WO2019129121A1 - Derivatives of phenylmethanone as fto inhibitors - Google Patents

Derivatives of phenylmethanone as fto inhibitors Download PDF

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WO2019129121A1
WO2019129121A1 PCT/CN2018/124186 CN2018124186W WO2019129121A1 WO 2019129121 A1 WO2019129121 A1 WO 2019129121A1 CN 2018124186 W CN2018124186 W CN 2018124186W WO 2019129121 A1 WO2019129121 A1 WO 2019129121A1
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compound
ring
alkyl
nitrogen atom
attached
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PCT/CN2018/124186
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French (fr)
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Wei Li
Wei Zhang
Niu Huang
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Rpxds Co., Ltd
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Priority to CN201880084491.9A priority Critical patent/CN111902386A/en
Publication of WO2019129121A1 publication Critical patent/WO2019129121A1/en

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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
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    • 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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    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings 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
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings 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 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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    • 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
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    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
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Definitions

  • a phenyl methanone derivative as an FTO inhibitor.
  • a pharmaceutical composition comprising the same, and a method for reducing food intake or appetite, inhibiting weight gain, promote weight loss, reducing blood glucose, reducing serum LDL, cholesterol, LDL-c, or triglycerides, or treating obesity or an obesity related disease (especially diabetes, hyperglycemia, diabetic nephropathy, hyperlipemia, coronary heart disease, atherosclerosis, hypertension, cardiovascular or cerebrovascular disease, liver, kidney or thyroid diseases) by inhibiting FTO by using the compound disclosed herein.
  • an obesity related disease especially diabetes, hyperglycemia, diabetic nephropathy, hyperlipemia, coronary heart disease, atherosclerosis, hypertension, cardiovascular or cerebrovascular disease, liver, kidney or thyroid diseases
  • Obesity is a severe health problem worldwide and many factors contribute to this chronic disease, including environmental factors and genetic factors.
  • Genome-wide association studies to investigate patients with obesity revealed a gene for FTO (fat mass and obesity) to strongly associate with obesity.
  • FTO’s functional role in obesity was confirmed in transgenic animal models, such as FTO knockout mouse, FTO-overexpression mouse and FTO-I367F mutation mouse. More specifically, FTO global-knockout and neuron-specific knockout induce body weight loss, while FTO gene overexpression results in obesity.
  • FTO knockout mouse FTO-overexpression mouse
  • FTO-I367F mutation mouse More specifically, FTO global-knockout and neuron-specific knockout induce body weight loss, while FTO gene overexpression results in obesity.
  • One mis-sense mutation was observed to inhibit FTO enzymatic function and protect mouse from obesity.
  • FTO protein is an ⁇ -ketoglutarate and iron (II) dependent nucleic acid demethylase. Its preferred substrate is N6-meA in message RNA, which locates near the stop codon and influences gene translation.
  • US2014/0148383A1 has identified entacapone, which used to be a COMT inhibitor for treating Parkinson disease, has the inhibitory activity of FTO.
  • WO2016206573 (published on December 29, 2016) also discloses a novel structural class of FTO inhibitors.
  • a phenyl methanone derivative of Formula (I) as an FTO inhibitor provides a compound of Formula I as an FTO inhibitor, or a pharmaceutical composition formulated and suitable for administration to a person and comprising in unit dosage the inhibitor.
  • the compounds disclosed herein show a surprisingly sensitive structure–activity relationship as compared with tolcapone.
  • the compounds disclosed herein wherein R 5 is -NR 9 R 10 , R 9 and R 10 together with the nitrogen atom to which they are attached form a ring show better dual inhibition against both FTO and COMT as compared with tolcapone.
  • R 1 and R 2 are each independently H or -C 1-4 alkyl
  • R 4 is a linking group selected from the group consisting of a direct bond, - (CR 7 R 8 ) n -, -O-, -NR 7 -, -S-, wherein R 7 and R 8 are each independently hydrogen, C 1-4 alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, and wherein n is an integer of 1 to 10;
  • R 5 is hydrogen, R 9 , -OR 9 , or -NR 9 R 10 , wherein R 9 and R 10 are each independently are -C 1- 6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, cycloalkyl, C-linked heterocyclyl, aryl, or C-linked heteroaryl, wherein said -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, cycloalkyl, C-linked heterocyclyl, aryl or C-linked heteroaryl are each independently optionally substituted with at least one substituent R 11 , wherein, optionally, two adjacent substituents R 11 , together with the atoms to which they are attached, may form a 3-to 12-membered saturated, partially or fully unsaturated ring comprising 0, 1 or 2 additional heteroatoms independently selected from -NH, -O-, -S-, -SO-or -SO 2 -;
  • R 9 and R 10 together with the nitrogen atom to which they are attached, form a 3-to 12-membered saturated, partially or fully unsaturated ring comprising 0, 1 or 2 additional heteroatoms independently selected from -NH, -O-, -S-, -SO-or -SO 2 -, and said ring is optionally substituted with at least one substituent R 12 ;
  • R 13 , R 14 and R 15 are each independently hydrogen, -C 1-6 alkyl, -C 2-6 alkenyl, -C 2- 6 alkynyl, haloC 1-6 alkyl, haloC 2-6 alkenyl, haloC 2-6 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl;
  • the compound is not (3, 4-dihydroxy-5-nitrophenyl) (p-tolyl) methanone,
  • R 1 and R 2 are both hydrogen.
  • R 3 is -NO 2 , -CN, -CF 3 , or halogen (preferably F or Br) .
  • R 4 is a direct bond. In another embodiment of the first aspect, R 4 is –CH 2 -.
  • R 5 is cycloalkyl, C-linked heterocyclyl, aryl, or C-linked heteroaryl, each of which is optionally substituted with at least one substituent R 11 .
  • R 5 is
  • a cycloalkyl group selected from a monocyclic C 3-12 cycloalkyl, a spiro C 5-12 bicycloalkyl, a bridged C 7-12 bicycloalkyl, and a bridged C 7- 12 tricycloalkyl;
  • R 5 is a monocyclic C 3-8 cycloalkyl (e.g., cyclohexyl) , or a bridged C 7- 12 tricycloalkyl (e.g., adamantanyl) , a C-linked heteroaryl group selected from pyridinyl (e.g., pyridine-2-yl, pyridine-3-yl, pyridine-4-yl) and pyrimidinyl (pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyrimidin-6-yl) , or a phenyl group, each of which is optionally substituted with at least one substituent R 11 .
  • pyridinyl e.g., pyridine-2-yl, pyridine-3-yl, pyridine-4-yl
  • pyrimidinyl pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl,
  • R 11 is selected from hydrogen, halogen, -C 1- 6 alkyl, haloC 1-6 alkyl, -NO 2 , oxo, -OR 13 , wherein R 13 is hydrogen or –C 1-4 alkyl.
  • R 5 is a phenyl group optionally substituted with halogen, -C 1- 6 alkyl, haloC 1-6 alkyl, -NO 2 , oxo, or –OH or 2, 2-difluorobenzo [d] [1, 3] dioxol-5-yl.
  • R 5 is a phenyl group optionally substituted with methyl, trifluoromethyl, OH or NO 2 .
  • R 5 is -NR 9 R 10 , wherein R 9 and R 10 are as defined for Formula I.
  • R 5 is -NR 9 R 10 , R 9 and R 10 together with the nitrogen atom to which they are attached, form a 3-to 12-membered saturated, partially or fully unsaturated ring comprising 0, 1 or 2 additional heteroatoms independently selected from -NH, -O-, -S-, -SO-or -SO 2 -, and said ring is optionally substituted with at least one substituent R 12 .
  • R 5 is -NR 9 R 10 , R 9 and R 10 together with the nitrogen atom to which they are attached, form a 3-, 4-, 5-, 6-, 7-or 8-membered saturated ring comprising 0 additional heteroatom, and said ring is optionally substituted with at least one substituent R 12 .
  • R 9 and R 10 together with the nitrogen atom to which they are attached form a azetidinyl, pyrrolidinyl, piperidinyl, azepanyl, or azocanyl ring; preferably, a azetidinyl, pyrrolidinyl, or piperidinyl ring.
  • R 5 is -NR 9 R 10 , R 9 and R 10 together with the nitrogen atom to which they are attached, form a 3-, 4-, 5-, 6-, 7-or 8-membered saturated ring comprising 1 or 2 additional heteroatoms independently selected from -NH, -O-, -S-, -SO-or -SO 2 -, and said ring is optionally substituted with at least one substituent R 12 .
  • R 9 and R 10 together with the nitrogen atom to which they are attached form a piperzinyl, hexahydropyrimidin-1-yl, or morpholinyl.
  • R 5 is -NR 9 R 10 , R 9 and R 10 together with the nitrogen atom to which they are attached, form a spiro azaC 5-12 bicycloalkyl ring comprising 0, 1 or 2 additional heteroatoms independently selected from -NH, -O-, -S-, -SO-or -SO 2 -, and said ring is optionally substituted with at least one substituent R 12 .
  • R 9 and R 10 together with the nitrogen atom to which they are attached form a spiro azaC 5-12 bicycloalkyl ring comprising 0 additional heteroatom, and said ring is optionally substituted with at least one substituent R 12 .
  • R 9 and R 10 together with the nitrogen atom to which they are attached form 2-azaspiro [3.3] heptan-2-yl, 3-azabicyclo [3.1.0] hexan-3-yl, 6-azaspiro [3.4] octan-6-yl, or 8-azaspiro [4.5] decan-8-yl ring.
  • R 9 and R 10 together with the nitrogen atom to which they are attached form a spiro azaC 5-12 bicycloalkyl ring comprising 1 or 2 additional heteroatoms independently selected from -NH, -O-, -S-, -SO-or -SO 2 -, and said ring is optionally substituted with at least one substituent R 12 .
  • R 9 and R 10 together with the nitrogen atom to which they are attached form a 2-oxa-6-azaspiro [3.3] heptan-6-yl, or 2, 6-diazaspiro [3.4] octan-2-yl ring.
  • R 9 and R 10 together with the nitrogen atom to which they are attached form a bridged C 7-12 bicycloalkyl ring comprising 0, 1 or 2 additional heteroatoms independently selected from -NH, -O-, -S-, -SO-or -SO 2 -, and said ring is optionally substituted with at least one substituent R 12 .
  • R 9 and R 10 together with the nitrogen atom to which they are attached form a bridged C 7-12 bicycloalkyl ring comprising 0 additional heteroatom.
  • R 9 and R 10 together with the nitrogen atom to which they are attached, form a 8-azabicyclo [3.2.1] octan-8-yl, or 2-azabicyclo [3.1.0] hexan-2-yl ring.
  • R 12 is hydrogen, halogen, -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, haloC 1-6 alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -CN, -NO 2 , oxo, or -COR 13 .
  • R 12 is hydrogen, halogen, -C 1-6 alkyl, haloC 1-6 alkyl, or -COR 13 . More preferably, R 12 is hydrogen, F, methyl, trifluoromethyl, or –COCH 3 .
  • the compounds disclosed herein including the above genus or subgenus or specific compounds, are optionally deuterated.
  • a pharmaceutical composition comprising the compound disclosed herein, or a stereoisomer thereof, a hydride thereof, a prodrug thereof, or a pharmaceutically-acceptable salt thereof and pharmaceutically acceptable excipient, optionally in combination with one or more different medicaments, e.g., for reducing food intake or appetite, inhibiting weight gain, promoting weight loss, reducing blood glucose, reducing serum LDL, cholesterol, LDL-c, or triglycerides, or treating atherosclerosis, or treating obesity or an obesity related disease (especially diabetes, hyperglycemia, diabetic nephropathy, hyperlipemia, coronary heart disease, atherosclerosis, hypertension, cardiovascular or cerebrovascular disease, liver, kidney or thyroid diseases) .
  • a method for controlling appetite and/or reducing food intake, for reducing weight gain and/or promoting weight loss, for reducing blood glucose, reducing serum LDL, cholesterol, LDL-c, or triglycerides, or for use in preventing or treating obesity or an obesity related disease in a subject comprising administering to the subject in need thereof a pharmaceutically effective amount of the compound disclosed herein, or a stereoisomer thereof, a hydride thereof, a prodrug thereof, or a pharmaceutically-acceptable salt thereof, optionally in combination with one or more different medicaments, e.g., for reducing food intake or appetite, inhibiting weight gain, promoting weight loss, reducing blood glucose, reducing serum LDL, cholesterol, LDL-c, or triglycerides, or treating atherosclerosis, and a pharmaceutically acceptable excipient.
  • the compound disclosed herein, or a stereoisomer thereof, a hydride thereof, a prodrug thereof, or a pharmaceutically-acceptable salt thereof is used as an FTO inhibitor.
  • the condition or disease disclosed herein is FTO-related.
  • obesity or the obesity related disease is FTO-related, i.e., FTO-related obesity or hyperglycemia, diabetic nephropathy, hyperlipemia, coronary heart disease, atherosclerosis, hypertension, cardiovascular or cerebrovascular disease, liver, kidney or thyroid diseases.
  • the compounds disclosed herein, or a stereoisomer thereof, a hydride thereof, a prodrug thereof, or a pharmaceutically acceptable salt thereof for controlling appetite and/or reducing food intake, for reducing weight gain and/or promoting weight loss, for reducing blood glucose, reducing serum LDL, cholesterol, LDL-c, or triglycerides, or for use in preventing or treating obesity or an obesity related disease.
  • the compound disclosed herein, or a stereoisomer thereof, a hydride thereof, a prodrug thereof, or a pharmaceutically-acceptable salt thereof is used as an FTO inhibitor.
  • the condition or disease disclosed herein is FTO-related.
  • obesity or the obesity related disease is FTO-related, i.e., FTO-related obesity or hyperglycemia, diabetic nephropathy, hyperlipemia, coronary heart disease, atherosclerosis, hypertension, cardiovascular or cerebrovascular disease, liver, kidney or thyroid diseases.
  • the different medicaments as mentioned above include, but not limited to,
  • Different anti-weight gain medicaments particularly a food intake inhibitor and/or a food absorption inhibitor; particularly Orlistat, Cetilistat, Sibutramine, Lorcaserin, Rimonabant, Metformin, Exenatide, Liraglutide, Semaglutide, Pramlintide, Qsymia, Contrave or a pharmaceutically-acceptable salt thereof;
  • statins including atorvastatin (Lipitor) , fluvastatin (Lescol) , lovastatin (Altoprev, Mevacor) , pravastatin (Pravachol) , rosuvastatin (Crestor) , simvastatin (Zocor) ) , or cholestyramine (Prevalite, Questran) , colesevelam (Welchol) , colestipol (Colestid) , ezetimibe (Zetia) , ezetimibe-simvastatin (Vytorin) , fenofibrate (Lofibra, TriCor) , gemfibrozil (Lopid) , Niacin (Niaspan) , Omega-3 fatty acid (Lovaza) , alirocumab
  • statins including atorvastatin (Lipitor) , fluvastatin (Lescol) , lovastatin (
  • Diabetes or hypoglycemia medicaments such as insulin, glibenclamide, glipizide, gliquidone, gliclazide, glimepiride, glibornuride, repaglinide, nateglinide, metformin, acarbose, voglibose, rosiglitazone, pioglitazone, exenatide, liraglutide, lixisenatide, albiglutide, dulaglutide, semaglutide, sitagliptin, saxagliptin, vildagliptin, alogliptin, linagliptin, anagliptin, teneligliptin, gemigliptin, trelagliptin, evogliptin, omarigliptin, canagliflozin, dapaglifozin, ipragliflozin, luseogliflozin, tofo
  • the invention encompasses all combination of the particular embodiments recited herein, as if each had been separately, laboriously recited.
  • the terms “a” and “an” mean one or more, the term “or” means and/or and polynucleotide sequences are understood to encompass opposite strands as well as alternative backbones described herein.
  • alkyl herein refers to a hydrocarbon group selected from linear and branched saturated hydrocarbon groups comprising from 1 to 18, such as from 1 to 12, further such as from 1 to 10, more further such as from 1 to 8, or from 1 to 6, or from 1 to 4, carbon atoms.
  • alkyl groups comprising from 1 to 6 carbon atoms include, but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl, and so on.
  • halogen herein refers to fluoro (F) , chloro (Cl) , bromo (Br) and iodo (I) .
  • alkenyl group e.g., C 2-6 alkenyl
  • examples of the alkenyl group, e.g., C 2-6 alkenyl include, but not limited to ethenyl or vinyl, prop-1-enyl, prop-2-enyl, , and so on.
