US20120149737A1 - Therapeutic Aryl-Amido-Aryl Compounds and Their Use - Google Patents

Therapeutic Aryl-Amido-Aryl Compounds and Their Use Download PDF

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US20120149737A1
US20120149737A1 US13/391,207 US201013391207A US2012149737A1 US 20120149737 A1 US20120149737 A1 US 20120149737A1 US 201013391207 A US201013391207 A US 201013391207A US 2012149737 A1 US2012149737 A1 US 2012149737A1
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independently
aaa
compound according
acid
methyl
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Jonathan Patrick Thomas Corcoran
Sarkis Barret Kalindjian
Alan David Borthwick
David Reginald Adams
Jane Theresa Brown
David Michel Adrien Taddei
Jason John Shiers
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Kings College London
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Kings College London
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Assigned to KING'S COLLEGE LONDON reassignment KING'S COLLEGE LONDON ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: ADAMS, DAVID REGINALD, KALINDJIAN, SARKIS BARRET, BORTHWICK, ALAN DAVID, CORCORAN, JONATHAN PATRICK THOMAS, BROWN, JANE THERESA, SHIERS, JASON JOHN, SYGNATURE DISCOVERY LIMITED, TADDEI, DAVID MICHEL ADRIEN
Publication of US20120149737A1 publication Critical patent/US20120149737A1/en
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    • C07C235/70—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/84—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • C07C233/64—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C233/67—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
    • C07C233/75—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
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    • C07C235/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C235/56—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
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    • C07C237/28—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton
    • C07C237/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated
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    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
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    • C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
    • C07D237/06—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D237/10—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D237/24—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
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    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated

Definitions

  • the present invention pertains generally to the field of therapeutic compounds, and more specifically to certain aryl-amido-aryl compounds (for convenience, collectively referred to herein as “AAA compounds”), which, inter alia, are (selective) retinoic acid receptor ⁇ (RAR ⁇ ) agonists.
  • AAA compounds aryl-amido-aryl compounds
  • RAR ⁇ retinoic acid receptor ⁇
  • the present invention also pertains to pharmaceutical compositions comprising such compounds, and the use of such compounds and compositions, both in vitro and in vivo, to (selectively) activate RAR ⁇ , and in the treatment of diseases and conditions that are mediated by RAR ⁇ , that are ameliorated by the activation of RAR ⁇ , etc., including cognitive disorders, memory impairment, memory deficit, senile dementia, Alzheimer's disease, early stage Alzheimer's disease, intermediate stage Alzheimer's disease, late stage Alzheimer's disease, cognitive impairment, and mild cognitive impairment.
  • cognitive disorders including cognitive disorders, memory impairment, memory deficit, senile dementia, Alzheimer's disease, early stage Alzheimer's disease, intermediate stage Alzheimer's disease, late stage Alzheimer's disease, cognitive impairment, and mild cognitive impairment.
  • Ranges are often expressed herein as from “about” one particular value, and/or to “about” another particular value. When such a range is expressed, another embodiment includes from the one particular value and/or to the other particular value. Similarly, when values are expressed as approximations, by the use of the antecedent “about,” it will be understood that the particular value forms another embodiment.
  • AD Alzheimer's disease
  • acetylcholinesterase inhibitors e.g., AriceptTM
  • non-competitive NMDA receptor blockers e.g., MemantineTM
  • the inventors have now determined the importance of RAR ⁇ signalling in processing the APP into the non-amyloidic pathway, and a key role of this pathway in modulating neuronal survival.
  • the retinoic acid receptor is a type of nuclear receptor which is activated by both all-trans retinoic acid and 9-cis retinoic acid.
  • RAR ⁇ The retinoic acid receptor
  • RAR ⁇ There are three retinoic acid receptors, known as RAR ⁇ , RAR ⁇ , and RAR ⁇ .
  • RAR retinoic acid receptor
  • AD Alzheimer's disease
  • RARs retinoic acid receptors
  • RXRs retinoid X receptors
  • RA retinoic acid
  • RAREs retinoic acid response elements
  • Vitamin A deficiency in rats leads to A ⁇ deposits in the brain vasculature and a down-regulation of RAR ⁇ in their cortical neurons; the same receptor deficit is found in the cortices in pathology samples of AD (see, e.g., Corcoran et al., 2004).
  • vitamin A deficiency produces spatial learning and memory impairments and this cognitive decline, which is a symptom of AD, can be reversed by normalization of brain retinoid signalling (see, e.g., Fischer et al., 1989; Cocco et al., 2002).
  • mice in aged mice, there is a loss of retinoid signalling in the brain and cognitive decline and this can also be reversed by supplementing their diet with retinoids (see, e.g., Etchamendy et al., 2001). Also, vitamin A deficiency in mice can lead to a loss in hippocampal synaptic plasticity, which can be reversed by the addition of retinoids to the diet (see, e.g., Misner et al., 2001).
  • amyloid precursor protein which gives rise to amyloid ⁇ protein
  • APP amyloid precursor protein
  • RA concentration of RA
  • the APP can be cleaved into A ⁇ 40 and A ⁇ 42 by ⁇ and ⁇ secretases (see, e.g., Selkoe, 2001).
  • APP can be cleaved by ⁇ secretases into a soluble neuroprotective fragment (see, e.g., Annaert and De, 2000).
  • ADAMS Disintegrin-metalloproteinases
  • RA Disintegrin-metalloproteinases
  • AD acetylcholine
  • chAT choline acetyltransferase
  • Ache acetylcholinesterase
  • RA can also increase chAT expression (see, e.g., Cervini et al., 1994; Berrard et al., 1995; Bejanin et al., 1994).
  • RAR ⁇ agonists are likely to be useful in the treatment of AD. They prevent neuronal cell death in the presence of A ⁇ 42; in culture, they up-regulate chAT, down-regulate APP and increase the expression of ADAM10.
  • the inventors' have shown that feeding RAR ⁇ agonists to Tg2576 mice (which overexpresses the Swedish mutation of the human APP leading to amyloid ⁇ deposits and cognitive decline) results in a significant reduction in the levels of both A ⁇ 40 and A ⁇ 42. Studies demonstrating these findings are described in more detail in the Examples below.
  • the substituents R 1 , R 2 , R 3 , R 4 , and R 5 when not hydrogen, are alkyl (e.g., -Et, -iPr, -tBu), cycloalkyl (e.g., cyclohexyl), or together form a ring fused to the parent phenyl ring.
  • alkyl e.g., -Et, -iPr, -tBu
  • cycloalkyl e.g., cyclohexyl
  • Kato et al., 1992 (EP 0 515 684 A1) describes compounds according to the following general formula. These compounds are said to be useful in treating arteriosclerosis, peptic ulcer, cancer, ischemic organ disease, inflammation and pulmonary silicosis.
  • Compound 132 on page 59 has the structure given below.
  • the document includes, as reference example 65 (see column 53 therein), a compound having the structure shown below, without attributing any particular activity to the compound.
  • Coppola et al., 2005 describes compounds said to have activity as inhibitors of 11 ⁇ -HSD1, and suggests that the compounds may “serve as useful tools to study the effect of 11 ⁇ -HSD1 inhibition in animal models of diabetes, dyslipidemia and obesity”.
  • compound 9a has the structure shown below.
  • AAA compounds aryl-amido-aryl compounds
  • compositions e.g., a pharmaceutical composition
  • a composition comprising an AAA compound, as described herein, and a pharmaceutically acceptable carrier or diluent.
  • compositions e.g., a pharmaceutical composition
  • a composition comprising the step of admixing an AAA compound, as described herein, and a pharmaceutically acceptable carrier or diluent.
  • Another aspect of the present invention pertains to a method of activating retinoic acid receptor ⁇ (RAR ⁇ ), in vitro or in vivo, comprising contacting RAR ⁇ with an effective amount of an AAA compound, as described herein.
  • RAR ⁇ retinoic acid receptor ⁇
  • RAR ⁇ retinoic acid receptor ⁇
  • Another aspect of the present invention pertains to a method of selectively activating retinoic acid receptor ⁇ (RAR ⁇ ) (e.g., with respect to RAR ⁇ and/or RAR ⁇ ), in vitro or in vivo, comprising contacting RAR ⁇ with an effective amount of an AAA compound, as described herein.
  • RAR ⁇ retinoic acid receptor ⁇
  • Another aspect of the present invention pertains to a method of activating retinoic acid receptor ⁇ (RAR ⁇ ) in a neuronal cell, in vitro or in vivo, comprising contacting the cell with an effective amount of an AAA compound, as described herein.
  • RAR ⁇ retinoic acid receptor ⁇
  • Another aspect of the present invention pertains to a method of selectively activating retinoic acid receptor ⁇ (RAR ⁇ ) (e.g., with respect to RAR ⁇ and/or RAR ⁇ ) in a neuronal cell, in vitro or in vivo, comprising contacting the cell with an effective amount of an AAA compound, as described herein.
  • RAR ⁇ retinoic acid receptor ⁇
  • Another aspect of the present invention pertains to a method of up-regulating chAT expression in a cortical neuron, comprising contacting the cortical neuron, in vitro or in vivo, with an effective amount of an AAA compound, as described herein.
  • Another aspect of the present invention pertains to a method of down-regulating APP expression in a cortical neuron, comprising contacting the cortical neuron, in vitro or in vivo, with an effective amount of an AAA compound, as described herein.
