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WO2017066742A1 - Composés inhibiteurs de bace-2 et procédés d'utilisation associés - Google Patents

Composés inhibiteurs de bace-2 et procédés d'utilisation associés Download PDF

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Publication number
WO2017066742A1
WO2017066742A1 PCT/US2016/057299 US2016057299W WO2017066742A1 WO 2017066742 A1 WO2017066742 A1 WO 2017066742A1 US 2016057299 W US2016057299 W US 2016057299W WO 2017066742 A1 WO2017066742 A1 WO 2017066742A1
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alkyl
alkoxy
optionally substituted
hydroxy
compound
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Sudha V. Ankala
John C. Lilly
Gopal PEDDABUDDI
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Jortan Pharmaceuticals Inc
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Jortan Pharmaceuticals Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/64—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C233/77—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups
    • C07C233/78—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C235/58—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring with carbon atoms of carboxamide groups and singly-bound oxygen atoms, bound in ortho-position to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C235/60—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring with carbon atoms of carboxamide groups and singly-bound oxygen atoms, bound in ortho-position to carbon atoms of the same non-condensed six-membered aromatic ring having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
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    • C07C237/28—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton
    • C07C237/40—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having the nitrogen atom of the carboxamide group bound to a carbon atom of a six-membered aromatic ring
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    • C07C237/28—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton
    • C07C237/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated
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    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/01—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms
    • C07C311/02—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
    • C07C311/08—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated 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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    • C07C311/30—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/37—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
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    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
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    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • C07D213/82—Amides; Imides in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D275/00—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings
    • C07D275/02—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings not condensed with other rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/04—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D279/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one sulfur atom as the only ring hetero atoms
    • C07D279/02—1,2-Thiazines; Hydrogenated 1,2-thiazines
    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/72—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 spiro-condensed with carbocyclic rings
    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
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    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated

Definitions

  • Diabetes affects ⁇ 29 million people in the U.S. and hundreds of millions worldwide and it causes symptoms such as frequent urination, extreme fatigue, blurry vision and tingling, pain and numbness in hands or feet due to an imbalance of insulin and glucose in the blood– with more severe symptoms (blindness, kidney failure, amputations, heart failure and stroke) developing over time.
  • pancreatic ⁇ cell health No currently available diabetes treatment addresses the problem of deteriorating pancreatic ⁇ cell health. Although billions of dollars are being spent on developing and marketing drugs that are designed to lower blood glucose in various ways, the problem of reduced pancreatic ⁇ cell mass and deteriorated ⁇ cell function is not addressed by current small molecule therapeutics. As diabetes is a progressive metabolic disease, the ultimate goal should be to address underlying disease biology by either stabilization or regeneration of ⁇ cells. Attempts to transplant pancreatic islets– which contain ⁇ cells– from deceased donors to diabetic patients have been successful, and represent a potential cure for the disease.
  • One embodiment of the invention relates to a compound represented by the following formula (I):
  • X 2 , X 3 , X 4 each independently H, D, C 1 -C 6 alk l-C 1 -C alkoxy, C 1 -C 3 alkoxy, C 1 -C 3 perhaloalkyl, C 1 -C 6 alkyl; -NR 4 -Z-
  • X absent, hydrogen, C 1 -C 6 alkyl-C 1 -C 3 alkoxy, C 1 -C 3 alkoxy, C 1 -C 3 perhaloalkyl, C 1 -C 6 alkyl; is an optional bond; R’: halogen, C 1 -C 6 alkyl-C 1 -C 3 alkoxy, C 1 -C 3 alkoxy, hydroxy, C 1 -C 3 perhaloalkyl, C 1 -C 6 alkyl; R’’: halogen, C 1 -C 6 alkyl-C 1 -C 3 alkoxy, C 1 -C 3 alkoxy, hydroxy, C 1 -C 3 perhaloalkyl, C 1 -C 6 alkyl; R 1 : H, D, C 1 -C 6 alkyl, optionally substituted by phenyl, halogen, C 1 -C 6 alkyl- C 1
  • Y and X are C-X 3 and C-X 4 , respectively.
  • Y is C-X 3
  • X is N and X 3 is hydroxy and the tautomer thereof.
  • R 1 and R 2 together form a ring containing a nitrogen and 3 to 5 carbon atoms, or a nitrogen and 3 to 4 carbon atoms and a sulfur atom, wherein the ring is optionally substituted by one of more halogen, C 1 -C 6 alkyl-C 1 -C 3 alkoxy C 1 -C 3 alkoxy, hydroxy, C 1 - C 3 perhaloalkyl, C 1 -C 6 alkyl.
  • X 1 is .
  • R 1 is H
  • R 2 is a C 1 -C 6 alkyl.
  • R 1 is a C 1 -C 6 alkyl
  • R 2 is a C 1 -C 6 alkyl
  • R 2 is .
  • Z is a carbonyl or Z is a sulfonyl.
  • Y is C-X 3 , and X 3 is selected from the group consisting of haloge , oxazole, methoxy, and -NR 4 -Z-C 1 -C 6 alkyl.
  • R’ is halogen, and a is 2.
  • b is 1 or 2
  • the 1 or 2 R’’ are meta substituted.
  • the compound is selected from Table 1.
  • b is 1 or 2
  • R’’ is selected from the group consisting of F, CF 3 , OMe, and t-Bu.
  • a and B together form a C - 3C 6 cycloalkyl, optionally substituted by one or more moieties selected from the group consisting of F, CF 3 , OMe, and t-Bu.
  • R 2 is selected from (CH 2 ) 1-6 CF 3 and (CH 2 ) 1- 6 Ph and (CH 2 ) 0-5 CH 3 , each of which may be optionally substituted.
  • X 2 is NO 2 , NH 2 , or NHCOC 1 -C 6 alkyl.
  • X 1 is optionally substituted aryl or optionally substituted heteroaryl.
  • in the compound of Formula (I) is a required bond.
  • Y C-X 3 or N-X 5 ; X: C-X 4 or N-X 5 ; X 1 is , optionally substituted aryl or optionally substituted heteroaryl; Z: carbonyl or sulfonyl; X 2 , X 3 , X 4 : each independently H, D, halogen, C 1 -C 6 alk l-C 1 -C 3 alkoxy, C 1 -C 3 alkoxy, C 1 -C 3 perhaloalkyl, C 1 -C 6 alkyl; - NR 4 -Z-C 1 -C 6 alkyl, , C 2 -C 5 heterocycle, optionally substituted heteroaryl, optionally substituted aryl, or when Y is N and X is C-X 4 , X 4 is selected from H, D, halo en C 1 -C 6 alk l-C 1 -C 3 alkox C 1 -C 3 alkoxy,
  • X 2 may also be NO 2 , NH 2 , NHCOC 1 -C 6 alkyl;
  • X 5 absent, hydrogen, C 1 -C 6 alkyl-C 1 -C 3 alkoxy, C 1 -C 3 alkoxy, C 1 -C 3 perhaloalkyl, C 1 -C 6 alkyl; is an optional bond;
  • R’ :
  • halogen C 1 -C 6 alkyl-C 1 -C 3 alkoxy, C 1 -C 3 alkoxy, hydroxy, C 1 -C 3 perhaloalkyl, C 1 -C 6 alkyl;
  • R’’ halogen, C 1 -C 6 alkyl-C 1 -C 3 alkoxy, C 1 -C 3 alkoxy, hydroxy, C 1 -C 3 perhaloalkyl, C 1 -C 6 alkyl;
  • R 1 H, D, C 1 -C 6 alkyl, optionally substituted by phenyl, halogen, C 1 -C 6 alkyl-C 1 -C 3 alkoxy C 1 -C 3 alkoxy, hydroxy, C 1 -C 3 perhaloalkyl;
  • R 2 C 1 -C 6 alkyl, optionally substituted by phenyl, halogen, C 1 -C 6 alkyl-C 1 -C 3 alkoxy C 1 -C 3
  • Y and X are C-X 3 and C- X 4 , respectively.
  • Y is C-X 3
  • X is N and X 3 is hydroxy and the tautomer thereof.
  • R 1 and R 2 together form a ring containing a nitrogen and 3 to 5 carbon atoms, or a nitrogen and 3 to 4 carbon atoms and a sulfur atom, wherein the ring is optionally substituted by one of more halogen, C 1 -C 6 alkyl-C 1 -C 3 alkoxy C 1 -C 3 alkoxy, hydroxy, C 1 - C 3 perhaloalkyl, C 1 -C 6 alkyl.
  • X 1 is .
  • R 1 is H, D, and R 2 is a C 1 -C 6 alkyl.
  • R 1 is a C 1 -C 6 alkyl
  • R 2 is a C 1 -C 6 alkyl.
  • R 2 is a C 1 -C 6 alkyl.
  • A is a carbonyl or A is a sulfonyl.
  • Y is C-X 3 , and X 3
  • R’ is halogen, and a is 2.
  • b is 1 or 2
  • the 1 or 2 R’’ are meta substituted.
  • the compound is selected from the compounds in Table 1.
  • a and B are each H.
  • b is 1 or 2
  • R’’ is selected from the group consisting of F, CF 3 , OMe, and t-Bu.
  • a and B together form a C - 3 C 6 cycloalkyl, optionally substituted by one or more moieties selected from the group consisting of F, CF 3 , OMe, and t-Bu.
  • R 2 is selected from (CH 2 ) 1-6 CF 3 and (CH 2 ) 1-6 Ph and (CH 2 ) 0-5 CH 3 , each of which may be optionally substituted.
  • X 2 is NO 2 , NH 2 , or NHCOC 1 -C 6 alkyl.
  • in the compound of Formula (II) is a required bond.
  • Other embodiment of the present disclosure include a method of treating diabetes by selectively inhibiting BACE2 in a subject, comprising administering to the patent in need thereof a therapeutically effective amount of an active compound having a substituted N- ((2S,3R)-4-(benzylamino)-3-hydroxy-1-phenylbutan-2-yl)formamide radical, wherein the active compound selectively inhibits BACE2 over BACE1.