  • alkynyl herein refers to a hydrocarbon group selected from linear and branched hydrocarbon group, comprising at least one C ⁇ C triple bond and from 2 to 18, such as 2 to 8, further such as from 2 to 6, carbon atoms.
  • alkynyl group e.g., C 2-6 alkynyl
  • examples of the alkynyl group include, but not limited to ethynyl, 1-propynyl, and so on.
  • alkyloxy herein refers to an alkyl group as defined above bonded to oxygen, represented by -Oalkyl.
  • alkyloxy e.g., C 1-6 alkyloxy or C 1-4 alkyloxy includes, but not limited to, methoxy, ethoxy, isopropoxy, propoxy, n-butoxy, tert-butoxy, pentoxy and hexoxy and the like.
  • cycloalkyl herein refers to a hydrocarbon group selected from saturated and partially unsaturated cyclic hydrocarbon groups, comprising monocyclic and polycyclic (e.g., bicyclic and tricyclic) groups.
  • polycyclic cycloalkyl group also comprises “spirocycloalkyl” and "bridged cycloalkyl” .
  • the cycloalkyl group may comprise from 3 to 12, such as from 3 to 10, further such as 3 to 8, further such as 3 to 6, 3 to 5, or 3 to 4 carbon atoms.
  • cycloalkyl comprises a monocyclic C 3- 12 cycloalkyl, a spiro C 5-12 bicycloalkyl, a bridged C 7-12 bicycloalkyl, or a bridged C 7- 12 tricycloalkyl.
  • Examples of the monocyclic cycloalkyl group include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, and cyclododecyl groups.
  • Examples of the saturated monocyclic cycloalkyl group include, but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups.
  • the cycloalkyl is a monocyclic ring comprising 3 to 6 carbon atoms (abbreviated as C3-6 cycloalkyl) , including but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • spirobicycloalkyl refers to a bicyclic saturated carbon ring system in which the two rings are connected through just one atom.
  • Spiro C 5-12 bicycloalkyl rings include, but not limited to spiro [2.2] pentanyl, spiro [2.3] hexanyl, spiro [2.4] heptanyl, spiro [3.3] heptanyl, spiro [2.5] octanyl, spiro [3.4] octanyl, spiro [2.6] nonanyl, spiro [3.5] nonanyl, spiro [4.4] nonanyl, spiro [2.7] decanyl, spiro [3.6] decanyl, spiro [4.5] decanyl, spiro [3.7] undecanyl, spiro [4.6] undecanyl, spiro [5.5] undecanyl, spiro [4.7] dodecanyl, and
  • bridged cycloalkyl refers to two or more cycloalkyl groups fused via adjacent or non-adjacent atoms.
  • bicyclic C 7-12 cycloalkyl groups include those having from 7 to 12 ring atoms arranged as a bicyclic ring selected from [4, 4] , [4, 5] , [5, 5] , [5, 6] and [6, 6] ring systems, or as a bridged bicyclic ring selected from bicyclo [2.2.1] heptane, bicyclo [2.2.2] octane, and bicyclo [3.2.2] nonane.
  • bicyclic cycloalkyl groups include those arranged as a bicyclic ring selected from [5, 6] and [6, 6] ring systems, such as wherein the wavy lines indicate the points of attachment.
  • the ring may be saturated or have at least one double bond (i.e. partially unsaturated) , but is not fully conjugated, and is not aromatic, as aromatic is defined herein.
  • tricyclic C 7-12 cycloalkyl groups include adamantane.
  • aryl used alone or in combination with other terms refers to a group selected from: 5-and 6-membered carbocyclic aromatic rings, e.g., phenyl; bicyclic ring systems such as 7 to 12 membered bicyclic ring systems, wherein at least one ring is carbocyclic and aromatic, e.g., naphthyl and indanyl; and, tricyclic ring systems such as 10 to 15 membered tricyclic ring systems wherein at least one ring is carbocyclic and aromatic, e.g., fluorenyl.
  • 5-and 6-membered carbocyclic aromatic rings e.g., phenyl
  • bicyclic ring systems such as 7 to 12 membered bicyclic ring systems, wherein at least one ring is carbocyclic and aromatic, e.g., naphthyl and indanyl
  • tricyclic ring systems such as 10 to 15 membered tricyclic ring systems wherein at least one ring is
  • the aryl group is a monocyclic or bicyclic aromatic hydrocarbon ring having 5 to 10 ring-forming carbon atoms (i.e., C 5-10 aryl) .
  • a monocyclic or bicyclic aromatic hydrocarbon ring includes, but not limited to, phenyl, naphth-1-yl, naphth-2-yl, anthracenyl, phenanthrenyl, and the like.
  • the aromatic hydrocarbon ring is a naphthalene ring (naphth-1-yl or naphth-2-yl) or phenyl ring.
  • the aromatic hydrocarbon ring is a phenyl ring.
  • heteroaryl refers to a group selected from: 5-, 6-or 7-membered aromatic, monocyclic rings comprising at least one heteroatom, for example, from 1 to 4, or, in some embodiments, from 1 to 3, in some embodiments, from 1 to 2, heteroatoms, selected from nitrogen (N) , sulfur (S) and oxygen (O) , with the remaining ring atoms being carbon; 8-to 12-membered bicyclic rings (preferably 9 or 10-membered bicyclic rings) comprising at least one heteroatom, for example, from 1 to 4, or, in some embodiments, from 1 to 3, or, in other embodiments, 1 or 2, heteroatoms, selected from N, O, and S, with the remaining ring atoms being carbon and wherein at least one ring is aromatic and at least one heteroatom is present in the aromatic ring; and 11-to 14-membered tricyclic rings comprising at least one heteroatom, for example, from 1 to 4, or in some embodiments, from 1 to 3, or, in other embodiments
  • heteroaryl is 5-or 6-membered monocyclic heteroaryl comprising one nitrogen atom and 0 or 1 additional heteroatom selected from N, O and S, including but not limited to pyridinyl, pyrizinyl, pyrimidinyl, thiazolyl, thiadiazolyl, pyridinyl, isoxazolyl, or oxazolyl.
  • heteroaryl is a 9 or 10-membered bicylic heteroaryl comprising one or two or three or four heteroatoms selected from NH, O, S and P, including but not limited to benzo [d] thiazolyl, 1H-indolyl, 1H-benzo [d] imidazolyl, 1H-pyrrolo [2, 3-c] pyridinyl, 1H-purinyl , or oxo-1, 4-dihydroquinolinyl.
  • C-linked heteroaryl as used herein means that the heteroaryl group is connected to the other part of the molecule by a bond from a C-atom of the heteroaryl ring.
  • heteroaryl group or the monocyclic or bicyclic aromatic heterocyclic ring examples include, but are not limited to, (as numbered from the linkage position assigned priority 1) pyridyl (such as 2-pyridyl, 3-pyridyl, or 4-pyridyl) , cinnolinyl, pyrazinyl, 2, 4-pyrimidinyl, 3, 5-pyrimidinyl, 2, 4-imidazolyl, imidazopyridinyl, isoxazolyl, oxazolyl, thiazolyl, isothiazolyl, thiadiazolyl (such as 1, 2, 3-thiadiazolyl, 1, 2, 4-thiadiazolyl, or 1, 3, 4-thiadiazolyl) , tetrazolyl, thienyl (such as thien-2-yl, thien-3-yl) , triazinyl, benzothienyl, furyl or furanyl, benzofuryl, benzoimidazo
  • heterocyclic or “heterocycle” or “heterocyclyl” herein refers to a ring selected from 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-or 12-membered monocyclic, bicyclic and tricyclic, saturated and partially unsaturated rings comprising at least one carbon atoms in addition to at least one heteroatom, such as from 1-4 heteroatoms, further such as from 1-3, or further such as 1 or 2 heteroatoms, selected from nitrogen (N) , sulfur (S) , oxygen (O) and phosphor (P) .
  • N nitrogen
  • S sulfur
  • O oxygen
  • P phosphor
  • a heterocyclyl group is 4-, 5-, 6-or 7-membered monocyclic ring with at least one heteroatom selected from N, O, S and P.
  • Heterocycle herein also refers to a 5-, 6-and/or 7-membered heterocyclic ring comprising at least one, such as 1, 2, 3 or 4, heteroatom selected from N, O, and S fused with 5-, 6-, and /or 7-membered cycloalkyl, carbocyclic aromatic or heteroaromatic ring, provided that the point of attachment is at the heterocyclic ring when the heterocyclic ring is fused with a carbocyclic aromatic or a heteroaromatic ring, and that the point of attachment can be at the cycloalkyl or heterocyclic ring when the heterocyclic ring is fused with cycloalkyl.
  • Heterocycle herein also refers to an aliphatic spirocyclic ring comprising at least one heteroatom selected from N, O, and S, provided that the point of attachment is at the heterocyclic ring.
  • the rings may be saturated or have at least one double bond (i.e. partially unsaturated) .
  • the heterocycle may be substituted with oxo.
  • the point of the attachment may be carbon or heteroatom in the heterocyclic ring.
  • a heterocycle is not a heteroaryl as defined herein.
  • heterocycle examples include, but not limited to, (as numbered from the linkage position assigned priority 1) 1-pyrrolidinyl, 2-pyrrolidinyl, 2, 4-imidazolidinyl, 2, 3-pyrazolidinyl, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 2, 5-piperazinyl, pyranyl, morpholinyl, morpholino, 2-morpholinyl, 3-morpholinyl, oxiranyl, aziridinyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, 1, 2-dithietanyl, 1, 3-dithietanyl, dihydropyridinyl, tetrahydropyridinyl, thiomorpholinyl, thioxanyl, piperazinyl, homopiperazinyl, homopiperidinyl, azepanyl, oxepan,
  • a substituted heterocycle also includes a ring system substituted with one or more oxo moieties, such as piperidinyl N-oxide, morpholinyl-N-oxide, 1-oxo-1-thiomorpholinyl and 1, 1-dioxo-1-thiomorpholinyl.
  • oxo moieties such as piperidinyl N-oxide, morpholinyl-N-oxide, 1-oxo-1-thiomorpholinyl and 1, 1-dioxo-1-thiomorpholinyl.
  • C-linked heterocyclyl as used herein means that the heterocyclyl group is connected to the other part of the molecule by a bond from a C-atom of the heterocyclyl ring.
  • Some of the compounds disclosed herein may exist with different points of attachment of hydrogen, referred to as tautomers.
  • keto and enol forms individually as well as mixtures thereof, are also intended to be included where applicable.
  • “Pharmaceutically-acceptable salts” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
  • a pharmaceutically-acceptable salt may be prepared in situ during the final isolation and purification of the compounds disclosed herein, or separately by reacting the free base function with a suitable organic acid or by reacting the acidic group with a suitable base.
  • the free base can be obtained by basifying a solution of the acid salt.
  • an addition salt such as a pharmaceutically acceptable addition salt, may be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, in accordance with conventional procedures for preparing acid addition salts from base compounds.
  • therapeutically effective amount refers to the amount of the subject compound that will elicit, to some significant extent, the biological or medical response of a tissue, system, animal or human that is being sought by the researcher, veterinarian, medical doctor or other clinician, such as when administered, is sufficient to prevent development of, or alleviate to some extent, one or more of the symptoms of the condition or disorder being treated.
  • the therapeutically effective amount will vary depending on the compound, the disease and its severity and the age, weight, etc., of the mammal to be treated.
  • prodrug refers to a derivative of the active compound, e.g., compound of Formula I that requires a transformation within the body to release the active compound. In some embodiments, the transformation is an enzymatic transformation. Prodrugs are frequently, although not necessarily, pharmacologically inactive until converted to the active agent.
  • deuterated compound refers to a compound wherein one or more carbon-bound hydrogen (s) are replaced by one or more deuterium (s) .
  • deuterated is be used herein to modify a chemical structure or an organic group or radical, wherein one or more carbon-bound hydrogen (s) are replaced by one or more deuterium (s) , e.g., “deuterated-alkyl” , “deuterated-cycloalkyl” , “deuterated-heterocycloalkyl” , “deuterated-aryl” , “deuterated-morpholinyl” , and the like.
  • deuterated-alkyl refers to an alkyl group as defined herein, wherein at least one hydrogen atom bound to carbon is replaced by a deuterium.
  • a deuterated alkyl group at least one carbon atom is bound to a deuterium; and it is possible for a carbon atom to be bound to more than one deuterium; it is also possible that more than one carbon atom in the alkyl group is bound to a deuterium.
  • At least one substituent includes, for example, from 1 to 5, such as from 1 to 4, further as 1, 2 or 3, substituents, provided that the valence allows.
  • at least one substituent R 11 disclosed herein includes from 1 to 4, such as from 1 to 3, further as 1 or 2, substituents selected from the list of R 11 as disclosed herein.
  • the invention also provides pharmaceutical compositions comprising the subject compounds and a pharmaceutically acceptable excipient, particularly such compositions comprising a unit dosage of the subject compounds, particularly such compositions copackaged with instructions describing use of the composition to treat an applicable disease or condition (herein) .
  • compositions for administration can take the form of bulk liquid solutions or suspensions, or bulk powders. More commonly, however, the compositions are presented in unit dosage forms to facilitate accurate dosing.
  • unit dosage forms refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient.
  • Typical unit dosage forms include prefilled, premeasured ampules or syringes of the liquid compositions or pills, tablets, capsules, lozenges or the like in the case of solid compositions.
  • the compound is usually a minor component (from about 0.1 to about 50%by weight or preferably from about 1 to about 40%by weight) with the remainder being various vehicles or carriers and processing aids helpful for forming the desired dosing form.
  • compositions may be administered separately, jointly, or combined in a single dosage unit.
  • the amount administered depends on the compound formulation, route of administration, etc. and is generally empirically determined in routine trials, and variations will necessarily occur depending on the target, the host, and the route of administration, etc.
  • the quantity of active compound in a unit dose of preparation may be varied or adjusted from about 1, 5, 25 or 100 to about 5, 25, 100, 500, 1000 or 2000 mg, according to the particular application.
  • unit dosage forms are packaged in a multipack adapted for sequential use, such as blisterpack, comprising sheets of at least 6, 9 or 12 unit dosage forms.
  • the actual dosage employed may be varied depending upon the requirements of the patient and the severity of the condition being treated. Determination of the proper dosage for a particular situation is within the skill of the art.
  • treatment is initiated with smaller dosages which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small amounts until the optimum effect under the circumstances is reached.
  • the total daily dosage may be divided and administered in portions during the day if desired.
  • the compounds can be administered by a variety of methods including, but not limited to, parenteral, topical, oral, or local administration, such as by aerosol or transdermally, for prophylactic and/or therapeutic treatment.
  • the therapeutic protocols e.g., dosage amounts and times of administration
  • the therapeutics of the invention can be administered in a therapeutically effective dosage and amount, in the process of a therapeutically effective protocol for treatment of the patient.
  • microgram (ug) amounts per kilogram of patient may be sufficient, for example, in the range of about 1, 10, 100, 1000, 10000, 20000 ug/kg to about 10, 100, 1000, 10000, 20000 or 80000 ug/kg of patient weight though optimal dosages are compound specific, and generally empirically determined for each compound.
  • a dosage regimen of the compounds can be oral administration of from 10 mg to 8000 mg/day, preferably 100 to 4000 mg/day, more preferably 200 to 2500 mg/day, in two to four (preferably two) divided doses. Intermittent therapy (e.g., one week out of three weeks or three out of four weeks) may also be used.
  • the person to be treated has a genotype associated with obesity or pathogenic or medically-undesirable weight gain, such as SNP rs7202116 (G) , rs1421085 (C) , or rs9939609 (A) , or a surrogate or proxy SNP in linkage disequilibrium therewith (with respect to the correlative phenotype; see references below) and having a r 2 value greater than 0.5; and/or (f) pathogenically expresses or over-expresses FTO or Fto (e.g. comprises and expresses a multi-copy fto gene) .
  • Re rs7202116 G see e.g.
