mL) was slowly added to the reaction mixture. The reaction mixture was warmed to room temperature and stirred for 16 h under argon. The reaction mixture was then concentrated. The solids were washed with diethyl ether (20 mL), filtered, and dried under vacuum to afford N-(6-nitro- 1 Hbenzo[d]imidazol-2-yl)acetamide (800 mg) as a brown solid. LCMS m/z 220.92 (M+H)+.
(b) N-(6-Amino-1 H-benzo[d]imidazol-2-yl)acetamide
Pd/C (0.483 g) was added to a solution of N-(6-nitro-1 H-benzo[d]imidazol-2-yl)acetamide (800 mg) in ethanol (10 mL) and stirred for 16 h under hydrogen. The reaction mixture was filtered and concentrated to afford crude N-(6-amino-1 Hbenzo[d]imidazol-2-yl)acetamide (600 mg) as a black semi-solid. This was carried directly on to the next step.
(c) 5-(N-(2-acetamido-1 Hbenzo[d]imidazol-6-yl)sulfamoyl)-3-chloro-2- hydroxybenzamide
Pyridine (0.225 mL) was added to a stirred solution of 3-carbamoyl-5-chloro-4- hydroxybenzene-1 -sulfonyl chloride (Int 5, 300 mg) in dichloromethane (DCM) (15 mL) at 0 °C. N-(6-Amino-1 H-benzo[d]imidazol-2-yl)acetamide (21 1 mg) was added to the reaction mixture, which was then warmed to room temperature. After 16 h. the reaction mixture was concentrated. The crude product was purified by silica gel column chromatography using an eluent of 50% EtOAc in hexanes. The product fractions were concentrated. The impure product was purified by prep-HPLC (XBridge C18) using an eluent of 10-26% acetonitrile to 10 mM aq ammonium bicarbonate and the product fractions were lyophilized to afford 5- (N-(2-acetamido-1 Hbenzo[d]imidazol-6-yl)sulfamoyl)-3-chloro-2-hydroxybenzamide (9 mg) as an off-white solid. LCMS m/z 424.06 (M+H)+; Ή NMR (400 MHz, DMSO-c/6) δ ppm 1 1 .90 (br s, 1 H), 1 1 .42 (br s, 1 H), 9.56 (br s, 1 H), 8.12 (br s, 1 H), 7.64 (br s, 2H), 7.32 - 7.04 (m, 4H), 6.80 (d, J=8.1 Hz, 1 H), 2.12 (s, 3H). Example 188
5-(N-(2-amino-1 Hbenzord1imidazol-6-yl)sulfamoyl)-3-chloro-2-hvdroxybenzamide,
trifluoroacetic acid salt
Figure imgf000242_0001
(a) 6-nitro-1 H-benzo[d]imidazol-2-amine
Cyanic bromide (15 mL) was added to a solution of 4-nitrobenzene-1 ,2-diamine (5 g) in 1 ,4-dioxane (70 mL) and water (20 mL) at room temperature. After stirring for 16 h, the solvent was removed under reduced pressure. The pH of the aqueous layer was adjusted to ~10-12 using aq NaOH (50 mL). The resultant precipitate was filtered and dried in vacuo to afford the title product as a brown solid (3 g). LCMS m/z 179.17 (M+H)+.
(b) 2,2,2-trifluoro-N-(5-nitro-1 H-benzo[d]imidazol-2-yl)acetamide
Trifluoroacetic anhydride (0.714 mL) was slowly added to an ice-chilled solution of 6-nitro- 1 H-benzo[d]imidazol-2-amine (900 mg) and DIPEA (2.206 mL) in toluene (10 mL). The reaction flask was sealed and heated at 100 °C for 16 h. The reaction mixture was then cooled to room temperature and concentrated in vacuo. The residue was washed with water (25 mL) and filtered to afford the crude product (600 mg), which was purified by silica gel column chromatography (50% ethyl acetate/hexanes) to yield the title product as a brown solid (500 mg). LCMS m/z 275.26 (M+H)+.
(c) N-(6-Amino-1 H-benzo[d]imidazol-2-yl)-2,2,2-trifluoroacetamide
To a solution of 2,2,2-trifluoro-N-(5-nitro-1 H-benzo[d]imidazol-2-yl)acetamide (500 mg) in ethanol (10 mL) was added 50% w/w Pd/C (388 mg). The reaction mixture was stirred under a hydrogen balloon for 16 h at room temperature. The reaction mixture was filtered through a bed of Celite and the filtrate was concentrated in vacuo to afford the crude title product as a black tar (450 mg). The crude product was used without purification in the next step. LCMS m/z 244.94 (M+H)+.
(d) 5-(N-(2-amino-1 Hbenzo[d]imidazol-6-yl)sulfamoyl)-3-chloro-2-hydroxybenzamide
Pyridine (0.374 mL) was added to a stirred solution of 3-carbamoyl-5-chloro-4- hydroxybenzene-1 -sulfonyl chloride (Int 5, 500 mg) in dichloromethane (DCM) (15 mL) at 0 °C. N-(6-Amino-1 H-benzo[d]imidazol-2-yl)-2,2,2-trifluoroacetamide (452 mg) was added to the reaction mixture, which was then warmed to room temperature. After 16 h, the reaction mixture was concentrated. The crude product was purified by silica gel column chromatography using an eluent of 50% EtOAc in hexanes. The product fractions were concentrated. The impure product was purified by prep-HPLC (Kinetex C8) using an eluent of 22% acetonitrile:methanol (1 :1) in water with 0.1 % TFA and the product fractions were lyophilized to afford 5-(N-(2-amino-1 Hbenzo[d]imidazol-6-yl)sulfamoyl)-3-chloro-2- hydroxybenzamide as a trifluoroacetic acid salt (81 mg, off-white solid). LCMS m/z 381 .99 (M+H)+; Ή NMR after D20 exchange (400 MHz, DMSO-c/6) δ ppm 8.22 (d, J=2.19 Hz, 1 H), 7.85 (d, J=2.19 Hz, 1 H), 7.25 (d, J=8.55 Hz, 1 H), 7.1 1 (d, J=1 .97 Hz, 1 H), 6.95 (dd, J=8.55, 2.19 Hz, 1 H).
Example 189
4-(benzylamino)-3-chloro-2-hvdroxy-5-(N-(4-isopropoxyphenyl)sulfamoyl)- benzamide
Figure imgf000243_0001
(a) 3-chloro-4-fluoro-2-hydroxybenzoic acid
To a stirred solution of 3-chloro-2,4-difluorobenzoic acid (9 g) in 1 ,3-dimethyl-2- imidazolidinone (3 mL) at room temperature was added NaOH (9.35 g) portion-wise. The reaction mixture was heated to 140 °C for 2 h. Ice water was added to the reaction mixture, which was then acidified to pH = 2 with 2N aq HCI. The solids were filtered and dried under vacuum. The solids were dissolved in methyl t-butyl ether (20 mL), washed with brine solution (10 mL), dried over anhydrous Na2S04, and evaporated in vacuum to obtain 3-chloro-4-fluoro-2-hydroxybenzoic acid (9.4 g) as an off-white solid. LCMS m/z 188.9 (M- H)-.
(b) methyl 3-chloro-4-fluoro-2-hydroxybenzoate
To a stirred solution of 3-chloro-4-fluoro-2-hydroxybenzoic acid (9.4 g) in methanol (100 mL) at 0 °C was added H2S04 (15 mL) drop-wise. The reaction mixture was heated at 60 °C for 48 h. The reaction mixture was then concentrated under vacuum. The residue was diluted with water and extracted with ethyl acetate (2 x 80 mL). The combined organic layers were washed with brine solution (5 mL), dried over sodium sulfate, and concentrated in vacuo to afford methyl 3-chloro-4-fluoro-2-hydroxybenzoate (6.5 g) as an off-white solid. LCMS m/z 202.9 (M-H)".
(c) 3-chloro-4-fluoro-2- hydroxybenzamide
Methyl 3-chloro-4-fluoro-2-hydroxybenzoate (2.4 g) was added to 70 mL of 7 M ammonia in MeOH at room temperature. The sealed reaction mixture was heated to 80 °C for 16 h. The reaction mixture was concentrated in vacuo to afford crude 3-chloro-4-fluoro-2- hydroxybenzamide (2.05 g) as an off-white solid. This was carried directly on to the next step. (d) 5-carbamoyl-3-chloro-2-fluoro-4-hydroxybenzene-1 -sulfonyl chloride
3-Chloro-4-fluoro-2-hydroxybenzamide (500 mg) was added to HSO3CI (922 mg) and thionyl chloride (0.289 mL) at 0 °C. The reaction mixture was heated at 90 °C for 1 h. The reaction mixture was concentrated to obtain crude 5-carbamoyl-3-chloro-2-fluoro-4- hydroxybenzene-1 -sulfonyl chloride (450 mg). LCMS m/z 285.93 (M-H)".
(e) 3-chloro-4-fluoro-2-hydroxy-5-(N-(4- isopropoxyphenyl)sulfamoyl)benzamide
To stirred solution of 5-carbamoyl-3-chloro-2-fluoro-4-hydroxybenzene-1 -sulfonyl chloride (450 mg) in dichloromethane (DCM) (15 mL) at 0 °C was added pyridine (0.632 mL) followed by addition of 4-isopropoxyaniline (283 mg). The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was then poured into water (10 mL) and was extracted with DCM (2 x 30 mL). The combined organic phase was washed with saturated brine solution (20 mL), dried over sodium sulfate, filtered, and concentrated. The crude compound was purified by silica gel column chromatography using an eluent of 70- 80% EtOAc/petroleum ether to afford 3-chloro-4-fluoro-2-hydroxy-5-(N-(4- isopropoxyphenyl)sulfamoyl)-benzamide (240 mg) as an off-white solid. LCMS m/z 400.99 (M-H)-.
(f) 4-(benzylamino)-3-chloro-2-hydroxy-5-(N-(4-isopropoxyphenyl)sulfamoyl)- benzamide
To a stirred solution of 3-chloro-4-fluoro-2-hydroxy-5-(N-(4-isopropoxyphenyl)sulfamoyl)- benzamide (150 mg) in ethanol (8 mL) was added phenylmethanamine (0.204 mL). The reaction mixture was heated at 70 °C in sealed tube for 48 h. The reaction mixture was then concentrated. The crude product was purified by prep-HPLC (Kinetex C18) using an eluent of 10-50% acetonitrile to 10 mM aq ammonium bicarbonate and the product fractions were lyophilized to afford 4-(benzylamino)-3-chloro-2-hydroxy-5-(N-(4- isopropoxyphenyl)sulfamoyl)-benzamide (53 mg) as an off-white solid. LCMS m/z 489.82 (M+H)+; Ή NMR after D20 exchange (400 MHz, DMSO-c/6) δ ppm 8.20 (s, 1 H), 7.22 - 7.46 (m, 5 H), 6.97 (d, J=8.99 Hz, 2 H), 6.81 (d, J=8.99 Hz, 2 H), 4.61 (br. s., 2 H), 4.39 - 4.55 (m, 1 H), 1 .21 (d, J=5.92 Hz, 6 H).
Example 190
3-chloro-5-(N-(4-ethoxy-1 H-indol-6-yl)sulfamoyl)-2-hvdroxybenzamide
Figure imgf000244_0001
(a) 1 -bromo-2-(2,2-dimethoxyethyl)-3,5-dinitrobenzene
To a stirred solution of 1 -bromo-2-methyl-3,5-dinitrobenzene (10 g) in N,N- dimethylformamide (DMF) (30 ml_) was added DMF-DMA (6.1 ml_) at room temperature. The reaction mixture was stirred for 16 h. The reaction mixture was diluted with ice water. The solids were filtered to afford crude (E)-2-(2-bromo-4,6-dinitrophenyl)-N,N- dimethylethenamine (8.0 g) as a brown solid. This was carried directly on to the next step.
(b) 1 -bromo-2-(2,2-dimethoxyethyl)-3,5-dinitrobenzene
To a solution of (E)-2-(2-bromo-4,6-dinitrophenyl)-N,N-dimethylethenamine (8 g) in methanol (70 ml_) at room temperature was added cone HCI (5 ml_). The reaction mixture was heated to 65 °C for 5 h. The reaction mixture was diluted with water (250 ml_) and extracted with ethyl acetate (3 x 250 ml_). The combined organic layers were dried over anhydrous Na2S04, filtered, and concentrated to afford crude 1 -bromo-2-(2,2- dimethoxyethyl)-3,5-dinitrobenzene (8.0 g) as a brown liquid. This was carried directly on to the next step.
(c) 2-(2,2-dimethoxyethyl)-3,5-dinitrophenol
1 -Bromo-2-(2,2-dimethoxyethyl)-3,5-dinitrobenzene (3.0 g) and KOH (1 .130 g) in 1 ,4- dioxane (25 ml_) and water (25 ml_) were stirred at room temperature under nitrogen. The reaction mixture was degassed with argon for 30 min. Pd2dba3 (0.246 g) and t-Butyl-X- Phos (0.684 g) were added to the reaction mixture. The sealed reaction mixture was heated to 80 °C for 16 h. The reaction mixture was then cooled to room temperature. The reaction mixture wa diluted with water (50 ml_) and was extracted with ethyl acetate (2 x 200 ml_). The combined organic layers were dried over anhydrous Na2S04, filtered, and concentrated. The crude product was purified by silica gel column chromatography using an eluent of 20% EtOAc in hexanes. The clean fractions were concentrated to afford 2- (2,2-dimethoxyethyl)-3,5-dinitrophenol (1 .5 g) as a yellow solid. LCMS m/z 270.99 (M-H)-.