  • Another aspect of the present invention pertains to a method of up-regulating ADAM10 expression in a cortical neuron, comprising contacting the cortical neuron, in vitro or in vivo, with an effective amount of an AAA compound, as described herein.
  • Another aspect of the present invention pertains to a method of down-regulating A ⁇ 40 and A ⁇ 42 expression in a cortical neuron, comprising contacting the cortical neuron, in vitro or in vivo, with an effective amount of an AAA compound, as described herein.
  • Another aspect of the present invention pertains to a method of up-regulating chAT expression in a cortical neuron in a patient, comprising administering to the patient a therapeutically effective amount of an AAA compound, as described herein.
  • Another aspect of the present invention pertains to a method of down-regulating APP expression in a cortical neuron in a patient, comprising administering to the patient a therapeutically effective amount of an AAA compound, as described herein.
  • Another aspect of the present invention pertains to a method of up-regulating ADAM10 expression in a cortical neuron in a patient, comprising administering to the patient a therapeutically effective amount of an AAA compound, as described herein.
  • Another aspect of the present invention pertains to a method of down-regulating A ⁇ 40 and A ⁇ 42 expression in a cortical neuron in a patient, comprising administering to the patient a therapeutically effective amount of an AAA compound, as described herein.
  • Another aspect of the present invention pertains to a method of preventing, reducing, or slowing cortical neuronal death in a patient, comprising administering to the patient a therapeutically effective amount of an AAA compound, as described herein.
  • Another aspect of the present invention pertains to a method of treatment comprising administering to a subject in need of treatment a therapeutically-effective amount of an AAA compound, as described herein, preferably in the form of a pharmaceutical composition.
  • Another aspect of the present invention pertains to an AAA compound as described herein for use treatment of the human or animal body by therapy.
  • Another aspect of the present invention pertains to use of an AAA compound, as described herein, in the manufacture of a medicament for use in treatment.
  • the treatment is treatment of a disease or condition that is mediated by RAR ⁇ .
  • the treatment is treatment of a disease or condition that is ameliorated by the activation of RAR ⁇ .
  • the treatment is treatment of a disease or condition that is ameliorated by the selective activation of RAR ⁇ (e.g., with respect to RAR ⁇ and/or RAR ⁇ ).
  • the treatment is treatment of a cognitive disorder, memory impairment, memory deficit, senile dementia, Alzheimer's disease, early stage Alzheimer's disease, intermediate stage Alzheimer's disease, late stage Alzheimer's disease, cognitive impairment, or mild cognitive impairment.
  • the treatment is treatment of Alzheimer's disease.
  • the treatment is treatment of early stage Alzheimer's disease.
  • the treatment is treatment of intermediate stage Alzheimer's disease.
  • the treatment is treatment of late stage Alzheimer's disease.
  • the treatment is treatment of cognitive impairment.
  • the treatment is treatment of mild cognitive impairment.
  • kits comprising (a) an AAA compound, as described herein, preferably provided as a pharmaceutical composition and in a suitable container and/or with suitable packaging; and (b) instructions for use, for example, written instructions on how to administer the compound.
  • Another aspect of the present invention pertains to an AAA compound obtainable by a method of synthesis as described herein, or a method comprising a method of synthesis as described herein.
  • Another aspect of the present invention pertains to an AAA compound obtained by a method of synthesis as described herein, or a method comprising a method of synthesis as described herein.
  • Another aspect of the present invention pertains to novel intermediates, as described herein, which are suitable for use in the methods of synthesis described herein.
  • Another aspect of the present invention pertains to the use of such novel intermediates, as described herein, in the methods of synthesis described herein.
  • One aspect of the present invention relates to certain compounds which are structurally related to the following compounds:
  • one aspect of the present invention pertains to compounds selected from compounds of the following formula, and pharmaceutically acceptable salts, hydrates, and solvates thereof, wherein —R 1 , —R 2 , —R 3 , -J-, —W ⁇ , —Y ⁇ , —Z ⁇ , and —R O are as defined herein (for convenience, collectively referred to herein as “aryl-amido-aryl compounds” or “AAA compounds”):
  • —R 1 and —R 2 and —R 3 are attached to one another other than as shown in the above formula.
  • —R 1 and —R 2 together form a ring fused to the benzene ring to which they are attached.
  • —R 2 and —R 3 together form a ring fused to the benzene ring to which they are attached.
  • —R 1 and —R 3 together form a ring fused to the benzene ring to which they are attached.
  • C 1-6 haloalkyl refers to a C 1-6 alkyl group that has one or more (e.g., 1, 2, 3, etc.) halo substituents, and includes, for example, —CF 3 , —CH 2 CF 3 , —CH 2 CH 2 F, etc.
  • agonist is intended to encompass compounds which are partial agonists.
  • the compounds are optionally as defined herein, but with one or more optional provisos, as defined herein.
  • the compounds are optionally as defined herein, but without the proviso regarding compounds (PP-01), (PP-02), and (PP-03).
  • the compounds are optionally as defined herein, but without the proviso regarding compounds (PP-01), (PP-02), (PP-03), (PP-04), (PP-05), (PP-06), (PP-07), and (PP-08).
  • a reference to a particular group of compounds “without the recited proviso regarding compounds (PP-01), (PP-02), and (PP-03)” is intended to be a reference to the compounds as defined, but wherein the definition no longer includes the indicated proviso. In such cases, it is as if the indicated proviso has been deleted from the definition of compounds, and the definition has been expanded to encompass those compounds which otherwise would have been excluded by the indicated proviso.
  • the compounds are optionally as defined herein, with the proviso regarding compounds (PP-01), (PP-02), and (PP-03).
  • the compounds are optionally as defined herein, with the proviso regarding compounds (PP-01), (PP-02), (PP-03), (PP-04), (PP-05), (PP-06), (PP-07), and (PP-08).
  • a compound according to (1) selected from compounds of the following formulae and pharmaceutically acceptable salts, hydrates, and solvates thereof:
  • AAA- 031 33 AAA- 032 34 AAA- 033 35 AAA- 034 36 AAA- 035 37 AAA- 036 38 AAA- 037 39 AAA- 038 40 AAA- 039 41 AAA- 040 42 AAA- 041 43 AAA- 042 44 AAA- 043 45 AAA- 044 46 AAA- 045 47 AAA- 046 48 AAA- 047 49 AAA- 048 50 AAA- 049 51 AAA- 050 52 AAA- 051 53 AAA- 052 54 AAA- 053 55 AAA- 054 56 AAA- 055 57 AAA- 056 58 AAA- 057 59 AAA- 058 60 AAA- 059 61 AAA- 060 62 AAA- 061 63 AAA- 062 64 AAA- 063 65 AAA- 064 66 AAA- 065 67 AAA- 066 68 AAA- 067 69 AAA- 068 70 AAA- 069 71 AAA- 070 72 AAA- 071 73 AAA- 072 74 AAA- 073 75 AAA- 074 76 AAA- 075
  • One aspect of the present invention pertains to AAA compounds, as described herein, in substantially purified form and/or in a form substantially free from contaminants.
  • the compound is in substantially purified form and/or in a form substantially free from contaminants.
  • the compound is in a substantially purified form with a purity of least 50% by weight, e.g., at least 60% by weight, e.g., at least 70% by weight, e.g., at least 80% by weight, e.g., at least 90% by weight, e.g., at least 95% by weight, e.g., at least 97% by weight, e.g., at least 98% by weight, e.g., at least 99% by weight.
  • a purity of least 50% by weight e.g., at least 60% by weight, e.g., at least 70% by weight, e.g., at least 80% by weight, e.g., at least 90% by weight, e.g., at least 95% by weight, e.g., at least 97% by weight, e.g., at least 98% by weight, e.g., at least 99% by weight.
  • the substantially purified form refers to the compound in any stereoisomeric or enantiomeric form.
  • the substantially purified form refers to a mixture of stereoisomers, i.e., purified with respect to other compounds.
  • the substantially purified form refers to one stereoisomer, e.g., optically pure stereoisomer.
  • the substantially purified form refers to a mixture of enantiomers.
  • the substantially purified form refers to an equimolar mixture of enantiomers (i.e., a racemic mixture, a racemate).
  • the substantially purified form refers to one enantiomer, e.g., optically pure enantiomer.
  • the compound is in a form substantially free from contaminants wherein the contaminants represent no more than 50% by weight, e.g., no more than 40% by weight, e.g., no more than 30% by weight, e.g., no more than 20% by weight, e.g., no more than 10% by weight, e.g., no more than 5% by weight, e.g., no more than 3% by weight, e.g., no more than 2% by weight, e.g., no more than 1% by weight.
  • the contaminants represent no more than 50% by weight, e.g., no more than 40% by weight, e.g., no more than 30% by weight, e.g., no more than 20% by weight, e.g., no more than 10% by weight, e.g., no more than 5% by weight, e.g., no more than 3% by weight, e.g., no more than 2% by weight, e.g., no more than 1% by weight.
  • the contaminants refer to other compounds, that is, other than stereoisomers or enantiomers. In one embodiment, the contaminants refer to other compounds and other stereoisomers. In one embodiment, the contaminants refer to other compounds and the other enantiomer.