  • the active compound has a substituted N-((2S,3R)-4-(benzylamino)-3-hydroxy-1-phenylbutan- 2-yl)benzamide or N-((2S,3R)-4-(benzylamino)-3-hydroxy-1-phenylbutan-2-yl)-2-oxo-2H- 1l2-pyridine-6-carboxamide radical.
  • the active compound is represented by the following formula (III):
  • Y C-X 3 or N-X 5 ;
  • X C-X 4 or N-X 5 ;
  • X 1 is , optionally substituted aryl or optionally substituted heteroaryl;
  • Z carbonyl or sulfonyl;
  • X 2 , X 3 , X 4 each independently H, D, halogen, C 1 -C 6 alkyl-C 1 -C 3 alkoxy, C 1 -C 3 alkoxy, C 1 -C 3 perhaloalkyl, C 1 -C 6 alkyl; -
  • X 2 may also be NO 2 , NH 2 , NHCOC 1 -C 6 alkyl;
  • X 5 absent, hydrogen, C 1 -C 6 alkyl-C 1 -C 3 alkoxy, C 1 -C 3 alkoxy, C 1 -C 3 perhaloalkyl, C 1 -C 6 alkyl; is an optional bond;
  • R’ :
  • R 1 H, D, C 1 -C 6 alkyl, optionally substituted by phenyl, halogen, C 1 -C 6 alkyl-C 1 -C 3 alkoxy C 1 -C 3 alkoxy, hydroxy, C 1 -C 3 perhaloalkyl
  • R 2 C 1 -C 6 alkyl, optionally substituted by phenyl, halogen, C 1 -C 6 alkyl-C 1 -C 3 alkoxy C 1 -C 3 alkoxy, hydroxy, C 1 -C 3 perhaloalkyl
  • R 2 C 1 -C 6 alkyl, optionally substituted by phenyl, halogen, C 1 -C 6 alkyl-C 1 -C 3 alkoxy C 1 -C 3 alkoxy, hydroxy, C 1 -C 3 perhaloalkyl; or R 1 and R 2 together form a ring containing a nitrogen and 3 to 5 carbon atoms, or a nitrogen and 3 to 4 carbon
  • the active compound selectively inhibits BACE2 over BACE1, and the ratio of Ki of BACE2 to Ki of BACE1 is in the range of about 1:50 to 1:5000. In some embodiments, the active compound selectively inhibits BACE2 over BACE1 and CatD, and the ratio of Ki of BACE2 to Ki of BACE1 is in the range of about 1:50 to 1:5000, and the ratio of Ki of BACE2 to Ki of CatD is in the range of about 1:25 to 1:5000. In some embodiments, the subject is a mammal. In some embodiments, the subject is a human. In some embodiments, the diabetes is type 1 or type 2 diabetes.
  • Other embodiments include a method of selectively inhibiting BACE2 in a subject, comprising administering to the patent in need thereof a therapeutically effective amount of an active compound having a substituted N-((2S,3R)-4-(benzylamino)-3-hydroxy-1- phenylbutan-2-yl)formamide radical, wherein the active compound selectively inhibits BACE2 over BACE1.
  • the active compound has a substituted N-((2S,3R)-4- (benzylamino)-3-hydroxy-1-phenylbutan-2-yl)benzamide or N-((2S,3R)-4-(benzylamino)- 3-hydroxy-1-phenylbutan-2-yl)-2-oxo-2H-1l2-pyridine-6-carboxamide radical.
  • the active compound is represented by the following formula (III)
  • Y C-X 3 or N-X 5 ; X: C-X 4 or N-X 5 ; X 1 is , optionally substituted aryl or optionally substituted heteroaryl; Z: carbonyl or sulfonyl; X 2 , X 3 , X 4 : each independently H, D, halogen, C 1 -C 6 alkyl-C 1 -C 3 alkoxy, C 1 -C 3 alkoxy, C 1 -C 3 perhaloalkyl, C 1 -C 6 alkyl; - NR 4 -Z-C 1 -C 6 alkyl, , C 2 -C 5 heterocycle, optionally substituted heteroaryl, optionally substituted aryl, or when Y is N and X is C-X 4 , X 4 is selected from H, D, halogen, C 1 -C 6 alkyl-C 1 -C 3 alkoxy, C 1 -C 3 alkoxy, hydroxy, C
  • the active compound is represented by one or more compounds according to any of the preceding embodiments.
  • the active compound selectively inhibits BACE2 over BACE1 and CatD.
  • the active compound selectively inhibits BACE2 over BACE1, and the ratio of Ki of BACE2 to Ki of BACE1 is in the range of about 1:50 to 1:5000.
  • the active compound selectively inhibits BACE2 over BACE1 and CatD, and the ratio of Ki of BACE2 to Ki of BACE1 is in the range of about 1:50 to 1:5000, and the ratio of Ki of BACE2 to Ki of CatD is in the range of about 1:25 to 1:5000.
  • the subject is a mammal.
  • the subject is a human.
  • FIG.1 shows various compounds within the scope of the disclosure.
  • FIG.2 shows various compounds, including compounds within the scope of the disclosure.
  • Compounds of the present disclosure include compounds capable of inhibiting BACE2 in a subject and having a substituted N-((2S,3R)-4-(benzylamino)-3-hydroxy-1- phenylbutan-2-yl)formamide radical, a substituted N-((2S,3R)-4-(benzylamino)-3-hydroxy- 1-phenylbutan-2-yl)benzamide or a N-((2S,3R)-4-(benzylamino)-3-hydroxy-1-phenylbutan- 2-yl)-2-oxo-2H-1l2-pyridine-6-carboxamide radical.
  • the novel compound is represented by Formula I, II or III.
  • the novel compound is represented by Formula I, which is represented by the formula:
  • Y C-X 3 or N-X 5 ;
  • X C-X 4 or N-X 5 ; , optionally substituted aryl, or optionally substituted heteroaryl;
  • Z carbonyl or sulfonyl
  • X 2 , X 3 , X 4 each independently H, D, C 1 -C 6 alkyl-C 1 -C 3 alkoxy, C 1 -C 3 alkoxy, C 1 -C 3 perhaloalkyl, C 1 -C 6 alkyl; , C 2 -C 5 heterocycle, optionally substituted heteroaryl, optionally substituted aryl, or
  • X 4 is selected from H, D, halogen, C 1 -C 6 alkyl-C 1 -C 3 alkoxy, C 1 -C 3 alkoxy, hydroxy, C 1 -C 3 perhaloalkyl, C 1 -C 6 alkyl, -NR 4 -Z-C 1 -C 6 alkyl,
  • X 2 may also be NO 2 , NH 2 , NHCOC 1 -C 6 alkyl
  • X 5 absent, hydrogen, C 1 -C 6 alkyl-C 1 -C 3 alkoxy, C 1 -C 3 alkoxy, C 1 -C 3 perhaloalkyl, C 1 -C 6 alkyl;
  • R’ halogen, C 1 -C 6 alkyl-C 1 -C 3 alkoxy, C 1 -C 3 alkoxy, hydroxy, C 1 -C 3 perhaloalkyl, C 1 -C 6 alkyl;
  • R’’ halogen, C 1 -C 6 alkyl-C 1 -C 3 alkoxy, C 1 -C 3 alkoxy, hydroxy, C 1 -C 3 perhaloalkyl, C 1 -C 6 alkyl;
  • R 1 H, D, C 1 -C 6 alkyl, optionally substituted by phenyl, halogen, C 1 -C 6 alkyl-C 1 -C 3 alkoxy C 1 -C 3 alkoxy, hydroxy, C 1 -C 3 perhaloalkyl;
  • R 2 C 1 -C 6 alkyl, optionally substituted by phenyl, halogen, C 1 -C 6 alkyl-C 1 -C 3 alkoxy C 1 -C 3 alkoxy, hydroxy, C 1 -C 3 perhaloalkyl; or
  • R 1 and R 2 together form a ring containing a nitrogen and 3 to 5 carbon atoms, or a nitrogen and 3 to 4 carbon atoms and a sulfur atom, wherein the ring is optionally substituted by one of more halogen, C 1 -C 6 alkyl-C 1 -C 3 alkoxy C 1 -C 3 alkoxy, hydroxy, C 1 -C 3 perhaloalkyl, C 1 - C 6 alkyl;
  • a and B are each C 1 -C 6 alkyl or together form a C - 3 C 6 cycloalkyl, optionally substituted by one or more halogen, C 1 -C 6 alkyl-C 1 -C 3 alkoxy, C 1 -C 3 alkoxy, hydroxy, C 1 -C 3 perhaloalkyl, C 1 -C 6 alkyl, or protected or unprotected carbonyl, or together form a ring containing a nitrogen and 3 to 5 carbon atoms, or a nitrogen and 3 to 4 carbon atoms and a sulfur atom, wherein the ring is optionally substituted by one of more halogen, C 1 -C 6 alkyl-C 1 -C 3 alkoxy C 1 -C 3 alkoxy, hydroxy, C 1 -C 3 perhaloalkyl, C 1 -C 6 alkyl, or together form a ring containing a oxygen and 3 to 5 carbon atoms, or a nitrogen and 3 to 4 carbon
  • a is zero or an integer of 1-5;
  • b is zero or an integer of 1-5, or tautomers thereof or pharmaceutically acceptable salts of any of the foregoing.
  • Some embodiments include prodrugs of Formula I (e.g., an ester or amide of Formula I).