(d) 2-(2,2-Dimethoxyethyl)-1 -ethoxy-3,5-dinitrobenzene
To a stirred solution of 2-(2,2-dimethoxyethyl)-3,5-dinitrophenol (200 mg) in acetone (15 ml_) at room temperature were added potassium carbonate (305 mg) and ethyl iodide (0.089 ml_). The reaction mixture was stirred for 1 h at 56 °C. The reaction mixture was then concentrated. The residue was dissolved in ethyl acetate (100 ml_) and washed with water (2 x 100 ml_). The organic layer was dried over anhydrous Na2S04, filtered, and concentrated to afford crude 2-(2,2-dimethoxyethyl)-1 -ethoxy-3,5-dinitrobenzene (250 mg) as a yellow solid. This was carried directly on to the next step.
(e) 4-(2,2-dimethoxyethyl)-5-ethoxybenzene-1 ,3-diamine
To a suspension of Pd/C (17.72 mg) in methanol (5 ml_) and tetrahydrofuran (THF) (1 ml_) was added ammonium formate (263 mg) at room temperature under nitrogen. The reaction mixture was heated to 32 °C. 2-(2,2-Dimethoxyethyl)-1 -ethoxy-3,5-dinitrobenzene (250 mg) and water (1 ml_) were added to the reaction mixture. The reaction mixture was heated to 42 °C for 5 h. The reaction mixture was then cooled to room temperature. The reaction mixture was filtered through a pad of celite and washed with ethyl acetate (30 ml_). The filtrate was concentrated. The residue was dissolved in ethyl acetate (50 ml_) and washed with water (2 x 50 ml_). The organic layer was dried over anhydrous Na2S04, filtered, and concentrated to afford 4-(2,2-dimethoxyethyl)-5-ethoxybenzene-1 ,3-diamine (180 mg) as a yellow solid. LCMS m/z 241 .1 (M+H)+.
(f) 4-ethoxy-1 H-indol-6-amine
To a solution of 4-(2,2-dimethoxyethyl)-5-ethoxybenzene-1 ,3-diamine (180 mg) in methanol (10 mL) at room temperature under nitrogen was added cone HCI (5 mL). After 16 h, the reaction mixture was concentrated. The residue was diluted with saturated NaHC03 solution (20 mL) and extracted with ethyl acetate (2 x 100 mL). The organic layers were dried over anhydrous Na2S04, filtered, and concentrated to afford 4-ethoxy-1 H-indol- 6-amine (100 mg) as a yellow liquid. LCMS m/z 177.03 (M+H)+.
(g) 3-chloro-5-(N-(4-ethoxy-1 H-indol-6-yl)sulfamoyl)-2-hydroxybenzamide
To a solution of 4-ethoxy-1 H-indol-6-amine (100 mg) in dichloromethane (DCM) (15 mL) at room temperature under nitrogen was added pyridine (0.138 mL) and 3-carbamoyl-5- chloro-4-hydroxybenzene-1 -sulfonyl chloride (Int 5, 153 mg). After 16 h, the reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (2 x 100 mL). The combined organic layers were dried over anhydrous Na2S04, filtered, and concentrated under reduced pressure to afford 3-chloro-5-(N-(4-ethoxy-1 H-indol-6-yl)sulfamoyl)-2- hydroxybenzamide (5 mg) as an off-white solid. LCMS m/z 410.06 (M+H)+; 1H NMR after D20 exchange (400 MHz, DMSO-c/6) δ ppm 8.17 (br. s., 1 H), 7.64 (br. s., 1 H), 7.1 1 (d, J=3.29 Hz, 1 H), 6.77 (s, 1 H), 6.26 - 6.35 (m, 2 H), 4.03 (q, J=6.87 Hz, 2 H), 1 .35 (t, J=7.02 Hz, 3 H).
Example 191
3-chloro-5-(N-(2.4-diethyl-1 Hbenzord1imidazol-6-yl)sulfamoyl)-2-hvdroxybenzamide
Figure imgf000246_0001
(a) 4-bromo-2-ethyl-6-nitro-1 H-benzo[d]imidazole
A solution of 3-bromo-5-nitrobenzene-1 ,2-diamine (Example 193(a), 7.5 g) in propionic acid (48.4 mL) was heated to 140 °C for 16 h. The reaction mixture was then cooled to room temperature and concentrated. The residue was diluted with water (40 mL) and basified to pH =7 with aq NaHC03 solution. The mixture was extracted with ethyl acetate (2 x 60 mL). The combined organic layers were washed with brine solution (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude compound was purified by silica gel column chromatography using an eluent of 20-30 %, EtOAc/petroleum ether to afford 4-bromo-2-ethyl-6-nitro-1 Hbenzo[d]imidazole (5.3 g) as a yellow solid. LCMS m/z 272.0 (M+H)+.
(b) 2-ethyl-6-nitro-4-vinyl-1 H-benzo[d]imidazole
To a stirred solution of 4-bromo-2-ethyl-6-nitro-1 H-benzo[d]imidazole (500 mg) and 2,4,6- trivinyl-1 ,3,5,2,4,6-trioxatriborinane (598 mg) in 1 ,4-dioxane (10 mL) and water (1 mL) was added tripotassium phosphate (1 179 mg). The reaction mixture was purged with argon for 10 min. X-Phos palladium G2 (146 mg) was added to the reaction mixture. The reaction mixture was heated at 100 °C for 16 h. The reaction mixture was cooled to room temperature and then filtered through a pad of celite, washed with ethyl acetate (20 mL), and concentrated. The residue was purified by silica gel using an eluent of 30-40% EtOAc/petroleum ether to afford the title compound (200 mg) as a yellow solid. LCMS m/z 218.09 (M+H)+.
(c) 2,4-diethyl-1 H-benzo[d]imidazol-6-amine
To a stirred solution of 2-ethyl-6-nitro-4-vinyl-1 H-benzo[d]imidazole (200 mg) in methanol (10 mL) at room temperature was added Pd/C (294 mg). The reaction mixture was placed under a balloon of hydrogen for 16 h. The reaction mixture was filtered through a pad of celite, washed with MeOH (20 mL), and concentrated to afford the 2,4-diethyl-1 H- benzo[d]imidazol-6-amine (130 mg). LCMS m/z 190.18 (M+H)+.
(d) 3-chloro-5-(N-(2,4-diethyl-1 Hbenzo[d]imidazol-6-yl)sulfamoyl)-2- hydroxybenzamide
To a stirred solution of 2,4-diethyl-1 H-benzo[d]imidazol-6-amine (126 mg) in dichloromethane (DCM) (10 mL) at O °C were added pyridine (0.067 mL) and 3-carbamoyl- 5-chloro-4-hydroxybenzene-1 -sulfonyl chloride (Int 5, 150 mg). The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was then concentrated. The residue was purified by prep-HPLC (Kinetex C18) using an eluent of 10-60% acetonitrile to 10 mM aq ammonium bicarbonate and the product fractions were lyophilized to afford 3- chloro-5-(N-(2,4-diethyl-1 Hbenzo[d]imidazol-6-yl)sulfamoyl)-2-hydroxybenzamide (80 mg) as an off-white solid. LCMS m/z 423.13 (M+H)+; Ή NMR after D20 exchange (400 MHz, DMSO-c/e) δ ppm 8.22 (d, J=2.41 Hz, 1 H), 7.77 (d, J=2.19 Hz, 1 H), 7.12 (d, J=1 .53 Hz, 1 H), 6.79 - 6.87 (m, 1 H), 2.89 (q, J=7.67 Hz, 2 H), 2.81 (q, J=7.53 Hz, 2 H), 1 .33 (t, J=7.56 Hz, 3 H), 1 .19 (t, J=7.56 Hz, 3 H).
Example 192
Figure imgf000247_0001
(a) 4-vinyl-1 H-indol-6-amine
To a solution of 4-bromo-1 H-indol-6-amine (600 mg) in 1 ,4-dioxane (15 mL) and water (1 mL) at room temperature under nitrogen was added 2,4,6-trivinyl-1 ,3,5,2,4,6- trioxatriborinane (1378 mg) and potassium phosphate dibasic (1485 mg). The reaction mixture was degassed with argon for 30 min. X-Phos palladium G2 (223 mg) was added to the reaction. The sealed reaction mixture was stirred at 100 °C for 16 h. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (2 x 200 mL). The combined organic layers were dried over anhydrous Na2S04, filtered, and concentrated. The residue was purified by silica gel column chromatography using an eluent of 20% EtOAc in hexanes. The clean fractions were concentrated to afford 4-vinyl-1 H-indol-6- amine (200 mg) as a brown liquid. LCMS m/z 159.07 (M+H)+.
(b) 4-ethyl-1 H-indol-6-amine
To a suspension of 10% Pd/C (1345 mg) in methanol (10 mL) under nitrogen at room temperature was added 4-vinyl-1 H-indol-6-amine (200 mg). The reaction mixture placed under a hydrogen atmosphere for 16 h. The reaction mixture was then filtered through a pad of celite and washed with methanol (20 mL). The filtrate was concentrated to afford 4- ethyl-1 H-indol-6-amine (80 mg) as a brown liquid. LCMS m/z 161 .0 (M+H)+.
(c) 3-chloro-5-(N-(4-ethyl-1 Hindol-6-yl)sulfamoyl)-2-hydroxybenzamide
To a solution of 4-ethyl-1 H-indol-6-amine (80 mg) in dichloromethane (DCM) (15 mL) under nitrogen at room temperature was added pyridine (0.121 mL) and 3-carbamoyl-5-chloro-4- hydroxybenzene-1 -sulfonyl chloride (Int 5, 135 mg). The reaction mixture was stirred for 16 h and then was diluted with water (10 mL) and extracted with ethyl acetate (2 x 100 mL). The combined organic layers were dried over anhydrous Na2S04, filtered, and concentrated. The residue was purified by silica gel column chromatography using an eluent of 40% EtOAc/hexanes. The combined product fractions were concentrated and then purified by prep-HPLC (Kinetex C18) using an eluent of 10-50% acetonitrile to 10 mM aq ammonium bicarbonate and the product fractions were concentrated to afford 3-chloro- 5-(N-(4-ethyl-1 Hindol-6-yl)sulfamoyl)-2-hydroxybenzamide (6 mg). LCMS m/z 391 .91 (M- H)-; Ή NMR after D20 exchange (400 MHz, DMSO-c/6) δ ppm 8.19 (d, J=2.19 Hz, 1 H), 7.75 (br. s., 1 H), 7.22 (d, J=3.07 Hz, 1 H), 6.99 (s, 1 H), 6.48 - 6.63 (m, 1 H), 6.39 (d, J=3.07 Hz, 1 H), 2.72 (q, J=7.60 Hz, 2 H), 1 .15 (t, J=7.56 Hz, 3 H).
Example 193
3-chloro-5-(N-(2-ethyl-4-propyl-1 Hbenzorcnimidazol-6-yl)sulfamoyl)-2- hydroxybenzamide
Figure imgf000249_0001
(a) 3-bromo-5-nitrobenzene-1 ,2-diamine
Water (40 mL) and ethanol (10 mL) were added to a flask charged with sodium sulfide (2.98 g) and sulfur (1 .224 g). The mixture was heated at 80 °C for 1 h. The solution was then added to a flask containing 2-bromo-4,6-dinitroaniline (10 g) and ammonium chloride (3.06 g) in water (40 mL) and ethanol (70 mL). The reaction mixture was heated at 80 °C for 30 min. A solution of 2N NaOH (40 mL) was added dropwise to the reaction mixture, which was then heated at 80 °C for 30 min. After cooling to room temperature, the reaction mixture was poured into ice water, neutralized to pH 7 with a 2N HCI solution, and then extracted with ethyl acetate (2 x 100 mL). The combined organic layers were washed with brine (30 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to afford the crude title product as a rust colored solid (9.4 g). The crude product was used directly in the next step. LCMS m/z 231 .98, 233.96 (M+H)+.
(b) 4-bromo-2-ethyl-6-nitro-1 H-benzo[d]imidazole
A solution of 3-bromo-5-nitrobenzene-1 ,2-diamine (7.5 g) in propionic acid (48.4 mL) was heated at 140 °C for 16 h. The reaction mixture was cooled to room temperature and then concentrated in vacuo. The residue was taken up in water (40 mL) and the solution pH was adjusted to pH 7 with sodium bicarbonate solution. The aqueous was then extracted with ethyl acetate (2 x 60 mL) and the combined organic layers were washed with brine (30 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Purification of the residue by silica gel column chromatography (20-30% ethyl acetate/petroleum ether) afforded the title product as a yellow solid (5.3 g). LCMS m/z 272.0, 273.0 (M+H)+.