  • the compound is in a substantially purified form with an optical purity of at least 60% (i.e., 60% of the compound, on a molar basis, is the desired stereoisomer or enantiomer, and 40% is undesired stereoisomer(s) or enantiomer), e.g., at least 70%, e.g., at least 80%, e.g., at least 90%, e.g., at least 95%, e.g., at least 97%, e.g., at least 98%, e.g., at least 99%.
  • Certain compounds may exist in one or more particular geometric, optical, enantiomeric, diasteriomeric, epimeric, atropic, stereoisomeric, tautomeric, conformational, or anomeric forms, including but not limited to, cis- and trans-forms; E- and Z-forms; c-, t-, and r-forms; endo- and exo-forms; R—, S—, and meso-forms; D- and L-forms; d- and l-forms; (+) and ( ⁇ ) forms; keto-, enol-, and enolate-forms; syn- and anti-forms; synclinal- and anticlinal-forms; ⁇ - and ⁇ -forms; axial and equatorial forms; boat-, chair-, twist-, envelope-, and halfchair-forms; and combinations thereof, hereinafter collectively referred to as “isomers” (or “isomeric forms”).
  • isomers are structural (or constitutional) isomers (i.e., isomers which differ in the connections between atoms rather than merely by the position of atoms in space).
  • a reference to a methoxy group, —OCH 3 is not to be construed as a reference to its structural isomer, a hydroxymethyl group, —CH 2 OH.
  • a reference to ortho-chlorophenyl is not to be construed as a reference to its structural isomer, meta-chlorophenyl.
  • a reference to a class of structures may well include structurally isomeric forms falling within that class (e.g., C 1-7 alkyl includes n-propyl and iso-propyl; butyl includes n-, iso-, sec-, and tert-butyl; methoxyphenyl includes ortho-, meta-, and para-methoxyphenyl).
  • C 1-7 alkyl includes n-propyl and iso-propyl
  • butyl includes n-, iso-, sec-, and tert-butyl
  • methoxyphenyl includes ortho-, meta-, and para-methoxyphenyl
  • keto/enol (illustrated below), imine/enamine, amide/imino alcohol, amidine/amidine, nitroso/oxime, thioketone/enethiol, N-nitroso/hydroxyazo, and nitro/aci-nitro.
  • H may be in any isotopic form, including 1 H, 2 H (D), and 3 H (T); C may be in any isotopic form, including 12 C, 13 C, and 14 C; O may be in any isotopic form, including 16 O and 18 O; and the like.
  • a reference to a particular compound includes all such isomeric forms, including mixtures (e.g., racemic mixtures) thereof.
  • Methods for the preparation (e.g., asymmetric synthesis) and separation (e.g., fractional crystallisation and chromatographic means) of such isomeric forms are either known in the art or are readily obtained by adapting the methods taught herein, or known methods, in a known manner.
  • a corresponding salt of the compound for example, a pharmaceutically-acceptable salt.
  • pharmaceutically acceptable salts are discussed in Berge et al., 1977, “Pharmaceutically Acceptable Salts,” J. Pharm. Sci ., Vol. 66, pp. 1-19.
  • a salt may be formed with a suitable cation.
  • suitable inorganic cations include, but are not limited to, alkali metal ions such as Na + and K + , alkaline earth cations such as Ca 2+ and Mg 2+ , and other cations such as Al 3+ .
  • Suitable organic cations include, but are not limited to, ammonium ion (i.e., NH 4 + ) and substituted ammonium ions (e.g., NH 3 R + , NH 2 R 2 + , NHR 3 + , NR 4 + ).
  • suitable substituted ammonium ions are those derived from: ethylamine, diethylamine, dicyclohexylamine, triethylamine, butylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, benzylamine, phenylbenzylamine, choline, meglumine, and tromethamine, as well as amino acids, such as lysine and arginine.
  • An example of a common quaternary ammonium ion is N(CH 3 ) 4 + .
  • a salt may be formed with a suitable anion.
  • suitable inorganic anions include, but are not limited to, those derived from the following inorganic acids: hydrochloric, hydrobromic, hydroiodic, sulfuric, sulfurous, nitric, nitrous, phosphoric, and phosphorous.
  • Suitable organic anions include, but are not limited to, those derived from the following organic acids: 2-acetyoxybenzoic, acetic, ascorbic, aspartic, benzoic, camphorsulfonic, cinnamic, citric, edetic, ethanedisulfonic, ethanesulfonic, fumaric, glucheptonic, gluconic, glutamic, glycolic, hydroxymaleic, hydroxynaphthalene carboxylic, isethionic, lactic, lactobionic, lauric, maleic, malic, methanesulfonic, mucic, oleic, oxalic, palmitic, pamoic, pantothenic, phenylacetic, phenylsulfonic, propionic, pyruvic, salicylic, stearic, succinic, sulfanilic, tartaric, toluenesulfonic, and valeric.
  • a reference to a particular compound also includes salt forms thereof.
  • solvate is used herein in the conventional sense to refer to a complex of solute (e.g., compound, salt of compound) and solvent. If the solvent is water, the solvate may be conveniently referred to as a hydrate, for example, a mono-hydrate, a di-hydrate, a tri-hydrate, etc.
  • a reference to a particular compound also includes solvate and hydrate forms thereof.
  • chemically protected form is used herein in the conventional chemical sense and pertains to a compound in which one or more reactive functional groups are protected from undesirable chemical reactions under specified conditions (e.g., pH, temperature, radiation, solvent, and the like).
  • specified conditions e.g., pH, temperature, radiation, solvent, and the like.
  • well known chemical methods are employed to reversibly render unreactive a functional group, which otherwise would be reactive, under specified conditions.
  • one or more reactive functional groups are in the form of a protected or protecting group (also known as a masked or masking group or a blocked or blocking group).
  • a wide variety of such “protecting,” “blocking,” or “masking” methods are widely used and well known in organic synthesis.
  • a compound which has two nonequivalent reactive functional groups both of which would be reactive under specified conditions, may be derivatized to render one of the functional groups “protected,” and therefore unreactive, under the specified conditions; so protected, the compound may be used as a reactant which has effectively only one reactive functional group.
  • the protected group may be “deprotected” to return it to its original functionality.
  • a hydroxy group may be protected as an ether (—OR) or an ester (—OC( ⁇ O)R), for example, as: a t-butyl ether; a benzyl, benzhydryl (diphenylmethyl), or trityl (triphenylmethyl)ether; a trimethylsilyl or t-butyldimethylsilyl ether; or an acetyl ester (—OC( ⁇ O)CH 3 , —OAc).
  • ether —OR
  • an ester —OC( ⁇ O)R
  • an aldehyde or ketone group may be protected as an acetal (R—CH(OR) 2 ) or ketal (R 2 C(OR) 2 ), respectively, in which the carbonyl group (>C ⁇ O) is converted to a diether (>C(OR) 2 ), by reaction with, for example, a primary alcohol.
  • the aldehyde or ketone group is readily regenerated by hydrolysis using a large excess of water in the presence of acid.
  • an amine group may be protected, for example, as an amide (—NRCO—R) or a urethane (—NRCO—OR), for example, as: a methyl amide (—NHCO—CH 3 ); a benzyloxy amide (—NHCO—OCH 2 C 6 H 5 , —NH-Cbz); as a t-butoxy amide (—NHCO—OC(CH 3 ) 3 , —NH-Boc); a 2-biphenyl-2-propoxy amide (—NHCO—OC(CH 3 ) 2 C 6 H 4 C 6 H 5 , —NH-Bpoc), as a 9-fluorenylmethoxy amide (—NH-Fmoc), as a 6-nitroveratryloxy amide (—NH-Nvoc), as a 2-trimethylsilylethyloxy amide (—NH-Teoc), as a 2,2,2-trichloroethyloxy amide (—NH-Troc),
  • a carboxylic acid group may be protected as an ester for example, as: an C 1-7 alkyl ester (e.g., a methyl ester; a t-butyl ester); a C 1-7 haloalkyl ester (e.g., a C 1-7 trihaloalkyl ester); a triC 1-7 alkylsilyl-C 1-7 alkyl ester; or a C 5-20 aryl-C 1-7 alkyl ester (e.g., a benzyl ester; a nitrobenzyl ester); or as an amide, for example, as a methyl amide.
  • an C 1-7 alkyl ester e.g., a methyl ester; a t-butyl ester
  • a C 1-7 haloalkyl ester e.g., a C 1-7 trihaloalkyl ester
  • a thiol group may be protected as a thioether (—SR), for example, as: a benzyl thioether; an acetamidomethyl ether (—S—CH 2 NHC( ⁇ O)CH 3 ).
  • SR thioether
  • benzyl thioether an acetamidomethyl ether (—S—CH 2 NHC( ⁇ O)CH 3 ).
  • prodrug refers to a compound which, when metabolised (e.g., in vivo), yields the desired active compound.
  • the prodrug is inactive, or less active than the desired active compound, but may provide advantageous handling, administration, or metabolic properties.
  • some prodrugs are esters of the active compound (e.g., a physiologically acceptable metabolically labile ester). During metabolism, the ester group (—C( ⁇ O)OR) is cleaved to yield the active drug.
  • esters may be formed by esterification, for example, of any of the carboxylic acid groups (—C( ⁇ O)OH) in the parent compound, with, where appropriate, prior protection of any other reactive groups present in the parent compound, followed by deprotection if required.