  • RPX-TOL-1 was prepared in three synthetic steps from 3, 4-dimethoxy-5-nitrobenzoic acid according to the following procedure:
  • RPX-TOL-2 was prepared in six synthetic steps from 1-methoxy-3- (trifluoromethyl) benzene according to the following procedure:
  • Step 3 Synthesis of 3, 4-dimethoxy-5- (trifluoromethyl) benzaldehyde (4)
  • Step 4 Synthesis of (3, 4-dimethoxy-5- (trifluoromethyl) phenyl) (p-tolyl) methanol (5)
  • Step 5 Synthesis of (3, 4-dimethoxy-5- (trifluoromethyl) phenyl) (p-tolyl) methanone (6)
  • Step 6 Synthesis of (3, 4-dihydroxy-5- (trifluoromethyl) phenyl) (p-tolyl) methanone (RPX-TOL-2)
  • RPX-TOL-3 was prepared in four synthetic steps from 3- bromo-4, 5-dimethoxybenzaldehyde, according to the following procedure:
  • Step 4 Synthesis of 2, 3-dihydroxy-5- (4-methylbenzoyl) benzonitrile (RPX-TOL-3)
  • RPX-TOL-4 was prepared in three synthetic steps from 3-bromo-4, 5-dimethoxybenzaldehyde, according to the following procedure:
  • RPX-TOL-5 was prepared in two synthetic steps from 3, 4-dimethoxy-5-nitrobenzoic acid, according to the following procedure:
  • Step 1 Synthesis of azetidin-1-yl (3, 4-dimethoxy-5-nitrophenyl) methanone (2)
  • Step 2 Synthesis of azetidin-1-yl (3, 4-dihydroxy-5-nitrophenyl) methanone (RPX-TOL-5)
  • RPX-TOL-6 was prepared in two synthetic steps from 3, 4-dimethoxy-5-nitrobenzoic acid, according to the following procedure:
  • RPX-TOL-7 was prepared in three synthetic steps methyl 3, 4-dimethoxy-5-nitrobenzoate, according to the following procedure:
  • Step 3 Synthesis of (3, 4-dihydroxy-5-nitrophenyl) (piperidin-1-yl) methanone (RPX-TOL-7)
  • RPX-TOL-8 was prepared in four synthetic steps from 4-hydroxy-3-methoxy-5- (trifluoromethyl) benzaldehyde, according to the following procedure:
  • Step 2 Synthesis of (3, 4-dimethoxy-5- (trifluoromethyl) phenyl) (4- (trifluoromethyl) phenyl) methanol (4)
  • Step 3 Synthesis of (3, 4-dimethoxy-5- (trifluoromethyl) phenyl) (4- (trifluoromethyl) phenyl) methanone (5)
  • Step 4 Synthesis of (3, 4-dihydroxy-5- (trifluoromethyl) phenyl) (4- (trifluoromethyl) phenyl) methanone (RPX-TOL-8)
  • RPX-TOL-32 was prepared in three synthetic steps from 2-cyanoacetic acid, according to the following procedure:
  • RPX-TOL-33 was prepared in three synthetic steps from 2-cyanoacetic acid, according to the following procedure:
  • RPX-TOL-34 was prepared in three synthetic steps from tert-butyl azetidin-3-ylcarbamate, according to the following procedure:
  • the reaction was quenched by water (10 mL) and adjusts the pH value to 6 with acetic acid, then exacted with ethyl acetate (3 x 40 mL) .
  • the combined organic layers was dried over anhydrous sodium sulfate.
  • FTO inhibition Assay Enzymatic Inhibition
  • the inhibition activity of the compounds disclosed herein in a demethylation reaction catalyzed by FTO was measured.
  • FTO-catalyzed demethylation activity was measured in a 100 ⁇ l reaction system containing 50 mM HEPES buffer (pH 7.5) , 100 ⁇ M a-KG, 100 ⁇ M (NH4) 2Fe (SO4) 2, 0.5 mM L-ascorbic acid, 50 ⁇ g/ml BSA, 0.5 ⁇ M ssDNA with m6A (5’-ATTGTCA (m6A) CAGCAGA-3’) , 0.1 ⁇ M FTO protein.
  • ssDNA was digested by nuclease P1 (Sigma) and alkaline phosphatase (Takara) .
  • concentrations of m6A and free A were analyzed by LC-MS/MS.
  • the measured IC 50 value of entacapone against FTO is ⁇ 3 ⁇ M.
  • the compounds in the following table 1 were consistently active, with IC 50 ’s less than 10 ⁇ M.
  • COMT Inhibition Assay The inhibition of the compounds against COMT was measured in reaction kinetic model.
  • the test compound was diluted with assay buffer to desired concentration.
  • the COMT enzyme was also diluted with assay buffer.
  • 5 ⁇ L diluted test article, 5 ⁇ L diluted COMT and 5 ⁇ L Esculetin were added into plate and incubated for 5 min at 37°C, sealed with TopSeal-A384, Clear Adhesive (PE) .
  • 5 ⁇ L AdoMet was added into the plate.
  • the reaction system contains 1U COMT enzyme, test compound, 4 ⁇ M Esculetin, 0.6 mM AdoMet, 50 mM K 3 PO 4 , and 10 mM MgCl 2 . Read plate by using kinetics model (Excitation at 360 nm &emission at 460 nm) . The inhibition was calculated from the slope.
  • the compounds disclosed herein showed better efficacy in inhibiting FTO.
  • the compounds disclosed herein wherein R 5 is -NR 9 R 10 , R 9 and R 10 together with the nitrogen atom to which they are attached form a ring showed better dual inhibition against FTO and COMT as compared with tolcapone.

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Abstract

Disclosed herein is a phenyl methanone derivative as an FTO inhibitor. Also disclosed herein is a pharmaceutical composition comprising the same, and a method for reducing food intake or appetite, inhibiting weight gain, promote weight loss, reducing blood glucose, reducing serum LDL, cholesterol, LDL-c, or triglycerides, or treating obesity or an obesity related disease (especially diabetes, hyperglycemia, diabetic nephropathy, hyperlipemia, coronary heart disease, atherosclerosis, hypertension, cardiovascular or cerebrovascular disease, liver, kidney or thyroid diseases) by inhibiting FTO by using the compound disclosed herein.

Description

DERIVATIVES OF PHENYLMETHANONE AS FTO INHIBITORS
CROSS REFERENCE TO RELATED APPLICATIONS
This application claims the benefit of PCT application No. PCT/CN2017/119404 filed on December 28, 2017, the disclosure of which is hereby incorporated by reference for all purposes.
FILED OF THE INVENTION
Disclosed herein is a phenyl methanone derivative as an FTO inhibitor. Also disclosed herein is a pharmaceutical composition comprising the same, and a method for reducing food intake or appetite, inhibiting weight gain, promote weight loss, reducing blood glucose, reducing serum LDL, cholesterol, LDL-c, or triglycerides, or treating obesity or an obesity related disease (especially diabetes, hyperglycemia, diabetic nephropathy, hyperlipemia, coronary heart disease, atherosclerosis, hypertension, cardiovascular or cerebrovascular disease, liver, kidney or thyroid diseases) by inhibiting FTO by using the compound disclosed herein.
BACKGROUND OF THE INVENTION
Obesity is a severe health problem worldwide and many factors contribute to this chronic disease, including environmental factors and genetic factors. Genome-wide association studies to investigate patients with obesity revealed a gene for FTO (fat mass and obesity) to strongly associate with obesity. FTO’s functional role in obesity was confirmed in transgenic animal models, such as FTO knockout mouse, FTO-overexpression mouse and FTO-I367F mutation mouse. More specifically, FTO global-knockout and neuron-specific knockout induce body weight loss, while FTO gene overexpression results in obesity. One mis-sense mutation was observed to inhibit FTO enzymatic function and protect mouse from obesity. Nevertheless, FTO is expressed in many tissues, especially in hypothalamic nuclei controlling energy expenditure, which is consistent with the suggestion that FTO affects energy homeostasis. FTO protein is an α-ketoglutarate and iron (II) dependent nucleic acid demethylase. Its preferred substrate is N6-meA in message RNA, which locates near the stop codon and influences gene translation.
US2014/0148383A1 has identified entacapone, which used to be a COMT inhibitor for treating Parkinson disease, has the inhibitory activity of FTO. WO2016206573 (published on December 29, 2016) also discloses a novel structural class of FTO inhibitors.
SUMMARY OF THE INVENTION
Disclosed herein is a phenyl methanone derivative of Formula (I) as an FTO inhibitor,  compositions and methods for inhibiting FTO and treating disease associated with excess FTO activity, including obesity and obesity-related diseases. In one aspect the invention provides a compound of Formula I as an FTO inhibitor, or a pharmaceutical composition formulated and suitable for administration to a person and comprising in unit dosage the inhibitor. The compounds disclosed herein show a surprisingly sensitive structure–activity relationship as compared with tolcapone. In particular, the compounds disclosed herein wherein R 5 is -NR 9R 10, R 9 and R 10 together with the nitrogen atom to which they are attached form a ring show better dual inhibition against both FTO and COMT as compared with tolcapone.
In the first aspect, disclosed herein is a compound of Formula I
Figure PCTCN2018124186-appb-000001
or a stereoisomer thereof, a hydride thereof, a prodrug thereof, or a pharmaceutically-acceptable salt thereof, wherein:
R 1 and R 2 are each independently H or -C 1-4alkyl;
R 3 is an electron withdrawn group selected from the group consisting of -NO 2, -CN, -CF 3, -OCF 3, -C (=O) CF 3, -SO 2CF 3, -SO 2CF 2, -COOR, and halogen;
R 4 is a linking group selected from the group consisting of a direct bond, - (CR 7R 8)  n-, -O-, -NR 7-, -S-, wherein R 7 and R 8 are each independently hydrogen, C 1-4alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, and wherein n is an integer of 1 to 10;
R 5 is hydrogen, R 9, -OR 9, or -NR 9R 10, wherein R 9 and R 10 are each independently are -C 1- 6alkyl, -C 2-6alkenyl, -C 2-6alkynyl, cycloalkyl, C-linked heterocyclyl, aryl, or C-linked heteroaryl, wherein said -C 1-6alkyl, -C 2-6alkenyl, -C 2-6alkynyl, cycloalkyl, C-linked heterocyclyl, aryl or C-linked heteroaryl are each independently optionally substituted with at least one substituent R 11, wherein, optionally, two adjacent substituents R 11, together with the atoms to which they are attached, may form a 3-to 12-membered saturated, partially or fully unsaturated ring comprising 0, 1 or 2 additional heteroatoms independently selected from -NH, -O-, -S-, -SO-or -SO 2-;
Alternatively, R 9 and R 10 together with the nitrogen atom to which they are attached, form a 3-to 12-membered saturated, partially or fully unsaturated ring comprising 0, 1 or 2 additional heteroatoms independently selected from -NH, -O-, -S-, -SO-or -SO 2-, and said ring is optionally substituted with at least one substituent R 12;
R 11 and R 12, which may be the same or different, are each independently hydrogen, halogen, -C 1-6alkyl, -C 2-6alkenyl, -C 2-6alkynyl, haloC 1-6alkyl, haloC 2-6alkenyl, haloC 2-6alkynyl,  cycloalkyl, heterocyclyl, aryl, heteroaryl, -CN, -NO 2, oxo, -OR 13, -SO 2R 13, -COR 13, -CO 2R 13, -CONR 13R 14, -C (=NR 13) NR 14R 15, -NR 13R 14, -NR 13COR 14, -NR 13CONR 14R 15, -NR 13CO 2R 14, -NR 13SONR 14R 15, -NR 13SO 2NR 14R 15, or -NR 13SO 2R 14;
wherein R 13, R 14 and R 15 are each independently hydrogen, -C 1-6alkyl, -C 2-6alkenyl, -C 2- 6alkynyl, haloC 1-6alkyl, haloC 2-6alkenyl, haloC 2-6alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl;
provided that the compound is not (3, 4-dihydroxy-5-nitrophenyl) (p-tolyl) methanone,
(3, 4-dihydroxy-5-nitrophenyl) (pyridin-2-yl) methanone,
(3, 4-dihydroxy-5-nitrophenyl) (4- (trifluoromethyl) phenyl) methanone, or
1- (3, 4-dihydroxy-5-nitrophenyl) -2-phenylethanone.
In one embodiment of the first aspect, R 1 and R 2 are both hydrogen.
In one embodiment of the first aspect, R 3 is -NO 2, -CN, -CF 3, or halogen (preferably F or Br) .
In one embodiment of the first aspect, R 4 is a direct bond. In another embodiment of the first aspect, R 4 is –CH 2-.
In one embodiment of the first aspect, R 5 is cycloalkyl, C-linked heterocyclyl, aryl, or C-linked heteroaryl, each of which is optionally substituted with at least one substituent R 11.
Preferably, R 5 is
a. a cycloalkyl group selected from a monocyclic C 3-12cycloalkyl, a spiro C 5-12bicycloalkyl, a bridged C 7-12bicycloalkyl, and a bridged C 7- 12tricycloalkyl;
b. a C-linked heterocyclyl group selected from those as defined herein;
c. an aryl group selected from phenyl and naphthyl;
d. a C-linked heteroaryl group selected from those as defined herein
each of which is optionally substituted with at least one substituent R 11.
More preferably, R 5 is a monocyclic C 3-8cycloalkyl (e.g., cyclohexyl) , or a bridged C 7- 12tricycloalkyl (e.g., adamantanyl) , a C-linked heteroaryl group selected from pyridinyl (e.g., pyridine-2-yl, pyridine-3-yl, pyridine-4-yl) and pyrimidinyl (pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyrimidin-6-yl) , or a phenyl group, each of which is optionally substituted with at least one substituent R 11. In one embodiment, R 11 is selected from hydrogen, halogen, -C 1- 6alkyl, haloC 1-6alkyl, -NO 2, oxo, -OR 13, wherein R 13 is hydrogen or –C 1-4alkyl.
In one embodiment, R 5 is a phenyl group optionally substituted with halogen, -C 1- 6alkyl, haloC 1-6alkyl, -NO 2, oxo, or –OH or 2, 2-difluorobenzo [d] [1, 3] dioxol-5-yl. Preferably, R 5 is a phenyl group optionally substituted with methyl, trifluoromethyl, OH or NO 2.
In another embodiment of the first aspect, R 5 is -NR 9R 10, wherein R 9 and R 10 are as defined for Formula I.
In yet another embodiment, R 5 is -NR 9R 10, R 9 and R 10 together with the nitrogen atom to which they are attached, form a 3-to 12-membered saturated, partially or fully unsaturated ring comprising 0, 1 or 2 additional heteroatoms independently selected from -NH, -O-, -S-, -SO-or -SO 2-, and said ring is optionally substituted with at least one substituent R 12.
In one embodiment, R 5 is -NR 9R 10, R 9 and R 10 together with the nitrogen atom to which they are attached, form a 3-, 4-, 5-, 6-, 7-or 8-membered saturated ring comprising 0 additional heteroatom, and said ring is optionally substituted with at least one substituent R 12. Specifically, R 9 and R 10 together with the nitrogen atom to which they are attached, form a azetidinyl, pyrrolidinyl, piperidinyl, azepanyl, or azocanyl ring; preferably, a azetidinyl, pyrrolidinyl, or piperidinyl ring.
In another embodiment, R 5 is -NR 9R 10, R 9 and R 10 together with the nitrogen atom to which they are attached, form a 3-, 4-, 5-, 6-, 7-or 8-membered saturated ring comprising 1 or 2 additional heteroatoms independently selected from -NH, -O-, -S-, -SO-or -SO 2-, and said ring is optionally substituted with at least one substituent R 12. Specifically, R 9 and R 10 together with the nitrogen atom to which they are attached, form a piperzinyl, hexahydropyrimidin-1-yl, or morpholinyl.
In one embodiment, R 5 is -NR 9R 10, R 9 and R 10 together with the nitrogen atom to which they are attached, form a spiro azaC 5-12bicycloalkyl ring comprising 0, 1 or 2 additional heteroatoms independently selected from -NH, -O-, -S-, -SO-or -SO 2-, and said ring is optionally substituted with at least one substituent R 12.
In one embodiment, R 9 and R 10 together with the nitrogen atom to which they are attached, form a spiro azaC 5-12bicycloalkyl ring comprising 0 additional heteroatom, and said ring is optionally substituted with at least one substituent R 12. Specifically, R 9 and R 10 together with the nitrogen atom to which they are attached, form 2-azaspiro [3.3] heptan-2-yl, 3-azabicyclo [3.1.0] hexan-3-yl, 6-azaspiro [3.4] octan-6-yl, or 8-azaspiro [4.5] decan-8-yl ring.
In one embodiment, R 9 and R 10 together with the nitrogen atom to which they are attached, form a spiro azaC 5-12bicycloalkyl ring comprising 1 or 2 additional heteroatoms independently selected from -NH, -O-, -S-, -SO-or -SO 2-, and said ring is optionally substituted with at least one substituent R 12. Specifically, R 9 and R 10 together with the nitrogen atom to which they are attached, form a 2-oxa-6-azaspiro [3.3] heptan-6-yl, or 2, 6-diazaspiro [3.4] octan-2-yl ring.