(c) 4-allyl-2-ethyl-6-nitro-1 H-benzo[d]imidazole
To a stirred solution of 4-bromo-2-ethyl-6-nitro-1 H-benzo[d]imidazole (500 mg) and 2-allyl- 4,4,5-trimethyl-1 ,3,2-dioxaborolane (570 mg) in 1 ,4-dioxane (5 mL) and water (0.50 mL) was added tripotassium phosphate (1 179 mg). The reaction was purged with argon for 10 min. X-Phos palladium G2 (146 mg) was added and the reaction mixture was purged with argon for 15 min. The sealed reaction mixture was heated at 100 °C for 16 h. The reaction mixture was then cooled to room temperature and filtered through a pad of celite, washed with ethyl acetate (30 mL), and concentrated. The residue was purified by silica gel column chromatography using an eluent of 30-40% EtOAc/petroleum ether to afford 4-allyl-2-ethyl- 6-nitro-1 Hbenzo[d]imidazole (220 mg) as a yellow solid. LCMS m/z 232.16 (M+H)+.
(d) 2-ethyl-4-propyl-1 H-benzo[d]imidazol-6-amine
To a stirred solution of 4-allyl-2-ethyl-6-nitro-1 H-benzo[d]imidazole (220 mg) in methanol (15 mL) at room temperature was added Pd/C (304 mg). The reaction mixture was placed under a balloon of hydrogen for 16 h. The reaction mixture was then filtered through a pad of celite, washed with MeOH (20 mL) and concentrated to afford 2-ethyl-4-propyl-1 H- benzo[d]imidazol-6-amine (170 mg). LCMS m/z 204.16 (M+H)+.
(e) 3-chloro-5-(N-(2-ethyl-4-propyl-1 Hbenzo[d]imidazol-6-yl)sulfamoyl)-2- hydroxybenzamide
To a stirred solution of 2-ethyl-4-propyl-1 H-benzo[d]imidazol-6-amine (181 mg) in dichloromethane (DCM) (10 mL) at 0°C were added pyridine (0.090 mL) and 3-carbamoyl- 5-chloro-4-hydroxybenzene-1 -sulfonyl chloride (Int 5, 200 mg). The reaction mixture was stirred at room temperature for 16 h and then was concentrated. The residue was purified by rep-HPLC (Kinetex C18) using an eluent of 10-60% acetonitrile to water with 0.1 % formic acid and the product fractions were lyophilized to afford 3-chloro-5-(N-(2-ethyl-4-propyl- 1 Hbenzo[d]imidazol-6-yl)sulfamoyl)-2-hydroxybenzamide (67 mg) as an off-white solid. LCMS m/z 437.09 (M+H)+; 1H NMR after D20 exchange (400 MHz, DMSO-c/6) δ ppm 8.14 - 8.22 (m, 1 H), 7.73 (br. s., 1 H), 7.08 - 7.14 (m, 1 H), 6.74 - 6.80 (m, 1 H), 2.87 (q, J=7.60 Hz, 2 H), 2.74 (t, J=7.34 Hz, 2 H), 1 .52 - 1 .64 (m, 2 H), 1 .32 (t, J=7.67 Hz, 3 H), 0.82 (t, J=7.23 Hz, 3 H).
Example 194
3-chloro-5-(N-(2-ethyl-4-isopropyl-1 H-indol-6-yl)sulfamoyl)-2-hvdroxybenzamide
Figure imgf000250_0001
(a) 1 -(2-bromo-4,6-dinitrophenyl)butan-2-one
To a solution of 1 -bromo-3,5-dinitrobenzene (10 g) in 2-butanone (100 mL) at room temperature under nitrogen was added KMn04 (10 g) and tetrabutylammonium fluoride trihydrate (128 g). After stirring at room temperature for 16 h, the reaction mixture was diluted with water (500 mL) and extracted with ethyl acetate (2 x 1000 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Purification of the residue by silica gel column chromatography (5% ethyl acetate/hexanes) and concentration of the product fractions in vacuo afforded the title product as a yellow solid (6 g). LCMS m/z 314.89, 316.85 (M-H)".
(b) 4-bromo-2-ethyl-1 H-indol-6-amine
To a stirred solution of 1 -(2-bromo-4,6-dinitrophenyl)butan-2-one (13 g) in ethyl acetate (100 mL) and water (100 mL) under nitrogen at room temperature were added ammonium chloride (8.77 g) and iron (1 1 .45 g). The reaction mixture was stirred for 16 h and then filtered through a pad of celite and washed with ethyl acetate (500 mL). The separated organic layer was dried over anhydrous Na2S04, filtered, and concentrated to afford 4- bromo-2-ethyl-1 H-indol-6-amine (10 g) as a brown liquid. LCMS m/z 238.9 (M+H)+.
(c) tert-butyl (4-bromo-2-ethyl-1 H-indol-6-yl)carbamate
To a stirred solution of 4-bromo-2-ethyl-1 H-indol-6-amine (10 g) in tetrahydrofuran (THF) (150 mL) under nitrogen at room temperature were added triethylamine (17.49 mL) and Boc20 (1 1 .65 mL). The reaction mixture was stirred for 16 h and then was diluted with water (500 mL) and extracted with ethyl acetate (2 x 1000 mL). The combined organic layers were dried over anhydrous Na2S04, filtered, and concentrated. The residue was purified by silica gel column chromatography using an eluent of 15% EtOAc in hexanes. The clean fractions were concentrated to afford tert-butyl (4-bromo-2-ethyl-1 H-indol-6- yl)carbamate (4.0 g) as a brown liquid. LCMS m/z 339.14 (M+H)+.
(d) tert-butyl (2-ethyl-4-(prop-1 -en-2-yl)-1 H-indol-6-yl)carbamate
To a stirred solution of tert-butyl (4-bromo-2-ethyl-1 H-indol-6-yl)carbamate (1 .0 g) in 1 ,4- dioxane (30 mL) under nitrogen at room temperature were added 4,4,5,5-tetramethyl-2- (prop-1 -en-2-yl)-1 ,3,2-dioxaborolane (0.991 g) and potassium phosphate tribasic (1 .877 g). The reaction mixture was degassed with argon for 30 min. X-Phos palladium G2 (0.232 g) was added to the reaction mixture. The reaction mixture was heated at 100 °C for 16 h. The reaction mixture was then diluted with water (50 mL) and extracted with ethyl acetate (2 x 200 mL). The combined organic layers were dried over anhydrous Na2S04, filtered, and concentrated. The residue was purified by silica gel column chromatography using an eluent of 15% EtOAc in hexanes. The clean fractions were concentrated to afford tert-butyl (2-ethyl-4-(prop-1 -en-2-yl)-1 H-indol-6-yl)carbamate (450 mg) as a yellow liquid. LCMS m/z 301 .24 (M+H)+.
(e) tert-butyl (2-ethyl-4-isopropyl-1 H-indol-6-yl)carbamate
To a suspension of 10% Pd/C (200 mg) in methanol (20 mL) under nitrogen at room temperature was added a solution of tert-butyl (2-ethyl-4-(prop-1 -en-2-yl)-1 H-indol-6- yl)carbamate (450 mg) in methanol (10 mL). The reaction mixture was stirred for 16 h under an atmosphere of hydrogen. The reaction mixture was filtered through celite pad and washed with methanol (30 mL). The filtrate was concentrated to afford tert-butyl (2- ethyl-4-isopropyl-1 H-indol-6-yl)carbamate (390 mg) as brown colour liquid. LCMS m/z 303.23 (M+H)+.
(f) 2-ethyl-4-isopropyl-1 H-indol-6-amine
To a stirred solution of tert-butyl (2-ethyl-4-isopropyl-1 H-indol-6-yl)carbamate (390 mg) in methanol (10 mL) under nitrogen at room temperature was added 7 mL of 4.0 M HCI in 1 ,4 dioxane. The reaction mixture was stirred for 4 h and then was concentrated. The residue was dissolved in ethyl acetate (100 mL) and washed with saturated NaHC03 solution (2 x 50 mL). The organic layer was dried over anhydrous Na2S04, filtered, and concentrated to afford 2-ethyl-4-isopropyl-1 H-indol-6-amine (1 10 mg) as a brown liquid. LCMS m/z 203.16 (M+H)+.
(g) 3-chloro-5-(N-(2^thyl-4-isopropyl-1 H-indol-6-yl)sulfamoyl)-2-hydroxybenzamide
To a stirred solution of 2-ethyl-4-isopropyl-1 H-indol-6-amine (100 mg) in dichloromethane (DCM) (10 mL) under nitrogen at room temperature were added pyridine (0.120 mL) and 3-carbamoyl-5-chloro-4-hydroxybenzene-1 -sulfonyl chloride (Int 5, 134 mg). The reaction mixture was stirred for 16 h. The reaction mixture was then diluted with water (50 mL) and extracted with ethyl acetate (2 x 100 mL). The combined organic layers were dried over anhydrous Na2S04, filtered and concentrated. The residue was purified by prep-HPLC (LUNA C18) using an eluent of 10-55% acetonitrile to 10 mM aq ammonium bicarbonate and the product fractions were lyophilized to afford 3-chloro-5-(N-(2-ethyl-4-isopropyl-1 H- indol-6-yl)sulfamoyl)-2-hydroxybenzamide (7 mg) as an off-white solid. LCMS m/z 436.09 (M+H)+; Ή NMR after D20 exchange (400 MHz, DMSO-c/6) δ ppm 8.16 (br. s., 1 H), 7.75 (br. s., 1 H), 6.90 (d, J=1 .75 Hz, 1 H), 6.41 (d, J=1 .75 Hz, 1 H), 6.1 1 - 6.13 (m, 1 H), 2.99 - 3.15 (m, 1 H), 2.69 (q, J=7.45 Hz, 2 H), 1 .24 (t, J=7.56 Hz, 3 H), 1 .14 (d, J=6.80 Hz, 6 H).
Example 195
4-(benzylamino)-3-chloro-5-(N-(2-ethyl-1 H-indol-6-yl)sulfamoyl)-2- hydroxybenzamide
Figure imgf000252_0001
(a) 1 -(2,4-dinitrophenyl)butan-2-one
To a solution of 1 ,3-dinitrobenzene (200 g) in butan-2-one (2000 mL) was added KMn04 (188 g) and tetrabutylammonium fluoride trihydrate (1877 g). The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was then poured into ice water (1000 mL) and extracted with ethyl acetate (2 x 2000 mL). The combined organice layers were washed with brine (1000 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Purification of the residue by silica gel column chromatography (10% ethyl acetate/hexanes) and concentration of the product fractions in vacuo afforded the title product (45 g) as a yellow solid.
(b) 2-ethyl-1 H-indol-6-amine
To a solution of 1 -(2,4-dinitrophenyl)butan-2-one (1 1 g) in ethanol (200 mL) and water (150 mL) was added iron (12.89 g) and ammonium chloride (12.35 g). The reaction mixture was heated at 70 °C for 16 h. The reaction mixture was then cooled to room temperature and filtered through a pad of Celite. The filtrate was extracted with ethyl acetate (2 x 100 ml_) and the combined organic layers were washed with brine (50 ml_), dried over sodium sulfate, filtered, and concentrated in vacuo to afford the crude title product as a brown solid (1 1 g). This was used directly in the next step. LCMS m/z 161 .1 (M+H)+.
(c) 3-chloro-5-(N-(2-ethyl-1 H-indol-6-yl)sulfamoyl)-4-fluoro-2-hydroxybenzamide To a stirred solution of 2-ethyl-1 H-indol-6-amine (500 mg) in dichloromethane (DCM) (20 ml_) at room temperature were added pyridine (1 .262 ml_) and 5-carbamoyl-3-chloro-2- fluoro-4-hydroxybenzene-1 -sulfonyl chloride (Example 189(d), 899 mg). After 16 h, the reaction mixture was concentrated. The residue was purified by silica gel column chromatography using an eluent of 50% EtOAc in hexanes to afford 3-chloro-5-(N-(2-ethyl- 1 H-indol-6-yl)sulfamoyl)-4-fluoro-2-hydroxybenzamide (350 mg) as an off-white solid. LCMS m/z 410.05 (M-H)".
(d) 4-(benzylamino)-3-chloro-5-(N-(2-ethyl-1 H-indol-6-yl)sulfamoyl)-2- hydroxybenzamide
To a stirred solution of 3-chloro-5-(N-(2-ethyl-1 H-indol-6-yl)sulfamoyl)-4-fluoro-2- hydroxybenzamide (100 mg) in ethanol (2 ml_) at room temperature was added phenylmethanamine (260 mg) and hexamethyldisilazane (1 18 mg). The reaction mixture was stirred in a sealed tube at 50 °C for 32 h. The reaction mixture was then cooled to room temperature and was concentrated. The residue was purified by prep-HPLC (KROMOSIL C18) using an eluent of 50-77% acetonitrile to water with 0.1 % formic acid and the product fractions were lyophilized to afford 4-(benzylamino)-3-chloro-5-(N-(2-ethyl- 1 H-indol-6-yl)sulfamoyl)-2-hydroxybenzamide (1 1 mg) as an off-white solid. LCMS m/z 499.02 (M+H)+; 1H NMR (400 MHz, DMSO-c/6) δ ppm 15.44 - 14.75 (m, 1 H), 10.82 (s, 1 H), 10.02 (br s, 1 H), 8.78 (s, 1 H), 8.24 (s, 1 H), 8.02 (s, 1 H), 7.57 - 7.05 (m, 6H), 6.99 (d, J=1 .8 Hz, 1 H), 6.73 - 6.53 (m, 1 H), 6.24 (br s, 1 H), 6.06 (d, J=0.9 Hz, 1 H), 4.73 - 3.68 (m, 2H), 2.86 - 2.52 (m, 2H), 1 .49 (m, 3H).