  • prodrugs are activated enzymatically to yield the active compound, or a compound which, upon further chemical reaction, yields the active compound (for example, as in ADEPT, GDEPT, LIDEPT, etc.).
  • the prodrug may be a sugar derivative or other glycoside conjugate, or may be an amino acid ester derivative.
  • certain compounds of the invention may conveniently be prepared by coupling a suitably substituted benzoic acid with a suitably protected para-amino benzoic acid compound. Deprotection gives the corresponding carboxylic acid compound, which can be converted to the corresponding amide.
  • Coupling may be carried out using a variety of agents, for example oxalyl chloride in the presence of diisopropylethylamine, triethylamine or catalytic quantities of dimethylformamide in a solvent such as dichloromethane where coupling proceeds via the acid chloride, or by using agents such as HATU, EEDQ, PyBOP, PyBrOP, EDC, or CDI under usual conditions.
  • agents for example oxalyl chloride in the presence of diisopropylethylamine, triethylamine or catalytic quantities of dimethylformamide in a solvent such as dichloromethane where coupling proceeds via the acid chloride, or by using agents such as HATU, EEDQ, PyBOP, PyBrOP, EDC, or CDI under usual conditions.
  • the protecting group can be removed using conventional methods to give the carboxylic acid compound (e.g., (1)(iv)).
  • the protecting group e.g., —R P
  • hydrolysis can be achieved using lithium hydroxide in a mixture of THF or dioxane and water.
  • the protecting group e.g., —R P
  • it may be removed by hydrogenation, for example by using hydrogen over a metal catalyst.
  • the carboxylic acid compound e.g., (1)(iv)
  • a corresponding amide compound e.g., (1)(v)
  • certain compounds of the invention may conveniently be prepared by coupling a suitably substituted aniline with a suitably protected and activated terephthalic acid compound. Deprotection gives the corresponding carboxylic acid compound, which can be converted to the corresponding amide.
  • a suitably substituted aniline e.g., (2)(i)
  • a suitably protected terephthalic acid compound e.g., (2)(ii)
  • —R P denotes a protecting group
  • -LG denotes a leaving group
  • a suitable leaving group is halogen (e.g., Cl)
  • the corresponding compound may be prepared, for example, from the corresponding benzoic acid by treatment with a variety of reagents including thionyl chloride and oxalyl chloride.
  • coupling may be achieved, for example, by mixing the two components in a suitable solvent such as dichloromethane in the presence of a base such as triethylamine or diisopropylethylamine.
  • a suitable leaving group is —OH.
  • coupling may be achieved, for example, using oxalyl chloride, HATU, EEDQ, PyBOP, PyBrOP, CDI or EDC under usual conditions.
  • the protecting group can be removed using conventional methods to give the carboxylic acid compound (e.g., (2)(iv)).
  • the protecting group e.g., —R P
  • hydrolysis can be achieved using lithium hydroxide in a mixture of THF or dioxane and water.
  • the protecting group e.g., —R P
  • it may be removed by hydrogenation, for example by using hydrogen over a metal catalyst.
  • the carboxylic acid compound e.g., (2)(iv)
  • a corresponding amide compound e.g., (2)(v)
  • benzoic acids are often commercially available, but if not, the requisite material can be prepared from commercially available starting materials in a few steps using conventional methods.
  • suitably protected hydroxyl-benzoic acids may be alkylated. Deprotection gives the corresponding substituted benzoic acid.
  • suitably protected hydroxyl-benzoic acid may be alkylated using a base such as potassium carbonate or sodium hydride in a suitable solvent to form the phenolate anion, which is then quenched with the requisite halide, to give the corresponding substituted protected benzoic acid compound (e.g., (3)(ii)).
  • the carboxylic acid protecting group may be removed using conventional methods to give the desired substituted benzoic acid compound (e.g., (3)(iii)).
  • the protecting group e.g., —R P
  • hydrolysis can be achieved using lithium hydroxide in a mixture of THF or dioxane and water.
  • the protecting group e.g., —R P
  • it may be removed by hydrogenation, for example by using hydrogen over a metal catalyst.
  • the amines are often commercially available, but if not, the requisite material can be prepared from commercially available starting materials in a few steps using conventional methods.
  • compounds where —R N is other than —H can be prepared by reductive amination of a suitably protected 4-aminobenzoic acid derivative.
  • one or more of the groups —R 1 , —R 2 , and —R 3 may be changed after coupling. For example, debenzylation of a pendant —OCH 2 Ph group gives a corresponding —OH group, which can then be alkylated.
  • This —OH group may be then be alkylated, for example, using a base such as potassium carbonate or sodium hydride in a suitable solvent to form the phenolate anion, which is then quenched with the requisite halide, to give the corresponding alkylated compound (e.g., (4)(v)).
  • a base such as potassium carbonate or sodium hydride in a suitable solvent
  • phenolate anion which is then quenched with the requisite halide, to give the corresponding alkylated compound (e.g., (4)(v)).
  • the protecting group can be removed using conventional methods to give the carboxylic acid compound (e.g., (4)(iv)).
  • the protecting group e.g., —R P
  • hydrolysis can be achieved using lithium hydroxide in a mixture of THF or dioxane and water.
  • the protecting group e.g., —R P
  • it may be removed by hydrogenation, for example by using hydrogen over a metal catalyst.
  • the carboxylic acid compound e.g., (4)(vi)
  • a corresponding amide compound e.g., (4)(vii)
  • one or more of the groups —R 1 , —R 2 , and —R 3 may be changed after coupling.
  • a pendant —OH may be alkylated.
  • one of —R 1 , —R 2 , and —R 3 in the starting material is —OH.
  • this —OH group may be then be alkylated, for example, using a base such as potassium carbonate or sodium hydride in a suitable solvent to form the phenolate anion, which is then quenched with the requisite halide, to give the corresponding alkylated compound (5)(iv).
  • the protecting group can be removed using conventional methods to give the carboxylic acid compound (e.g., (5)(v)).
  • the protecting group e.g., —R P
  • hydrolysis can be achieved using lithium hydroxide in a mixture of THF or dioxane and water.
  • the protecting group e.g., —R C
  • it may be removed by hydrogenation, for example by using hydrogen over a metal catalyst.
  • the carboxylic acid compound e.g., (5)(v)
  • a corresponding amide compound e.g., (5)(vi)
  • the core 1,4-phenylene group of the protected para-amino benzoic acid compound (e.g., (1)(ii) and (4)(ii)) and of the activated terephthalic acid compound (e.g., (2)(ii) and (5)(ii)) may bear additional substituents (e.g., —R YY , —R ZZ , —R WW ), or may be replaced with a pyridine-diyl group (e.g., ⁇ Y— is ⁇ N— or —Z ⁇ is —N ⁇ ), which may itself bear additional substituents (e.g., —R YY , —R ZZ , —R WW ).
  • additional substituents e.g., —R YY , —R ZZ , —R WW
  • compositions e.g., a pharmaceutical composition
  • a composition comprising an AAA compound, as described herein, and a pharmaceutically acceptable carrier, diluent, or excipient.
  • compositions e.g., a pharmaceutical composition
  • a composition comprising admixing an AAA compound, as described herein, and a pharmaceutically acceptable carrier, diluent, or excipient.
  • the compounds described herein are useful, for example, in the treatment of diseases and conditions that are ameliorated by the (selective) activation of RAR ⁇ , such as, for example, Alzheimer's disease.
  • One aspect of the present invention pertains to a method of activating retinoic acid receptor ⁇ (RAR ⁇ ), in vitro or in vivo, comprising contacting RAR ⁇ with an effective amount of an AAA compound, as described herein.
  • RAR ⁇ retinoic acid receptor ⁇
  • One aspect of the present invention pertains to a method of selectively activating retinoic acid receptor ⁇ (RAR ⁇ ) (e.g., with respect to RAR ⁇ and/or RAR ⁇ ), in vitro or in vivo, comprising contacting RAR ⁇ with an effective amount of an AAA compound, as described herein.
  • RAR ⁇ retinoic acid receptor ⁇
  • the method is performed in vitro.
  • the method is performed in vivo.
  • One aspect of the present invention pertains to a method of activating retinoic acid receptor ⁇ (RAR ⁇ ) in a neuronal cell, in vitro or in vivo, comprising contacting the cell with an effective amount of an AAA compound, as described herein.
  • RAR ⁇ retinoic acid receptor ⁇
  • One aspect of the present invention pertains to a method of selectively activating retinoic acid receptor ⁇ (RAR ⁇ ) (e.g., with respect to RAR ⁇ and/or RAR ⁇ ) in a neuronal cell, in vitro or in vivo, comprising contacting the cell with an effective amount of an AAA compound, as described herein.
  • RAR ⁇ retinoic acid receptor ⁇
  • the AAA compound is provided in the form of a pharmaceutically acceptable composition.
  • Suitable assays for determining RAR ⁇ activation are described herein and/or are known in the art.
  • AAA compounds described herein are useful in the up-regulation of chAT expression in cortical neurons; the down-regulation of APP expression in cortical neurons, the up-regulation of ADAM10 expression in cortical neurons; and the down-regulation of A ⁇ 40 and A ⁇ 42 expression in cortical neurons.
  • One aspect of the present invention pertains to a method of up-regulating chAT expression in a cortical neuron, comprising contacting the cortical neuron, in vitro or in vivo, with an effective amount of an AAA compound, as described herein.