  • Formula II is represented by:
  • X C-X 4 or N-X 5 ;
  • X 2 , X 3 , X 4 each independently H, D, halogen, C 1 -C 6 alkyl-C 1 -C 3 alkoxy, C 1 -C 3 alkoxy, C 1 -
  • C 3 perhaloalkyl C 1 -C 6 alkyl; -NR 4 -Z-C 1 -C 6 alkyl, , C 2 -C 5 heterocycle, optionally substituted heteroaryl, optionally substituted aryl, or
  • X 4 is selected from H, D, halogen, C 1 -C 6 alkyl-C 1 -C 3 alkoxy, C 1 -C 3 alkoxy, hydroxy, C 1 -C 3 perhaloalkyl, C 1 -C 6 alkyl, -NR 4 -Z-C 1 -C 6 alkyl
  • X 2 may also be NO 2 , NH 2 , NHCOC 1 -C 6 alkyl;
  • X 5 absent, hydrogen, C 1 -C 6 alkyl-C 1 -C 3 alkoxy, C 1 -C 3 alkoxy, C 1 -C 3 perhaloalkyl, C 1 -C 6 alkyl;
  • R’ halogen, C 1 -C 6 alkyl-C 1 -C 3 alkoxy, C 1 -C 3 alkoxy, hydroxy, C 1 -C 3 perhaloalkyl, C 1 -C 6 alkyl;
  • R’’ halogen, C 1 -C 6 alkyl-C 1 -C 3 alkoxy, C 1 -C 3 alkoxy, hydroxy, C 1 -C 3 perhaloalkyl, C 1 -C 6 alkyl;
  • R 1 H, D, C 1 -C 6 alkyl, optionally substituted by phenyl, halogen, C 1 -C 6 alkyl-C 1 -C 3 alkoxy C 1 -C 3 alkoxy, hydroxy, C 1 -C 3 perhaloalkyl;
  • R 2 C 1 -C 6 alkyl, optionally substituted by phenyl, halogen, C 1 -C 6 alkyl-C 1 -C 3 alkoxy C 1 -C 3 alkoxy, hydroxy, C 1 -C 3 perhaloalkyl; or
  • R 1 and R 2 together form a ring containing a nitrogen and 3 to 5 carbon atoms, or a nitrogen and 3 to 4 carbon atoms and a sulfur atom, wherein the ring is optionally substituted by one of more halogen, C 1 -C 6 alkyl-C 1 -C 3 alkoxy C 1 -C 3 alkoxy, hydroxy, C 1 -C 3 perhaloalkyl, C 1 - C 6 alkyl;
  • a and B are each H, D, C 1 -C 6 alkyl or together form a C - 3 C 6 cycloalkyl, optionally substituted by one or more halogen, C 1 -C 6 alkyl-C 1 -C 3 alkoxy, C 1 -C 3 alkoxy, hydroxy, C 1 - C 3 perhaloalkyl, C 1 -C 6 alkyl, or protected or unprotected carbonyl, or together form a ring containing a nitrogen and 3 to 5 carbon atoms, or a nitrogen and 3 to 4 carbon atoms and a sulfur atom, wherein the ring is optionally substituted by one of more halogen, C 1 -C 6 alkyl- C 1 -C 3 alkoxy C 1 -C 3 alkoxy, hydroxy, C 1 -C 3 perhaloalkyl, C 1 -C 6 alkyl;
  • a is zero or an integer of 1-5;
  • b is zero or an integer of 1-4
  • Some embodiments include prodrugs of Formula II (e.g., an ester or amide of Formula II).
  • Y C-X 3 or N-X 5 ;
  • X C-X 4 or N-X 5 ;
  • X 1 is , optionally substituted aryl or optionally substituted heteroaryl
  • X 2 , X 3 , X 4 each independently H, D, halogen, C 1 -C 6 alkyl-C 1 -C 3 alkoxy, C 1 -C 3 alkoxy, C 1 -
  • C 3 perhaloalkyl C 1 -C 6 alkyl; -NR 4 -Z-C 1 -C 6 alkyl, , C 2 -C 5 heterocycle, optionally substituted heteroaryl, optionally substituted aryl, or
  • X 4 is selected from H, D, halogen, C 1 -C 6 alkyl-C 1 -C 3 alkoxy, C 1 -C 3 alkoxy, hydroxy, C 1 -C 3 perhaloalkyl, C 1 -C 6 alkyl, -NR 4 -Z-C 1 -C 6 alkyl, , C 2 -C 5 heterocycle optionally substituted heteroaryl, optionally substituted aryl;
  • X 2 may also be NO 2 , NH 2 , NHCOC 1 -C 6 alkyl
  • X 5 absent, hydrogen, C 1 -C 6 alkyl-C 1 -C 3 alkoxy, C 1 -C 3 alkoxy, C 1 -C 3 perhaloalkyl, C 1 -C 6 alkyl;
  • R’ halogen, C 1 -C 6 alkyl-C 1 -C 3 alkoxy, C 1 -C 3 alkoxy, hydroxy, C 1 -C 3 perhaloalkyl, C 1 -C 6 alkyl;
  • R’ halogen, C 1 -C 6 alkyl-C 1 -C 3 alkoxy, C 1 -C 3 alkoxy, hydroxy, C 1 -C 3 perhaloalkyl, C 1 -C 6 alkyl;
  • R 1 H, D, C 1 -C 6 alkyl, optionally substituted by phenyl, halogen, C 1 -C 6 alkyl-C 1 -C 3 alkoxy C 1 -C 3 alkoxy, hydroxy, C 1 -C 3 perhaloalkyl;
  • R 2 C 1 -C 6 alkyl, optionally substituted by phenyl, halogen, C 1 -C 6 alkyl-C 1 -C 3 alkoxy C 1 -C 3 alkoxy, hydroxy, C 1 -C 3 perhaloalkyl; or
  • R 1 and R 2 together form a ring containing a nitrogen and 3 to 5 carbon atoms, or a nitrogen and 3 to 4 carbon atoms and a sulfur atom, wherein the ring is optionally substituted by one of more halogen, C 1 -C 6 alkyl-C 1 -C 3 alkoxy C 1 -C 3 alkoxy, hydroxy, C 1 -C 3 perhaloalkyl, C 1 - C 6 alkyl;
  • a and B H, D, C 1 -C 6 alkyl or together form a C - 3 C 6 cycloalkyl, optionally substituted by one or more halogen, C 1 -C 6 alkyl-C 1 -C 3 alkoxy, C 1 -C 3 alkoxy, hydroxy, C 1 -C 3 perhaloalkyl, C 1 -C 6 alkyl, or protected or unprotected carbonyl or A and B together form a ring containing a nitrogen and 3 to 5 carbon atoms, or a nitrogen and 3 to 4 carbon atoms and a sulfur atom, wherein the ring is optionally substituted by one of more halogen, C 1 -C 6 alkyl- C 1 -C 3 alkoxy C 1 -C 3 alkoxy, hydroxy, C 1 -C 3 perhaloalkyl, C 1 -C 6 alkyl;
  • C H or phenyl optionally substituted by one or more halogen, C 1 -C 6 alkyl-C 1 -C 3 alkoxy C 1 -C 3 alkoxy, hydroxy, C 1 -C 3 perhaloalkyl, C 1 -C 6 alkyl;
  • R 4 H, D, C 1 -C 6 alkyl
  • a is zero or an integer of 1-5
  • Some embodiments include prodrugs of Formula III (e.g., an ester or amide of Formula III).
  • Y and X are C-X 3 and C-X 4 , respectively, or Y is C-X 3 , X is N.
  • Other embodiments include where Y is C-X 3 , X is N and X 3 is hydroxy and the tautomer thereof.
  • Y is C-X 3 , and X 3
  • R 1 and R 2 together form a ring containing a nitrogen and 3 to 5 carbon atoms, or a nitrogen and 3 to 4 carbon atoms and a sulfur atom, wherein the ring is optionally substituted by one of more halogen, C 1 -C 6 alkyl-C 1 -C 3 alkoxy C 1 -C 3 alkoxy, hydroxy, C 1 -C 3 perhaloalkyl, C 1 -C 6 alkyl.
  • X 1 is .
  • Other embodiments include where R 1 is H, and R 2 is a C 1 -C 6 alkyl, or
  • R 1 is a C 1 -C 6 alkyl
  • R 2 is a C 1 -C 6 alkyl.
  • R 2 is or R 2 is selected from (CH 2 ) 1-6 CF 3 and (CH 2 ) 1-6 Ph and (CH 2 ) 0-5 CH 3 , each of which may be optionally substituted.
  • R’ is halogen, and a is 2.
  • Other embodiments include where b is 1 or 2, and the 1 or 2 R’’ are meta substituted.
  • Still yet other embodiments include where b is 1 or 2, and R’’ is selected from the group consisting of F, CF 3 , OMe, and t-Bu.
  • Additional embodiments include where A and B together form a C - 3 C 6 cycloalkyl, optionally substituted by one or more moieties selected from the group consisting of F, CF 3 , OMe, and t-Bu.
  • a and B form a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl ring.
  • R’’ is an OMe or F (or in Formula III, A is a phenyl optionally substituted by an OMe or F).
  • R 1 and R 2 are each a C1-C6 alkyl, e.g., methyl, ethyl or propyl.
  • Y and X are C-X 3 and C-X 4 , respectively, X 3 is H and X 4 is F or OMe.
  • X 1 when X 1 is an optionally substituted heteroaryl, it may be selected from the group consisting of pyrrolo[2,3-b]pyridine, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiophenyl, benzothiophenyl, furanyl, benzofuranyl, indolyl, azaindolyl (pyrrolopyridyl), indazolyl, benzimidazolyl, imidazopyridyl (azabenzimidazolyl), pyrazolopyridyl, triazolopyridyl, benzotriazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, imidazopyridyl, isoxazo
  • X 1 is a fused heterocycle, such as (a) indole, isoindole, indazole or purine and structurally possible hydrides thereof, (b) structurally possible hydrides of quinoline, isoquinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline or pteridine, (c) carbazole or carboline and structurally possible hydrides thereof, (d) structurally possible hydrides of phenanthridine, acridine, phenanthroline or phenazine, (e) phenothiazine or phenoxazin.