Example 196
2-hvdroxy-3-(hvdroxymethyl)-5-(N-(4-isopropoxyphenyl)sulfamoyl)benzamide
Figure imgf000253_0001
(a) 3-bromo-2-hydroxybenzamide
To a sealable tube containing methyl 3-bromo-2-hydroxybenzoate (6 g) was added ammonia (7M in MeOH, 45 mL). The reaction flask was sealed and heated at 75 °C for 16 h. The reaction mixture was then cooled to room temperature and concentrated in vacuo to afford the crude title product (6 g) as an off-white solid. LCMS m/z 215.87 (M+H)+. (b) 3-bromo-5-carbamoyl-4-hydroxybenzene-1 -sulfonyl chloride
To chlorosulfonic acid (7.44 mL) under nitrogen at room temperature was added 3-bromo- 2-hydroxybenzamide (6.0 g) portion-wise over 5 min. The reaction mixture was stirred at 60 °C for 3 h. The reaction mixture was then cooled to room temperature and poured into an ice/water mixture (500 mL). The resultant precipitate was filtered, washed with n- pentane (2 x 20 mL), and air dried to obtain 3-bromo-5-carbamoyl-4-hydroxybenzene-1 - sulfonyl chloride (7 g) as an off-white solid. LCMS m/z 31 1 .93 (M-H)-.
(c) 3-bromo-2-hydroxy-5-(N-(4-isopropoxyphenyl)sulfamoyl)benzamide
To a solution of 4-isopropoxyaniline (9.23 g) and pyridine (4.94 mL) in dichloromethane (DCM) (10 mL) under nitrogen at 0 °C was added 3-bromo-5-carbamoyl-4- hydroxybenzene-1 -sulfonyl chloride (6.4 g) portion-wise. The reaction mixture was warmed to room temperature and stirred for 16 h. The reaction mixture was then diluted with EtOAc (500 mL). The organic phase was washed with water (100 mL) and brine ( 100 mL) and then dried over anhydrous sodium sulphate, filtered, and concentrated. The crude solid was purified by silica gel column chromatography using an eluent of 20% EtOAc in hexanes to afford 3-bromo-2-hydroxy-5-(N-(4-isopropoxyphenyl)sulfamoyl)benzamide (5.9 g) as a brown solid. LCMS m/z 426.97 (M-H)-.
(d) 8-bromo-N-(4-isopropoxyphenyl)-2,2-dimethyl-4-oxo-3,4-dihydro-2H- benzo[e][1 ,3]oxazine-6-sulfonamide
To a solution of 3-bromo-2-hydroxy-5-(N-(4-isopropoxyphenyl)sulfamoyl)benzamide (4.9 g) and triethyl orthoformate (19.01 mL) in acetone (100 mL) under nitrogen at 25 °C was added p-TsOH (1 .086 g). After 16 h, 2 g of NaHC03 was added to the reaction mixture and the reaction mixture was diluted with EtOAc (500 mL). The organic phase was washed with water (2 x 150 mL) and brine (100 mL), dried over sodium sulphate, filtered, and concentrated. The crude solid was triturated with pentane (3 x 25 mL) to afford 8-bromo- N-(4-isopropoxyphenyl)-2,2-dimethyl-4-oxo-3,4-dihydro-2H-benzo[e][1 ,3]oxazine-6- sulfonamide (4.8 g) as a brown solid. LCMS m/z 468.95 (M-H)+.
(e) 2-hydroxy-5-(N-(4-isopropoxyphenyl)sulfamoyl)-3-vinylbenzamide
To a stirred solution of 8-bromo-N-(4-isopropoxyphenyl)-2,2-dimethyl-4-oxo-3,4-dihydro- 2H-benzo[e][1 ,3]oxazine-6-sulfonamide (1 .2 g), 2,4,6-trivinyl-1 ,3,5,2,4-trioxadiborinane, trispyridine salt (1 .538 g) in 1 ,4-dioxane (8 mL) and water (2 mL) was added tripotassium phosphate (1 .085 g). The reaction mixture was purged with argon for 10 min. X-Phos palladium G2 (0.100 g) was added to the reaction mixture. The reaction mixture was heated at 100 °C for 16 h. The reaction mixture was then cooled to room temperature and concentrated. The tacky oil was suspended between water (40 mL) and EtOAc (2 x 100 mL). The combined organic layers were dried over Na2S04, filtered, and concentrated. The crude solid was purified by silica gel column chromatography using an eluent of 25% EtOAc in hexanes. The clean product fractions were concentrated to afford the title product (400 mg) as a brown solid. LCMS m/z 375.30 (M-H)".
(f) 3-formyl-2-hydroxy-5-(N-(4-isopropoxyphenyl)sulfamoyl)-benzamide
A stirred solution of 2-hydroxy-5-(N-(4-isopropoxyphenyl)sulfamoyl)-3-vinylbenzamide (300 mg) in tetrahydrofuran (THF) (10 mL) at -78 °C was purged with 03 gas for 1 h. The reaction mixture was then concentrated in vacuo to afford crude 3-formyl-2-hydroxy-5-(N- (4-isopropoxyphenyl)sulfamoyl)benzamide (300 mg) as an off-white solid. LCMS m/z 377.10 (M-H)-.
(g) 2-hydroxy-3-(hydroxymethyl)-5-(N-(4-isopropoxyphenyl)sulfamoyl)benzamide To a stirred solution of 3-formyl-2-hydroxy-5-(N-(4-isopropoxyphenyl)sulfamoyl)- benzamide (300 mg) in methanol (10 mL) at 0 °C was added NaBH4 (150 mg) portion-wise. The reaction mixture was then stirred at room temperature for 16 h. The reaction mixture was quenched with methanol (15 mL) and concentrated in vacuo. The residue was purified by prep-HPLC (Luna C18) using an eluent of 20-40% acetonitrile to 10 mM aq ammonium bicarbonate and the product fractions were lyophilized to afford 2-hydroxy-3- (hydroxymethyl)-5-(N-(4-isopropoxyphenyl)sulfamoyl)benzamide (39 mg) as an off-white solid. LCMS m/z 379.1 1 (M-H)"; 1H NMR (400 MHz, DMSO-c/6) δ ppm 13.54 (br s, 1 H), 9.67 (br s, 1 H), 9.00 (s, 1 H), 8.12 (s, 1 H), 7.83 (br s, 2H), 7.01 - 6.92 (m, 2H), 6.74 - 6.72 (m, 2H), 4.58 (s, 1 H), 4.48 - 4.44 (m, 3H), 1 .20 - 1 .16 (m, 6H).
Example 197
5-(N-(1 H-indol-6-yl)sulfamoyl)-2-hvdroxy-4-((5-hvdroxypentyl)amino)benzamide
Figure imgf000255_0001
(a) 5-(N-(1 H-indol-6-yl)sulfamoyl)-4-fluoro-2-hydroxybenzamide
A 250 mL round-bottomed flask was charged with 1 H-indol-6-amine (2.084 g) and pyridine (6.38 mL) in dichloromethane (DCM) (31 .5 mL) at room temperature under nitrogen to give a brown solution. 5-Carbamoyl-2-fluoro-4-hydroxybenzenesulfonyl chloride (Int 2, 4 g) was added to the reaction mixture. After stirring overnight, the reaction mixture was concentrated. The residue was stirred with 0.5 N aq HCI (60 mL). The solids were filtered and washed with water. The residue was purified by silica gel column chromatography using an eluent of 10-50% ethyl acetate/hexanes and the clean fractions were concentrated to obtain 5-(N-(1 H-indol-6-yl)sulfamoyl)-4-fluoro-2-hydroxybenzamide (3.84 g). LCMS m/z 348.1 (M-H)".
(b) 5-(N-(1 H-indol-6-yl)sulfamoyl)-2-hydroxy-4-((5-hydroxypentyl)amino)benzamide
A 5 mL sealable tube was charged with 5-(N-(1 H-indol-6-yl)sulfamoyl)-4-fluoro-2- hydroxybenzamide (50 mg), 5-aminopentan-1 -ol (16.24 mg), N,N-diisopropylethylamine (0.052 mL) and tert-butanol (1 mL) to give a colorless solution at room temperature under nitrogen. The reaction mixture was sealed and heated to 120 °C. After overnight, the reaction mixture was concentrated in vacuo. This sequence was repeated two more times. The combined residue from all three reaction mixtures was purified by prep-HPLC (XSelect CSH C18 column) using an eluent of 15-55% acetonitrile to 10 mM aq ammonium bicarbonate with 0.075% ammonium hydroxide and the product fractions were concentrated to afford 5-(N-(1 H-indol-6-yl)sulfamoyl)-2-hydroxy-4-((5- hydroxypentyl)amino)benzamide (15 mg) as an off-white solid. LCMS m/z 433.1 (M+H)+; Ή NMR (400 MHz, DMSO-c/6) δ ppm 13.64 (s, 1 H), 10.96 (s, 1 H), 9.84 (br. s., 1 H), 8.25 (br. s., 1 H), 8.12 (s, 1 H), 7.54 (br. s., 1 H), 7.35 (d, J=8.36 Hz, 1 H), 7.18 - 7.30 (m, 1 H), 7.01 - 7.18 (m, 1 H), 6.74 (dd, J=8.36, 1 .77 Hz, 1 H), 6.23 - 6.37 (m, 1 H), 6.08 (br. s., 1 H), 5.97 (s, 1 H), 4.41 (t, J=5.07 Hz, 1 H), 3.36 - 3.45 (m, 2 H), 2.97 - 3.1 1 (m, 2 H), 1 .37 - 1 .53 (m, 4 H), 1 .22 - 1 .37 (m, 2 H).
Example 198
5-(N-(1 H-indol-6-yl)sulfamoyl)-2-hvdroxy-4-((3-hvdroxybutyl)amino)benzamide
Figure imgf000256_0001
A 20 mL sealable tube was charged with 5-(N-(1 H-indol-6-yl)sulfamoyl)-4-fluoro-2- hydroxybenzamide (Example 197(a), 150 mg), 4-aminobutan-2-ol (80 mg) and tert-butanol (4 mL) to give a colorless solution at room temperature under nitrogen. The reaction mixture was heated to 80 °C. After overnight, the reaction mixture was concentrated. The residue was purified by prep-HPLC (XSelect CSH C18 column) using an eluent of 15-55% acetonitrile to 10 mM aq ammonium bicarbonate with 0.075% ammonium hydroxide and the clean product fractions were concentrated to obtain 5-(N-(1 H-indol-6-yl)sulfamoyl)-2- hydroxy-4-((3-hydroxybutyl)amino)benzamide (60 mg) as a white solid. LCMS m/z 419.1 (M+H)+; 1H NMR (400 MHz, DMSO-c/6) δ ppm 13.65 (s, 1 H), 10.96 (br. s., 1 H), 9.80 (s, 1 H), 8.21 (br. s., 1 H), 8.1 1 (s, 1 H), 7.56 (br. s., 1 H), 7.35 (d, J=8.36 Hz, 1 H), 7.24 (t, J=2.66 Hz, 1 H), 7.09 (s, 1 H), 6.74 (dd, J=8.36, 1 .77 Hz, 1 H), 6.31 (t, J=2.03 Hz, 1 H), 6.17 (t, J=5.32 Hz, 1 H), 6.01 (s, 1 H), 4.61 (d, J=4.82 Hz, 1 H), 3.67 (dt, J=1 1 .66, 5.83 Hz, 1 H), 3.07 - 3.23 (m, 2 H), 1 .41 - 1 .59 (m, 2 H), 1 .08 (d, J=6.34 Hz, 3 H).