  • One aspect of the present invention pertains to a method of down-regulating APP expression in a cortical neuron, comprising contacting the cortical neuron, in vitro or in vivo, with an effective amount of an AAA compound, as described herein.
  • One aspect of the present invention pertains to a method of up-regulating ADAM10 expression in a cortical neuron, comprising contacting the cortical neuron, in vitro or in vivo, with an effective amount of an MA compound, as described herein.
  • One aspect of the present invention pertains to a method of down-regulating A ⁇ 40 and A ⁇ 42 expression in a cortical neuron, comprising contacting the cortical neuron, in vitro or in vivo, with an effective amount of an AAA compound, as described herein.
  • the method is performed in vitro.
  • the method is performed in vivo.
  • One aspect of the present invention pertains to a method of up-regulating chAT expression in a cortical neuron in a patient, comprising administering to the patient a therapeutically effective amount of an AAA compound, as described herein.
  • One aspect of the present invention pertains to a method of down-regulating APP expression in a cortical neuron in a patient, comprising administering to the patient a therapeutically effective amount of an AAA compound, as described herein.
  • One aspect of the present invention pertains to a method of up-regulating ADAM10 expression in a cortical neuron in a patient, comprising administering to the patient a therapeutically effective amount of an AAA compound, as described herein.
  • One aspect of the present invention pertains to a method of down-regulating A ⁇ 40 and A ⁇ 42 expression in a cortical neuron in a patient, comprising administering to the patient a therapeutically effective amount of an AAA compound, as described herein.
  • the AAA compound is provided in the form of a pharmaceutically acceptable composition.
  • Suitable assays for determining up-regulation of chAT expression; down-regulation of APP expression; up-regulation of ADAM10 expression; and down-regulation of A ⁇ 40 and A ⁇ 42 expression; are described herein and/or are known in the art.
  • AAA compounds described herein are useful in preventing, reducing, or slowing cortical neuronal death.
  • One aspect of the present invention pertains to a method of preventing, reducing, or slowing cortical neuronal death in a patient, comprising administering to the patient a therapeutically effective amount of an AAA compound, as described herein.
  • Another aspect of the present invention pertains to an AAA compound, as described herein, for treatment of the human or animal body by therapy.
  • Another aspect of the present invention pertains to use of an AAA compound, as described herein, in the manufacture of a medicament for use in treatment.
  • the medicament comprises the AAA compound.
  • Another aspect of the present invention pertains to a method of treatment comprising administering to a patient in need of treatment a therapeutically effective amount of an AAA compound, as described herein, preferably in the form of a pharmaceutical composition.
  • the treatment is treatment of a disease or condition that is mediated by RAR ⁇ .
  • the treatment is treatment of: a disease or condition that is ameliorated by the activation of RAR ⁇ .
  • the treatment is treatment of: a disease or condition that is ameliorated by the selective activation of RAR ⁇ (e.g., with respect to RAR ⁇ and/or RAR ⁇ ).
  • the treatment is treatment of a cognitive disorder, memory impairment, memory deficit, senile dementia, Alzheimer's disease, early stage Alzheimer's disease, intermediate stage Alzheimer's disease, late stage Alzheimer's disease, cognitive impairment, or mild cognitive impairment.
  • the treatment is treatment of Alzheimer's disease.
  • the treatment is treatment of early stage Alzheimer's disease.
  • the treatment is treatment of intermediate stage Alzheimer's disease.
  • the treatment is treatment of late stage Alzheimer's disease.
  • the treatment is treatment of cognitive impairment.
  • the treatment is treatment of mild cognitive impairment.
  • treatment pertains generally to treatment and therapy, whether of a human or an animal (e.g., in veterinary applications), in which some desired therapeutic effect is achieved, for example, the inhibition of the progress of the condition, and includes a reduction in the rate of progress, a halt in the rate of progress, alleviation of symptoms of the condition, amelioration of the condition, and cure of the condition.
  • Treatment as a prophylactic measure i.e., prophylaxis
  • treatment that is, treatment of condition encompasses reducing the risk of that condition).
  • treatment includes the prophylaxis of Alzheimer's disease, reducing the risk of Alzheimer's disease, alleviating the symptoms of Alzheimer's disease, etc.
  • terapéuticaally-effective amount pertains to that amount of a compound, or a material, composition or dosage form comprising a compound, which is effective for producing some desired therapeutic effect, commensurate with a reasonable benefit/risk ratio, when administered in accordance with a desired treatment regimen.
  • treatment includes combination treatments and therapies, in which two or more treatments or therapies are combined, for example, sequentially or simultaneously.
  • the compounds described herein may also be used in combination therapies, e.g., in conjunction with other agents.
  • treatments and therapies include, but are not limited to, chemotherapy (the administration of active agents, including, e.g., drugs, antibodies (e.g., as in immunotherapy), prodrugs (e.g., as in photodynamic therapy, GDEPT, ADEPT, etc.); surgery; radiation therapy; photodynamic therapy; gene therapy; and controlled diets.
  • a compound as described herein may be beneficial to combine treatment with a compound as described herein with one or more other (e.g., 1, 2, 3, 4) agents or therapies, e.g., that treat Alzheimer's disease.
  • one or more other agents or therapies e.g., that treat Alzheimer's disease.
  • One aspect of the present invention pertains to a compound as described herein, in combination with one or more additional therapeutic agents, as described below.
  • the agents may be administered simultaneously or sequentially, and may be administered in individually varying dose schedules and via different routes.
  • the agents can be administered at closely spaced intervals (e.g., over a period of 5-10 minutes) or at longer intervals (e.g., 1, 2, 3, 4 or more hours apart, or even longer periods apart where required), the precise dosage regimen being commensurate with the properties of the therapeutic agent(s).
  • agents i.e., the compound described here, plus one or more other agents
  • the agents may be formulated together in a single dosage form, or alternatively, the individual agents may be formulated separately and presented together in the form of a kit, optionally with instructions for their use.
  • AAA compounds described herein may also be used as cell culture additives to activate RAR ⁇ , e.g., to up-regulate chAT expression; to down-regulate APP expression; to up-regulate ADAM10 expression; to down-regulate A ⁇ 40 and A ⁇ 42 expression; to prevent, reduce, or slow cortical neuronal death.
  • RAR ⁇ e.g., to up-regulate chAT expression; to down-regulate APP expression; to up-regulate ADAM10 expression; to down-regulate A ⁇ 40 and A ⁇ 42 expression; to prevent, reduce, or slow cortical neuronal death.
  • AAA compounds described herein may also be used, for example, as part of an in vitro assay, for example, in order to determine whether a candidate host is likely to benefit from treatment with the compound in question.
  • AAA compounds described herein may also be used as a standard, for example, in an assay, in order to identify other compounds, other RAR ⁇ agonists, etc.
  • kits comprising (a) an AAA compound as described herein, or a composition comprising an AAA compound as described herein, e.g., preferably provided in a suitable container and/or with suitable packaging; and (b) instructions for use, e.g., written instructions on how to administer the compound or composition.
  • the written instructions may also include a list of indications for which the active ingredient is a suitable treatment.
  • the AAA compound or pharmaceutical composition comprising the AAA compound may be administered to a subject by any convenient route of administration, whether systemically/peripherally or topically (i.e., at the site of desired action).
  • Routes of administration include, but are not limited to, oral (e.g., by ingestion); buccal; sublingual; transdermal (including, e.g., by a patch, plaster, etc.); transmucosal (including, e.g., by a patch, plaster, etc.); intranasal (e.g., by nasal spray); ocular (e.g., by eyedrops); pulmonary (e.g., by inhalation or insufflation therapy using, e.g., via an aerosol, e.g., through the mouth or nose); rectal (e.g., by suppository or enema); vaginal (e.g., by pessary); parenteral, for example, by injection, including subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular
  • the subject/patient may be a chordate, a vertebrate, a mammal, a placental mammal, a marsupial (e.g., kangaroo, wombat), a rodent (e.g., a guinea pig, a hamster, a rat, a mouse), murine (e.g., a mouse), a lagomorph (e.g., a rabbit), avian (e.g., a bird), canine (e.g., a dog), feline (e.g., a cat), equine (e.g., a horse), porcine (e.g., a pig), ovine (e.g., a sheep), bovine (e.g., a cow), a primate, simian (e.g., a monkey or ape), a monkey (e.g., marmoset, baboon), an ape (e.g
  • the subject/patient may be any of its forms of development, for example, a foetus.
  • the subject/patient is a human.
  • AAA compound While it is possible for the AAA compound to be administered alone, it is preferable to present it as a pharmaceutical formulation (e.g., composition, preparation, medicament) comprising at least one AAA compound, as described herein, together with one or more other pharmaceutically acceptable ingredients well known to those skilled in the art, including, but not limited to, pharmaceutically acceptable carriers, diluents, excipients, adjuvants, fillers, buffers, preservatives, anti-oxidants, lubricants, stabilisers, solubilisers, surfactants (e.g., wetting agents), masking agents, colouring agents, flavouring agents, and sweetening agents.
  • the formulation may further comprise other active agents, for example, other therapeutic or prophylactic agents.
  • the present invention further provides pharmaceutical compositions, as defined above, and methods of making a pharmaceutical composition comprising admixing at least one AAA compound, as described herein, together with one or more other pharmaceutically acceptable ingredients well known to those skilled in the art, e.g., carriers, diluents, excipients, etc. If formulated as discrete units (e.g., tablets, etc.), each unit contains a predetermined amount (dosage) of the compound.