  • a fused heterocycle such as (a) indole, isoindole, indazole or purine and structurally possible hydrides thereof, (b) structurally possible hydrides of quinoline, isoquinoline, phthalazine, naphthyridine, quinoxaline, quinazoline,
  • the heteroaryl of the present disclosure is replaced by a fused heterocycle, such as such as (a) indole, isoindole, indazole or purine and structurally possible hydrides thereof, (b) structurally possible hydrides of quinoline, isoquinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline or pteridine, (c) carbazole or carboline and structurally possible hydrides thereof, (d) structurally possible hydrides of phenanthridine, acridine, phenanthroline or phenazine, (e) phenothiazine or phenoxazin, or cyclopentenopyridine, cyclohexanopyridine, cyclopentanopyrimidine,
  • a fused heterocycle such as such as (a) indole, isoindole, indazole or purine and structurally possible hydrides thereof, (b)
  • cyclopentanopyridazine cyclopentanoindole, cyclohexanoindole, cyclobenzimidazole, cyclopentanoimidazole, cyclohexanoimidazole, cyclopentanothiophene and
  • the compound is selected from the compounds of Table 1, or a pharmaceutically acceptable salt or tautomer thereof. Note: in the following Table, when Y is C it may be C-X 3 and when X is C, it may be C-X 4 .
  • One aspect of the present technology includes a method for selectively inhibiting BACE2 in a subject, comprising administering to the patent in need thereof a
  • Another aspect of the disclosure is a method of treating a disease that is treatable by inhibiting BACE2 comprising administering to the patent in need thereof a therapeutically effective amount of an active compound having a substituted N-((2S,3R)-4-(benzylamino)-3-hydroxy-1-phenylbutan-2-yl)formamide radical, wherein the active compound selectively inhibits BACE2 over BACE1.
  • diseases that are treatable by inhibiting BACE2 include: Types 1 and 2 diabetes, hypertension, heart disease, diabetic retinopathy, diabetic nephropathy, diabetic skin ulceration and other secondary disorders associated with Type 1 or 2 diabetes.
  • some embodiments include a method of treating one or more of the foregoing diseases comprising administering to the patent in need thereof a therapeutically effective amount of an active compound having a substituted N-((2S,3R)-4-(benzylamino)-3- hydroxy-1-phenylbutan-2-yl)formamide radical, wherein the active compound selectively inhibits BACE2 over BACE1, or a compound of Formula I, II, or III, or any specific compound disclosed herein.
  • a preferred embodiment includes methods of treating diabetes by selectively inhibiting BACE2 in a subject, comprising administering to the patent in need thereof a therapeutically effective amount of an active compound having a substituted N-((2S,3R)-4- (benzylamino)-3-hydroxy-1-phenylbutan-2-yl)formamide radical, wherein the active compound selectively inhibits BACE2 over BACE1.
  • Specific subpopulations of diabetes sufferers may be treated according to the disclosure, including but not limited to type 1 diabetes mellitus, type 2 diabetes mellitus, gestational diabetes, prediabetes and/or latent autoimmune diabetes of adults.
  • the diabetes may be caused by one or more of genetic defects of ⁇ -cell function (e.g. maturity onset diabetes of the young and
  • mitochondrial DNA mutations genetic defects in insulin processing or insulin action (e.g., defects in proinsulin conversion, insulin gene mutations, insulin receptor mutations), exocrine pancreatic defects (e.g. chronic pancreatitis, pancreatectomy, pancreatic neoplasia, cystic fibrosis, hemochromatosis, fibrocalculous pancreatopathy), endocrinopathies (e.g., growth hormone excess (acromegaly), cushing syndrome, hyperthyroidism, pheochromocytoma, glucagonoma), infections (e.g. cytomegalovirus infection,
  • coxsackievirus B coxsackievirus B
  • drugs e.g., glucocorticoids, thyroid hormone, ⁇ -adrenergic agonists, statins.
  • Other embodiments include use or manufacture of an active compound having a substituted N-((2S,3R)-4-(benzylamino)-3-hydroxy-1-phenylbutan-2-yl)formamide radical that selectively inhibits BACE2, for example, in treating diabetes.
  • the active compound has a substituted N-((2S,3R)-4- (benzylamino)-3-hydroxy-1-phenylbutan-2-yl)benzamide or N-((2S,3R)-4-(benzylamino)- 3-hydroxy-1-phenylbutan-2-yl)-2-oxo-2H-1l2-pyridine-6-carboxamide radical.
  • the active compound is a compound represented by on of Formulae I, II or III, or a pharmaceutically acceptable salt or tautomer thereof.
  • the active compound may be one or more compounds selected from Table 1.
  • the active compound selectively inhibits BACE2 over BACE1.
  • the active compound selectively inhibits BACE2 over BACE1 and CatD.
  • Some embodiments include an active compound that selectively inhibits BACE2 over BACE1, and the ratio of Ki of BACE2 to Ki of BACE1 is above 1:50 or 1:100 or 1:500 or 1:1000 or 1:200 or 1:300 or 1:400, for example, is in the range of about 1:50 to 1:5000, or 1:100 to 1:5000, or 1:500 to 1:5000, or 1:1000 to 1:5000, or 1:200 to 1:5000, or 1:300 to 1:5000, or 1:400 to 1:5000.
  • Compounds of Formula I, II and III can each be administered to a patient or subject in need of treatment either individually, or in combination with other therapeutic agents that have similar biological activities.
  • Formulae I, II and III compounds and compositions can be administered as a single dose or as multiple daily doses by a practicing medical practitioner.
  • the compound and the other therapeutic agent are administered separately at different time intervals, or
  • compositions may include a compound of formula I, II or III, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • the composition further contains, in accordance with accepted practices of pharmaceutical compounding, one or more additional therapeutic agents, pharmaceutically acceptable excipients, diluents, adjuvants, stabilizers, emulsifiers, preservatives, colorants, buffers, flavor imparting agents.
  • the pharmaceutical composition includes a compound according to Formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.
  • the pharmaceutical composition includes a compound according to Formula II, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.
  • the pharmaceutical composition includes a compound according to Formula III, or a
  • the pharmaceutical composition includes a compound selected from Table 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.
  • a pharmaceutically acceptable carrier is a phrase that denotes a carrier such as but not limited to a diluent, an excipient, a wetting agent, a buffering agent, a suspending agent, a lubricating agent, an adjuvant, a vehicle, a delivery system, an emulsifier, a disintegrant, an absorbent, a preservative, a surfactant, a colorant, a flavorant, a sweetener, or a mixture of any two or more thereof.
  • Pharmaceutically acceptable excipients and carriers are generally known and, hence, are included in the instant invention. Such materials are described, for example, in REMINGTON: THE SCIENCE AND PRACTICE OF PHARMACY, 21st ed., The University of Philadelphia (2005). Suitable
  • pharmaceutically acceptable carriers include water, salt solutions (such as Ringer’s solution), alcohols, oils, gelatins and carbohydrates such as lactose, amylose or starch, fatty acid esters, hydroxymethycellulose, and polyvinyl pyrrolidine.
  • Such preparations can be sterilized and, if desired, mixed with auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, and/or aromatic substances and the like which do not deleteriously react with the compounds of the invention.
  • Additional carriers or excipients that may be used are understood in the art, such as in Handbook of Pharmaceutical Excipients, Rowe, Raymond C; Sheskey, Paul J; Cook, Walter G; Fenton, Marian E., which is hereby incorporated by reference.
  • liquid or solid formulations may be used.
  • oral dosage formulations include tablets, gelatin capsules, pills, troches, elixirs, suspensions, syrups, wafers, chewing gum and the like.
  • the compounds can be mixed with a suitable pharmaceutical carrier (vehicle) or excipient as understood by practitioners in the art.
  • suitable pharmaceutical carrier include starch, milk, sugar, certain types of clay, gelatin, lactic acid, stearic acid or salts thereof, including magnesium or calcium stearate, talc, vegetable fats or oils, gums and glycols.
  • formulations of the compounds useful in the methods of the present technology may utilize conventional diluents, carriers, or excipients etc., such as are known in the art can be employed to deliver the compounds.
  • the formulations may comprise one or more of the following: a stabilizer, a surfactant, such as a nonionic surfactant, and optionally a salt and/or a buffering agent.
  • the compound may be delivered in the form of a solution, or in a lyophilized form.
  • the stabilizer may, for example, be an amino acid, such as for instance, glycine; or an oligosaccharide, such as for example, sucrose, tetralose, lactose or a dextran.
  • the stabilizer may be a sugar alcohol, such as for instance, mannitol; or a combination thereof.
  • the stabilizer or combination of stabilizers constitutes from about 0.1% to about 10% weight for weight of the compound.
  • the surfactant is a nonionic surfactant, such as a polysorbate.
  • suitable surfactants include Tween20, Tween80; a polyethylene glycol or a polyoxyethylene polyoxypropylene glycol, such as Pluronic F-68 at from about 0.001% (w/v) to about 10% (w/v).
  • a salt or buffering agent may be any salt or buffering agent, such as for example, sodium chloride, or sodium/potassium phosphate, respectively.
  • the buffering agent maintains the pH of the pharmaceutical composition in the range of about 5.5 to about 7.5.
  • the salt and/or buffering agent is also useful to maintain the osmolality at a level suitable for administration to a human or an animal.
  • the salt or buffering agent is present at a roughly isotonic concentration of about 150 mM to about 300 mM.
  • the formulations of the compounds useful in the methods of the present technology may additionally contain one or more conventional additives.
  • additives include a solubilizer such as, for example, glycerol; an antioxidant such as for example, benzalkonium chloride (a mixture of quaternary ammonium compounds, known as "quats"), benzyl alcohol, chloretone or chlorobutanol; anaesthetic agent such as for example a morphine derivative; or an isotonic agent etc., such as described above.
  • a solubilizer such as, for example, glycerol
  • an antioxidant such as for example, benzalkonium chloride (a mixture of quaternary ammonium compounds, known as "quats"), benzyl alcohol, chloretone or chlorobutanol
  • anaesthetic agent such as for example a morphine derivative
  • an isotonic agent etc. such as described above.
  • the pharmaceutical compositions may be stored under nitrogen gas in vials sealed with
  • the mammal can be any mammal, including, for example, farm animals, such as sheep, pigs, cows, and horses; pet animals, such as dogs and cats; laboratory animals, such as rats, mice and rabbits.