Table 1. LCMS Data for Examples
Figure imgf000256_0002
7 309.05 307.04 306.93
8 309.05 308.98 307.04
9 377.04 376.97 375.03
10 391 .06 389.04 389.00
1 1 351 .10 349.09 348.98
12 31 1 .05 309.03 308.95
13 371 .04 369.02 368.91
14 399.10 397.09 397.02
15 339.05 337.03 336.91
16 365.12 363.10 362.97
17 336.10 334.09 333.90
18 385.09 385.0 383.07
19 322.09 322.01 320.07
20 372.03 370.02 369.93
21 333.09 332.9 331 .08
22 308.07 308.0 306.05
23 343.08 342.9 341 .06
24 344.07 343.9 342.05
25 332.07 331 .9 330.05
26 332.07 332.00 330.05
27 333.07 332.90 331 .05
28 336.10 336.03 334.09
29 308.07 307.94 306.05
30 349.03 348.99 347.02
31 283.05 283.00 281 .03
32 346.09 346.0 344.07
33 333.05 331 .04 331 .1
34 349.03 348.95 347.02
35 346.09 346.00 344.07
36 360.07 360.00 358.05
37 346.09 346.03 344.07
38 360.07 359.97 358.05
39 360.07 360.04 358.05
40 360.07 360.00 358.05
41 334.09 334.05 332.07
42 412.06 412.1 410.05
43 412.06 412.02 410.05
44 448.06 448.06 446.05
45 386.05 386.03 384.03
46 386.05 386.03 384.03
47 448.06 448.10 446.05
48 350.08 350.03 348.07 49 350.08 350.07 348.07
50 348.07 346.05
51 350.06 348.05
52 333.07 333.07 331 .05
53 337.05 337.00 335.03
54 333.07 333.0 331 .05
55 346.09 346.0 344.07
56 448.15 448.10 446.14
57 333.07 333.0 331 .05
58 346.09 346.00 344.07
59 448.15 448.10 446.14
60 346.09 346.03 344.07
61 448.15 448.13 446.14
62 348.10 348.09 346.08
63 333.07 333.0 331 .05
64 351 .10 351 .07 349.09
65 299.02 298.94 297.00
66 377.12 377.10 375.10
67 347.08 347.04 345.07
68 448.15 448.13 446.14
69 360.10 360.1 1 358.09
70 361 .10 361 .07 359.08
71 391 .13 391 .19 389.12
72 333.07 333.10 331 .05
73 333.07 333.06 331 .05
74 374.12 374.10 372.10
75 360.10 360.09 358.09
77 350.06 350.09 348.05
78 350.06 350.09 348.05
79 366.03 366.0 364.02
80 372.10 372.05 370.09
81 349.09 349.20 347.07
82 379.09 379.10 377.07
83 348.36 348.04 346.34
84 351 .06 351 .06 349.04
85 365.07 365.10 363.06
86 375.1 1 375.10 373.10
88 367.03 367.0 365.01
91 359.08 359.3 357.07
92 332.98 332.99 330.96
93 359.08 359.1 357.07
94 313.03 313.05 31 1 .02 95 313.03 313.01 311.02
96 390.08 390.08 388.06
97 366.03 366.0 364.02
98 408.10 408.07 406.09
99 313.03 313.01 311.02
100 390.08 309.04 388.06
101 409.98 407.97 407.90
102 347.08 347.14 345.07
103 283.05 283.5 281.03
104 350.06 350.05 348.05
105 362.08 360.07 360.06
106 403.14 403.18 401.13
107 369.09 367.08
108 490.12 490.18 488.10
109 390.08 388.06 388.06
110 410.14 408.12 408.18
111 403.14 403.18 401.13
112 490.12 490.15 488.10
113 409.48 409.23 407.46
114 470.18 470.24 468.16
115 465.16 463.14 463.24
116 410.98 411.2 408.96
117 346.09 346.00 344.07
118 347.37 347.05 345.35
119 365.12 365.09 363.10
120 347.08 347.06 345.07
121 346.09 346.09 344.07
122 360.10 360.09 358.09
123 360.10 360.13 358.09
124 375.11 374.9 373.10
125 374.12 372.10 372.15
126 374.12 372.10 372.04
127 350.12 350.09 348.10
128 375.11 375.3 373.10
129 375.11 375.3 373.10
130 361.10 361.3 359.08
131 361.10 361.3 359.08
132 366.03 364.02 364.11
133 367.03 366.99 365.01
134 380.05 380.03 378.03
135 385.06 385.1 383.05
136 395.06 395.08 393.04 137 367.03 367.04 365.01
138 380.05 378.03
139 366.03 366.03 364.02
140 370.06 370.06 368.05
141 394.06 394.14 392.05
142 394.06 394.07 392.05
143 424.04 422.02 422.00
144 443.94 444.18 441 .93
145 424.04 422.02
146 396.04 394.03 394.04
147 424.04 422.02 422.0
148 399.99 397.98 398.07
149 382.03 380.01 380.0
150 395.06 395.04 393.04
151 380.05 378.03 378.02
152 351 .06 351 .2 349.04
153 401 .05 401 .5 399.04
154 375.08 375.1 373.06
155 380.13 380.14 378.1 1
156 394.14 394.22 392.13
157 456.16 456.20 454.14
Example 199: CD73 Assay Compounds of the invention were assayed for CD73 enzyme inhibitory activity.
Human CD73 catalyzes the conversion of AMP to adenosine. A RapidFire mass spectrometry assay is used to directly measure the formation of adenosine from CD73. Typically 15uL of human flag-CD73 (1 -552, Thr376Ala) in assay buffer (20mM Tris pH 7.5, 25mM NaCI, 1 mM MgCI2, 0.002% Tween-20, 0.5mM DTT, 0.01 mg/ml_ BSA) is added to a 384 well plate containing 300nl_ of test compound in DMSO, serially diluted 1 :3 in an 1 1 point titration. The compound and enzyme are incubated for 10 minutes at room temperature. Next 15uL of AMP in assay buffer is added to the plate. The final concentration of CD73 and AMP in the reaction are 50pM and 20uM respectively. Following a 30 minute reaction at room temperature, the reaction is quenched with 20uL of 0.1 % TFA in water with 2.5uM C13-adenosine internal standard at 2.5 times their final concentration. Adenosine is then detected using a RapidFire/Sciex 4000 Q-Trap RF-MS. The adenosine generated is normalized to the C13-adenosine internal standard. Test compound inhibition is expressed as percent inhibition of internal assay controls and a four parameter curve fit is applied in Activity Base XE to determine the potency of the test compound.
Example 200 - Capsule Composition
An oral dosage form for administering the present invention is produced by filing a standard two piece hard gelatin capsule with the ingredients in the proportions shown in Table 2, below.
Table 2
INGREDIENTS AMOUNTS
5-(N-(3-Ethoxyphenyl)sulfamoyl)-2-hydroxybenzamide 7 mg
(Compound of Example 1 )
Lactose 53 mg
Talc 16 mg
Magnesium Stearate 4 mg
Example 201 - Injectable Parenteral Composition
An injectable form for administering the present invention is produced by stirring 1 .7% by weight of 2-Hydroxy-5-(N-(4-methoxyphenyl)sulfamoyl)benzamide (Compound of Example 2) in 10% by volume propylene glycol in water.
Example 202 Tablet Composition
The sucrose, calcium sulfate dihydrate and a CD73 inhibitor as shown in Table 3 below, are mixed and granulated in the proportions shown with a 10% gelatin solution. The wet granules are screened, dried, mixed with the starch, talc and stearic acid;, screened and compressed into a tablet.
Table 3
INGREDIENTS AMOUNTS
5-(N-(3,4-Diethoxyphenyl)sulfamoyl)-2-hydroxybenzamide 12 mg
(Compound of Example 3)
calcium sulfate dihydrate 30 mg
sucrose 4 mg
starch 2 mg
talc 1 mg
stearic acid 0.5 mg Biological Activity
Those of skill in the art will recognise that the above assay is subject to experimental variability. Accordingly, it is to be understood that the values given below are exemplary only.
Compounds of the invention are tested for activity against CD73 generally according to the above assay. All the compounds of the Examples were tested generally according to the above
CD73 enzyme assay and in at least one set of experimental runs exhibited a plC50 value from 5 to 7.4 against CD73.
The compounds of Examples 69, 75, 80, 120, 125, 127,134, 137, 140, 142, 145, 147, 149, 150, 151 , 163, 168, 179, 188 and 193 were tested generally according to the above CD73 assay and in at least one set of experimental runs exhibited an average plC50 value to≥ 6.5.
The compound of Example 25 was tested generally according to the above CD73 enzyme assay and in at least one set of experimental runs exhibited an average pICso value of 6.0 against CD73.
The compound of Example 61 was tested generally according to the above CD73 enzyme assay and in at least one set of experimental runs exhibited an average pICso value of 5.5 against CD73.
The compound of Example 125 was tested generally according to the above CD73 enzyme assay and in at least one set of experimental runs exhibited an average pICso value of 7.0 against CD73.
The compound of Example 167 was tested generally according to the above CD73 enzyme assay and in at least one set of experimental runs exhibited an average pICso value of 7.1 against CD73. While the preferred embodiments of the invention are illustrated by the above, it is to be understood that the invention is not limited to the precise instructions herein disclosed and that the right to all modifications coming within the scope of the following claims is reserved.

Claims

What is claimed is:
1. A compound according to Formula (I):
Figure imgf000264_0001
wherein:
R is selected from:
aryl,
aryl substituted with from one to five substituents independently selected from:
fluoro,
chloro,
bromo,
iodo,
Cl-6alkyl,
Ci-6alkyl substituted with from 1 to 9 substituents
independently selected from: fluoro, chloro, bromo, iodo, oxo, Cl -4alkyloxy, -OH, -COOH, -NR3 0R320,
-N(H)Cl-4alkyl, -N(Cl -4alkyl)2 and -CN, cycloalkyl,
heteroaryl,
Cl-6alkoxy,
Ci-6alkoxy substituted with from 1 to 9 substituents
independently selected from: fluoro, chloro, bromo, oxo, -OH, phenyl and -CN,
-CN,
oxo,
-OH, -Ocycloalkyl,
-Ophenyl,
-C(0)OC(CH3)3,
-COOH,
-Cl -4alkylOCl -4alkyl,
-NO2,
-NH2,
-N(H)Cl-4alkyl,
-N(H)Ci-4alkyl substituted with from 1 to 9 substituents independently selected from: fluoro, chloro, bromo, oxo, -OH, and -CN,
-N(Cl-4alkyl)2,
-Cl -4alkylNHBoc,
-N(H)aryl,
-N(H)C(0)aryl,
-N(H)OC(0)Cl-4alkyl,
-N(H)C(0)Cl-4alkyl,
-N(H)S(0)2Cl-4alkyl,
-N(H)S(0)2cycloalkyl,
-N(H)S(0)2phenyl,
-SCl -6alkyl,
-SCi -6alkyl substituted with from 1 to 9 substituents
independently selected from: fluoro, chloro, bromo, oxo, -OH, and -CN,
-SO2NH2, and
heteroaryl,
heteroaryl substituted with from one to five substituents independently selected from:
fluoro, chloro,
bromo,
iodo,
Cl-6alkyl,
Ci-6alkyl substituted with from 1 to 9 substituents
independently selected from: fluoro, chloro, bromo, iodo, oxo, -OH, -NR31 0R320, and -CN, aryl,
Cl-4alkoxy,
-CN,
oxo,
-OH,
-COOH,
-NO2,
-IMH2, and
SO2NH2,
bicycloheteroaryl,
bicycloheteroaryl substituted with from one to five substituents
independently selected from:
fluoro,
chloro,
bromo,
iodo,
Cl-6alkyl,
Ci-6alkyl substituted with from 1 to 9 substituents
independently selected from: fluoro, chloro, bromo, iodo, oxo, -OH, -COOH, -NR3 0R320, and -CN,
-C(0)0Cl-6alkyl,
cycloalkyl,
aryl,
Cl-4alkoxy, Ci-4alkoxy substituted with from 1 to 5 substituents
independently selected from: fluoro, chloro, bromo, oxo, -OH and -CN,
-CN,
oxo,
-OH,
-Ophenyl,
-COOH,
-NO2,
-NH2,
-N(H)Cl-4alkyl,
-N(Cl-4alkyl)2,
-N(H)aryl, and
-N(H)C(0)aryl; and
R and R2 are independently selected from:
hydrogen,
Cl-6alkyl,
Ci-6alkyl substituted with from one to five substituents independently selected from: fluoro, chloro, oxo, -OH, and -NH2,
fluoro,
chloro,
bromo,
iodo,
-N(H)Cl -6alkyl,
-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;
where,
R310 and R320 are independently selected from hydrogen and C-| -C4alkyl, or R310 and 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;
or a pharmaceutically acceptable salt thereof.
2. The compound of Formula (I) according to Claim 1 represented by the following Formula (II):
Figure imgf000268_0001
is selected from:
aryl,
aryl substituted with from one to five substituents independently selected from:
fluoro,
chloro,
bromo,
Cl-6alkyl,
Ci-6alkyl substituted with from 1 to 5 substituents
independently selected from: fluoro, chloro, bromo, iodo, oxo, Cl -4alkyloxy, -OH, -COOH, and
_NR311 R321
cycloalkyl,
heteroaryl,
Cl-6alkoxy,
Ci-6alkoxy substituted with from 1 to 5 substituents
independently selected from: fluoro, chloro, bromo, oxo, -OH, phenyl and -CN,
-CN,
oxo,
-OH,
-Ocycloalkyl,
-Ophenyl,
-COOH,
-NO2,
-NH2,
-N(H)Cl-4alkyl,
-N(H)Ci-4alkyl substituted with from 1 to 5 substituents independently selected from: fluoro, chloro, bromo, oxo, -OH, and -CN,
-N(Cl-4alkyl)2,
-N(H)aryl,
-N(H)C(0)aryl,
-N(H)0C(0)Cl-4alkyl,
-N(H)C(0)Cl-4alkyl,
-N(H)S(0)2Cl -4alkyl,
-N(H)S(0)2cycloalkyl,
-N(H)S(0)2phenyl,
-SCl -6alkyl,
-SCi -6alkyl substituted with from 1 to 5 substituents
independently selected from: fluoro, chloro, bromo, oxo, -OH, and -CN, and
-SO2NH2,
heteroaryl,
heteroaryl substituted with from one to five substituents independently selected from:
fluoro, chloro,
bromo,
iodo,
Cl-6alkyl,
Ci-6alkyl substituted with from 1 to 5 substituents
independently selected from: fluoro, chloro, bromo, iodo, oxo, -OH, -NR31 1 R321 and -CN, aryl,
Cl-4alkoxy,
-CN,
oxo,
-OH,
-COOH,
-NO2,
-IMH2, and
SO2NH2,
bicycloheteroaryl,
bicycloheteroaryl substituted with from one to five substituents
independently selected from:
fluoro,
chloro,
bromo,
iodo,
Cl-6alkyl,
Ci-6alkyl substituted with from 1 to 5 substituents
independently selected from: fluoro, chloro, bromo, iodo, oxo, -OH, -COOH, -NR3 R32 and -CN,
-C(0)0Cl-6alkyl,
cycloalkyl,
aryl,
Cl-4alkoxy, Ci -4alkoxy substituted with from 1 to 5 substituents
independently selected from: fluoro, chloro, bromo, oxo, -OH and -CN,
-CN,
oxo,
-OH,
-Ophenyl,
-COOH,
-NO2,
-IMH2, and
-N(H)Cl -4alkyl; and
R and R 2 are independently selected from:
hydrogen,
Cl -6alkyl,
Ci -6alkyl substituted with from one to five substituents independently selected from: fluoro, chloro, oxo, -OH, and -NH2,
fluoro,
chloro,
bromo,
iodo,
-N(H)Cl -6alkyl,
-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,
R31 1 and R321 are independently selected from hydrogen and C-| -C4alkyl, or R31 1 and
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;
or a pharmaceutically acceptable salt thereof.