In one embodiment, R 9 and R 10 together with the nitrogen atom to which they are attached, form a bridged C 7-12bicycloalkyl ring comprising 0, 1 or 2 additional heteroatoms independently selected from -NH, -O-, -S-, -SO-or -SO 2-, and said ring is optionally  substituted with at least one substituent R 12. Preferably, R 9 and R 10 together with the nitrogen atom to which they are attached, form a bridged C 7-12bicycloalkyl ring comprising 0 additional heteroatom. Specifically, R 9 and R 10 together with the nitrogen atom to which they are attached, form a 8-azabicyclo [3.2.1] octan-8-yl, or 2-azabicyclo [3.1.0] hexan-2-yl ring.
In one embodiment, R 12 is hydrogen, halogen, -C 1-6alkyl, -C 2-6alkenyl, -C 2-6alkynyl, haloC 1-6alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -CN, -NO 2, oxo, or -COR 13. Preferably, R 12 is hydrogen, halogen, -C 1-6alkyl, haloC 1-6alkyl, or -COR 13. More preferably, R 12 is hydrogen, F, methyl, trifluoromethyl, or –COCH 3.
In one embodiment of the first aspect, disclosed herein are compounds selected from:
Figure PCTCN2018124186-appb-000002
Figure PCTCN2018124186-appb-000003
In one embodiment of the first aspect, the compounds disclosed herein, including the above genus or subgenus or specific compounds, are optionally deuterated.
In another aspect, disclosed herein is a pharmaceutical composition comprising the compound disclosed herein, or a stereoisomer thereof, a hydride thereof, a prodrug thereof, or a pharmaceutically-acceptable salt thereof and pharmaceutically acceptable excipient, optionally in combination with one or more different medicaments, e.g., for reducing food intake or appetite, inhibiting weight gain, promoting weight loss, reducing blood glucose, reducing serum LDL, cholesterol, LDL-c, or triglycerides, or treating atherosclerosis, or treating obesity or an obesity related disease (especially diabetes, hyperglycemia, diabetic nephropathy, hyperlipemia, coronary heart disease, atherosclerosis, hypertension, cardiovascular or cerebrovascular disease, liver, kidney or thyroid diseases) .
In yet another aspect, disclosed herein is a method for controlling appetite and/or reducing food intake, for reducing weight gain and/or promoting weight loss, for reducing blood glucose, reducing serum LDL, cholesterol, LDL-c, or triglycerides, or for use in preventing or treating obesity or an obesity related disease in a subject, comprising administering to the subject in need thereof a pharmaceutically effective amount of the compound disclosed herein, or a stereoisomer thereof, a hydride thereof, a prodrug thereof, or a pharmaceutically-acceptable salt thereof, optionally in combination with one or more different medicaments, e.g., for reducing food intake or appetite, inhibiting weight gain, promoting weight loss, reducing blood glucose, reducing serum LDL, cholesterol, LDL-c, or triglycerides, or treating atherosclerosis, and a pharmaceutically acceptable excipient.
In one embodiment, the compound disclosed herein, or a stereoisomer thereof, a hydride thereof, a prodrug thereof, or a pharmaceutically-acceptable salt thereof is used as an FTO inhibitor. In another embodiment, the condition or disease disclosed herein is FTO-related. For example, obesity or the obesity related disease is FTO-related, i.e., FTO-related obesity or hyperglycemia, diabetic nephropathy, hyperlipemia, coronary heart disease, atherosclerosis, hypertension, cardiovascular or cerebrovascular disease, liver, kidney or thyroid diseases.
In further another aspect, disclosed herein is the compounds disclosed herein, or a stereoisomer thereof, a hydride thereof, a prodrug thereof, or a pharmaceutically acceptable salt thereof for controlling appetite and/or reducing food intake, for reducing weight gain and/or promoting weight loss, for reducing blood glucose, reducing serum LDL, cholesterol, LDL-c, or triglycerides, or for use in preventing or treating obesity or an obesity related disease.
In one embodiment, the compound disclosed herein, or a stereoisomer thereof, a hydride thereof, a prodrug thereof, or a pharmaceutically-acceptable salt thereof is used as an FTO inhibitor. In another embodiment, the condition or disease disclosed herein is FTO-related. For example, obesity or the obesity related disease is FTO-related, i.e., FTO-related obesity or hyperglycemia, diabetic nephropathy, hyperlipemia, coronary heart disease, atherosclerosis, hypertension, cardiovascular or cerebrovascular disease, liver, kidney or thyroid diseases.
The different medicaments as mentioned above include, but not limited to,
a. Different anti-weight gain medicaments, particularly a food intake inhibitor and/or a food absorption inhibitor; particularly Orlistat, Cetilistat, Sibutramine, Lorcaserin, Rimonabant, Metformin, Exenatide, Liraglutide, Semaglutide, Pramlintide, Qsymia, Contrave or a pharmaceutically-acceptable salt thereof;
b. Medicaments for reducing serum LDL, cholesterol, LDL-c, or triglycerides or cholesterol lowering drugs, such as statins (including atorvastatin (Lipitor) , fluvastatin (Lescol) , lovastatin (Altoprev, Mevacor) , pravastatin (Pravachol) , rosuvastatin (Crestor) , simvastatin (Zocor) ) , or cholestyramine (Prevalite, Questran) , colesevelam (Welchol) , colestipol (Colestid) , ezetimibe (Zetia) , ezetimibe-simvastatin (Vytorin) , fenofibrate (Lofibra, TriCor) , gemfibrozil (Lopid) , Niacin (Niaspan) , Omega-3 fatty acid (Lovaza) , alirocumab, evolocumab or a pharmaceutically-acceptable salt thereof; and
c. Diabetes or hypoglycemia medicaments, such as insulin, glibenclamide, glipizide, gliquidone, gliclazide, glimepiride, glibornuride, repaglinide, nateglinide, metformin, acarbose, voglibose, rosiglitazone, pioglitazone, exenatide, liraglutide, lixisenatide, albiglutide, dulaglutide, semaglutide, sitagliptin, saxagliptin,  vildagliptin, alogliptin, linagliptin, anagliptin, teneligliptin, gemigliptin, trelagliptin, evogliptin, omarigliptin, canagliflozin, dapaglifozin, ipragliflozin, luseogliflozin, tofogliflozin, empagliflozin or a pharmaceutically-acceptable salt thereof.
The invention encompasses all combination of the particular embodiments recited herein, as if each had been separately, laboriously recited.
DETAILED DESCRIPTION OF THE INVENTION
The following descriptions of particular embodiments and examples are provided by way of illustration and not by way of limitation. Those skilled in the art will readily recognize a variety of noncritical parameters that could be changed or modified to yield essentially similar results.
Unless contraindicated or noted otherwise, in these descriptions and throughout this specification, the terms “a” and “an” mean one or more, the term “or” means and/or and polynucleotide sequences are understood to encompass opposite strands as well as alternative backbones described herein.
The term "alkyl" herein refers to a hydrocarbon group selected from linear and branched saturated hydrocarbon groups comprising from 1 to 18, such as from 1 to 12, further such as from 1 to 10, more further such as from 1 to 8, or from 1 to 6, or from 1 to 4, carbon atoms. Examples of alkyl groups comprising from 1 to 6 carbon atoms (i.e., C 1-6 alkyl) include, but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl, and so on.
The term "halogen” herein refers to fluoro (F) , chloro (Cl) , bromo (Br) and iodo (I) .
The term "alkenyl" herein refers to a hydrocarbon group selected from linear and branched hydrocarbon groups comprising at least one C=C double bond and from 2 to 18, such as from 2 to 8, further such as from 2 to 6, carbon atoms. Examples of the alkenyl group, e.g., C 2-6 alkenyl, include, but not limited to ethenyl or vinyl, prop-1-enyl, prop-2-enyl, , and so on.
The term "alkynyl" herein refers to a hydrocarbon group selected from linear and branched hydrocarbon group, comprising at least one C≡C triple bond and from 2 to 18, such as 2 to 8, further such as from 2 to 6, carbon atoms. Examples of the alkynyl group, e.g., C 2-6 alkynyl, include, but not limited to ethynyl, 1-propynyl, and so on.
The term "alkyloxy" herein refers to an alkyl group as defined above bonded to oxygen, represented by -Oalkyl. Examples of an alkyloxy, e.g., C 1-6alkyloxy or C 1-4 alkyloxy includes, but not limited to, methoxy, ethoxy, isopropoxy, propoxy, n-butoxy, tert-butoxy, pentoxy and hexoxy and the like.
The term "cycloalkyl" herein refers to a hydrocarbon group selected from saturated and partially unsaturated cyclic hydrocarbon groups, comprising monocyclic and polycyclic  (e.g., bicyclic and tricyclic) groups. As a polycyclic cycloalkyl group, the term "cycloalkyl" also comprises "spirocycloalkyl" and "bridged cycloalkyl" . For example, the cycloalkyl group may comprise from 3 to 12, such as from 3 to 10, further such as 3 to 8, further such as 3 to 6, 3 to 5, or 3 to 4 carbon atoms. In this regard, the term "cycloalkyl" comprises a monocyclic C 3- 12cycloalkyl, a spiro C 5-12bicycloalkyl, a bridged C 7-12bicycloalkyl, or a bridged C 7- 12tricycloalkyl. Examples of the monocyclic cycloalkyl group include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, and cyclododecyl groups. In particular, Examples of the saturated monocyclic cycloalkyl group, e.g., C3-8 cycloalkyl, include, but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups. In a preferred embedment, the cycloalkyl is a monocyclic ring comprising 3 to 6 carbon atoms (abbreviated as C3-6 cycloalkyl) , including but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
The term “spirobicycloalkyl” refers to a bicyclic saturated carbon ring system in which the two rings are connected through just one atom. Spiro C 5-12bicycloalkyl rings include, but not limited to spiro [2.2] pentanyl, spiro [2.3] hexanyl, spiro [2.4] heptanyl, spiro [3.3] heptanyl, spiro [2.5] octanyl, spiro [3.4] octanyl, spiro [2.6] nonanyl, spiro [3.5] nonanyl, spiro [4.4] nonanyl, spiro [2.7] decanyl, spiro [3.6] decanyl, spiro [4.5] decanyl, spiro [3.7] undecanyl, spiro [4.6] undecanyl, spiro [5.5] undecanyl, spiro [4.7] dodecanyl, and spiro [5.6] dodecanyl.
The term “bridged cycloalkyl” refers to two or more cycloalkyl groups fused via adjacent or non-adjacent atoms. Examples of the bicyclic C 7-12cycloalkyl groups include those having from 7 to 12 ring atoms arranged as a bicyclic ring selected from [4, 4] , [4, 5] , [5, 5] , [5, 6] and [6, 6] ring systems, or as a bridged bicyclic ring selected from bicyclo [2.2.1] heptane, bicyclo [2.2.2] octane, and bicyclo [3.2.2] nonane. Further Examples of the bicyclic cycloalkyl groups include those arranged as a bicyclic ring selected from [5, 6] and [6, 6] ring systems, such as
Figure PCTCN2018124186-appb-000004
wherein the wavy lines indicate the points of attachment. The ring may be saturated or have at least one double bond (i.e. partially unsaturated) , but is not fully conjugated, and is not aromatic, as aromatic is defined herein. Examples of the tricyclic C 7-12cycloalkyl groups include adamantane.
The term "aryl" used alone or in combination with other terms refers to a group selected from: 5-and 6-membered carbocyclic aromatic rings, e.g., phenyl; bicyclic ring systems such as 7 to 12 membered bicyclic ring systems, wherein at least one ring is carbocyclic and aromatic, e.g., naphthyl and indanyl; and, tricyclic ring systems such as 10 to 15 membered tricyclic ring systems wherein at least one ring is carbocyclic and aromatic, e.g.,  fluorenyl. In some embodiments, the aryl group is a monocyclic or bicyclic aromatic hydrocarbon ring having 5 to 10 ring-forming carbon atoms (i.e., C 5-10 aryl) . Examples of a monocyclic or bicyclic aromatic hydrocarbon ring includes, but not limited to, phenyl, naphth-1-yl, naphth-2-yl, anthracenyl, phenanthrenyl, and the like. In some embodiments, the aromatic hydrocarbon ring is a naphthalene ring (naphth-1-yl or naphth-2-yl) or phenyl ring. In some embodiments, the aromatic hydrocarbon ring is a phenyl ring.
The term "heteroaryl" herein refers to a group selected from: 5-, 6-or 7-membered aromatic, monocyclic rings comprising at least one heteroatom, for example, from 1 to 4, or, in some embodiments, from 1 to 3, in some embodiments, from 1 to 2, heteroatoms, selected from nitrogen (N) , sulfur (S) and oxygen (O) , with the remaining ring atoms being carbon; 8-to 12-membered bicyclic rings (preferably 9 or 10-membered bicyclic rings) comprising at least one heteroatom, for example, from 1 to 4, or, in some embodiments, from 1 to 3, or, in other embodiments, 1 or 2, heteroatoms, selected from N, O, and S, with the remaining ring atoms being carbon and wherein at least one ring is aromatic and at least one heteroatom is present in the aromatic ring; and 11-to 14-membered tricyclic rings comprising at least one heteroatom, for example, from 1 to 4, or in some embodiments, from 1 to 3, or, in other embodiments, 1 or 2, heteroatoms, selected from N, O, and S, with the remaining ring atoms being carbon and wherein at least one ring is aromatic and at least one heteroatom is present in an aromatic ring. In a preferred embodiment, heteroaryl is 5-or 6-membered monocyclic heteroaryl comprising one nitrogen atom and 0 or 1 additional heteroatom selected from N, O and S, including but not limited to pyridinyl, pyrizinyl, pyrimidinyl, thiazolyl, thiadiazolyl, pyridinyl, isoxazolyl, or oxazolyl. In another preferred embodiment, heteroaryl is a 9 or 10-membered bicylic heteroaryl comprising one or two or three or four heteroatoms selected from NH, O, S and P, including but not limited to benzo [d] thiazolyl, 1H-indolyl, 1H-benzo [d] imidazolyl, 1H-pyrrolo [2, 3-c] pyridinyl, 1H-purinyl , or oxo-1, 4-dihydroquinolinyl.
The term “C-linked heteroaryl” as used herein means that the heteroaryl group is connected to the other part of the molecule by a bond from a C-atom of the heteroaryl ring.
Examples of the heteroaryl group or the monocyclic or bicyclic aromatic heterocyclic ring include, but are not limited to, (as numbered from the linkage position assigned priority 1) pyridyl (such as 2-pyridyl, 3-pyridyl, or 4-pyridyl) , cinnolinyl, pyrazinyl, 2, 4-pyrimidinyl, 3, 5-pyrimidinyl, 2, 4-imidazolyl, imidazopyridinyl, isoxazolyl, oxazolyl, thiazolyl, isothiazolyl, thiadiazolyl (such as 1, 2, 3-thiadiazolyl, 1, 2, 4-thiadiazolyl, or 1, 3, 4-thiadiazolyl) , tetrazolyl, thienyl (such as thien-2-yl, thien-3-yl) , triazinyl, benzothienyl, furyl or furanyl, benzofuryl, benzoimidazolyl, indolyl, isoindolyl, indolinyl, oxadiazolyl (such as 1, 2, 3-oxadiazolyl, 1, 2, 4-oxadiazolyl, or 1, 3, 4-oxadiazolyl) , phthalazinyl, pyrazinyl, pyridazinyl, pyrrolyl, triazolyl (such as 1, 2, 3-triazolyl, 1, 2, 4-triazolyl, or 1, 3, 4-triazolyl) , quinolinyl, isoquinolinyl, pyrazolyl,  pyrrolopyridinyl (such as 1H-pyrrolo [2, 3-b] pyridin-5-yl) , pyrazolopyridinyl (such as 1H-pyrazolo [3, 4-b] pyridin-5-yl) , benzoxazolyl (such as benzo [d] oxazol-6-yl) , pteridinyl, purinyl, 1-oxa-2, 3-diazolyl, 1-oxa-2, 4-diazolyl, 1-oxa-2, 5-diazolyl, 1-oxa-3, 4-diazolyl, 1-thia-2, 3-diazolyl, 1-thia-2, 4-diazolyl, 1-thia-2, 5-diazolyl, 1-thia-3, 4-diazolyl, furazanyl (such as furazan-2-yl, furazan-3-yl) , benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, furopyridinyl, benzothiazolyl (such as benzo [d] thiazol-6-yl) , indazolyl (such as 1H-indazol-5-yl) and 5, 6, 7, 8-tetrahydroisoquinoline.