  • the mammal is a human.
  • “pharmaceutically acceptable” is meant a material that is not biologically or otherwise undesirable, i.e., the material may be incorporated into a pharmaceutical composition administered to a patient without causing any undesirable biological effects or interacting in a deleterious manner with any of the other components of the composition in which it is contained.
  • pharmaceutical carrier or excipient it is implied that the carrier or excipient has met the required standards of toxicological and manufacturing testing or that it is included on the Inactive Ingredient Guide prepared by the U.S. and Drug administration.
  • patient is meant any animal for which treatment is desirable. Patients may be mammals, and typically, as used herein, a patient is a human individual.
  • salts or zwitterionic forms of the compounds of the present invention which are water or oil-soluble or dispersible; which are suitable for treatment of diseases without undue toxicity, irritation, and allergic-response; which are commensurate with a reasonable benefit/risk ratio; and which are effective for their intended use.
  • the salts can be prepared during the final isolation and purification of the compounds or separately by reacting the appropriate compound in the form of the free base with a suitable acid.
  • Representative acid addition salts include acetate, adipate, alginate, L-ascorbate, aspartate, benzoate, benzenesulfonate (besylate), bisulfate, butyrate, camphorate, camphorsulfonate, citrate, digluconate, formate, fumarate, gentisate, glutarate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hippurate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethansulfonate (isethionate), lactate, maleate, malonate, DL-mandelate, mesitylenesulfonate,
  • basic groups in the compounds of the present invention can be quaternized with methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides;
  • acids which can be employed to form pharmaceutically acceptable addition salts include inorganic acids such as hydrochloric, hydrobromic, sulfuric, and phosphoric, and organic acids such as oxalic, maleic, succinic, and citric. Salts can also be formed by coordination of the compounds with an alkali metal or alkaline earth ion.
  • the present invention contemplates sodium, potassium, magnesium, and calcium salts of the compounds of the compounds of the present invention and the like.
  • substituted refers to an organic group as defined below (e.g., an alkyl group) in which one or more bonds to a hydrogen atom contained therein are replaced by a bond to non-hydrogen or non-carbon atoms.
  • Substituted groups also include groups in which one or more bonds to a carbon(s) or hydrogen(s) atom are replaced by one or more bonds, including double or triple bonds, to a heteroatom.
  • a substituted group will be substituted with one or more substituents, unless otherwise specified.
  • a substituted group is substituted with 1, 2, 3, 4, 5, or 6 substituents.
  • substituent groups include: halogens (i.e., F, Cl, Br, and I); hydroxyls; alkoxy, alkenoxy, alkynoxy, aryloxy, aralkyloxy, heterocyclyloxy, and heterocyclylalkoxy groups; carbonyls (oxo); carboxyls; esters; urethanes; oximes; hydroxylamines; alkoxyamines; aralkoxyamines; thiols; sulfides; sulfoxides; sulfones; sulfonyls; sulfonamides; amines; N- oxides; hydrazines; hydrazides; hydrazones; azides; amides; ureas; amidines; guanidines; enamines; imides; isocyanates; isothiocyanates; cyanates; thiocyanates; imines; nitro groups; nitriles (i.e.
  • Substituted ring groups such as substituted cycloalkyl, aryl, heterocyclyl and heteroaryl groups also include rings and fused ring systems in which a bond to a hydrogen atom is replaced with a bond to a carbon atom. Therefore, substituted cycloalkyl, aryl, heterocyclyl and heteroaryl groups may also be substituted with substituted or unsubstituted alkyl, alkenyl, and alkynyl groups
  • halogen alone or in combination, refers to fluorine, chlorine, bromine, or iodine. When the term halogen is used, it is intended to provide explicit written support for fluorine, chlorine, bromine, or iodine as a group or as an individual moieties.
  • alkyl alone or in combination, refers to a straight-chain, branched, or cyclic alkyl radical, or a radical consisting of any combination of straight, branched, and/or cyclic radicals, which is a saturated aliphatic hydrocarbon group containing from 1- 20 carbon atoms. In many embodiments, alkyl groups comprise 1-10 carbon atoms. In many other embodiments, alkyl groups comprise 1-6 carbon atoms. The term“alkyl groups” is used in its broadest sense. Alkyl groups may be optionally substituted as defined herein.
  • alkyl radicals include methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclopropylmethyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclobutyl, pentyl, neopentyl, iso-amyl, hexyl, cyclohexyl, trans-1,2-di-ethylcyclohexyl, octyl, nonyl and the like.
  • the abbreviation“(C1-C6)-alkyl groups” includes (C3-C6)-cycloalkyl groups as well as straight and branched alkyl groups
  • “O(C1-C8)-alkyl groups” includes the straight-chain O(C1-C8)-alkyl groups, branched O(C1-C6′′)-alkyl groups, and cyclic O(C1- C6)-alkyl groups.
  • alkoxy alone or in combination, refers to an alkyl ether radical, wherein the term alkyl is as defined herein.
  • suitable alkyl ether radicals include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, cyclopentoxy, and the like.
  • heterocycloalkyl refers to an alkyl group where all of the hydrogen atoms are replaced by halogen atoms.
  • heterocycloalkyl and, interchangeably,“heterocycle,” as used herein, alone or in combination, each refer to a saturated, partially unsaturated, or fully unsaturated monocyclic, bicyclic, or tricyclic heterocyclic radical containing one or more heteroatoms as ring members, wherein each said heteroatom may be independently selected from the group consisting of nitrogen, oxygen, and sulfur, and wherein there are typically 3 to 8 ring members in each ring. Most commonly heterocyclic rings contain 5 to 6 ring members. In some embodiments of this invention heterocyclic rings contain 1 to 4 heteroatoms; in other embodiments, heterocyclic rings contain 1 to 2 heteroatoms.
  • Heterocycloalkyl and“heterocycle” are intended to include sulfones, sulfoxides, N-oxides of tertiary nitrogen ring members, and carbocyclic fused and benzo fused ring systems; additionally, both terms also include systems where a heterocycle ring is fused to an aryl group, as defined herein, or an additional heterocycle group.
  • Heterocycle groups of the invention are exemplified by aziridinyl, azetidinyl, 1,3-benzodioxolyl, dihydroisoindolyl, dihydroisoquinolinyl, dihydrocinnolinyl, dihydrobenzodioxinyl, dihydro[1,3]oxazolo[4,5- b]pyridinyl, benzothiazolyl, dihydroindolyl, dihy-dropyridinyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3-dioxolanyl, isoindolinyl, morpholinyl, piperazinyl, pyrrolidinyl, tetrahydropyridinyl, piperidinyl, thiomorpholinyl, and the like.
  • the heterocycle groups may be optionally substituted unless specifically prohibited.
  • cycloalkyl alone or in combination, refers to a saturated or partially saturated monocyclic, bicyclic or tricyclic alkyl radical wherein each cyclic moiety contains from 3 to 12, preferably three to seven, carbon atom ring members and which may optionally be a benzo fused ring system which is optionally substituted as defined herein.
  • cycloalkyl radicals include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, octahydronaphthyl, 2,3-dihydro-1H-indenyl, adamantyl and the like.
  • Aryl groups are cyclic aromatic hydrocarbons that do not contain heteroatoms.
  • Aryl groups include monocyclic, bicyclic and polycyclic ring systems.
  • aryl groups include, but are not limited to, phenyl, azulenyl, heptalenyl, biphenylenyl, indacenyl, fluorenyl, phenanthrenyl, triphenylenyl, pyrenyl, naphthacenyl, chrysenyl, biphenyl, anthracenyl, indenyl, indanyl, pentalenyl, and naphthyl groups.
  • aryl groups contain 6-14 carbons, and in others from 6 to 12 or even 6-10 carbon atoms in the ring portions of the groups.
  • the phrase“aryl groups” includes groups containing fused rings, such as fused aromatic-aliphatic ring systems (e.g., indanyl, tetrahydronaphthyl, and the like), it does not include aryl groups that have other groups, such as alkyl or halo groups, bonded to one of the ring members. Rather, groups such as tolyl are referred to as substituted aryl groups.
  • Representative substituted aryl groups may be mono-substituted or substituted more than once.
  • monosubstituted aryl groups include, but are not limited to, 2-, 3-, 4-, 5-, or 6-substituted phenyl or naphthyl groups, which may be substituted with substituents such as those listed above.
  • Heteroaryl groups are aromatic ring compounds containing 5 or more ring members, of which, one or more is a heteroatom such as, but not limited to, N, O, and S.
  • Heteroaryl groups include, but are not limited to, groups such as pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiophenyl, benzothiophenyl, furanyl, benzofuranyl, indolyl, azaindolyl (pyrrolopyridyl), indazolyl, benzimidazolyl, imidazopyridyl (azabenzimidazolyl), pyrazolopyridyl, triazolopyridyl, benzotriazolyl, benzoxazolyl, benzothi
  • heteroaryl groups are aromatic ring compounds containing 5 or more ring members, of which, one or more is a heteroatom such as, but not limited to, N, O, and S, which includes, e.g., fused ring compounds such as indolyl and 2,3-dihydro indolyl, the phrase does not include heteroaryl groups that have other groups bonded to one of the ring members, such as alkyl groups. Rather, heteroaryl groups with such substitution are referred to as“substituted heteroaryl groups.” Representative substituted heteroaryl groups may be substituted one or more times with various substituents such as those listed above.
  • NR 5 R 6 groups wherein R 4 , R 5 and R 6 are independently hydrogen, or a substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclylalkyl or heterocyclyl group as defined herein.
  • the amine is NH 2 ,
  • methylamino dimethylamino, ethylamino, diethylamino, propylamino, isopropylamino, phenylamino, or benzylamino.
  • prodrugs Certain compounds within the scope of the invention are derivatives referred to as prodrugs.