  • pharmaceutically acceptable pertains to compounds, ingredients, materials, compositions, dosage forms, etc., which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of the subject in question (e.g., human) without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • Each carrier, diluent, excipient, etc. must also be “acceptable” in the sense of being compatible with the other ingredients of the formulation.
  • Suitable carriers, diluents, excipients, etc. can be found in standard pharmaceutical texts, for example, Remington's Pharmaceutical Sciences, 18th edition, Mack Publishing Company, Easton, Pa., 1990; and Handbook of Pharmaceutical Excipients, 5th edition, 2005.
  • the formulations may be prepared by any methods well known in the art of pharmacy. Such methods include the step of bringing into association the compound with a carrier which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association the compound with carriers (e.g., liquid carriers, finely divided solid carrier, etc.), and then shaping the product, if necessary.
  • carriers e.g., liquid carriers, finely divided solid carrier, etc.
  • the formulation may be prepared to provide for rapid or slow release; immediate, delayed, timed, or sustained release; or a combination thereof.
  • Formulations may suitably be in the form of liquids, solutions (e.g., aqueous, non-aqueous), suspensions (e.g., aqueous, non-aqueous), emulsions (e.g., oil-in-water, water-in-oil), elixirs, syrups, electuaries, mouthwashes, drops, tablets (including, e.g., coated tablets), granules, powders, losenges, pastilles, capsules (including, e.g., hard and soft gelatin capsules), cachets, pills, ampoules, boluses, suppositories, pessaries, tinctures, gels, pastes, ointments, creams, lotions, oils, foams, sprays, mists, or aerosols.
  • solutions e.g., aqueous, non-aqueous
  • suspensions e.g., aqueous, non-aqueous
  • Formulations may suitably be provided as a patch, adhesive plaster, bandage, dressing, or the like which is impregnated with one or more compounds and optionally one or more other pharmaceutically acceptable ingredients, including, for example, penetration, permeation, and absorption enhancers. Formulations may also suitably be provided in the form of a depot or reservoir.
  • the compound may be dissolved in, suspended in, or admixed with one or more other pharmaceutically acceptable ingredients.
  • the compound may be presented in a liposome or other microparticulate which is designed to target the compound, for example, to blood components or one or more organs.
  • Formulations suitable for oral administration include liquids, solutions (e.g., aqueous, non-aqueous), suspensions (e.g., aqueous, non-aqueous), emulsions (e.g., oil-in-water, water-in-oil), elixirs, syrups, electuaries, tablets, granules, powders, capsules, cachets, pills, ampoules, boluses.
  • Formulations suitable for buccal administration include mouthwashes, losenges, pastilles, as well as patches, adhesive plasters, depots, and reservoirs.
  • Losenges typically comprise the compound in a flavored basis, usually sucrose and acacia or tragacanth.
  • Pastilles typically comprise the compound in an inert matrix, such as gelatin and glycerin, or sucrose and acacia.
  • Mouthwashes typically comprise the compound in a suitable liquid carrier.
  • Formulations suitable for sublingual administration include tablets, losenges, pastilles, capsules, and pills.
  • Formulations suitable for oral transmucosal administration include liquids, solutions (e.g., aqueous, non-aqueous), suspensions (e.g., aqueous, non-aqueous), emulsions (e.g., oil-in-water, water-in-oil), mouthwashes, losenges, pastilles, as well as patches, adhesive plasters, depots, and reservoirs.
  • solutions e.g., aqueous, non-aqueous
  • suspensions e.g., aqueous, non-aqueous
  • emulsions e.g., oil-in-water, water-in-oil
  • mouthwashes e.g., losenges, pastilles, as well as patches, adhesive plasters, depots, and reservoirs.
  • Formulations suitable for non-oral transmucosal administration include liquids, solutions (e.g., aqueous, non-aqueous), suspensions (e.g., aqueous, non-aqueous), emulsions (e.g., oil-in-water, water-in-oil), suppositories, pessaries, gels, pastes, ointments, creams, lotions, oils, as well as patches, adhesive plasters, depots, and reservoirs.
  • solutions e.g., aqueous, non-aqueous
  • suspensions e.g., aqueous, non-aqueous
  • emulsions e.g., oil-in-water, water-in-oil
  • suppositories e.g., pessaries, gels, pastes, ointments, creams, lotions, oils, as well as patches, adhesive plasters, depots, and reservoirs.
  • Formulations suitable for transdermal administration include gels, pastes, ointments, creams, lotions, and oils, as well as patches, adhesive plasters, bandages, dressings, depots, and reservoirs.
  • Tablets may be made by conventional means, e.g., compression or moulding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing in a suitable machine the compound in a free-flowing form such as a powder or granules, optionally mixed with one or more binders (e.g., povidone, gelatin, acacia, sorbitol, tragacanth, hydroxypropylmethyl cellulose); fillers or diluents (e.g., lactose, microcrystalline cellulose, calcium hydrogen phosphate); lubricants (e.g., magnesium stearate, talc, silica); disintegrants (e.g., sodium starch glycolate, cross-linked povidone, cross-linked sodium carboxymethyl cellulose); surface-active or dispersing or wetting agents (e.g., sodium lauryl sulfate); preservatives (e.g., methyl p-hydroxybenzoate, propyl
  • Moulded tablets may be made by moulding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • the tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the compound therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile.
  • Tablets may optionally be provided with a coating, for example, to affect release, for example an enteric coating, to provide release in parts of the gut other than the stomach.
  • Ointments are typically prepared from the compound and a paraffinic or a water-miscible ointment base.
  • Creams are typically prepared from the compound and an oil-in-water cream base.
  • the aqueous phase of the cream base may include, for example, at least about 30% w/w of a polyhydric alcohol, i.e., an alcohol having two or more hydroxyl groups such as propylene glycol, butane-1,3-diol, mannitol, sorbitol, glycerol and polyethylene glycol and mixtures thereof.
  • the topical formulations may desirably include a compound which enhances absorption or penetration of the compound through the skin or other affected areas. Examples of such dermal penetration enhancers include dimethylsulfoxide and related analogues.
  • Emulsions are typically prepared from the compound and an oily phase, which may optionally comprise merely an emulsifier (otherwise known as an emulgent), or it may comprises a mixture of at least one emulsifier with a fat or an oil or with both a fat and an oil.
  • an emulsifier also known as an emulgent
  • a hydrophilic emulsifier is included together with a lipophilic emulsifier which acts as a stabiliser. It is also preferred to include both an oil and a fat.
  • the emulsifier(s) with or without stabiliser(s) make up the so-called emulsifying wax
  • the wax together with the oil and/or fat make up the so-called emulsifying ointment base which forms the oily dispersed phase of the cream formulations.
  • Suitable emulgents and emulsion stabilisers include Tween 60, Span 80, cetostearyl alcohol, myristyl alcohol, glyceryl monostearate and sodium lauryl sulfate.
  • suitable oils or fats for the formulation is based on achieving the desired cosmetic properties, since the solubility of the compound in most oils likely to be used in pharmaceutical emulsion formulations may be very low.
  • the cream should preferably be a non-greasy, non-staining and washable product with suitable consistency to avoid leakage from tubes or other containers.
  • Straight or branched chain, mono- or dibasic alkyl esters such as di-isoadipate, isocetyl stearate, propylene glycol diester of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate or a blend of branched chain esters known as Crodamol CAP may be used, the last three being preferred esters. These may be used alone or in combination depending on the properties required. Alternatively, high melting point lipids such as white soft paraffin and/or liquid paraffin or other mineral oils can be used.
  • Formulations suitable for intranasal administration, where the carrier is a liquid include, for example, nasal spray, nasal drops, or by aerosol administration by nebuliser, include aqueous or oily solutions of the compound.
  • Formulations suitable for intranasal administration, where the carrier is a solid include, for example, those presented as a coarse powder having a particle size, for example, in the range of about 20 to about 500 microns which is administered in the manner in which snuff is taken, i.e., by rapid inhalation through the nasal passage from a container of the powder held close up to the nose.
  • Formulations suitable for pulmonary administration include those presented as an aerosol spray from a pressurised pack, with the use of a suitable propellant, such as dichlorodifluoromethane, trichlorofluoromethane, dichoro-tetrafluoroethane, carbon dioxide, or other suitable gases.
  • a suitable propellant such as dichlorodifluoromethane, trichlorofluoromethane, dichoro-tetrafluoroethane, carbon dioxide, or other suitable gases.
  • Formulations suitable for ocular administration include eye drops wherein the compound is dissolved or suspended in a suitable carrier, especially an aqueous solvent for the compound.
  • Formulations suitable for rectal administration may be presented as a suppository with a suitable base comprising, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols, for example, cocoa butter or a salicylate; or as a solution or suspension for treatment by enema.
  • a suitable base comprising, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols, for example, cocoa butter or a salicylate; or as a solution or suspension for treatment by enema.
  • Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the compound, such carriers as are known in the art to be appropriate.
  • Formulations suitable for parenteral administration include aqueous or non-aqueous, isotonic, pyrogen-free, sterile liquids (e.g., solutions, suspensions), in which the compound is dissolved, suspended, or otherwise provided (e.g., in a liposome or other microparticulate).