The term "heterocyclic" or "heterocycle" or "heterocyclyl" herein refers to a ring selected from 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-or 12-membered monocyclic, bicyclic and tricyclic, saturated and partially unsaturated rings comprising at least one carbon atoms in addition to at least one heteroatom, such as from 1-4 heteroatoms, further such as from 1-3, or further such as 1 or 2 heteroatoms, selected from nitrogen (N) , sulfur (S) , oxygen (O) and phosphor (P) . In some embodiments, a heterocyclyl group is 4-, 5-, 6-or 7-membered monocyclic ring with at least one heteroatom selected from N, O, S and P. "Heterocycle" herein also refers to a 5-, 6-and/or 7-membered heterocyclic ring comprising at least one, such as 1, 2, 3 or 4, heteroatom selected from N, O, and S fused with 5-, 6-, and /or 7-membered cycloalkyl, carbocyclic aromatic or heteroaromatic ring, provided that the point of attachment is at the heterocyclic ring when the heterocyclic ring is fused with a carbocyclic aromatic or a heteroaromatic ring, and that the point of attachment can be at the cycloalkyl or heterocyclic ring when the heterocyclic ring is fused with cycloalkyl. "Heterocycle" herein also refers to an aliphatic spirocyclic ring comprising at least one heteroatom selected from N, O, and S, provided that the point of attachment is at the heterocyclic ring. The rings may be saturated or have at least one double bond (i.e. partially unsaturated) . The heterocycle may be substituted with oxo. The point of the attachment may be carbon or heteroatom in the heterocyclic ring. A heterocycle is not a heteroaryl as defined herein.
Examples of the heterocycle include, but not limited to, (as numbered from the linkage position assigned priority 1) 1-pyrrolidinyl, 2-pyrrolidinyl, 2, 4-imidazolidinyl, 2, 3-pyrazolidinyl, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 2, 5-piperazinyl, pyranyl, morpholinyl, morpholino, 2-morpholinyl, 3-morpholinyl, oxiranyl, aziridinyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, 1, 2-dithietanyl, 1, 3-dithietanyl, dihydropyridinyl, tetrahydropyridinyl, thiomorpholinyl, thioxanyl, piperazinyl, homopiperazinyl, homopiperidinyl, azepanyl, oxepanyl, thiepanyl, 1, 4-oxathianyl, 1, 4-dioxepanyl, 1, 4-oxathiepanyl, 1, 4-oxaazepanyl, 1, 4-dithiepanyl, 1, 4-thiazepanyl and 1, 4-diazepanyl, 1, 4-dithianyl, 1, 4-azathianyl, oxazepinyl, diazepinyl, thiazepinyl, dihydrothienyl, dihydropyranyl, dihydrofuranyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, 1-pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, 1, 4-dioxanyl, 1, 3- dioxolanyl, pyrazolinyl, pyrazolidinyl, dithianyl, dithiolanyl, pyrazolidinyl, imidazolinyl, pyrimidinonyl, 1, 1-dioxo-thiomorpholinyl, 3-azabicyco [3.1.0] hexanyl, 3-azabicyclo [4.1.0] heptanyl and azabicyclo [2.2.2] hexanyl. A substituted heterocycle also includes a ring system substituted with one or more oxo moieties, such as piperidinyl N-oxide, morpholinyl-N-oxide, 1-oxo-1-thiomorpholinyl and 1, 1-dioxo-1-thiomorpholinyl.
The term “C-linked heterocyclyl” as used herein means that the heterocyclyl group is connected to the other part of the molecule by a bond from a C-atom of the heterocyclyl ring.
When compounds disclosed herein contain olefinic double bonds, unless specified otherwise, such double bonds are meant to include both E and Z geometric isomers.
Some of the compounds disclosed herein may exist with different points of attachment of hydrogen, referred to as tautomers. For example, the compound disclosed herein wherein R 3 is hydroxyl comprising hydroxyl -CH=C (OH) -groups (enol forms) may undergo tautomerism to form carbonyl -CH 2C (O) -groups (keto forms) . Both keto and enol forms, individually as well as mixtures thereof, are also intended to be included where applicable.
"Pharmaceutically-acceptable salts" refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. A pharmaceutically-acceptable salt may be prepared in situ during the final isolation and purification of the compounds disclosed herein, or separately by reacting the free base function with a suitable organic acid or by reacting the acidic group with a suitable base.
In addition, if a compound disclosed herein is obtained as an acid addition salt, the free base can be obtained by basifying a solution of the acid salt. Conversely, if the product is a free base, an addition salt, such as a pharmaceutically acceptable addition salt, may be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, in accordance with conventional procedures for preparing acid addition salts from base compounds. Those skilled in the art will recognize various synthetic methodologies that may be used without undue experimentation to prepare non-toxic pharmaceutically acceptable addition salts.
The term "therapeutically effective amount" refers to the amount of the subject compound that will elicit, to some significant extent, the biological or medical response of a tissue, system, animal or human that is being sought by the researcher, veterinarian, medical doctor or other clinician, such as when administered, is sufficient to prevent development of, or alleviate to some extent, one or more of the symptoms of the condition or disorder being treated. The therapeutically effective amount will vary depending on the compound, the disease and its severity and the age, weight, etc., of the mammal to be treated.
The term “prodrug” refers to a derivative of the active compound, e.g., compound of Formula I that requires a transformation within the body to release the active compound. In some embodiments, the transformation is an enzymatic transformation. Prodrugs are frequently, although not necessarily, pharmacologically inactive until converted to the active agent.
The term “deuterated compound” refers to a compound wherein one or more carbon-bound hydrogen (s) are replaced by one or more deuterium (s) . Similarly, the term “deuterated” is be used herein to modify a chemical structure or an organic group or radical, wherein one or more carbon-bound hydrogen (s) are replaced by one or more deuterium (s) , e.g., “deuterated-alkyl” , “deuterated-cycloalkyl” , “deuterated-heterocycloalkyl” , “deuterated-aryl” , “deuterated-morpholinyl” , and the like. For example, the term “deuterated-alkyl” defined above refers to an alkyl group as defined herein, wherein at least one hydrogen atom bound to carbon is replaced by a deuterium. In a deuterated alkyl group, at least one carbon atom is bound to a deuterium; and it is possible for a carbon atom to be bound to more than one deuterium; it is also possible that more than one carbon atom in the alkyl group is bound to a deuterium.
The term "at least one substituent" disclosed herein includes, for example, from 1 to 5, such as from 1 to 4, further as 1, 2 or 3, substituents, provided that the valence allows. For example, "at least one substituent R 11" disclosed herein includes from 1 to 4, such as from 1 to 3, further as 1 or 2, substituents selected from the list of R 11 as disclosed herein.
The invention also provides pharmaceutical compositions comprising the subject compounds and a pharmaceutically acceptable excipient, particularly such compositions comprising a unit dosage of the subject compounds, particularly such compositions copackaged with instructions describing use of the composition to treat an applicable disease or condition (herein) .
The compositions for administration can take the form of bulk liquid solutions or suspensions, or bulk powders. More commonly, however, the compositions are presented in unit dosage forms to facilitate accurate dosing. The term "unit dosage forms" refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient. Typical unit dosage forms include prefilled, premeasured ampules or syringes of the liquid compositions or pills, tablets, capsules, lozenges or the like in the case of solid compositions. In such compositions, the compound is usually a minor component (from about 0.1 to about 50%by weight or preferably from about 1 to about 40%by weight) with the remainder being various vehicles or carriers and processing aids helpful for forming the desired dosing form.
Suitable excipients or carriers and methods for preparing administrable compositions are known or apparent to those skilled in the art and are described in more detail in such  publications as Remington's Pharmaceutical Science, Mack Publishing Co, NJ (1991) . In addition, the compounds may be advantageously used in conjunction with other therapeutic agents as described herein or otherwise known in the art, particularly other anti-necrosis agents. Hence the compositions may be administered separately, jointly, or combined in a single dosage unit.
The amount administered depends on the compound formulation, route of administration, etc. and is generally empirically determined in routine trials, and variations will necessarily occur depending on the target, the host, and the route of administration, etc. Generally, the quantity of active compound in a unit dose of preparation may be varied or adjusted from about 1, 5, 25 or 100 to about 5, 25, 100, 500, 1000 or 2000 mg, according to the particular application. In a particular embodiment, unit dosage forms are packaged in a multipack adapted for sequential use, such as blisterpack, comprising sheets of at least 6, 9 or 12 unit dosage forms. The actual dosage employed may be varied depending upon the requirements of the patient and the severity of the condition being treated. Determination of the proper dosage for a particular situation is within the skill of the art. Generally, treatment is initiated with smaller dosages which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small amounts until the optimum effect under the circumstances is reached. For convenience, the total daily dosage may be divided and administered in portions during the day if desired.
The compounds can be administered by a variety of methods including, but not limited to, parenteral, topical, oral, or local administration, such as by aerosol or transdermally, for prophylactic and/or therapeutic treatment. Also, in accordance with the knowledge of the skilled clinician, the therapeutic protocols (e.g., dosage amounts and times of administration) can be varied in view of the observed effects of the administered therapeutic agents on the patient, and in view of the observed responses of the disease to the administered therapeutic agents.
The therapeutics of the invention can be administered in a therapeutically effective dosage and amount, in the process of a therapeutically effective protocol for treatment of the patient. For more potent compounds, microgram (ug) amounts per kilogram of patient may be sufficient, for example, in the range of about 1, 10, 100, 1000, 10000, 20000 ug/kg to about 10, 100, 1000, 10000, 20000 or 80000 ug/kg of patient weight though optimal dosages are compound specific, and generally empirically determined for each compound.
In general, routine experimentation in clinical trials will determine specific ranges for optimal therapeutic effect, for each therapeutic, each administrative protocol, and administration to specific patients will also be adjusted to within effective and safe ranges depending on the patient condition and responsiveness to initial administrations. However, the  ultimate administration protocol will be regulated according to the judgment of the attending clinician considering such factors as age, condition and size of the patient as well as compounds potency, severity of the disease being treated. For example, a dosage regimen of the compounds can be oral administration of from 10 mg to 8000 mg/day, preferably 100 to 4000 mg/day, more preferably 200 to 2500 mg/day, in two to four (preferably two) divided doses. Intermittent therapy (e.g., one week out of three weeks or three out of four weeks) may also be used.
In particular embodiments thereof, the person to be treated has a genotype associated with obesity or pathogenic or medically-undesirable weight gain, such as SNP rs7202116 (G) , rs1421085 (C) , or rs9939609 (A) , or a surrogate or proxy SNP in linkage disequilibrium therewith (with respect to the correlative phenotype; see references below) and having a r 2 value greater than 0.5; and/or (f) pathogenically expresses or over-expresses FTO or Fto (e.g. comprises and expresses a multi-copy fto gene) . Re rs7202116 G, see e.g. Yang et al., FTO genotype is associated with phenotypic variability of body mass index, Nature, Sep 16, 2012, doi: 10.1038/nature11401 [epub] ; re rs9939609 A, see e.g. Freathy RM, et al (2008) . "Common variation in the FTO gene alters diabetes-related metabolic traits to the extent expected, given its effect on BMI" . Diabetes 57 (5) : 1419–26. doi: 10.2337/db07-1466. PMC 3073395. PMID 18346983; re rs1421085 C, see e.g. Dina C, et al., (2007) . "Variation in FTO contributes to childhood obesity and severe adult obesity" . Nature Genetics 39 (6) : 724–6. doi: 10.1038/ng2048. PMID 17496; and for multi-copy fto gene mouse, see e.g. Church et al., Overexpression of Fto leads to increased food intake and results in obesity, Nature Genetics, published online 14 Nov 2010, doi: 10.1038/ng. 713.
It is understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be included within the spirit and purview of this application and scope of the appended claims. All publications, patents, and patent applications cited herein, including citations therein, are hereby incorporated by reference in their entirety for all purposes.
Examples: Compound Preparation.
Compound RPX-TOL-1: RPX-TOL-1 was prepared in three synthetic steps from 3, 4-dimethoxy-5-nitrobenzoic acid according to the following procedure:
Figure PCTCN2018124186-appb-000005
Step 1: Synthesis of N, 3, 4-trimethoxy-N-methyl-5-nitrobenzamide (2)
A solution of 3, 4-dimethoxy-5-nitrobenzoic acid (936 mg, 4.1 mmol) and HATU (1.87 g, 4.9 mmol) and N, O-dimethylhydroxylamine hydrogen chloride (482 mg, 4.9 mmol) in DMF (10 mL) was added into DIEA (1.68 mL, 9.8 mmol) . The reaction mixture was stirred at room temperature for 30 min. TLC showed no starting material left. After 25 mL of water was added to the reaction mixture, the mixture was extracted by ethyl acetate (25 mL X 2) . The combined organic layers were dried over anhydrous Na 2SO 4, filtered and concentrated in vacuum to give the crude product. Further purification by column chromatography (silica gel, PE /EA = 50/1) afforded the desired product as a yellow oil (910 mg, 83%) . MS [MH]  + calcd for C 11H 14N 2O 6 270.1 found 271.1.
Step 2: Synthesis of (3, 4-dimethoxy-5-nitrophenyl) (4-methylpyridin-2-yl) methanone (3)
Into a solution of 2-bromo-4-methylpyridine (631 mg, 3.67 mmol) in dry THF (15 mL) , n-BuLi (2.5 mL, 1.8 M in hexanes) was added dropwise at -78 ℃ under nitrogen atmosphere. After the reaction mixture was stirred at -78 ℃ for 45 min, the solution of N, 3, 4-trimethoxy-N-methyl-5-nitrobenzamide (910 mg, 3.34 mmol) in dry THF (5 mL) was added dropwise, maintaining the temperature below -70 ℃. After the addition was completed, the reaction mixture was slowly warmed to room temperature for 3 hours. The reaction was quenched by 1N.HCl, extracted by ethyl acetate. The combined organic layers was dried over anhydrous sodium sulfate, filtered and concentrated in vacuum to give the crude product. Further Purification by column chromatography (silica gel, PE /EA = 30/1) gave the desired product as a yellow solid (130 mg, 13%) . MS [MH]  +calcd for C 15H 14N 2O 5 303.0 found 303.0.
Step 3: Synthesis of (3, 4-dihydroxy-5-nitrophenyl) (4-methylpyridin-2-yl) methanone (RPX-TOL-1)
To a suspension of (3, 4-dimethoxy-5-nitrophenyl) (4-methylpyridin-2-yl) methanone (130 mg, 0.43 mmol) in dichloromethane (10 mL) was added BBr 3 (0.25 mL) dropwise at -5℃ under nitrogen atmosphere. After addition, the mixture was warmed to room temperature and then it was stirred at this temperature for 48 hours. The reaction mixture was poured into ice water, extracted by ethyl acetate. The combined organic layers was dried over anhydrous  sodium sulfate, filtered and concentrated in vacuum to give the crude product. Purification by Prep-HPLC (0.5%TFA, MeOH/H 2O) afforded the desired product as a yellow solid (10 mg, 8%) .  1H NMR (400 MHz, DMSO) δ 8.58 (d, J = 4.9 Hz, 1H) , 8.18 –8.13 (m, 1H) , 7.75 (s, 1H) , 7.61 (s, 1H) , 7.49 (d, J = 4.9 Hz, 1H) , 2.44 (s, 3H) . MS [MH]  -calcd for C 13H 10N 2O 5 273.1 found 273.1.
Compound RPX-TOL-2: RPX-TOL-2 was prepared in six synthetic steps from 1-methoxy-3- (trifluoromethyl) benzene according to the following procedure:
Figure PCTCN2018124186-appb-000006
Step 1: Synthesis of 2-methoxy-6- (trifluoromethyl) phenol (2)
A solution of n-butyllithium (4 mL, 10 mmol) and TEDA (1.8 mL, 12 mmol) in anhydrous THF (10 mL) was cooled -78 ℃. 1-methoxy-3- (trifluoromethyl) benzene (2 g, 11 mmol) was added dropwise and the reaction mixture was stirred at -78 ℃ for 15 min then allowed to warm to RT and stirred for 10 min. The reaction mixture was cooled to -78 ℃ and trimethyl borate (3 g, 28 mmol) was added slowly, dropwise, and the reaction mixture was stirred at -78 ℃ for 15 min then allowed to warm to RT and stirred for 20 h. 7N NH 3/MeOH (4 mL) was added and the solvent was removed in vacuum. The residue was dissolved in formic acid (4 mL) and cooled to 0 ℃ before hydrogen peroxide (1.2 mL, 13 mmol) was added and the solution was allowed to warm to RT and stirred for 2 h. The product was extracted with EtOAc (10 mL X 3) , and then the combined organics were shaken with NaOH (10 mL X 2) . The aq phase was acidified with 1 M HCl and the product was extracted with DCM (10 mL X 3) . The organic solution was washed with brine, dried over MgSO 4, and filtered. The solvent was removed in vacuum and the residue was purified by silica gel chromatography (30 g, 0-5%MeOH in DCM) to afford 2-methoxy-6- (trifluoromethyl) phenol (1 g, 46%) as a colourless oil. MS [MH]  -calcd for C8H7F3O2 191, found 191.