  • the expression“prodrug” denotes a derivative of a known direct acting drug, e.g. esters and amides, which derivative has enhanced delivery characteristics and therapeutic value as compared to the drug, and is transformed into the active drug by an enzymatic or chemical process; see Notari, R.
  • N-((2S,3R)-4-(cyclopropylamino)-3-hydroxy-1-phenylbutan-2-yl)-3-(N,N- dipropylsulfamoyl)benzamide was synthesized from methyl 3-(chlorosulfonyl)benzoate in a manner similar to that described in Synthetic Example 1 using 3-(chlorosulfonyl)benzoate.
  • N1-((2S,3R)-4-(cyclopropylamino)-3-hydroxy-1-phenylbutan-2-yl)-4-methoxy-N3-((R)-1- phenylethyl)isophthalamide was synthesized from 5-bromo2-methoxy benzoic acid in a manner described above.
  • N-((2S,3R)-3-hydroxy-1-phenyl-4-((3-(trifluoromethyl)benzyl)amino)butan-2-yl)-3- (N-methyl-N-propylsulfamoyl)benzamide was synthesized from 3- (chlorosulfolnyl)benzoate in a manner described for the synthesis of N-((2S,3R)-4- (cyclopropylamino)-3-hydroxy-1-phenylbutan-2-yl)-3-(N-((R)-1- phenylethyl)sulfamoyl)benzamide.
  • N-((2S,3R)-1-(3,5-difluorophenyl)-3-hydroxy-4-((3- (trifluoromethyl)benzyl)amino)butan-2-yl)-3-(N,N-dipropylsulfamoyl)benzamide was synthesized from 3-(chlorosulfolnyl)benzoate in a manner described for the synthesis of N- ((2S,3R)-4-(cyclopropylamino)-3-hydroxy-1-phenylbutan-2-yl)-3-(N-((R)-1- phenylethyl)sulfamoyl)benzamide.
  • N-((2S,3R)-1-(3,5-difluorophenyl)-3-hydroxy-4-((1-(3- methoxyphenyl)cyclohexyl)amino)butan-2-yl)-3-(N,N-dipropylsulfamoyl)benzamide was synthesized from 3-(chlorosulfolnyl)benzoate in a manner described for the synthesis of N- ((2S,3R)-4-(cyclopropylamino)-3-hydroxy-1-phenylbutan-2-yl)-3-(N-((R)-1- phenylethyl)sulfamoyl)benzamide.
  • N-((2S,3R)-4-((3-(tert-butyl)benzyl)amino)-3-hydroxy-1-phenylbutan-2-yl)-3- chloro-5-(N,N-dipropylsulfamoyl)benzamide was synthesized from 3- (chlorosulfolnyl)benzoate in a manner described for the synthesis of N-((2S,3R)-4- (cyclopropylamino)-3-hydroxy-1-phenylbutan-2-yl)-3-(N-((R)-1- phenylethyl)sulfamoyl)benzamide.
  • N-((2S,3R)-4-((3-(tert-butyl)benzyl)amino)-1-(3,5-difluorophenyl)-3-hydroxybutan- 2-yl)-5-(N,N-dipropylsulfamoyl)nicotinamide was synthesized from methyl 5- (chlorosulfonyl)nicotinate in a manner described above.
  • N-((2S,3R)-1-(3,5-difluorophenyl)-4-((3-fluoro-5-(trifluoromethyl)benzyl)amino)-3- hydroxybutan-2-yl)-5-(N,N-dipropylsulfamoyl)nicotinamide was synthesized from methyl 5-(chlorosulfonyl)nicotinate in a manner described above.
  • N-((2S,3R)-1-(3,5-difluorophenyl)-3-hydroxy-4-((1-(3- methoxyphenyl)cyclohexyl)amino)butan-2-yl)-5-(N,N-dipropylsulfamoyl)nicotinamide was synthesized from methyl 5-(chlorosulfonyl)nicotinate in a manner described above.
  • N-((2S,3R)-4-((1-(3-(tert-butyl)phenyl)cyclohexyl)amino)-3-hydroxy-1- phenylbutan-2-yl)-3-(N,N-dipropylsulfamoyl)benzamide was synthesized from 3- (chlorosulfolnyl)benzoate in a manner described for the synthesis of N-((2S,3R)-4- (cyclopropylamino)-3-hydroxy-1-phenylbutan-2-yl)-3-(N-((R)-1- phenylethyl)sulfamoyl)benzamide.
  • N-((2S,3R)-4-((1-(3-(tert-butyl)phenyl)cyclohexyl)amino)-1-(3,5-difluorophenyl)-3- hydroxybutan-2-yl)-3-(N,N-dipropylsulfamoyl)benzamide was synthesized from 3- (chlorosulfolnyl)benzoate in a manner described for the synthesis of N-((2S,3R)-4- (cyclopropylamino)-3-hydroxy-1-phenylbutan-2-yl)-3-(N-((R)-1- phenylethyl)sulfamoyl)benzamide.
  • N-((2S,3R)-1-(3,5-difluorophenyl)-3-hydroxy-4-((3-methoxybenzyl)amino)butan-2- yl)-3-(N-methyl-N-(4,4,4-trifluorobutyl)sulfamoyl)benzamide was synthesized from 3- (chlorosulfolnyl)benzoate in a manner described for the synthesis of N-((2S,3R)-4- (cyclopropylamino)-3-hydroxy-1-phenylbutan-2-yl)-3-(N-((R)-1- phenylethyl)sulfamoyl)benzamide.
  • N-((2S,3R)-4-(cyclopropylamino)-3-hydroxy-1-phenylbutan-2-yl)-4-fluoro-3-((R)- 2-(methoxymethyl)pyrrolidine-1-carbonyl)benzamide was synthesized from methyl (R)-4- fluoro-2-(2-(methoxymethyl)pyrrolidine-1-carbonyl)benzoate in a manner described for N1-((2S,3R)-4-(cyclopropylamino)-3-hydroxy-1-phenylbutan-2-yl)-4-methoxy-N3-((R)-1- phenylethyl)isophthalamide.
  • N-((2S,3R)-3-hydroxy-1-phenyl-4-((3-(trifluoromethyl)benzyl)amino)butan-2-yl)-3- methyl-5-(thiazolidine-3-carbonyl)benzamide was synthesized from thiazolidine as described above.
  • N-((2S,3R)-3-hydroxy-4-((1-(3-methoxyphenyl)cyclohexyl)amino)-1-phenylbutan- 2-yl)-3-methyl-5-(thiazolidine-3-carbonyl)benzamide was synthesized from thiazolidine as described above.
  • N-((2S,3R)-1-(3,5-difluorophenyl)-3-hydroxy-4-((3- (trifluoromethyl)benzyl)amino)butan-2-yl)-3-(thiazolidine-3-carbonyl)benzamide was synthesized from thiazolidine as described above.
  • N-((2S,3R)-4-((3-(tert-butyl)benzyl)amino)-3-hydroxy-1-phenylbutan-2-yl)-3- chloro-5-(thiazolidine-3-carbonyl)benzamide was synthesized from thiazolidine as described above.
  • N-((2S,3R)-3-hydroxy-1-phenyl-4-((1-(3- (trifluoromethyl)phenyl)cyclohexyl)amino)butan-2-yl)-3-(thiazolidine-3- carbonyl)benzamide was synthesized from thiazolidine as described above.
  • reaction mixture was stirred overnight t room temperature. Then reaction mixture was partitioned between ether and water. Organic layer was washed with aqueous sodium bicarbonate solution, water and dried. Crude residue was passed through a bed of silica. Silica was washed repeatedly with hexanes. All the organics were collected, dried over sodium sulfate and volatiles were removed under vacuum. The so obtained 1-(1- azidocyclopentyl)-3-methoxybenzene was carried to the next step without further purification.
  • N3-((2S,3R)-3-hydroxy-4-((1-(3-methoxyphenyl)cyclohexyl)amino)-1-phenylbutan- 2-yl)-N5-methyl-N5-((R)-1-phenylethyl)pyridine-3,5-dicarboxamide was synthesized from 5-(methoxycarbonyl)nicotinic acid in a manner similar to that of yield N3-((2S,3R)-3- hydroxy-1-phenyl-4-((3-(trifluoromethyl)benzyl)amino)butan-2-yl)-N5,N5- dipropylpyridine-3,5-dicarboxamide.
  • N3-((2S,3R)-3-hydroxy-4-((1-(3-methoxyphenyl)cyclohexyl)amino)-1-phenylbutan- 2-yl)-N5-methyl-N5-((R)-1-phenylethyl)pyridine-3,5-dicarboxamide was synthesized from 5-(methoxycarbonyl)nicotinic acid in a manner similar to that of yield N3-((2S,3R)-3- hydroxy-1-phenyl-4-((3-(trifluoromethyl)benzyl)amino)butan-2-yl)-N5,N5- dipropylpyridine-3,5-dicarboxamide.
  • N3-((2S,3R)-3-hydroxy-1-phenyl-4-((1-(3- (trifluoromethyl)phenyl)cyclohexyl)amino)butan-2-yl)-N5-methyl-N5-((R)-1- phenylethyl)pyridine-3,5-dicarboxamide was synthesized from 5- (methoxycarbonyl)nicotinic acid in a manner similar to that of yield N3-((2S,3R)-3- hydroxy-1-phenyl-4-((3-(trifluoromethyl)benzyl)amino)butan-2-yl)-N5,N5- dipropylpyridine-3,5-dicarboxamide.
  • N3-((2S,3R)-1-(3,5-difluorophenyl)-3-hydroxy-4-((1-(3- methoxyphenyl)cyclohexyl)amino)butan-2-yl)-N5,N5-dipropylpyridine-3,5-dicarboxamide was synthesized from 5-(methoxycarbonyl)nicotinic acid in a manner similar to that of yield N3-((2S,3R)-3-hydroxy-1-phenyl-4-((3-(trifluoromethyl)benzyl)amino)butan-2-yl)-N5,N5- dipropylpyridine-3,5-dicarboxamide.