  • sterile liquids e.g., solutions, suspensions
  • Such liquids may additional contain other pharmaceutically acceptable ingredients, such as anti-oxidants, buffers, preservatives, stabilisers, bacteriostats, suspending agents, thickening agents, and solutes which render the formulation isotonic with the blood (or other relevant bodily fluid) of the intended recipient.
  • excipients include, for example, water, alcohols, polyols, glycerol, vegetable oils, and the like.
  • suitable isotonic carriers for use in such formulations include Sodium Chloride Injection, Ringer's Solution, or Lactated Ringer's Injection.
  • concentration of the compound in the liquid is from about 1 ng/mL to about 10 ⁇ g/mL, for example from about 10 ng/ml to about 1 ⁇ g/mL.
  • the formulations may be presented in unit-dose or multi-dose sealed containers, for example, ampoules and vials, and may be stored in a freeze-dried (lyophilised) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use.
  • sterile liquid carrier for example water for injections, immediately prior to use.
  • Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules, and tablets.
  • appropriate dosages of the AAA compounds, and compositions comprising the AAA compounds can vary from patient to patient. Determining the optimal dosage will generally involve the balancing of the level of therapeutic benefit against any risk or deleterious side effects.
  • the selected dosage level will depend on a variety of factors including, but not limited to, the activity of the particular AAA compound, the route of administration, the time of administration, the rate of excretion of the AAA compound, the duration of the treatment, other drugs, compounds, and/or materials used in combination, the severity of the condition, and the species, sex, age, weight, condition, general health, and prior medical history of the patient.
  • the amount of AAA compound and route of administration will ultimately be at the discretion of the physician, veterinarian, or clinician, although generally the dosage will be selected to achieve local concentrations at the site of action which achieve the desired effect without causing substantial harmful or deleterious side-effects.
  • Administration can be effected in one dose, continuously or intermittently (e.g., in divided doses at appropriate intervals) throughout the course of treatment. Methods of determining the most effective means and dosage of administration are well known to those of skill in the art and will vary with the formulation used for therapy, the purpose of the therapy, the target cell(s) being treated, and the subject being treated. Single or multiple administrations can be carried out with the dose level and pattern being selected by the treating physician, veterinarian, or clinician.
  • a suitable dose of the AAA compound is in the range of about 10 ⁇ g to about 250 mg (more typically about 100 ⁇ g to about 25 mg) per kilogram body weight of the subject per day.
  • the compound is a salt, an ester, an amide, a prodrug, or the like
  • the amount administered is calculated on the basis of the parent compound and so the actual weight to be used is increased proportionately.
  • DIPEA N,N-diisopropylethylamine
  • Hydrogenations were performed either on a Thales H-cube flow reactor or with a suspension of the catalyst under a balloon of hydrogen.
  • Microwave reactions were carried out on a Personal Chemistry SmithSynthesizer Workstation with a 300 W single mode microwave cavity.
  • SCX was purchased from Sigma Aldrich and washed with methanol prior to use.
  • the reaction mixture to be purified was first dissolved in methanol and then loaded directly onto the SCX and washed with methanol.
  • the desired material was then eluted by washing with 1% NH 3 in methanol.
  • the system consisted of a Gilson HPLC and an Agilent 5 ⁇ m Prep-C18 21.2 ⁇ 50 mm column. Detection was achieved using a UV detector at 254 nm.
  • Mobile phase A 0.1% aqueous formic acid
  • Mobile phase B 0.1% formic acid in methanol.
  • Method 1 Flow rate 40 mL/min. Gradient: 0.0-0.8 min 5% B; 0.8-7.3 min 5-95% B; 7.3-8.3 min 95% B; 8.3-8.4 min 95-5% B.
  • NMR spectra were recorded using a Bruker Avance IIITM 400 MHz instrument, using either residual non-deuterated solvent or tetra-methylsilane as reference.
  • Methyl 3,5-dichloro-4-hydroxybenzoate (1) (1.00 g, 4.52 mmol) was dissolved in DMF (8 mL) and treated with bromocyclopentane (534 ⁇ L, 4.98 mmol), followed by potassium carbonate (937 mg, 6.79 mmol). The mixture was stirred at 80° C. for 3 h and then partitioned between EtOAc (100 mL) and H 2 O (100 mL). The aqueous phase was extracted with EtOAc (50 mL) and the combined organic phases washed successively with water (5 ⁇ 50 mL) and brine (50 mL), then dried over MgSO 4 and filtered.
  • Methyl 3,5-dichloro-4-(cyclopentyloxy)benzoate (2) (1.05 g, 3.63 mmol) and lithium hydroxide (174 mg, 7.26 mmol) were combined in THF (10 mL) and water (ca. 1.5 mL) was added dropwise until a solution formed. The resultant mixture was stirred at RT for 12 h. The THF was removed in vacuo and the residue acidified using aqueous HCl (1 M). The resultant precipitate was filtered to afford 3,5-dichloro-4-(cyclopentyloxy)benzoic acid (3) (820 mg, 82%): m/z 273 (M ⁇ H) ⁇ (ES ⁇ ).
  • reaction mixture was stirred for 12 h at RT and then partitioned between DCM (20 mL) and aqueous HCl (20 mL, 1 M). The phases were separated and the organic phase was washed successively with water (2 ⁇ 20 mL), and brine (20 mL), dried over MgSO 4 , filtered and then the solvent was removed in vacuo. The residue was purified by silica gel chromatography (12 g, 0-100% EtOAc in isohexane) to afford methyl 4-(3,5-dichloro-4-(cyclopentyloxy)benzamido)benzoate (AAA-002) (30 mg, 20%): m/z 406 (M ⁇ H) ⁇ (ES ⁇ ).
  • AAA-003 4-(3,5-Dichloro-4-propoxybenzamido)benzoic acid (AAA-003) (34 mg, 71% for final step) was prepared in essentially the same manner as in Steps (iii) and (iv) for AAA-001 except that 3,5-dichloro-4-propoxybenzoic acid was used instead of 3,5-dichloro-4-(cyclopentyloxy)-benzoic acid in step (iii): m/z 366 (M ⁇ H) ⁇ (ES ⁇ ).
  • AAA-004 4-(3,5-Dichloro-4-isopropoxybenzamido)benzoic acid (AAA-004) (48.5 mg, 53% for final step) was prepared in essentially the same manner as AAA-001 except that isopropyl bromide was used instead of cyclopentyl bromide in step (i): m/z 366 (M ⁇ H) ⁇ (ES ⁇ ), 368 (M+H) + (ES + ). 1 H NMR (400 MHz, MeOH-d 4 ) ⁇ : 8.03 (4H, m), 7.83 (2H, d), 4.77 (1H, m), 1.38 (6H, s).
  • AAA-005 4-(4-Benzyloxy-3,5-dichlorobenzamido)benzoic acid (AAA-005) (21 mg, 46% for final step) was prepared in essentially the same manner as for AAA-001 except that benzyl bromide was used instead of cyclopentyl bromide in step (i): m/z 414 (M ⁇ H) ⁇ (ES ⁇ ).
  • AAA-006 4-(3-Chloro-4-(cyclopentyloxy)-5-methoxybenzamido)benzoic acid (AAA-006) (56 mg, 57% for final step) was prepared in essentially the same manner as in Steps (iii) and (iv) for AAA-001 except that 3-chloro-4-(cyclopentyloxy)-5-methoxybenzoic acid was used instead of 3,5-dichloro-4-(cyclopentyloxy)benzoic acid in step (iii): m/z 388 (M ⁇ H) ⁇ (ES ⁇ ), 390 (M+H) + (ES + ).
  • AAA-007 4-(3,5-Dichloro-4-ethoxybenzamido)-2-fluorobenzoic acid (AAA-007) (380 mg, 48% for final step) was prepared in essentially the same manner as for AAA-001 except that ethyl iodide was used instead of cyclopentyl bromide in step (i) and methyl 4-amino-2-fluorobenzoate (prepared by the action of hydrogen and 10% Pd/C on methyl 2-fluoro-4-nitrobenzoate) was used instead of methyl 4-aminobenzoate in step (iii): m/z 370 (M ⁇ H) ⁇ (ES ⁇ ), 372 (M+H) + (ES + ).
  • 4-(4-Ethoxy-3,5-diisopropoxybenzamido)benzoic acid (AAA-008) (288 mg, 57% for final step) was prepared in essentially the same manner as in Steps (iii) and (iv) for AAA-001 except that 4-ethoxy-3,5-diisopropoxybenzoic acid (prepared in 3 steps from methyl 3,4,5-trihydroxybenzoate by sequential treatment with ethyl iodide and base, isopropyl bromide and base and then lithium hydroxide) was used instead of 3,5-dichloro-4-(cyclopentyloxy)benzoic acid in step (iii): m/z 400 (M ⁇ H) ⁇ (ES ⁇ ), 402 (M+H) + (ES + ).
  • AAA-009 4-(3,4-Diethoxy-5-isopropoxybenzamido)benzoic acid (AAA-009) (5 mg, 15% for final step) was prepared in essentially the same manner as in Steps (iii) and (iv) for AAA-001 except that 3,4-diethoxy-5-diisopropoxybenzoic acid (prepared in 3 steps from methyl 3,4,5-trihydroxybenzoate by sequential treatment with ethyl iodide and base, isopropyl bromide and base and then lithium hydroxide, the product being a by-product of the preparation of 4-ethoxy-3,5-diisopropoxybenzoic acid shown in the synthesis of AAA-008) was used instead of 3,5-dichloro-4-(cyclopentyloxy)benzoic acid in step (iii): m/z 386 (M ⁇ H) ⁇ (ES ⁇ ), 388 (M+H) + (ES + ).