Step 2: Synthesis of 4-hydroxy-3-methoxy-5- (trifluoromethyl) benzaldehyde (3)
A solution of 2-methoxy-6- (trifluoromethyl) phenol (1 g, 5 mmol) and hexamethylenetetramine (0.73 g, 1.6 mmol) in TFA (20 mL) was stirred under reflux for 3 h. The mixture was removed in vacuum and the residue was dissolved in 1 M HCl (10 mL) . The product was extracted with DCM (10 mL X 3) , the combined organics were washed with brine (20 mL X 3) and then the solvent was removed in vacuo. The residue was purified by silica gel chromatography (50 g, 0-100%EtOAc in isohexane) to afford 4-hydroxy-3-methoxy-5-  (trifluoromethyl) benzaldehyde (360 mg, 31%) as a white solid. MS [MH]  -calcd for C9H7F3O3 219, found 219.
Step 3: Synthesis of 3, 4-dimethoxy-5- (trifluoromethyl) benzaldehyde (4)
A solution of 4-hydroxy-3-methoxy-5- (trifluoromethyl) benzaldehyde (360 mg, 1.6 mmol) and MeI (464 mg, 3.3 mmol) in THF (20 mL) was refluxed for overnight. The mixture was cooled to RT, and quenched by water (10 mL) . The mixture was extracted by ethyl acetate (20 mL X 3) and dried by Na 2SO 4, then filtered and concentrated in vacuum to afford the crude product (310 mg, 81%) . MS [MH]  + calcd for C10H9F3O3 235, found 235.
Step 4: Synthesis of (3, 4-dimethoxy-5- (trifluoromethyl) phenyl) (p-tolyl) methanol (5)
3, 4-dimethoxy-5- (trifluoromethyl) benzaldehyde (310 mg, 1.3 mmol) in THF (5 mL) was added to a solution of p-tolylmagnesium bromide (517 mg, 2.6 mmol) in THF (15 mL) under nitrogen atmosphere. After the addition was completed, the mixture was stirred at toom temperature for overnight. Water (15 mL) was added. The mixture was extracted by ethyl acetate (30 mL X 3) and dried by Na 2SO 4. Further purification by column chromatography (silica gel, PE /EA = 5/1) afforded the desired product as a yellow solid (260 mg, 60%) . MS [MH]  + calcd for C17H17F3O3 327, found 327.
Step 5: Synthesis of (3, 4-dimethoxy-5- (trifluoromethyl) phenyl) (p-tolyl) methanone (6)
A solution of (3, 4-dimethoxy-5- (trifluoromethyl) phenyl) (p-tolyl) methanol (260 mg, 0.80 mmol) and Dess-Martin (676 mg, 1.6 mmol) in DCM (20 mL) was stirred at room temperature for overnight. NaHCO 3 (15 mL) was added. The mixture was extracted by ethyl acetate (15 mL X 3) and dried by Na 2SO 4. The mixture was filtered and concentrated in vacuum to afford the crude product as a yellow solid (178 mg, 68%) . MS [MH]  + calcd for C17H15F3O3 325, found 325.
Step 6: Synthesis of (3, 4-dihydroxy-5- (trifluoromethyl) phenyl) (p-tolyl) methanone (RPX-TOL-2)
A solution of (3, 4-dihydroxy-5- (trifluoromethyl) phenyl) (p-tolyl) methanone (178 mg, 0.55 mmol) in DCM (10 mL) was added BBr 3 (0.2 mL) at -5 ℃. After the addition was completed, the reaction mixture was sealed in a tube at room temperature for overnight. The mixture was re-cooled to -5 ℃ and quenched by water (5 mL) . The remained DCM was removed, the residue was diluted by H 2O (5 mL) with stirred at room temperature for 30 min. The mixture was extracted by ethyl acetate (15 mL X 3) and dried by Na 2SO 4, then filtered and concentrated in vacuum to afford the crude product. Further purification by Prep-HPLC (0.05%TFA; ACN-H 2O) afford the desired product (21 mg, 12%) .  1H NMR (400 MHz, DMSO) δ 10.61 (s, 2H) , 7.61 (d, J = 7.9 Hz, 2H) , 7.47 (s, 1H) , 7.42-7.43 (m, J = 7.6 Hz, 3H) , 2.41 (s, 3H) . MS [MH]  -calcd for C15H11F3O3 294.8, found 294.8.
Compound RPX-TOL-3: RPX-TOL-3 was prepared in four synthetic steps from 3- bromo-4, 5-dimethoxybenzaldehyde, according to the following procedure:
Figure PCTCN2018124186-appb-000007
Step 1: Synthesis of (3-bromo-4, 5-dimethoxyphenyl) (p-tolyl) methanol (2)
3-bromo-4, 5-dimethoxybenzaldehyde (1 g, 4mmol) in THF (10 mL) was added to a solution of p-tolylmagnesium bromide (1.6 g, 8 mmol) in THF (15 mL) under nitrogen atmosphere. After the addition was completed, the mixture was stirred at toom temperature for overnight. Water (15 mL) was added. The mixture was extracted by ethyl acetate (30 mL X 3) and dried by Na 2SO 4. Further purification by column chromatography (silica gel, PE /EA = 1/1) afforded the desired product as a yellow solid (650 mg, 48%) . MS [MH]  + calcd for C16H17BrO3 338, found 338.
Step 2: Synthesis of (3-bromo-4, 5-dimethoxyphenyl) (p-tolyl) methanone (3)
A solution of (3-bromo-4, 5-dimethoxyphenyl) (p-tolyl) methanone (650 mg, 1.9 mmol) and Dess-Martin (1.6 g, 3.8 mmol) in DCM (20 mL) was stirred at room temperature for overnight. NaHCO 3 (15 mL) was added. The mixture was extracted by ethyl acetate (30 mL X 3) and dried by Na 2SO 4. The mixture was filtered and concentrated in vacuum to afford the crude product as a yellow solid (420 mg, 65%) . MS [MH]  + calcd for C16H15BrO3 336, found 336.
Step 3: Synthesis of 2, 3-dimethoxy-5- (4-methylbenzoyl) benzonitrile (4)
A solution of 2, 3-dimethoxy-5- (4-methylbenzoyl) benzonitrile (300 mg, 0.90 mmol) in DMF (5 mL) was added CuCN (160 mg, 1.8 mmol) at rt. After the addition was completed, the reaction mixture was refluxed for overnight. The mixture was re-cooled to rt, and quenched by water (10 mL) . The mixture was extracted by ethyl acetate (20 mL X 3) and dried by Na 2SO 4, then filtered and concentrated in vacuum to afford the crude product (230 mg, 91%) . MS [MH]  + calcd for C17H15NO3 282, found 282.
Step 4: Synthesis of 2, 3-dihydroxy-5- (4-methylbenzoyl) benzonitrile (RPX-TOL-3)
A solution of 2, 3-dihydroxy-5- (4-methylbenzoyl) benzonitrile (230 mg, 0.82 mmol) in DCM (5 mL) was added BBr 3 (0.5 mL) at -5 ℃. After the addition was completed, the reaction mixture was sealed in a tube at room temperature for overnight. The mixture was re-cooled to -5 ℃ and quenched by water (10 mL) . The remained DCM was removed, the residue was  diluted by H 2O (5 mL) with stirred at room temperature for 30 min. The mixture was extracted by ethyl acetate (15 mL X 3) and dried by Na 2SO 4, then filtered and concentrated in vacuum to afford the crude product. Further purification by Prep-HPLC (0.05%TFA; ACN-H 2O) afford the desired product (22 mg, 11%) .  1H NMR (400 MHz, DMSO) δ 10.94 (s, 2H) , 7.61 (d, J = 8 Hz, 2H) , 7.46 (s, 1H) , 7.37 (d, J = 7.6 Hz, 3H) , 2.41 (s, 3H) . MS [MH]  -calcd for C15H11NO3 251.9, found 251.9.
Compound RPX-TOL-4: RPX-TOL-4 was prepared in three synthetic steps from 3-bromo-4, 5-dimethoxybenzaldehyde, according to the following procedure:
Figure PCTCN2018124186-appb-000008
Step 1: Synthesis of (3-bromo-4, 5-dimethoxyphenyl) (p-tolyl) methanol (2)
3-bromo-4, 5-dimethoxybenzaldehyde (1 g, 4mmol) in THF (10 mL) was added to a solution of p-tolylmagnesium bromide (1.6 g, 8 mmol) in THF (15 mL) under nitrogen atmosphere. After the addition was completed, the mixture was stirred at toom temperature for overnight. Water (15 mL) was added. The mixture was extracted by ethyl acetate (30 mL X 3) and dried by Na 2SO 4. Further purification by column chromatography (silica gel, PE /EA = 1/1) afforded the desired product as a yellow solid (650 mg, 48%) . MS [MH]  + calcd for C16H17BrO3 338, found 338.
Step 2: Synthesis of (3-bromo-4, 5-dimethoxyphenyl) (p-tolyl) methanone (3)
A solution of (3-bromo-4, 5-dimethoxyphenyl) (p-tolyl) methanone (650 mg, 1.9 mmol) and Dess-Martin (1.6 g, 3.8 mmol) in DCM (20 mL) was stirred at room temperature for overnight. NaHCO 3 (15 mL) was added. The mixture was extracted by ethyl acetate (30 mL X 3) and dried by Na 2SO 4. The mixture was filtered and concentrated in vacuum to afford the crude product as a yellow solid (420 mg, 65%) . MS [MH]  + calcd for C16H15BrO3 336, found 336.
Step 3: Synthesis of (3-bromo-4, 5-dihydroxyphenyl) (p-tolyl) methanone (RPX-TOL-4)
A solution of (3-bromo-4, 5-dimethoxyphenyl) (p-tolyl) methanone (120 mg, 0.36 mmol) in DCM (10 mL) was added BBr 3 (0.2 mL) at -5 ℃. After the addition was completed, the reaction mixture was sealed in a tube at room temperature for overnight. The mixture was re-cooled to -5 ℃ and quenched by water (5 mL) . The remained DCM was removed, the residue was diluted by H 2O (5 mL) with stirred at room temperature for 30 min. The mixture was  extracted by ethyl acetate (15 mL X 3) and dried by Na 2SO 4, then filtered and concentrated in vacuum to afford the crude product. Further purification by Prep-HPLC (0.05%TFA; ACN-H 2O) afford the desired product (6 mg, 5%) .  1H NMR (400 MHz, DMSO) δ 10.27 (s, 1H) , 7.58 (d, J = 8 Hz, 2H) , 7.37 (d, J = 7.9 Hz, 2H) , 7.31 (d, J = 1.8 Hz, 1H) , 7.23 (d, J = 1.8 Hz, 1H) , 2.41 (s, 3H) . MS [MH]  + calcd for C14H11BrO3 306.7, found 306.
Compound RPX-TOL-5: RPX-TOL-5 was prepared in two synthetic steps from 3, 4-dimethoxy-5-nitrobenzoic acid, according to the following procedure:
Figure PCTCN2018124186-appb-000009
Step 1: Synthesis of azetidin-1-yl (3, 4-dimethoxy-5-nitrophenyl) methanone (2)
To a solution of 3, 4-dimethoxy-5-nitrobenzoic acid (500 mg, 2.20 mmol) , azetidine (126 mg, 2.20 mmol) , HATU (836 mg, 2.20 mmol) , DIPEA (568 mg, 4.40 mmol) in DCM was stirred at room temperature for 2 h. Then extracted by DCM, and dried by Na 2SO 4. Further purification by column chromatography (silica gel, PE /EA = 1/1) afforded the desired product as yellow solid (150 mg, 26%) . MS [MH]  + calcd for C 12H 14N 2O 5 266.0, found 267.1.
Step 2: Synthesis of azetidin-1-yl (3, 4-dihydroxy-5-nitrophenyl) methanone (RPX-TOL-5)
A solution of azetidin-1-yl (3, 4-dimethoxy-5-nitrophenyl) methanone (150 mg, 0.56 mmol) in DCM (5 mL) was added BBr 3 (1 mL) at -5 ℃. After the addition was completed, the reaction mixture was sealed in a tube at room temperature for overnight. The mixture was re-cooled to -5 ℃ and quenched by water (10 mL) . The remained DCM was removed, the residue was diluted by H 2O (50 mL) with stirred at room temperature for 30 min. The solid was formed, then filtered and dried in vacuum to afford the crude product. Further purification by Prep-HPLC (0.5%TFA; MeCN-H 2O) afford the desired product (32 mg, 20%) .  1H NMR (400 MHz, DMSO) δ 10.62 (s, 1H) , 7.56 (s, 1H) , 7.35 (s, 1H) , 4.34 (s, 2H) , 4.03 (s, 2H) , 2.35 –2.15 (m, 2H) . MS [MH]  + calcd for C 10H 10N 2O 5 238.2, found 238.9.
Compound RPX-TOL-6: RPX-TOL-6 was prepared in two synthetic steps from 3, 4-dimethoxy-5-nitrobenzoic acid, according to the following procedure:
Figure PCTCN2018124186-appb-000010
Step 1: Synthesis of (3, 4-dimethoxy-5-nitrophenyl) (pyrrolidin-1-yl) methanone (2)
To a solution of 3, 4-dimethoxy-5-nitrobenzoic acid (300 mg, 1.32 mmol) , pyrrolidine (94 mg, 1.32 mmol) , HATU (502 mg, 1.32 mmol) , DIPEA (341 mg, 2.64 mmol) in DCM was stirred at room temperature for 2 h. Then extracted by DCM, and dried by Na 2SO 4. Further purification  by column chromatography (silica gel, PE /EA = 1/1) afforded the desired product as yellow solid (200 mg, 54%) . MS [MH]  + calcd for C 13H 16N 2O 5 280.2, found 281.4.
Step2: Synthesis of (3, 4-dihydroxy-5-nitrophenyl) (pyrrolidin-1-yl) methanone (RPX-TOL-6)
A solution of (3, 4-dimethoxy-5-nitrophenyl) (pyrrolidin-1-yl) methanone (200 mg, 0.71 mmol) in DCM (5 mL) was added BBr 3 (1 mL) at -5 ℃. After the addition was completed, the reaction mixture was sealed in a tube at room temperature for overnight. The mixture was re-cooled to -5 ℃ and quenched by water (10 mL) . The remained DCM was removed, the residue was diluted by H 2O (50 mL) with stirred at room temperature for 30 min. The solid was formed, then filtered and dried in vacuum to afford the crude product. Further purification by Prep-HPLC (0.5%TFA; MeCN-H 2O) afford the desired product (30 mg, 17%) . 1H NMR (400 MHz, DMSO) δ 10.52 (s, 1H) , 7.50 (s, 1H) , 7.24 (s, 1H) , 3.44 (s, 4H) , 1.83 (s, 4H) . MS [MH]  + calcd for C 11H 12N 2O 5 252.2, found 252.9.
Compound RPX-TOL-7: RPX-TOL-7 was prepared in three synthetic steps methyl 3, 4-dimethoxy-5-nitrobenzoate, according to the following procedure:
Figure PCTCN2018124186-appb-000011
Step 1: Synthesis of 3, 4-dimethoxy-5-nitrobenzoic acid (2)
To a solution of methyl 3, 4-dimethoxy-5-nitrobenzoate (5.0 g, 20.75 mmol) and NaOH (1.66 g, 41.5 mmol) in H 2O/MeOH (V=20 mL: 8 mL) was stirred at room temperature for 3 h. Then MeOH was evaporated, and the mixture was acidified with c-HCl to pH = 2, filtered, washed with H 2O, and dried in vacuum to get product as a white solid (4.2 g, 89%) . MS [MH]  -calcd for C 9H 9NO 6 227.1, found 226.2.