  • reaction mixture was then heated at 110 oC for 16 hours, after which reaction mixture was cooled to room temperature and diluted with ether. Organic layer was washed with water, brine and dried over sodium sulfate. The crude product was purified by column chromatography to yield methyl 2-fluoro-5-(pyridin- 3-yl)benzoate in 80% yield.
  • N-((2S,3R)-1-(3,5-difluorophenyl)-3-hydroxy-4-((1-(3- methoxyphenyl)cyclohexyl)amino)butan-2-yl)-2-fluoro-5-(1H-pyrrolo[2,3-b]pyridin-5- yl)benzamide was synthesized from 5-bromo-2-fluorobenzoate in a manner similar to the synthesis of 2-fluoro-N-((2S,3R)-3-hydroxy-1-phenyl-4-((1-(3- (trifluoromethyl)phenyl)cyclohexyl)amino)butan-2-yl)-5-(pyridin-3-yl)benzamide.
  • N-((2S,3R)-1-(3,5-difluorophenyl)-4-((3-fluoro-5-(trifluoromethyl)benzyl)amino)-3- hydroxybutan-2-yl)-2-fluoro-5-(1H-pyrrolo[2,3-b]pyridin-5-yl)benzamide was synthesized from 5-bromo-2-fluorobenzoate in a manner similar to the synthesis of 2-fluoro-N- ((2S,3R)-3-hydroxy-1-phenyl-4-((1-(3-(trifluoromethyl)phenyl)cyclohexyl)amino)butan-2- yl)-5-(pyridin-3-yl)benzamide.
  • the aqueous layer was cooled to 0 °C and adjusted to pH ⁇ 3 with 1N HCl.
  • the resulting mixture was extracted with EtOAc (x1), and the layers were separated.
  • the organic layer was washed with water (x2), brine (x1), and dried over Na 2 SO 4 .
  • the solids were filtered off, and the volatiles were removed via rotary evaporation. 0.33 g of impure 8 was collected as a white solid.
  • a 16x125 mm culture tube was charged with 11 (0.100 g, 0.29 mmol, 1 eq), Pd(OAc) 2 (6.4 mg, 0.029 mmol, 0.1 eq), Xantphos (33 mg, 0.057 mmol, 0.2 eq) and a stir bar.
  • the tube was sealed with a septum and purged with Ar.
  • Anhydrous MeOH and 1,4- dioxane (1:1, 6 mL) was added.
  • the resulting stirred mixture was sparged with Ar (10 min).
  • Et 3 N (0.08 mL, 0.0579 g, 0.57 mmol, 2 eq, sparged with Ar) was added to the resulting green solution.
  • a 25 mL round bottom flask was charged with 15 (0.0433 g, 0.15 mmol, 1 eq) and a stir bar. The flask was evacuated and back-filled with Ar (x3). Anhydrous DCM (5 mL) was added. The resulting stirred solution was cooled to 0 °C. Acetyl chloride (AcCl) (13 ⁇ L, 0.0141 g, 0.18 mmol, 1.2 eq) was added followed by DIPEA (51 ⁇ L, 0.038 g, 0.29 mmol, 2 eq) 5 min later. The reaction was stirred at 0 °C to room temperature overnight.
  • AcCl Acetyl chloride
  • DIPEA 51 ⁇ L, 0.038 g, 0.29 mmol, 2 eq
  • the volatiles were removed via rotary evaporation.
  • the residue was partitioned between EtOAc/water, and the layers were separated.
  • the organic layer was washed with water (x1), NH 4 Cl (aq, saturated) (x2), brine (x1), and dried over Na 2 SO 4 .
  • the solids were filtered off, and the volatiles were removed via rotary evaporation.
  • the residue was dissolved in toluene, and the volatiles were removed via rotary evaporation. 0.434 g (1.89 mmol, 90% yield) of 18 was collected as an off-white solid.
  • the resulting mixture was filtered through Celite, rinsing with additional water.
  • the reaction flask and filter cake were washed with EtOAc (x3).
  • the combined EtOAc fractions were washed with brine (x1) and dried over Na 2 SO 4 .
  • the solids were filtered off, and the volatiles were removed via rotary evaporation.
  • the crude was plug filtered through silica gel eluting with 4% EtOAc in hexanes. The volatiles were removed via rotary evaporation yielding 0.905 g (3.3 mmol, 67% yield) of 21 with a small amount of impurity.
  • a 16x125 mm culture tube was charged with 23 (0.084 g, 0.24 mmol, 1 eq), Pd(OAc) 2 (5.4 mg, 0.02 mmol, 0.1 eq), Xantphos (28 mg, 0.05 mmol, 0.2 eq) and a stir bar.
  • the tube was sealed with a septum, and the system was evacuated and back-filled with Ar (x3). 1,4-dioxane/water (4:1, 5 mL, sparged with Ar) was added. After stirring for 10 min the resulting green-black solution was treated with Et 3 N (0.34 mL, 0.245 g, 2.4 mmol, 10 eq, sparged with Ar).
  • a 25 mL round bottom flask was charged with 29 (0.029 g, 0.11 mmol, 1 eq) and a stir bar. The flask was evacuated and back-filled with Ar (x3). Anhydrous DMF (2 mL) was added, and the resulting solution was cooled to 0 °C with stirring. NaH (60% dispersion in oil, 0.010 g, 0.25 mmol, 2.3 eq) was added. After 1 h iodomethane (16 ⁇ L, 0.036g, 0.25 mmol, 2.3 eq) was added. The flask was protected from light, and the reaction was stirred at 0 °C to room temperature overnight.
  • the reaction was quenched with water and diluted with NaHCO 3 (aq, saturated). The resulting solution was washed with DCM (x2). The aqueous fraction was adjusted to pH ⁇ 4 with 2N HCl. The solution was extracted with EtOAc (x2). The combined EtOAc fractions were washed with brine (x1) and dried over Na 2 SO 4 . The solids were filtered off, and the volatiles were removed via rotary evaporation yielding a mixture of 29, 30, and some O-methylated material. The mixture was carried forward without purification.
  • the residue was diluted with water and adjusted to pH ⁇ 9 with 2N NaOH.
  • the aqueous layer was washed with DCM (x3).
  • the aqueous fraction was adjusted to pH ⁇ 3 with 1N HCl.
  • the mixture was extracted repeatedly with 10% MeOH in DCM. The combined
  • MeOH/DCM fractions were dried over Na 2 SO 4 .
  • the solids were filtered off, and the volatiles were removed via rotary evaporation yielding 0.030 g (0.11 mmol, 26% yield) of 47 as a solid.
  • a sealed tube vessel was charged with (2S,3S)-N-t-Boc-3-amino-1,2-epoxy-4- phenylbutane (Matrix, 1.0 g, 3.7 mmol, 1eq) and a stir bar.
  • the vessel was sealed with a septum.
  • the vessel was evacuated and back-filled with Ar (x3).
  • Anhydrous i PrOH (11 mL) was added.
  • the resulting stirred mixture was treated with cyclopropylamine (2.3 mL, 1.8 g, 32.9 mmol, 8.6 eq).
  • the vessel was closed with the lid, and the reaction was heated to 50 °C overnight.
  • the organic layer was washed with water (x2), brine (x1), and dried over Na 2 SO 4 .
  • the solids were filtered off, and the volatiles were removed via rotary evaporation.
  • the residue was DCM and dilute HCl (pH ⁇ 2), and the layers were separated.
  • the aqueous layer was washed with DCM (x1).
  • the aqueous layer was adjusted to pH ⁇ 9 with NH 4 OH (aq, saturated) and extracted with EtOAc (x2).
  • the combined EtOAc fractions were washed with brine (x1), and dried over Na 2 SO 4 .
  • the solids were filtered off, and the volatiles were removed via rotary evaporation yielding 0.728 g (3.55 mmol) of 58 as a colorless oil.
  • a pressure vessel was charged with 4-Amino-2,6-dichloropyridine (Combi-Blocks, 1.0 g, 6.1 mmol, 1 eq) and a stir bar. The system was purged with Ar. NaOMe (0.5 N in MeOH, 20 mL, 10 mmol, 1.63 eq) was added. The vessel was closed, and the reaction was heated to 130 °C. After 4 days only partial conversion was observed. The temperature was increased to 160 °C. After 20 h the reaction was cooled to room temperature, and the volatiles were removed via rotary evaporation. The residue was partitioned between EtOAc/water, and the layers were separated.
  • Flask #1 was charged with water (5 mL) and a stir bar. After cooling to -5 °C SOCl 2 (0.83 mL, 1.35 g, 11.4 mmol, 4.5 eq) was added dropwise. The cooling bath was removed and the solution was warmed to room temperature. After 2h at room temperature CuCl (0.0125 g, 0.13 mmol, 0.05 eq) was added. The resulting mixture was cooled to -5 °C. Flask #2 was charged with 187 (0.400 g, 2.5 mmol, 1 eq) and a stir bar.
  • Cyclopentanone was converted to 195 in a manner similar to that described for 59 above using 3-(trifluoromethyl)benzylamine and tert-Butyl ((S)-2-(3,5-difluorophenyl)-1- ((S)-oxiran-2-yl)ethyl)carbamate.
  • Pd(dppf)Cl 2 (Sigma Aldrch, 0.225g, 0.308 mmol, 0.05 eq) was added with continued sparging (1 min). A reflux condenser was attached, and the reaction was heated to reflux for 16h. The volatiles were removed via rotary evaporation. The residue was partitioned between EtOAc/water, and the mixture was filtered through Celite. The layers were separated. The organic layer was washed with water (x2), brine (x1), and dried over Na 2 SO 4 . The solids were filtered off, and the volatiles were removed via rotary evaporation. Purification via flash chromatography eluting with 0-50% EtOAc in hexanes yielded 0.800 g (2.960 mmol, 48% yield) of 215.
  • Ethyl magnesium bromide, 3M in diethyl ether, (2.3 mL, 6.90 mmol) was slowly added dropwise to a solution of 3-(tert-Butyl)benzonitrile (500 mg, 3.14 mmol) and titanium(IV)isopropoxide (1.02 mL, 3.45 mmol) in diethyl ether (30 mL) at 0 °C.