3. A compound according to claim 1 or claim 2 represented by the following Formula (III):
Figure imgf000272_0001
is selected from:
aryl,
aryl substituted with from one to five substituents independently selected from:
fluoro,
Cl-6alkyl,
Cl-6alkyl substituted 1 to 5 times by fluoro,
-CONR312R322,
heteroaryl,
Cl-6alkoxy,
Ci-6alkoxy substituted with from 1 to 5 substituents
independently selected from: fluoro and phenyl,
-OH,
-Ocycloalkyl,
-Ophenyl,
-NH2,
-N(H)Cl-4alkyl,
-N(H)Ci-4alkyl substituted with from 1 to 5 substituents independently selected from: fluoro, oxo, and -OH, -N(Cl-4alkyl)2,
-N(H)S(0)2Cl-4alkyl,
-N(H)S(0)2cycloalkyl,
-N(H)S(0)2phenyl,
-SCl -6alkyl,
-SCi -6alkyl substituted 1 to 5 times by fluoro, and -SO2NH2,
heteroaryl,
heteroaryl substituted with from one to five substituents independently selected from:
fluoro,
chloro,
Cl-6alkyl,
Cl-6alkyl substituted 1 to 5 times by fluoro,
-CONR3 2R322,
aryl, and
Cl-4alkoxy,
bicycloheteroaryl,
bicycloheteroaryl substituted with from one to five substituents
independently selected from:
fluoro,
chloro,
bromo,
Cl-6alkyl,
Ci-6alkyl substituted with from 1 to 5 substituents independently selected from: fluoro, and -OH, -CONR312R322,
-C(0)OCl-6alkyl,
cycloalkyl, aryl,
Cl -4alkoxy,
Ci -4alkoxy substituted with from 1 to 5 substituents
independently selected from: fluoro, chloro, bromo, oxo, -OH and -CN,
oxo, and
-NH2; and
R2 and R22 are independently selected from:
hydrogen,
Cl -6alkyl,
Ci -6alkyl substituted with from one to five substituents independently selected from: fluoro, chloro, oxo, -OH, and -NH2,
fluoro,
chloro,
bromo,
iodo,
-N(H)Cl -6alkyl,
-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 and R322 are independently selected from hydrogen and C-| -C4alkyl, or R312 and
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;
or a pharmaceutically acceptable salt thereof.
4. A compound according to any one of claims 1 to 3 represented by the following Formula (IV):
Figure imgf000275_0001
elected from:
aryl substituted with from one to five substituents independently selected from:
fluoro,
Cl-6alkyl,
Cl-6alkyl substituted 1 to 3 times by fluoro,
-CONR31 3R323,
heteroaryl,
Cl-6alkoxy,
Ci-6alkoxy substituted with from 1 to 3 substituents independently selected from: fluoro and phenyl,
-OH,
-Ocycloalkyl,
-Ophenyl,
-NH2,
-N(H)Cl-4alkyl,
-N(H)Cl-4alkyl substituted by oxo, -N(Cl-4alkyl)2,
-N(H)S(0)2Cl-4alkyl,
-N(H)S(0)2cycloalkyl,
-N(H)S(0)2phenyl,
-SCi -6alkyl, and -SO2NH2,
heteroaryl,
heteroaryl substituted with from one to five substituents independently selected from:
fluoro,
chloro,
Cl-6alkyl,
-CONR31 3R323,
aryl, and
Cl-4alkoxy,
bicycloheteroaryl,
bicycloheteroaryl substituted with from one to five substituents
independently selected from:
fluoro,
chloro,
bromo,
Cl-6alkyl,
Cl-6alkyl substituted by -OH,
-CONR31 3R323,
-C(0)OCl-6alkyl,
cycloalkyl,
aryl,
Cl-4alkoxy,
Ci-4alkoxy substituted with from 1 to 5 substituents
independently selected from: fluoro, chloro, bromo, oxo, -OH and -CN,
oxo, and
-NH2; and
and R32 are independently selected from:
hydrogen, Cl-6alkyl,
Ci-6alkyl substituted with from one to five substituents independently selected from: fluoro, chloro, oxo, -OH, and -NH2,
fluoro,
chloro,
bromo,
iodo,
-N(H)Cl -6alkyl,
-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,
R313 an( R323 are independently selected from hydrogen and C-| -C4alkyl, or R313 and 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;
or a pharmaceutically acceptable salt thereof.
5. A compound according to any one of claims 1 to 4 represented by the following
Formula (XIV):
Figure imgf000277_0001
is selected from:
6-indolyl, 6-indazolyl, and 5-benzimidazolyl, each of which are optionally substituted with from one to five substituents independently selected from:
fluoro,
chloro,
bromo,
Cl-6alkyl,
Cl-6alkyl substituted by -OH,
-CONR314R324,
-C(0)OCl-6alkyl,
cycloalkyl,
aryl,
Cl-4alkoxy,
Cl-4alkoxy substituted with from 1 to 5 substituents
independently selected from: fluoro, chloro, bromo, oxo, -OH and -CN,
oxo, and
-NH2; and
R7 is selected from:
hydrogen,
-N(H)Cl -6alkyl,
-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
R72 is selected from:
hydrogen,
methyl,
chloro, and
bromo;
where,
R314 and R324 are independently selected from hydrogen and C-| -C4alkyl, or R3 4 and
R324 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;
or a pharmaceutically acceptable salt thereof.
6. A compound according to any one of claims 1 to 5 represented by the following Formula (V):
Figure imgf000279_0001
R is selected from:
hydrogen,
Cl -6alkyl,
Ci -6alkyl substituted with from one to five substituents independently selected from: fluoro, chloro, oxo, -OH, and -NH2,
fluoro,
chloro,
bromo,
iodo,
-N(H)Cl -6alkyl, and
-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
R4 , R42, and R43, are independently selected from:
hydrogen,
fluoro,
chloro, bromo,
Cl-6alkyl,
Ci-6alkyl substituted with from 1 to 5 substituents independently selected from: fluoro, and -OH,
-CONH2,
heteroaryl,
aryl,
Cl-6alkoxy,
Ci-6alkoxy substituted with from 1 to 3 substituents independently
selected from: fluoro, chloro, bromo, oxo, -OH, -CN, and phenyl,
-OH,
0X0,
-C(0)0Cl -6alkyl,
cycloalkyl,
-Ocycloalkyl,
-Ophenyl,
-NH2,
-N(H)Cl -4alkyl,
-N(H)Cl -4alkyl substituted by oxo,
-N(Cl-4alkyl)2,
-N(H)S(0)2Cl -4alkyl,
-N(H)S(0)2cycloalkyl,
-N(H)S(0)2phenyl,
-SCl-6alkyl, and
-SO2NH2;
pharmaceutically acceptable salt thereof.
7. A compound according to any one of claims 1 to 5 represented by the following Formula (VIII):
Figure imgf000281_0001
wherein:
the A ring contains an optional double bond where indicated by the dotted line,
R50 is selected from:
hydrogen,
Cl-6alkyl,
Ci-6alkyl substituted with from one to five substituents independently selected from: fluoro, chloro, oxo, -OH, and -NH2,
fluoro,
chloro,
bromo,
lodo, and
-N(H)Cl -6alkyl;
R5 is selected from:
hydrogen,
fluoro,
chloro,
Cl-6alkyl,
Ci-6alkyl substituted with from 1 to 5 substituents independently selected from: fluoro, and -OH, Cl-6alkoxy,
Ci-6alkoxy substituted with from 1 to 3 substituents independently
selected from: fluoro, chloro, bromo, oxo, -OH, -CN, and phenyl, -OH, and
-C(0)OCl -6alkyl;
R52 is absent or selected from:
hydrogen,
fluoro,
chloro,
Cl-6alkyl,
Ci-6alkyl substituted with from 1 to 5 substituents independently selected from: fluoro, and -OH,
Cl-6alkoxy,
Ci-6alkoxy substituted with from 1 to 3 substituents independently
selected from: fluoro, chloro, bromo, oxo, -OH, -CN, and phenyl, -OH, and
-C(0)OCl -6alkyl; and
R is selected from:
hydrogen,
fluoro,
chloro,
Cl-6alkyl,
Ci-6alkyl substituted with from 1 to 5 substituents independently selected from: fluoro, and -OH,
Cl-6alkoxy,
Ci-6alkoxy substituted with from 1 to 3 substituents independently
selected from: fluoro, chloro, bromo, oxo, -OH, -CN, and phenyl, -OH, and
-C(0)OCl -6alkyl; and pharmaceutically acceptable salts thereof;
52
provided that when R is not absent, the A ring does not contain a double bond where indicted by the dotted line.
8. A compound according to any one of claims 1 to 5 represented by the following Formula (XI):
Figure imgf000283_0001
wherein:
RDU is selected from:
hydrogen,
Cl-6alkyl,
Ci-6alkyl substituted with from one to five substituents independently selected from: fluoro, chloro, oxo, -OH, and -NH2,
fluoro,
chloro,
bromo,
iodo, and
-N(H)Cl -6alkyl; and
R62, R63, and R64 are independently selected from:
hydrogen,
fluoro,
chloro,
bromo,
Cl-6alkyl,
Ci-6alkyl substituted with from 1 to 5 substituents independently selected from: fluoro, and -OH, Cl-6alkoxy,
Ci-6alkoxy substituted with from 1 to 3 substituents independently selected from: fluoro, chloro, bromo, oxo, -OH, -CN, and phe
-OH,
-C(0)OCl -6alkyl,
-NH2,
-N(H)Cl -4alkyl,
-N(H)Cl -4alkyl substituted by oxo, and
-N(Cl -4alkyl)2;
pharmaceutically acceptable salts thereof.