Step 2: Synthesis of (3, 4-dimethoxy-5-nitrophenyl) (piperidin-1-yl) methanone (3)
To a solution of 3, 4-dimethoxy-5-nitrobenzoic acid (200 mg, 0.88 mmol) , piperidine (75 mg, 0.88 mmol) , HATU (334 mg, 0.88 mmol) , DIPEA (227 mg, 1.76 mmol) in DCM was stirred at room temperature for 2 h. Then extracted by DCM, and dried by Na 2SO 4. Further purification by column chromatography (silica gel, PE /EA = 1/1) afforded the desired product as yellow solid (100 mg, 39%) . MS [MH]  + calcd for C 14H 18N 2O 5 294.3, found 295.4.
Step 3: Synthesis of (3, 4-dihydroxy-5-nitrophenyl) (piperidin-1-yl) methanone (RPX-TOL-7)
A solution of (3, 4-dimethoxy-5-nitrophenyl) (piperidin-1-yl) methanone (100 mg, 0.34  mmol) in DCM (5 mL) was added BBr 3 (1 mL) at -5 ℃. After the addition was completed, the reaction mixture was sealed in a tube at room temperature for overnight. The mixture was re-cooled to -5 ℃ and quenched by water (10 mL) . The remained DCM was removed, the residue was diluted by H 2O (50 mL) with stirred at room temperature for 30 min. The solid was formed, then filtered and dried in vacuum to afford the crude product. Further purification by Prep-HPLC (0.5%TFA; MeCN-H 2O) afford the desired product as a yellow solid (30 mg, 33%) .  1H NMR (400 MHz, DMSO) δ 10.50 (s, 1H) , 7.33 (s, 1H) , 7.06 (s, 1H) , 3.44 (s, 2H) , 3.33 (s, 2H) 1.61 (d, J = 4.0 Hz, 2H) , 1.51 (s, 4H) . MS [MH]  -calcd for C 12H 14N 2O 5 266.2, found 264.9.
Compound RPX-TOL-8: RPX-TOL-8 was prepared in four synthetic steps from 4-hydroxy-3-methoxy-5- (trifluoromethyl) benzaldehyde, according to the following procedure:
Figure PCTCN2018124186-appb-000012
Step 1: Synthesis of 3, 4-dimethoxy-5- (trifluoromethyl) benzaldehyde (2)
A solution of 4-hydroxy-3-methoxy-5- (trifluoromethyl) benzaldehyde (1.0 g, 4.55 mmol) , Dimethyl sulfate (1.4g, 11.38mmol) and K 2CO 3 (1.3g, 9.1 mmol) in acetone (30 mL) was stirred at 56℃ for 3 h. After the mixture was cooled down, added ice water (50 mL) , filtered, washed by H 2O and dried in vacuum to afford the product as a yellow solid (380 mg, 36%) . MS [MH]  + calcd for C 10H 9F 3O 3 234.1, found 235.6.
Step 2: Synthesis of (3, 4-dimethoxy-5- (trifluoromethyl) phenyl) (4- (trifluoromethyl) phenyl) methanol (4)
To a solution of 1-bromo-4- (trifluoromethyl) benzene (1.0 g, 4.44 mmol) and Mg powder (160 mg, 6.66 mmol) in anhydrous THF (15 mL) was added I 2 (11 mg, 0.04 mmol) under nitrogen atmosphere, then the reaction mixture was heated to 40℃ until the Mg powder was disappeared. 3, 4-dimethoxy-5- (trifluoromethyl) benzaldehyde (380 mg, 1.62 mmol) in THF (3 mL) was added dropwise. After the addition was completed, the mixture was stirred at room temperature for overnight. Water (5 mL) was added. The mixture was extracted by ethyl  acetate (25 mL X 2) and dried by Na 2SO 4. Further purification by column chromatography (silica gel, EA) afforded the desired product as a yellow solid (210 mg, 34%) . MS [MH]  + calcd for C 17H 14F 6O 3 380.2, found 381.5.
Step 3: Synthesis of (3, 4-dimethoxy-5- (trifluoromethyl) phenyl) (4- (trifluoromethyl) phenyl) methanone (5)
A solution of (3, 4-dimethoxy-5- (trifluoromethyl) phenyl) (4- (trifluoromethyl) phenyl) methanol (210 mg, 0.55 mmol) and Dess-Martin (469 mg, 1.11 mmol) in DCM (25 mL) was stirred at room temperature for 2 h. The mixture was filtered and concentrated in vacuum to afford the crude product as a yellow solid (175 mg, 84%) . MS [MH]  + calcd for C 17H 12F 6O 3 378.2, found 379.1.
Step 4: Synthesis of (3, 4-dihydroxy-5- (trifluoromethyl) phenyl) (4- (trifluoromethyl) phenyl) methanone (RPX-TOL-8)
A solution of (3, 4-dimethoxy-5- (trifluoromethyl) phenyl) (4- (trifluoromethyl) phenyl) methanone (175 mg, 0.46 mmol) in DCM (5 mL) was added BBr 3 (1 mL) at -5℃. After the addition was completed, the reaction mixture was sealed in a tube at room temperature for overnight. The mixture was re-cooled to -5 ℃ and quenched by water (10 mL) . The remained DCM was removed, the residue was diluted by H 2O (50 mL) with stirred at room temperature for 30 min. The solid was formed, then filtered and dried in vacuum to afford the crude product. Further purification by Prep-HPLC (0.5%TFA; MeCN-H 2O) afforded the desired product (100mg, 62%) .  1H NMR (400 MHz, DMSO) δ 10.73 (s, 2H) , 7.95 (d, J = 4.0 Hz, 2H) , 7.89 (d, J = 4.0 Hz, 2H) , 7.48 (s, 1H) , 7.39 (s, 1H) . MS [MH]  + calcd for C 15H 8F 6O 3 350.2, found 350.7.
The following compounds were prepared in a similar procedure:
Figure PCTCN2018124186-appb-000013
Figure PCTCN2018124186-appb-000014
Figure PCTCN2018124186-appb-000015
Compound RPX-TOL-32: RPX-TOL-32 was prepared in three synthetic steps from 2-cyanoacetic acid, according to the following procedure:
Figure PCTCN2018124186-appb-000016
Step 1. Synthesis of tert-butyl 4- (2-cyanoacetyl) piperazine-1-carboxylate (2)
To a mixture of 2-cyanoacetic acid (417 mg, 4.90 mmol, ) and tert-butyl piperazine-1-carboxylate (1.0 g, 5.37 mmol) in dichloromethane (20 mL) was added HATU (2.23 g, 5.86 mmol) . The resulting mixture was stirred for 16 h at room temperature. The resulting mixture was concentrated under reduced pressure and the residue was purified by reversed phase chromatography with a C18 column, eluted with 30%～50%acetonitrile in water (plus 5 mM AcOH) to give tert-butyl 4- (2-cyanoacetyl) piperazine-1-carboxylate (0.6 g, 48%) as colorless oil: MS [M-H]  -calcd for C12H19N3O3 253.30, found 252.10.
Step 2. Synthesis of (Z) -tert-butyl 4- (2-cyano-3- (3, 4-dimethoxy-5-nitrophenyl) -3-hydroxyacryloyl) piperazine-1-carboxylate (3)
A solution of tert-butyl 4- (2-cyanoacetyl) piperazine-1-carboxylate (600 mg, 2.36 mmol) in tetrahydrofuran (10 mL) was treated with sodium hydride (97 mg, 2.42 mmol, 60%v/v dispersed into mineral oil) at 0 ℃ for 30 min, followed by the addition of a solution of 3, 4-dimethoxy-5-nitrobenzoyl chloride (492 mg, 2.00 mmol) in tetrahydrofuran (4 mL) . The resulting solution was stirred for 1 h at room temperature, then quenched by the addition of ice water (5 mL) . The pH value of the solution was adjusted to 6.0 with acetic acid. The resulting solution was extracted with of ethyl acetate (3 x 30 mL) . The combined organic layers was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and the residue was purified by a silica gel column chromatography, eluted with 5%methanol in dichloromethane to give of (Z) -tert-butyl 4- (2-cyano-3- (3, 4-dimethoxy-5-nitrophenyl) -3-hydroxyacryloyl) piperazine-1-carboxylate (0.2 g, 22%) as brown solid: MS [M-H]  -calcd for C21H26N4O8 462.45, found 461.30;  1HNMR (300 MHz, CDCl 3, ppm) : δ 7.93 (d, J = 2.1 Hz, 1H) , 7.67 (d, J = 2.1 Hz, 1H) , 4.04 (s, 3H) , 3.97 (s, 3H) , 3.81 (q, J = 3.9, 2.7 Hz, 4H) , 3.61 –3.51 (m, 4H) , 1.46 (s, 9H) .
Step 3. Synthesis of (2Z) -3- (3, 4-dimethoxy-5-nitrophenyl) -3-hydroxy-2- [ (Z) - (piperazin-1-yl) carbonyl] prop-2-enenitrile (RPX-TOL-32)
A solution of tert-butyl 4- [ (2Z) -2-cyano-2- [ (3, 4-dimethoxy-5-nitrophenyl) (hydroxy) methylidene] acetyl] piperazine-1-carboxylate (300 mg, 0.65 mmol) in dichloromethane (5 mL) was treated with tribromoborane (15 mL, 1.0 M in dichloromethane) for 16 h at room temperature. The reaction was then quenched by ice water (10 mL) . The resulting solution was extracted with ethyl acetate (3 x 30 mL) . The combined organic layer was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and the residue was purified by Prep-HPLC with the following conditions: column: XBridge C18 OBD Prep column
Figure PCTCN2018124186-appb-000017
10 μm, 19 mm x 250 mm; Mobile Phase A: water (plus 0.05%TFA ) , Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 20%B to 70%B in 13 min; Detector: 254/210 nm; RT: 6.99 min to give (2Z) -3- (3, 4-dimethoxy-5-nitrophenyl) -3-hydroxy-2- [ (Z) - (piperazin-1-yl) carbonyl] prop-2-enenitrile (15 mg, 6%) as a yellow solid: MS [M-H]  -calcd for C14H14N4O6 334.28, found 333.10; HNMR (400 MHz, DMSO-d 6, ppm) : δ 7.53 (s, 1H) , 7.27 –7.21 (m, 1H) , 3.50 (t, J = 5.0 Hz, 4H) , 3.05 (s, 4H) .
Compound RPX-TOL-33: RPX-TOL-33 was prepared in three synthetic steps from 2-cyanoacetic acid, according to the following procedure:
Figure PCTCN2018124186-appb-000018
Step 1. Synthesis of tert-butyl 3- (2-cyanoacetamido) azetidine-1-carboxylate (2)
To a mixture of 2-cyanoacetic acid (1.0 g, 11.76 mmol) and tert-butyl 3-aminoazetidine-1-carboxylate (1.01 g, 5.88 mmol) in dichloromethane (40 mL) was added HATU (4.47 g, 11.76 mmol) . The resulting mixture was stirred for 16 h at room temperature. The resulting mixture was concentrated under reduced pressure and the residue was purified by reversed phase chromatography with a C18 column, eluted with 30%～50%acetonitrile in water (plus 5 mM AcOH) to give tert-butyl 3- (2-cyanoacetamido) azetidine-1-carboxylate  (0.85g, 60%) as a colorless solid: MS [M+H]  + calcd for C11H17N3O3 239.27, found 240.10; HNMR (300 MHz, CDCl 3, ppm) : δ 6.81 (s, 1H) , 4.69 –4.53 (m, 1H) , 4.33 –4.21 (m, 2H) , 3.86 –3.75 (m, 2H) , 3.40 (s, 2H) , 1.45 (s, 9H) .
Step 2. Synthesis of (Z) -tert-butyl 3- (2-cyano-3- (3, 4-dimethoxy-5-nitrophenyl) -3-hydroxyacrylamido) azetidine-1-carboxylate (3)
A solution of tert-butyl 3- (2-cyanoacetamido) azetidine-1-carboxylate (1.12 g, 4.68 mmol) in tetrahydrofuran (10 mL) . was treated with sodium hydride (188 mg, 4.68 mmol, 60%w/w dispersed into mineral oil) at 0 ℃ for 30 min. This was followed by addition of a solution of 3, 4-dimethoxy-5-nitrobenzoyl chloride (575 mg, 2.34 mmol) in tetrahydrofuran (4 mL) at 0 ℃. The resulting solution was stirred for 1 h at room temperature, then quenched by ice water (5 mL) . The pH value of the solution was adjusted to 6.0 with acetic acid. The resulting solution was extracted with of ethyl acetate (3 x 30 mL) and the combined organic layers was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluted with 5%methanol in dichloromethane to give of (Z) -tert-butyl 3- (2-cyano-3- (3, 4-dimethoxy-5-nitrophenyl) -3-hydroxyacrylamido) azetidine-1-carboxylate (0.55 g, 52%) as an orange solid: MS [M-H]  -calcd for C20H24N4O8 448.43, found 447.30. HNMR (300 MHz, CDCl 3, ppm) : δ 7.98 (d, J = 2.2 Hz, 1H) , 7.75 (d, J = 2.2 Hz, 1H) , 6.68 (d, J = 6.9 Hz, 1H) , 4.78 –4.62 (m, 1H) , 4.39 –4.27 (m, 2H) , 4.14 (s, 3H) , 3.98 (s, 3H) , 3.93 (dd, J = 9.6, 5.2 Hz, 2H) , 1.46 (s, 9H) .
Step 3. Synthesis of (Z) -tert-butyl 3- (2-cyano-3- (3, 4-dihydroxy-5-nitrophenyl) -3-hydroxyacrylamido) azetidine-1-carboxylate (RPX-TOL-33)
A solution of (Z) -tert-butyl 3- (2-cyano-3- (3, 4-dimethoxy-5-nitrophenyl) -3-hydroxyacrylamido) azetidine-1-carboxylate (550 mg, 1.23 mmol) in dichloromethane (5 mL) was treated with BBr 3 (20 mL, 1.0 M in dichloromethane) for 16 h at room temperature. The reaction was poured into ice water (10 mL) and extracted with ethyl acetate (3 x 30 mL) . The combined organic layers was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and the residue was purified by Prep-HPLC with the following conditions: column: XBridge C18 OBD Prep column
Figure PCTCN2018124186-appb-000019
10 μm, 19 mm x 250 mm;Mobile Phase A: water (plus 0.1%FA) , Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 5%B to 25%B in 8 min; Detector: 254/210 nm; RT: 7.23 min to give (Z) -tert-butyl 3- (2-cyano-3- (3, 4-dihydroxy-5-nitrophenyl) -3-hydroxyacrylamido) azetidine-1-carboxylate (39.7 mg, 10%) as a yellow solid: MS [M-H]  -calcd for C13H12N4O6 320.26, found 319.20;  1HNMR (400 MHz, DMSO-d 6, ppm) : δ 7.85 (s, 1H) , 7.45 (s, 1H) , 4.90-4.80 (m, 1H) , 4.56-4.50 (m, 2H) , 3.19-3.17 (m, 2H) .
Compound RPX-TOL-34: RPX-TOL-34 was prepared in three synthetic steps from tert-butyl azetidin-3-ylcarbamate, according to the following procedure:
Figure PCTCN2018124186-appb-000020
Step 1. Synthesis of tert-butyl N- [1- (2-cyanoacetyl) azetidin-3-yl] carbamate (2)
To a sealed tube was placed a mixture of tert-butyl azetidin-3-ylcarbamate (800 mg, 3.84 mmol) and DIPEA (992 mg, 7.69 mmol) in 3-oxopentanenitrile (15 mL) . The resulting mixture was irradiated at 150 ℃ for 3 h by a microwave. The resulting solution was cooled down to ambient temperature and concentrated under reduced pressure. The residue was purified by reversed phase chromatography with a C18 column, eluted with 30%～50%acetonitrile in water (plus 5 mM AcOH) to give tert-butyl N- [1- (2-cyanoacetyl) azetidin-3-yl] carbamate (800 mg, 72%) as a colorless solid: MS [M-H]  -calcd for C11H17N3O3 239, found 238.1; 1H NMR (400 MHz, Methanol-d 4, ppm) : δ 4.45 –4.40 (m, 2H) , 4.30 –4.20 (m, 1H) , 4.10 –4.06 (m, 1H) , 3.88 –3.85 (m, 1H) , 3.33 (s, 2H) , 1.44 (s, 9H) .