  • the solution turned orange and the ice bath was removed after 15 minutes.
  • boron trifluoride diethyl etherate (0.8 mL, 6.28 mmol) was added rapidly. After stirring for 30 minutes, the brown heterogeneous mixture was diluted with 10% aqueous hydrochloric acid.
  • the heterogenous mixture was made alkaline via the addition of 3N aqueous sodium hydroxide. After stirring for an additional 15 minutes, the heterogeneous mixture was extracted with methylene chloride. The combined organic extracts were dried over Na 2 SO 4 , filtered, and concentrated. The residue was flash chromatographed with methylene chloride:methanol:concentrated as the eluent to yield 389mg (65% yield) of product 219 as an oil.
  • phenyl)cyclopropyl)amino)butan-2-yl)-2-fluoro-5-(1H-pyrrolo[2,3-b]pyridin-5- yl)benzamide was synthesized from 5-bromo-2-fluorobenzoate in a manner similar to the synthesis of 2-fluoro-N-((2S,3R)-3-hydroxy-1-phenyl-4-((1-(3- (trifluoromethyl)phenyl)cyclohexyl)amino)butan-2-yl)-5-(pyridin-3-yl)benzamide.
  • N-((2S,3R)-1-(3,5-difluorophenyl)-3-hydroxy-4-((1-(3- trifluormethyl)phenyl)cyclopropyl)amino)butan-2-yl)-2-fluoro-5-(1H-pyrrolo[2,3- b]pyridin-5-yl)benzamide was synthesized from 5-bromo-2-fluorobenzoate in a manner similar to the synthesis of 2-fluoro-N-((2S,3R)-3-hydroxy-1-phenyl-4-((1-(3- (trifluoromethyl)phenyl)cyclohexyl)amino)butan-2-yl)-5-(pyridin-3-yl)benzamide.
  • N-((2S,3R)-1-(3-(tert-butyl)phenyl)cyclopropyl)amino)-3-hydroxy-1-phenylbutan- 2-yl)-2-fluoro-5-(1H-pyrrolo[2,3-b]pyridin-5-yl)benzamide was synthesized from 5-bromo- 2-fluorobenzoate in a manner similar to the synthesis of 2-fluoro-N-((2S,3R)-3-hydroxy-1- phenyl-4-((1-(3-(trifluoromethyl)phenyl)cyclohexyl)amino)butan-2-yl)-5-(pyridin-3- yl)benzamide.
  • N-((2S,3R)-1-(3,5-difluorophenyl)-3-hydroxy-4-((1-(3- trifluoromethyl)phenyl)cyclohexyl)amino)butan-2-yl)-2-fluoro-5-(1H-pyrrolo[2,3- b]pyridin-5-yl)benzamide was synthesized from 5-bromo-2-fluorobenzoate in a manner similar to the synthesis of 2-fluoro-N-((2S,3R)-3-hydroxy-1-phenyl-4-((1-(3- (trifluoromethyl)phenyl)cyclohexyl)amino)butan-2-yl)-5-(pyridin-3-yl)benzamide.
  • N-((2S,3R)-1-(3,5-difluorophenyl)-3-hydroxy-4-((1-(3- methoxyphenyl)cyclohexyl)amino)butan-2-yl)-2-fluoro-5-(1H-pyrrolo[2,3-b]pyridin-5- yl)benzamide was synthesized from 5-bromo-2-fluorobenzoate in a manner similar to the synthesis of 2-fluoro-N-((2S,3R)-3-hydroxy-1-phenyl-4-((1-(3- (trifluoromethyl)phenyl)cyclohexyl)amino)butan-2-yl)-5-(pyridin-3-yl)benzamide.
  • N-((2S,3R)-1-(3,5-difluorophenyl)-3-hydroxy-4-((1-(3- methoxyphenyl)cyclohexyl)amino)butan-2-yl)-2-fluoro-5-(1H-pyrrolo[2,3-b]pyridin-5- yl)benzamide was synthesized from 5-bromo-2-fluorobenzoate in a manner similar to the synthesis of 2-fluoro-N-((2S,3R)-3-hydroxy-1-phenyl-4-((1-(3- (trifluoromethyl)phenyl)cyclohexyl)amino)butan-2-yl)-5-(pyridin-3-yl)benzamide.
  • N-((2S,3R)-1-(3,5-difluorophenyl)-4-((3-fluoro-5-(trifluoromethyl)benzyl)amino)-3- hydroxybutan-2-yl)-2-fluoro-5-(1H-pyrrolo[2,3-b]pyridin-5-yl)benzamide was synthesized from 5-bromo-2-fluorobenzoate in a manner similar to the synthesis of 2-fluoro-N- ((2S,3R)-3-hydroxy-1-phenyl-4-((1-(3-(trifluoromethyl)phenyl)cyclohexyl)amino)butan-2- yl)-5-(pyridin-3-yl)benzamide.
  • Fluorogenic substrates for BACE is (Mca- SEVNLDAEFRK(Dnp)RR-amide; Bachem) and Cathepsin D is (Mca-Gly-Lys-Pro-Ile- Leu-Phe-Phe-Arg-Leu- Lys(Dnp)-D-Arg-NH2; Anaspec Inc.). These substrates were incubated with recombinant BACE-1, BACE-2 or bovine Cathepsin D with or without the candidate compounds for 20 minutes at 37C. Fluorescence intensity was read by a microplate spectrofluorometer (Infinate M200, Tecan). The rate of substrate hydrolysis was determined from the measurement of initial fluorescence and that of varying compound concentrations. Ki values were obtained using the nonlinear regression analysis software, GraFit 5 (Erithacus).
  • MIN6 Detection of Tmem27 shedding in the pancreatic b cell line MIN6 was used to determine cell-based potency of candidate compounds in inhibition of BACE-2.
  • BACE-2 is the sheddase of the transmembrane protein Tmem27 in pancreatic b cells [19].
  • MIN6 cells were incubated with 2.5 nM to 1 mM of each compound for 16 h at 37C. Following incubation, cells were lysed and protein extracts were separated and analyzed for Tmem27 fragments by Western blotting. The IC50 will be determined from quantification of the C- terminal fragment of Tmem27 for each candidate.
  • the g-secretase inhibitor IX The g-secretase inhibitor IX
  • mice are fasted for 6 h and then injected with 20% glucose solution. Blood is collected before and at 30 min after injection for analysis of serum insulin levels by ELISA assay. After 20 consecutive days of compound administration, mice are sacrificed by CO2 asphyxiation. The pancreas from each mouse is dissected, weighed and fixed. Pancreata from the mice are further processed for histopathology.
  • in vivo example 2
  • mice Effect of BACE2 inhibitor on salt-sensitive hypertension.
  • Selected BACE-2 inhibitors of the present disclosure including from Synthetic Examples 1-58, or placebo is administered to 129S6 male mice at 12 weeks of age. Blood pressure is measured over a 2 week period and then the mice re fed a high salt diet, and blood pressure is averaged over the two week period on high salt diet.
  • mice are placed in metabolic cages for urine collection for measurement of oxidative stress and nitrates/nitrites.10 metabolic cages, 24 hour period per mouse -> 3 days for 30 mice. There are three groups of mice, 10 each
  • mice are administered to 129S6 male mice at 10 weeks of age that have undergone 3 ⁇ 4 nephrectomy and allowed to recover for 4 weeks
  • mice are trained for blood pressure measurement daily at the same time for 2 weeks. After the training period, mice have blood pressure measured and recorded daily for 2 weeks. Blood pressure is averaged during these two weeks of recording.3 groups of mice, 10 each (need to account for 30% mortality rate related to surgery) are used:
  • mice At the end of week 12 after nephrectomy, mice will be placed in metabolic cages for urine collection for measurement of albuminuria, a marker of kidney injury, and will be sacrificed for tissue harvesting. 10 metabolic cages, 24 hour period per mouse -> 3 days for 30 mice.

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Abstract

La présente invention concerne de nouveaux composés de formule I à III, et des procédés d'utilisation de ceux-ci pour inhiber sélectivement BACE2.
PCT/US2016/057299 2015-10-16 2016-10-17 Composés inhibiteurs de bace-2 et procédés d'utilisation associés Ceased WO2017066742A1 (fr)

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WO2019075358A1 (fr) * 2017-10-13 2019-04-18 Ghosh Arun K Inhibiteurs de bace1 pour le traitement de la maladie d'alzheimer
CN111072554A (zh) * 2019-12-30 2020-04-28 郑州华赞医药科技有限公司 一种4-溴-2-氯-6-甲氧基吡啶的合成方法
US12043631B2 (en) 2017-10-13 2024-07-23 Purdue Research Foundation BACE1 inhibitors for the treatment of Alzheimer's disease

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WO2003072535A2 (fr) * 2002-02-27 2003-09-04 Elan Pharmaceuticals, Inc. Hydroxyethylamines substituees
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WO2003072535A2 (fr) * 2002-02-27 2003-09-04 Elan Pharmaceuticals, Inc. Hydroxyethylamines substituees
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Cited By (5)

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Publication number Priority date Publication date Assignee Title
WO2019075358A1 (fr) * 2017-10-13 2019-04-18 Ghosh Arun K Inhibiteurs de bace1 pour le traitement de la maladie d'alzheimer
US11214579B2 (en) 2017-10-13 2022-01-04 Purdue Research Foundation BACE1 inhibitors for the treatment of Alzheimer's disease
US12043631B2 (en) 2017-10-13 2024-07-23 Purdue Research Foundation BACE1 inhibitors for the treatment of Alzheimer's disease
CN111072554A (zh) * 2019-12-30 2020-04-28 郑州华赞医药科技有限公司 一种4-溴-2-氯-6-甲氧基吡啶的合成方法
CN111072554B (zh) * 2019-12-30 2023-06-16 郑州华赞医药科技有限公司 一种4-溴-2-氯-6-甲氧基吡啶的合成方法

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