9. The compound of claim 1 selected from:
5-(N-(3-ethoxyphenyl)sulfamoyl)-2-hydroxybenzamide;
2-hydroxy-5-(N-(4-methoxyphenyl)sulfamoyl)benzamide;
5-(N-(3,4-diethoxyphenyl)sulfamoyl)-2-hydroxybenzamide;
5-(N-(3,4-dimethoxyphenyl)sulfamoyl)-2-hydroxybenzamide;
2-hydroxy-5-(N-(3-methoxyphenyl)sulfamoyl)benzamide;
2-hydroxy-5-(N-(4-(trifluoromethyl)phenyl)sulfamoyl)benzamide;
2-hydroxy-5-(N-(3-hydroxyphenyl)sulfamoyl)benzamide;
2-hydroxy-5-(N-(4-hydroxyphenyl)sulfamoyl)benzamide;
2-hydroxy-5-(N-(4-(trifluoromethoxy)phenyl)sulfamoyl)benzamide;
2-hydroxy-5-(N-(4-(methylsulfonyl)phenyl)sulfamoyl)benzamide;
2-hydroxy-5-(N-(4-(2,2,2-trifluoroethoxy)phenyl)sulfamoyl)benzamide;
2-hydroxy-5-(N-(4-isopropoxyphenyl)sulfamoyl)benzamide;
5-(N-(2-fluorophenyl)sulfamoyl)-2-hydroxybenzamide;
5-(N-(4-(benzyloxy)phenyl)sulfamoyl)-2-hydroxybenzamide; 2-hydroxy-5-(N-(4-(methylthio)phenyl)sulfamoyl)benzamide;
5-(N-(4-(tert-butoxy)phenyl)sulfamoyl)-2-hydroxybenzamide;
5-(N-(4-(dimethylamino)phenyl)sulfamoyl)-2-hydroxybenzamide;
2-hydroxy-5-(N-(3-(phenylsulfonamido)phenyl)sulfamoyl)benzamide; 2-hydroxy-5-(N-(4-phenoxyphenyl)sulfamoyl)benzamide;
2-hydroxy-5-(N-(4-(methylamino)phenyl)sulfamoyl)benzamide;
2-hydroxy-5-(N-(4-sulfamoylphenyl)sulfamoyl)benzamide;
5-(N-(2,3-dihydro-1 H-inden-5-yl)sulfamoyl)-2-hydroxybenzamide;
5-(N-(3-aminophenyl)sulfamoyl)-2-hydroxybenzamide;
2-hydroxy-5-(N-(naphthalen-2-yl)sulfamoyl)benzamide;
2-hydroxy-5-(N-(quinolin-6-yl)sulfamoyl)benzamide;
5-(N-(1 H-indol-6-yl)sulfamoyl)-2-hydroxybenzamide;
5-(N-(1 H-indol-5-yl)sulfamoyl)-2-hydroxybenzamide;
5-(N-(1 H-benzo[d]imidazol-5-yl)sulfamoyl)-2-hydroxybenzamide; 5-(N-(4-(ethylamino)phenyl)sulfamoyl)-2-hydroxybenzamide;
5-(N-(4-aminophenyl)sulfamoyl)-2-hydroxybenzamide;
5-(N-(benzo[b]thiophen-5-yl)sulfamoyl)-2-hydroxybenzamide;
5-(N-(1 H-pyrazol-5-yl)sulfamoyl)-2-hydroxybenzamide;
2-hydroxy-5-(N-(2-methyl-1 H-indol-6-yl)sulfamoyl)benzamide;
5-(N-(benzofuran-5-yl)sulfamoyl)-2-hydroxybenzamide;
5-(N-(benzo[b]thiophen-6-yl)sulfamoyl)-2-hydroxybenzamide;
2-hydroxy-5-(N-(1 -methyl-1 H-indol-6-yl)sulfamoyl)benzamide;
2-hydroxy-5-(N-(3-(oxazol-2-yl)phenyl)sulfamoyl)benzamide;
2-hydroxy-5-(N-(3-methyl-1 H-indol-6-yl)sulfamoyl)benzamide;
2-hydroxy-5-(N-(4-(oxazol-2-yl)phenyl)sulfamoyl)benzamide;
2-hydroxy-5-(N-(3-(oxazol-4-yl)phenyl)sulfamoyl)benzamide;
2-hydroxy-5-(N-(4-(oxazol-4-yl)phenyl)sulfamoyl)benzamide; 2-hydroxy-5-(N-(indolin-6-yl)sulfamoyl)benzamide;
5-(N-(4-(cyclopropanesulfonamido)phenyl)sulfamoyl)-2-hydroxybenzamide;
5-(N-(3-(cyclopropanesulfonamido)phenyl)sulfamoyl)-2-hydroxybenzamide;
2-hydroxy-5-(N-(4-(phenylsulfonamido)phenyl)sulfamoyl)benzamide;
2-hydroxy-5-(N-(4-(methylsulfonamido)phenyl)sulfamoyl)benzamide;
2-hydroxy-5-(N-(3-(methylsulfonamido)phenyl)sulfamoyl)benzamide;
5-(N-(1 H-indazol-5-yl)sulfamoyl)-2-hydroxybenzamide;
2-hydroxy-5-(N-(2-methyl-1 H-indol-5-yl)sulfamoyl)benzamide;
tert-butyl 7-(3-carbamoyl-4-hydroxyphenylsulfonamido)-3,4-dihydroisoquinoline-(1 H)-carboxylate;
5-(N-(1 H-pyrrolo[2,3-b]pyridin-6-yl)sulfamoyl)-2-hydroxybenzamide;
2-hydroxy-5-(N-(1 -methyl-1 H-indol-5-yl)sulfamoyl)benzamide;
tert-butyl 6-(3-carbamoyl-4-hydroxyphenylsulfonamido)-3,4-dihydroisoquinoline-(1 H)-carboxylate;
2-hydroxy-5-(N-(3-methyl-1 H-indol-5-yl)sulfamoyl)benzamide;
5-(N-(1 H-indol-5-yl)sulfamoyl)-2-hydroxy-3-methylbenzamide;
5-(N-(4-fluoro-1 H-indol-5-yl)sulfamoyl)-2-hydroxybenzamide;
5-(N-(4-acetamidophenyl)sulfamoyl)-2-hydroxybenzamide;
5-(N-(3-acetamidophenyl)sulfamoyl)-2-hydroxybenzamide;
2-hydroxy-5-(N-(2-oxoindolin-6-yl)sulfamoyl)benzamide;
5-(N-(4-fluoro-1 H-indol-6-yl)sulfamoyl)-2-hydroxybenzamide;
5-(N-(1 H-indazol-6-yl)sulfamoyl)-2-hydroxybenzamide;
5-(N-(benzo[d][1 ,3]dioxol-5-yl)sulfamoyl)-2-hydroxybenzamide;
5-(N-(1 H-indol-6-yl)sulfamoyl)-2-hydroxyisophthalamide;
5-(N-(1 H-indol-5-yl)sulfamoyl)-3-chloro-2-hydroxybenzamide;
2-hydroxy-5-(N-(1 ,2,3,4-tetrahydroquinolin-7-yl)sulfamoyl)benzamide, tert-butyl 7-(3-carbamoyl-4-hydroxyphenylsulfonamido)-3,4-dihydroquinoline-(2H)-carboxylate;
5-(N-(1 H-pyrrolo[2,3-b]pyridin-5-yl)sulfamoyl)-2-hydroxybenzamide;
5-(N-(1 H-benzo[d]imidazol-5-yl)sulfamoyl)-2-hydroxy-3-methylbenzamide;
2-hydroxy-5-(N-(3-isopropoxyphenyl)sulfamoyl)benzamide;
2-hydroxy-5-(N-(thiophen-3-yl)sulfamoyl)benzamide;
5-(N-(4-(cyclopentyloxy)phenyl)sulfamoyl)-2-hydroxybenzamide;
2-hydroxy-5-(N-(2-methyl-1 H-benzo[d]imidazol-5-yl)sulfamoyl)benzamide;
tert-butyl 6-(3-carbamoyl-4-hydroxyphenylsulfonamido)-3,4-dihydroquinoline-(2H)-carboxylate;
5-(N-(3-ethyl-1 H-indol-6-yl)sulfamoyl)-2-hydroxybenzamide;
5-(N-(1 H-benzo[d]imidazol-5-yl)sulfamoyl)-3-chloro-2-hydroxybenzamide;
5-(N-(2-ethyl-1 H-benzo[d]imidazol-5-yl)sulfamoyl)-2-hydroxybenzamide;
5-(N-(4-(cyclohexyloxy)phenyl)sulfamoyl)-2-hydroxybenzamide;
2-hydroxy-5-(N-(imidazo[1 ,2-a]pyridin-6-yl)sulfamoyl)benzamide;
5-(N-(1 H-benzo[d]imidazol-7-yl)sulfamoyl)-2-hydroxybenzamide;
2-hydroxy-5-(N-(2-isopropyl-1 H-indol-6-yl)sulfamoyl)benzamide;
5-(N-(2-ethyl-1 H-indol-6-yl)sulfamoyl)-2-hydroxybenzamide;
4- fluoro-2-hydroxy-5-(N-(4-isopropoxyphenyl)sulfamoyl)benzamide;
2-hydroxy-5-(N-(4-isopropoxyphenyl)sulfamoyl)-3-methylbenzamide;
5- (N-(7-fluoro-1 H-indol-5-yl)sulfamoyl)-2-hydroxybenzamide;
5-(N-(1 H-indazol-6-yl)sulfamoyl)-2-hydroxy-3-methylbenzamide;
5-(N-(5-chloro-1 H-indol-6-yl)sulfamoyl)-2-hydroxybenzamide;
5-(N-(2-cyclopropyl-1 H-indol-6-yl)sulfamoyl)-2-hydroxybenzamide;
5-(N-(4-cyclopropoxyphenyl)sulfamoyl)-2-hydroxybenzamide;
5-(N-(2-ethyl-4-fluoro-1 H-benzo[d]imidazol-5-yl)sulfamoyl)-2-hydroxybenzamide; 5-(N-(2-amino-1 H-benzo[d]imidazol-5-yl)sulfamoyl)-2-hydroxybenzamide, 5-(N-(4-fluoro-2-methyl-1 H-benzo[d]imidazol-5-yl)sulfamoyl)-2-hydroxybenzamide; 5-(N-(1 H-indol-6-yl)sulfamoyl)-2-hydroxy-3-methylbenzamide;
2- hydroxy-3-methyl-5-(N-(2-methyl-1 H-indol-6-yl)sulfamoyl)benzamide;
5-(N-(4-fluoro-1 H-benzo[d]imidazol-5-yl)sulfamoyl)-2-hydroxybenzamide;
3- chloro-2-hydroxy-5-(N-(4-isopropoxyphenyl)sulfamoyl)benzamide;
2-hydroxy-5-(N-(2-isopropyl-1 H-benzo[d]imidazol-6-yl)sulfamoyl)benzamide; 2-hydroxy-5-(N-(4-isopropoxyphenyl)sulfamoyl)-4-(methylamino)benzamide; 5-(N-(1 H-benzo[d]imidazol-5-yl)sulfamoyl)-2-hydroxy-3-isopropylbenzamide;
2- hydroxy-3-methyl-5-(N-(3-methyl-1 H-indol-6-yl)sulfamoyl)benzamide;
3- chloro-2-hydroxy-5-(N-(3-methyl-1 H-indol-6-yl)sulfamoyl)benzamide;
5-(N-(4-chloro-1 H-benzo[d]imidazol-6-yl)sulfamoyl)-2-hydroxybenzamide;
4- (ethylamino)-2-hydroxy-5-(N-(4-isopropoxyphenyl)sulfamoyl)benzamide;
5- (N-(2-ethyl-1 H-benzo[d]imidazol-5-yl)sulfamoyl)-2-hydroxy-3-methylbenzamide; 5-(N-(5-chlorothiophen-3-yl)sulfamoyl)-2-hydroxybenzamide;
5-(N-(1 H-indazol-6-yl)sulfamoyl)-2-hydroxy-3-isopropylbenzamide;
3-chloro-5-(N-(2-ethyl-1 H-benzo[d]imidazol-5-yl)sulfamoyl)-2-hydroxybenzamide; 5-(N-(1 H-indazol-6-yl)sulfamoyl)-3-chloro-2-hydroxybenzamide;
3- chloro-2-hydroxy-5-(N-(2-methyl-1 H-indol-6-yl)sulfamoyl)benzamide;
5-(N-(1 H-indol-6-yl)sulfamoyl)-3-chloro-2-hydroxybenzamide;
4- (benzylamino)-2-hydroxy-5-(N-(4-isopropoxyphenyl)sulfamoyl)benzamide;
5- (N-(1 H-indazol-6-yl)sulfamoyl)-3-ethyl-2-hydroxybenzamide;
5-(N-(1 H-benzo[d]imidazol-6-yl)sulfamoyl)-3-ethyl-2-hydroxybenzamide;
2-hydroxy-5-(N-(1 -phenyl-1 H-pyrazol-4-yl)sulfamoyl)benzamide;
2-hydroxy-5-(N-(1 -phenyl-1 H-pyrazol-3-yl)sulfamoyl)benzamide;
methyl 6-(3-carbamoyl-4-hydroxyphenylsulfonamido)-1 H-indole-2-carboxylate;
2-hydroxy-5-(N-(5-methylthiophen-2-yl)sulfamoyl)benzamide;
2-hydroxy-5-(N-(5-methylthiophen-3-yl)sulfamoyl)benzamide; 3-chloro-5-(N-(4-(ethylamino)phenyl)sulfamoyl)-2-hydroxybenzamide;
methyl 6-(3-carbamoyl-4-hydroxyphenylsulfonamido)-1 H-indole-3-carboxylate;
5-(N-(3-chloro-1 H-indol-6-yl)sulfamoyl)-2-hydroxybenzamide;
2-hydroxy-5-(N-(2-phenyl-1 H-indol-6-yl)sulfamoyl)benzamide;
5-(N-(1 H-benzo[d]imidazol-6-yl)sulfamoyl)-3-fluoro-2-hydroxybenzamide;
5-(N-(1 H-benzo[d]imidazol-6-yl)sulfamoyl)-2-hydroxy-3- (trifluoromethyl)benzamide;
2- hydroxy-5-(N-(4-methylthiophen-2-yl)sulfamoyl)benzamide;
3- chloro-5-(N-(3-ethyl-1 H-indol-6-yl)sulfamoyl)-2-hydroxybenzamide;
5-(N-(3-ethyl-1 H-indol-6-yl)sulfamoyl)-2-hydroxy-3-methylbenzamide;
5-(N-(4-bromo-1 H-indol-6-yl)sulfamoyl)-2-hydroxybenzamide;
5-(N-(2-ethyl-1 H-indol-6-yl)sulfamoyl)-2-hydroxy-3-methylbenzamide;
3- chloro-5-(N-(2-ethyl-1 H-indol-6-yl)sulfamoyl)-2-hydroxybenzamide;
2-hydroxy-5-(N-(7-methyl-1 H-benzo[d]imidazol-5-yl)sulfamoyl)benzamide; methyl 6-(3-carbamoyl-4-hydroxyphenylsulfonamido)-1 H-indole-4-carboxylate; 5-(N-(1 H-pyrazol-4-yl)sulfamoyl)-2-hydroxybenzamide;
5-(N-(4-(ethylamino)phenyl)sulfamoyl)-2-hydroxy-3-methylbenzamide;
5-(N-(6-fluoro-1 H-indol-5-yl)sulfamoyl)-2-hydroxybenzamide;
2- hydroxy-5-(N-(2-(hydroxymethyl)-1 H-indol-6-yl)sulfamoyl)benzamide;
5-(N-(1 H-benzo[d]imidazol-6-yl)sulfamoyl)-3-bromo-2-hydroxybenzamide; 5-(N-(3-ethyl-1 H-indol-6-yl)sulfamoyl)-4-(ethylamino)-2-hydroxybenzamide;
4- ((2-chlorobenzyl)amino)-2-hydroxy-5-(N-(4- isopropoxyphenyl)sulfamoyl)benzamide;
methyl 6-(3-carbamoyl-5-chloro-4-hydroxyphenylsulfonamido)-1 H-indole-2- carboxylate;
5- (N-(4-bromo-1 H-indol-6-yl)sulfamoyl)-3-chloro-2-hydroxybenzamide;
3- chloro-5-(N-(3-chloro-1 H-indol-6-yl)sulfamoyl)-2-hydroxybenzamide; methyl 6-(3-carbamoyl-5-chloro-4-hydroxyphenylsulfonamido)-1 H-indole-4- carboxylate;
3- chloro-2-hydroxy-5-(N-(2-(hydroxymethyl)-1 H-indol-6-yl)sulfamoyl)benzamide;
2- hydroxy-4-((2-hydroxyethyl)amino)-5-(N-(4- isopropoxyphenyl)sulfamoyl)benzamide;
5-(N-(2-ethyl-1 H-indol-6-yl)sulfamoyl)-4-(ethylamino)-2-hydroxybenzamide; methyl 6-(3-carbamoyl-5-chloro-4-hydroxyphenylsulfonamido)-1 H-indole-3- carboxylate;