Step 2. Synthesis of (Z) -tert-butyl 1- (2-cyano-3- (3, 4-dimethoxy-5-nitrophenyl) -3-hydroxyacryloyl) azetidin-3-ylcarbamate (3)
A solution of tert-butyl N- [1- (2-cyanoacetyl) azetidin-3-yl] carbamate (450 mg, 1.88 mmol) in tetrahydrofuran (15 mL) was treated with sodium hydride (75 mg, 3.12 mmol, 60%w/w dispersed into mineral oil) at 0 ℃ for 30 min followed by the addition of 3, 4-dimethoxy-5-nitrobenzoyl chloride (486 mg, 1.88 mmol, in 4 mL THF) . The resulting mixture was stirred for another 2 hours at ambient temperature. The reaction was quenched by water (10 mL) and adjusts the pH value to 6 with acetic acid, then exacted with ethyl acetate (3 x 40 mL) . The combined organic layers was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and the residue was purified by reversed phase  chromatography with C18 column, eluted with 30%～50%acetonitrile in water (plus 5 mM AcOH) to give (Z) -tert-butyl 1- (2-cyano-3- (3, 4-dimethoxy-5-nitrophenyl) -3-hydroxyacryloyl) azetidin-3-ylcarbamate (300 mg, 71%) as yellow oil: MS [M-H]  -calcd for C20H24N4O8 448.4, found 447.3; 1H NMR (400 MHz, CDCl 3, ppm) : δ 7.93 (d, J = 2.1 Hz, 1H) , 7.71 (d, J = 2.1 Hz, 1H) , 4.98 (s, 2H) , 4.53 (s, 3H) , 4.05 (s, 3H) , 3.98 (s, 3H) , 1.46 (s, 9H) .
Step 3. Synthesis of Z) -2- (3-aminoazetidine-1-carbonyl) -3- (3, 4-dihydroxy-5-nitrophenyl) -3-hydroxyacrylonitrile trifluoroacetic acid salt (RPX-TOL-34)
A solution of tert-butyl N- [1- [ (2Z) -2-cyano-2- [ (3, 4-dimethoxy-5-nitrophenyl) (hydroxy) methylidene] acetyl] azetidin-3-yl] carbamate (260 mg, 0.58 mmol) in dichloromethane (1 mL) was treated with BBr 3 (10 mL, 1M in dichloromethane) for 16 h at ambient temperature. The resulting mixture was poured into ice water (10 mL) and exacted with ethyl acetate (4 x 30 mL) . The combined organic layers was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and the residue was purified with following conditions: column: XSelect CSH Prep C18 OBD column, 19 x 250 mm, 5 um; Mobile Phase A: water (plus 0.05%TFA) ; Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 13%B to 30%B in 9 min; Detector: 254/210 nm; RT: 7.15 min to give (Z) -2- (3-aminoazetidine-1-carbonyl) -3- (3, 4-dihydroxy-5-nitrophenyl) -3-hydroxyacrylonitrile trifluoroacetic acid salt (11.8 mg, 6%) as an off-white solid: MS [M-H]  -calcd for C13H12N4O6 320.2, found 319.2;  1H NMR (300 MHz, DMSO-d 6, ppm) : δ 8.90-7.90 (m, 4H) , 7.18 (d, J = 2.4 Hz, 1H) , 4.37-4.23 (s, 2H) , 4.10-3.88 (m, 3H) ; FNMR (282 MHz, DMSO-d 6, ppm) : δ -73.434.
FTO inhibition Assay (Enzymatic Inhibition) . The inhibition activity of the compounds disclosed herein in a demethylation reaction catalyzed by FTO (US2014/0148383A1) was measured. FTO-catalyzed demethylation activity was measured in a 100 μl reaction system containing 50 mM HEPES buffer (pH 7.5) , 100 μM a-KG, 100 μM (NH4) 2Fe (SO4) 2, 0.5 mM L-ascorbic acid, 50 μg/ml BSA, 0.5 μM ssDNA with m6A (5’-ATTGTCA (m6A) CAGCAGA-3’) , 0.1 μM FTO protein. The reaction system was incubated at 37℃ for 2h and was stopped by heating to 95℃ for 5 min. ssDNA was digested by nuclease P1 (Sigma) and alkaline phosphatase (Takara) . The concentrations of m6A and free A were analyzed by LC-MS/MS. the measured IC 50 value of entacapone against FTO is ～ 3 μM. The compounds in the following table 1 were consistently active, with IC 50’s less than 10 μM.
COMT Inhibition Assay. The inhibition of the compounds against COMT was measured in reaction kinetic model. The test compound was diluted with assay buffer to desired concentration. The COMT enzyme was also diluted with assay buffer. Then 5 μL diluted test article, 5 μL diluted COMT and 5 μL Esculetin were added into plate and  incubated for 5 min at 37℃, sealed with TopSeal-A384, Clear Adhesive (PE) . Then 5 μL AdoMet was added into the plate. The reaction system contains 1U COMT enzyme, test compound, 4 μM Esculetin, 0.6 mM AdoMet, 50 mM K 3PO 4, and 10 mM MgCl 2. Read plate by using kinetics model (Excitation at 360 nm &emission at 460 nm) . The inhibition was calculated from the slope.
Table 1: Exemplary IC50 Data of representative compounds against FTO and COMT
Figure PCTCN2018124186-appb-000021
Figure PCTCN2018124186-appb-000022
ND: not determined.
As shown in the above table 1, the compounds disclosed herein showed better efficacy in inhibiting FTO. In particular, the compounds disclosed herein wherein R 5 is -NR 9R 10, R 9 and R 10 together with the nitrogen atom to which they are attached form a ring showed better dual inhibition against FTO and COMT as compared with tolcapone.
It is interesting to note that Compounds RPX-TOL-32, RPX-TOL-33 and RPX-TOL-34 showed better activity against COMT, but not FTO as shown in below Table 2.
Table 2: Compounds inhibiting COMT but not FTO
Figure PCTCN2018124186-appb-000023
It is understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be included within the spirit and purview of this application and scope of the appended claims. All publications, patents, and patent applications cited herein, including citations therein, are hereby incorporated by reference in their entirety for all purposes.

Claims (27)

  1. A compound of Formula I
    Figure PCTCN2018124186-appb-100001
    or a stereoisomer thereof, a hydride thereof, or a prodrug thereof, or a pharmaceutically-acceptable salt thereof, wherein:
    R 1 and R 2 are each independently H or -C 1-4alkyl;
    R 3 is an electron withdrawn group selected from the group consisting of -NO 2, -CN, -CF 3, -OCF 3, -C (=O) CF 3, -SO 2CF 3, -SO 2CF 2, -COOR, and halogen;
    R 4 is a linking group selected from the group consisting of a direct bond, - (CR 7R 8)  n-, -O-, -NR 7-, -S-, wherein R 7 and R 8 are each independently hydrogen, C 1-4alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, and wherein n is an integer of 1 to 10;
    R 5 is hydrogen, R 9, -OR 9, or -NR 9R 10, wherein R 9 and R 10 are each independently are -C 1- 6alkyl, -C 2-6alkenyl, -C 2-6alkynyl, cycloalkyl, C-linked heterocyclyl, aryl, or C-linked heteroaryl, wherein said -C 1-6alkyl, -C 2-6alkenyl, -C 2-6alkynyl, cycloalkyl, C-linked heterocyclyl, aryl or C-linked heteroaryl are each independently optionally substituted with at least one substituent R 11, wherein, optionally, two adjacent substituents R 11, together with the atoms to which they are attached, may form a 3-to 12-membered saturated, partially or fully unsaturated ring comprising 0, 1 or 2 additional heteroatoms independently selected from -NH, -O-, -S-, -SO-or -SO 2-;
    Alternatively, R 9 and R 10 together with the nitrogen atom to which they are attached, form a 3-to 12-membered saturated, partially or fully unsaturated ring comprising 0, 1 or 2 additional heteroatoms independently selected from -NH, -O-, -S-, -SO-or -SO 2-, and said ring is optionally substituted with at least one substituent R 12;
    R 11 and R 12, which may be the same or different, are each independently hydrogen, halogen, -C 1-6alkyl, -C 2-6alkenyl, -C 2-6alkynyl, haloC 1-6alkyl, haloC 2-6alkenyl, haloC 2-6alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -CN, -NO 2, oxo, -OR 13, -SO 2R 13, -COR 13, -CO 2R 13, -CONR 13R 14, -C (=NR 13) NR 14R 15, -NR 13R 14, -NR 13COR 14, -NR 13CONR 14R 15, -NR 13CO 2R 14, -NR 13SONR 14R 15, -NR 13SO 2NR 14R 15, or -NR 13SO 2R 14;
    wherein R 13, R 14 and R 15 are each independently hydrogen, -C 1-6alkyl, -C 2-6alkenyl, -C 2- 6alkynyl, haloC 1-6alkyl, haloC 2-6alkenyl, haloC 2-6alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl;
    provided that the compound is not (3, 4-dihydroxy-5-nitrophenyl) (p-tolyl) methanone, (3, 4-dihydroxy-5-nitrophenyl) (pyridin-2-yl) methanone, (3, 4-dihydroxy-5-nitrophenyl) (4- (trifluoromethyl) phenyl) methanone, or 1- (3, 4-dihydroxy-5-nitrophenyl) -2-phenylethanone.
  2. The compound of claim 1, wherein R 1 and R 2 are both hydrogen.
  3. The compound of claim 1, wherein R 3 is -NO 2, -CN, -CF 3, or halogen.
  4. The compound of claim 1, wherein R 4 is a direct bond or - (CR 7R 8)  n-, -O-, -NR 7-, -S-, wherein R 7 and R 8 are each independently hydrogen, C 1-4alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, and wherein n is an integer of 1 to 10.
  5. The compound of claim 1, wherein R 4 is -CH 2-.
  6. The compound of any one of claims 1-5, wherein R 5 is cycloalkyl, C-linked heterocyclyl, aryl, or C-linked heteroaryl, each of which is optionally substituted with at least one substituent R 11.
  7. The compound of claim 6, wherein R 5 is
    a. a cycloalkyl group selected from a monocyclic C 3-12cycloalkyl, a spiro C 5-12bicycloalkyl, a bridged C 7-12bicycloalkyl, and a bridged C 7- 12tricycloalkyl;
    b. a C-linked heterocyclyl group selected from those as defined herein;
    c. an aryl group selected from phenyl and naphthyl;
    d. a C-linked heteroaryl group selected from those as defined herein each of which is optionally substituted with at least one substituent R 11.
  8. The compound of claim 7, wherein R 5 is a monocyclic C 3-8cycloalkyl, or a bridged C 7- 12tricycloalkyl, a C-linked heteroaryl group selected from pyridinyl and pyrimidinyl, or a phenyl group, each of which is optionally substituted with at least one substituent R 11.
  9. The compound of any one of claims 6-8, wherein R 11 is selected from hydrogen, halogen, -C 1-6alkyl, haloC 1-6alkyl, -NO 2, oxo, -OR 13, wherein R 13 is hydrogen or –C 1-4alkyl.
  10. The compound of any one of claims 1-5, wherein R 5 is -NR 9R 10, wherein R 9 and R 10 are as defined for Formula I.
  11. The compound of any one of claims 1-5, wherein R 5 is -NR 9R 10, R 9 and R 10 together with the nitrogen atom to which they are attached, form a 3-to 12-membered saturated, partially or fully unsaturated ring comprising 0, 1 or 2 additional heteroatoms independently selected from -NH, -O-, -S-, -SO-or -SO 2-, and said ring is optionally substituted with at least one substituent R 12.
  12. The compound of any one of claims 1-5, wherein R 5 is -NR 9R 10, R 9 and R 10 together with the nitrogen atom to which they are attached, form a 3-, 4-, 5-, 6-, 7-or 8-membered  saturated ring comprising 0 additional heteroatom, and said ring is optionally substituted with at least one substituent R 12.
  13. The compound of claim 12, wherein R 9 and R 10 together with the nitrogen atom to which they are attached, form a azetidinyl, pyrrolidinyl, piperidinyl, azepanyl, or azocanyl ring; preferably, a azetidinyl, pyrrolidinyl, or piperidinyl ring.
  14. The compound of any one of claims 1-5, wherein R 5 is -NR 9R 10, R 9 and R 10 together with the nitrogen atom to which they are attached, form a 3-, 4-, 5-, 6-, 7-or 8-membered saturated ring comprising 1 or 2 additional heteroatoms independently selected from -NH, -O-, -S-, -SO-or -SO 2-, and said ring is optionally substituted with at least one substituent R 12.
  15. The compound of any one of claims 1-5, wherein R 5 is -NR 9R 10, R 9 and R 10 together with the nitrogen atom to which they are attached, form a spiro azaC 5-12bicycloalkyl ring comprising 0, 1 or 2 additional heteroatoms independently selected from -NH, -O-, -S-, -SO-or -SO 2-, and said ring is optionally substituted with at least one substituent R 12.
  16. The compound of claim 15, wherein R 9 and R 10 together with the nitrogen atom to which they are attached, form a spiro azaC 5-12bicycloalkyl ring comprising 0 additional heteroatom, and said ring is optionally substituted with at least one substituent R 12.
  17. The compound of claim 16, wherein R 9 and R 10 together with the nitrogen atom to which they are attached, form 2-azaspiro [3.3] heptan-2-yl, 3-azabicyclo [3.1.0] hexan-3-yl, 6-azaspiro [3.4] octan-6-yl, or 8-azaspiro [4.5] decan-8-yl ring.
  18. The compound of claim 15, wherein R 9 and R 10 together with the nitrogen atom to which they are attached, form a spiro azaC 5-12bicycloalkyl ring comprising 1 or 2 additional heteroatoms independently selected from -NH, -O-, -S-, -SO-or -SO 2-, and said ring is optionally substituted with at least one substituent R 12.
  19. The compound of claim 18, wherein R 9 and R 10 together with the nitrogen atom to which they are attached, form a 2-oxa-6-azaspiro [3.3] heptan-6-yl, or 2, 6-diazaspiro [3.4] octan-2-yl ring.
  20. The compound of claim 15, wherein R 9 and R 10 together with the nitrogen atom to which they are attached, form a bridged C 7-12bicycloalkyl ring comprising 0, 1 or 2 additional heteroatoms independently selected from -NH, -O-, -S-, -SO-or -SO 2-, and said ring is optionally substituted with at least one substituent R 12.
  21. The compound of any one of claims 11, 12, 14, 15, 16, 18 and 20, wherein R 12 is hydrogen, halogen, -C 1-6alkyl, haloC 1-6alkyl, or -COR 13, wherein R 13 is C 1-6alkyl.
  22. The compound of claim 20, wherein R 9 and R 10 together with the nitrogen atom to  which they are attached, form a bridged C 7-12bicycloalkyl ring comprising 0 additional heteroatom.
  23. The compoupnd of claim 21, wherein R 9 and R 10 together with the nitrogen atom to which they are attached, form a 8-azabicyclo [3.2.1] octan-8-yl, or 2-azabicyclo [3.1.0] hexan-2-yl ring.
  24. The compound of claim 1, selected from:
    Figure PCTCN2018124186-appb-100002
    Figure PCTCN2018124186-appb-100003
  25. A pharmaceutical composition comprising the compound of any one of claims 1-24, or a stereoisomer thereof, a hydride thereof, a prodrug thereof, or a pharmaceutically-acceptable salt thereof and pharmaceutically acceptable excipient, optionally in combination with one or more different medicaments, e.g., for reducing food intake or appetite, inhibiting weight gain, promoting weight loss, reducing blood glucose, reducing serum LDL, cholesterol, LDL-c, or triglycerides, or treating atherosclerosis, or treating obesity or an obesity related disease.
  26. A method for controlling appetite and/or reducing food intake, for reducing weight gain and/or promoting weight loss, for reducing blood glucose, reducing serum LDL, cholesterol, LDL-c, or triglycerides, or for use in preventing or treating obesity or an obesity related disease in a subject, comprising administering to the subject in need thereof a pharmaceutically effective amount of the compound of any one of claims 1-24 or a stereoisomer thereof, a hydride thereof, a prodrug thereof, or a pharmaceutically-acceptable salt thereof, optionally in combination with one or more different medicaments, e.g., for reducing food intake or appetite, inhibiting weight gain, promoting weight loss, reducing blood glucose, reducing serum LDL, cholesterol, LDL-c, or triglycerides, or treating atherosclerosis, and a pharmaceutically acceptable excipient.
  27. The method of claim 26, wherein the obesity related disease is diabetes, hyperglycemia, diabetic nephropathy, hyperlipemia, coronary heart disease, atherosclerosis, hypertension, cardiovascular or cerebrovascular disease, liver, kidney or thyroid diseases.
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