(S)-2-hydroxy-5-(N-(4-isopropoxyphenyl)sulfamoyl)-4-((1 - phenylethyl)amino)benzamide;
4- ((3-chlorobenzyl)amino)-2-hydroxy-5-(N-(4- isopropoxyphenyl)sulfamoyl)benzamide;
3- chloro-2-hydroxy-5-(N-(2-oxoindolin-6-yl)sulfamoyl)benzamide;
4- ((2-aminoethyl)amino)-2-hydroxy-5-(N-(4- isopropoxyphenyl)sulfamoyl)benzamide;
3- chloro-2-hydroxy-5-(N-(1 -methyl-1 H-indol-5-yl)sulfamoyl)benzamide;
4- (benzylamino)-5-(N-(3-ethyl-1 H-indol-6-yl)sulfamoyl)-2-hydroxybenzamide; 3-chloro-5-(N-(3-ethyl-1 H-indazol-6-yl)sulfamoyl)-2-hydroxybenzamide; 2-hydroxy-5-(/V-(4-isopropoxyphenyl)sulfamoyl)-4-((pyridin-4- ylmethyl)amino)benzamide;
4-(((1 /-/-pyrazol-3-yl)methyl)amino)-2-hydroxy-5-(/V-(4- isopropoxyphenyl)sulfamoyl)-benzamide;
2-hydroxy-5-(/V-(4-isopropoxyphenyl)sulfamoyl)-4-((isoxazol-5- ylmethyl)amino)benzamide;
2-hydroxy-5-(/V-(4-isopropoxyphenyl)sulfamoyl)-4-((thiophen-2-ylmethyl)amino)- benzamide;
2-hydroxy-4-((2-hydroxybenzyl)amino)-5-(N-(4- isopropoxyphenyl)sulfamoyl)benzamide; 2-hydroxy-4-((3-hydroxybenzyl)amino)-5-(N-(4- isopropoxyphenyl)sulfamoyl)benzamide;
4- (((4H-1 ,2,4-triazol-3-yl)methyl)amino)-2-hydroxy-5-(N-(4- isopropoxyphenyl)sulfamoyl)benzamide;
2-hydroxy-4-((3-hydroxypropyl)amino)-5-(N-(4- isopropoxyphenyl)sulfamoyl)benzamide;
2- hydroxy-4-((1 -hydroxypropan-2-yl)amino)-5-(N-(4- isopropoxyphenyl)sulfamoyl)benzamide;
6-(3-carbamoyl-5-chloro-4-hydroxyphenylsulfonamido)-1 Hindole-3-carboxamide;
3- chloro-2-hydroxy-5-(N-(3-methyl-1 H-indazol-6-yl)sulfamoyl)benzamide;
3-chloro-2-hydroxy-5-(N-(2-phenyl-1 H-indol-6-yl)sulfamoyl)benzamide;
3-chloro-2-hydroxy-5-(N-(4-(hydroxymethyl)-1 H-indol-6-yl)sulfamoyl)benzamide;
6-(3-carbamoyl-5-chloro-4-hydroxyphenylsulfonamido)-1 H-indole-2-carboxamide;
3-chloro-5-(N-(1 ,2-dimethyl-1 H-indol-5-yl)sulfamoyl)-2-hydroxybenzamide;
3-chloro-5-(N-(2-ethyl-2H-indazol-6-yl)sulfamoyl)-2-hydroxybenzamide;
3-chloro-2-hydroxy-5-(N-(3-phenyl-1 H-indol-6-yl)sulfamoyl)benzamide;
3-chloro-2-hydroxy-5-(N-(4-methyl-1 H-indol-6-yl)sulfamoyl)benzamide;
3-chloro-5-(N-(2-(dimethylamino)-1 Hbenzo[d]imidazol-6-yl)sulfamoyl)-2- hydroxybenzamide;
5- (N-(1 H-benzo[d][1 ,2,3]triazol-6-yl)sulfamoyl)-3-chloro-2-hydroxybenzamide;
6- (3-carbamoyl-5-chloro-4-hydroxyphenylsulfonamido)-1 H-indole-4-carboxamide;
3-chloro-2-hydroxy-5-(N-(2-isopropyl-1 H-indol-6-yl)sulfamoyl)benzamide;
3-chloro-5-(N-(1 -ethyl-1 H-indol-5-yl)sulfamoyl)-2-hydroxybenzamide;
3-chloro-2-hydroxy-5-(N-(2-(methylamino)-1 H-benzo[d]imidazol-6- yl)sulfamoyl)benzamide;
3-chloro-5-(N-(2,3-dimethyl-1 H-indol-6-yl)sulfamoyl)-2-hydroxybenzamide;
3-chloro-5-(N-(1 ,3-dimethyl-1 Hindol-5-yl)sulfamoyl)-2-hydroxybenzamide;
3-chloro-5-(N-(4-chloro-1 H-indol-6-yl)sulfamoyl)-2-hydroxybenzamide; 3-chloro-5-(N-(2-(ethylamino)-1 H-benzo[d]imidazol-6-yl)sulfamoyl)-2- hydroxybenzamide;
3- chloro-2-hydroxy-5-(N-(1 -methyl-1 Hbenzo[d]imidazol-5-yl)sulfamoyl)benzamide;
5-(N-(2-acetamido-1 Hbenzo[d]imidazol-6-yl)sulfamoyl)-3-chloro-2- hydroxybenzamide;
5-(N-(2-amino-1 Hbenzo[d]imidazol-6-yl)sulfamoyl)-3-chloro-2-hydroxybenzamide;
4- (benzylamino)-3-chloro-2-hydroxy-5-(N-(4-isopropoxyphenyl)sulfamoyl)- benzamide;
3-chloro-5-(N-(4-ethoxy-1 H-indol-6-yl)sulfamoyl)-2-hydroxybenzamide;
3-chloro-5-(N-(2,4-diethyl-1 Hbenzo[d]imidazol-6-yl)sulfamoyl)-2- hydroxybenzamide;
3-chloro-5-(N-(4-ethyl-1 Hindol-6-yl)sulfamoyl)-2-hydroxybenzamide;
3- chloro-5-(N-(2-ethyl-4-propyl-1 Hbenzo[d]imidazol-6-yl)sulfamoyl)-2- hydroxybenzamide;
3-chloro-5-(N-(2-ethyl-4-isopropyl-1 H-indol-6-yl)sulfamoyl)-2-hydroxybenzamide;
4- (benzylamino)-3-chloro-5-(N-(2-ethyl-1 H-indol-6-yl)sulfamoyl)-2- hydroxybenzamide;
2-hydroxy-3-(hydroxymethyl)-5-(N-(4-isopropoxyphenyl)sulfamoyl)benzamide;
5- (N-(1 H-indol-6-yl)sulfamoyl)-2-hydroxy-4-((5-hydroxypentyl)amino)benzamide; and
5-(N-(1 H-indol-6-yl)sulfamoyl)-2-hydroxy-4-((3-hydroxybutyl)amino)benzamide; or a pharmaceutically acceptable salt thereof.
10. A pharmaceutical composition comprising a compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.
1 1 . A method of treating a disease selected from: cancer, pre-cancerous syndromes, AIDS, HIV, autoimmune diseases, infections, atherosclerosis, and ischemia- reperfusion injury, in a mammal in need thereof, which comprises administering to such mammal a therapeutically effective amount of a compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof.
12. The method of claim 1 1 wherein the mammal is a human.
13. A method of treating a disease selected from: cancer, pre-cancerous syndromes, AIDS, HIV, autoimmune diseases, infections, atherosclerosis, and ischemia- reperfusion injury, in a mammal in need thereof, which comprises administering to such mammal a therapeutically effective amount of a compound of claim 9 or a pharmaceutically acceptable salt thereof.
14. The method of claim 13 wherein the mammal is a human.
15. The method according to claim 1 1 wherein said cancer is selected from: brain (gliomas), glioblastomas, astrocytomas, glioblastoma multiforme, Bannayan-Zonana syndrome, Cowden disease, Lhermitte-Duclos disease, breast, colon, head and neck, kidney, lung, liver, melanoma, ovarian, pancreatic, adenocarcinoma, ductal adenocarcinoma, adenosquamous carcinoma, acinar cell carcinoma, glucagonoma, insulinoma, prostate, sarcoma and thyroid.
16. The method according to claim 13 wherein: said cancer is selected from brain (gliomas), glioblastomas, astrocytomas, glioblastoma multiforme, Bannayan-Zonana syndrome, Cowden disease, Lhermitte-Duclos disease, breast, colon, head and neck, kidney, lung, liver, melanoma, ovarian, pancreatic, adenocarcinoma, ductal adenocarcinoma, adenosquamous carcinoma, acinar cell carcinoma, glucagonoma, insulinoma, prostate, sarcoma and thyroid.
17. Use of a compound of Formula (I), as described in any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in treating or lessening the severity of cancer.
18. The method of inhibiting CD73 activity in a mammal in need thereof, which comprises administering to such mammal a therapeutically effective amount of a compound of Formula (I), as described in any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof.
19. The method of claim 18 wherein the mammal is a human.
20. A method of treating cancer in a mammal in need thereof, which comprises: administering to such mammal a therapeutically effective amount of
a) a compound as described in any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof; and
b) at least one anti-neoplastic agent.
21 . The method according to claim 20, wherein the at least one anti-neoplastic agent is selected from the group consisting of: anti-microtubule agents, platinum coordination complexes, alkylating agents, antibiotic agents, topoisomerase II inhibitors, antimetabolites, topoisomerase I inhibitors, hormones and hormonal analogues, signal transduction pathway inhibitors, non-receptor tyrosine kinase angiogenesis, inhibitors, immunotherapeutic agents, proapoptotic agents, cell cycle signaling inhibitors, proteasome inhibitors, inhibitors of cancer metabolism, anti-PD-L1 agents, PD-1 antagonist, immuno- modulators, STING modulating compounds, CD39 inhibitors, A2a and A2a adenosine antagonists, TLR4 antagonists, antibodies to ICOS, and OX40.
22. A compound of Formula (I), as described in claim 1 or a pharmaceutically acceptable salt thereof for use in therapy.
23. Use of a compound of Formula (I), as described in claim 1 or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in treating or lessening the severity of cancer.
24. The method according to claim 1 1 wherein said cancer is selected from: breast cancer, inflammatory breast cancer, ductal carcinoma, lobular carcinoma, colon cancer, pancreatic cancer, insulinomas, adenocarcinoma, ductal adenocarcinoma, adenosquamous carcinoma, acinar cell carcinoma, glucagonoma, skin cancer, melanoma, metastatic melanoma, lung cancer, small cell lung cancer, non-small cell lung cancer, squamous cell carcinoma, adenocarcinoma, large cell carcinoma, 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, acute lymphoblastic leukemia, acute myelogenous leukemia, chronic neutrophilic leukemia, acute lymphoblastic T cell leukemia, plasmacytoma, Immunoblastic large cell leukemia, mantle cell leukemia, multiple myeloma, megakaryoblastic leukemia, multiple myeloma, acute megakaryocyte leukemia, promyelocytic leukemia, erythroleukemia,
malignant lymphoma, hodgkins lymphoma, non-hodgkins lymphoma, lymphoblastic T cell lymphoma, Burkitt's lymphoma, follicular lymphoma,
neuroblastoma, bladder cancer, urothelial cancer, vulval cancer, cervical cancer, endometrial cancer, renal cancer, mesothelioma, esophageal cancer, salivary gland cancer, hepatocellular cancer, gastric cancer, nasopharangeal cancer, buccal cancer, cancer of the mouth, GIST (gastrointestinal stromal tumor), neuroendocrine cancers and testicular cancer.
25. The method of claim 24 wherein the mammal is a human.
26. A process for preparing a pharmaceutical composition containing a pharmaceutically acceptable excipient and an effective amount of a compound of Formula (I) as described in any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof, which process comprises bringing the compound of Formula (I) or a pharmaceutically acceptable salt thereof into association with a pharmaceutically acceptable excipient.
27. The method according to claim 1 1 wherein said pre-cancerous syndrome is selected from: cervical intraepithelial neoplasia, monoclonal gammapathy of unknown significance (MGUS), myelodysplastic 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.
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