  • Methyl 4-(4-(benzyloxy)-3,5-dichlorobenzamido)benzoate (4) (9.81 g, 51%) was prepared from 4-(benzyloxy)-3,5-dichlorobenzoic acid (3) (12.8 g, 43.2 mmol) using a procedure essentially the same as in Step (iii) for AAA-001, except the crude product was crystallised from isohexane/EtOAc to afford the product as a white solid. m/z 428 (M ⁇ H) ⁇ (ES ⁇ ).
  • Methyl 4-(3,5-dichloro-4-(cyclopropylmethoxy)benzamido)benzoate (6) (120 mg, 100%) was prepared from methyl 4-(3,5-dichloro-4-hydroxybenzamido)benzoate (5) (100 mg, 294 ⁇ mol) and (bromomethyl)cyclopropane (57 ⁇ L, 588 ⁇ mol) using a procedure essentially the same as in Step (i) for AAA-001 except the mixture was stirred at 50° C. for 18 h: m/z 392 (M ⁇ H) ⁇ (ES ⁇ ).
  • AAA-010 4-(3,5-Dichloro-4-(cyclopropylmethoxy)benzamido)benzoic acid (AAA-010) (82 mg, 71%) was prepared from methyl 4-(3,5-dichloro-4-(cyclopropylmethoxy)benzamido)-benzoate (6) (120 mg, 304 ⁇ mol) using a procedure essentially the same as in Step (iv) for AAA-001: m/z 378 (M ⁇ H) ⁇ (ES ⁇ ).
  • AAA-011 4-(3,5-Dichloro-4-cyclobutoxybenzamido)benzoic acid (AAA-011) (23 mg, 31% for final step) was prepared in essentially the same manner as in Steps (v) and (vi) for AAA-010 except that bromocyclobutane was used instead of (bromomethyl)cyclopropane in step (v): m/z 378 (M ⁇ H) ⁇ (ES ⁇ ).
  • 1 H NMR 400 MHz, MeOH-d 4 ) ⁇ : 8.01 (4H, d), 7.85 (2H, s), 4.78-4.71 (1H, m), 2.4-2.35 (4H, m) 1.8-1.75 (1H, m), 1.64-1.49 (1H, m).
  • AAA-012 4-(3,5-Dichloro-4-(pyridin-4-ylmethoxy)benzamido)benzoic acid (AAA-012) (47 mg, 63% for final step) was prepared in essentially the same manner as in Steps (v) and (vi) for AAA-010 except that 4-(chloromethyl)pyridine was used instead of (bromomethyl)cyclopropane in step (v): m/z 415 [M ⁇ H] ⁇ (ES ⁇ ), 417 [M+H] + (ES + ), 1H NMR (400 MHz, MeOH-d 4 ) ⁇ : 10.43 (1H, s), 8.92 (2H, d), 8.30 (2H, d), 8.13 (2H, s), 8.04 (2H, d), 7.86 (2H, d), 5.54 (2H, s).
  • 3,5-Dibromo-4-ethoxyaniline (2) (100 mg, 339 ⁇ mol) was dissolved in DCM (2.5 mL) and treated with triethylamine (143 ⁇ L, 1.02 mmol).
  • 4-(Chlorocarbonyl)benzoic acid methyl ester (3) (135 mg, 678 ⁇ mol) was added in one portion and the resultant dark orange mixture was stirred at RT for 3 h then partitioned between EtOAc and aqueous 1M HCl. The organic layer was washed successively with saturated aqueous NaHCO 3 , water and brine. The organic layer was then dried over MgSO 4 , filtered and the solvent evaporated in vacuo. The residue was triturated from Et 2 O and filtered.
  • AAA-014 4-(3,5-Dibromo-4-ethoxyphenylcarbamoyl)benzoic acid (AAA-014) (31 mg, 71%) was prepared from methyl 4-(3,5-dibromo-4-ethoxyphenylcarbamoyl)benzoate (4) (45 mg, 98 ⁇ mol) using a procedure essentially the same as in Step (iii) for AAA-013, except the mixture was stirred overnight: m/z 442 [M ⁇ H] ⁇ (ES ⁇ ).
  • AAA-015 4-(4-Ethoxy-3,5-bis(trifluoromethyl)phenylcarbamoyl)benzoic acid (AAA-015) (107 mg, 70%) was prepared from methyl 4-(4-ethoxy-3,5-bis(trifluoromethyl)phenyl carbamoyl)benzoate (5) (150 mg, 345 ⁇ mol) using a procedure essentially the same as in Step (vi) for AAA-010: m/z 422 [M+H] + (ES + ).
  • 3,5-Dichloro-4-ethoxybenzoic acid (1) (100 mg, 425 ⁇ mol) was dissolved in DCM (2 mL) and treated with EDC (204 mg, 1.06 mmol) and DMAP (10 mg, 85 ⁇ mol). The resultant mixture was stirred at RT for 30 min. 4-Aminobenzamide (2) (58 mg, 425 ⁇ mol) was added and the resultant mixture was stirred at RT for 4 h. The mixture was filtered and the solid washed with DCM to afford N-(4-carbamoylphenyl)-3,5-dichloro-4-ethoxybenzamide (AAA-016) (98 mg, 64%) as a white solid: m/z 355 [M+H] + (ES + ).
  • Methyl 4-(3,5-dichloro-4-ethoxybenzamido)-2-chlorobenzoate (AAA-017) (175 mg, 39%) was prepared in essentially the same manner as in Step (iii) for AAA-001, except that 3,5-dichloro-4-ethoxybenzoic acid was used instead of 3,5-dichloro-4-(cyclopentyloxy)benzoic acid and methyl 4-amino-2-chlorobenzoate was used instead of methyl 4-aminobenzoate: m/z 402 (M ⁇ H) ⁇ (ES ⁇ ).
  • 6-(3,5-Dichloro-4-ethoxyphenylcarbamoyl)nicotinic acid (AAA-020) (19 mg, 109%) was prepared from methyl 6-(3,5-dichloro-4-ethoxyphenylcarbamoyl)nicotinate (3) (18 mg, 49 ⁇ mol) using a procedure essentially the same as in Step (iii) for AAA-013, except methanol (0.5 mL) was also added and the reaction mixture was stirred at RT overnight: m/z 353 [M ⁇ H] ⁇ (ES ⁇ ).
  • AAA-021 4-(4-Ethoxy-3,5-difluorophenylcarbamoyl)benzoic acid (AAA-021) (7 mg, 17%) was prepared was prepared in essentially the same manner as in Steps (ii) and (iii) for AAA-014, except that 3,5-difluoro-4-ethoxyaniline was used instead of 3,5-dibromo-4-ethoxyaniline in step (ii) and purification was effected by trituration with Et 2 O/EtOAc 8:1 and purification by preparative HPLC (Method 1): m/z 320 [M ⁇ H] ⁇ (ES ⁇ ).
  • AAA-024 4-(3-Chloro-4-ethoxy-5-methoxybenzamido)benzoic acid (AAA-024) (80 mg, 79% for final step) was prepared in essentially the same manner as in Steps (iii) and (iv) for AAA-001, except that 3-chloro-4-ethoxy-5-methoxybenzoic acid was used instead of 3,5-dichloro-4-(cyclopentyloxy)-benzoic acid in step (iii): m/z 348 (M ⁇ H) ⁇ (ES ⁇ ).
  • 5-(3,5-Dichloro-4-ethoxybenzamido)picolinic acid (AAA-026) (20 mg, quant. for final step) was prepared in essentially the same manner as in Steps (iii) and (iv) for AAA-001, except that 3,5-dichloro-4-ethoxybenzoic acid and methyl 5-aminopicolinate (prepared by treating 5-aminopyridine-2-carboxylic acid with acetyl chloride and methanol) were used instead of 3,5-dichloro-4-(cyclopentyloxy)benzoic acid and methyl 4-aminobenzoate respectively in step (iii): m/z 355 (M+H) + (ES + ).
  • 6-(3,5-Dichloro-4-ethoxybenzamido)nicotinic acid (28 mg, 29% for final step) was prepared in essentially the same manner as in Steps (iii) and (iv) for AAA-001, except that 3,5-dichloro-4-ethoxybenzoic acid and methyl 6-aminonicotinate were used instead of 3,5-dichloro-4-(cyclopentyloxy)benzoic acid and methyl 4-aminobenzoate respectively in step (iii): m/z 353 (M ⁇ H) ⁇ (ES ⁇ ).
  • AAA-028 4-(3,4,5-Triethoxybenzamido)benzoic acid (AAA-028) (42 mg, 68% for final step) was prepared in essentially the same manner as in Steps (iii) and (iv) for AAA-001, except that 3,4,5-triethoxybenzoic acid was used instead of 3,5-dichloro-4-(cyclopentyloxy)benzoic acid in step (iii): m/z 374 (M+H) + (ES + ).
  • the title compound was obtained from commercial sources.
  • the title compound was obtained from commercial sources.
  • 4-(4-Ethoxy-3-(trifluoromethyl)benzamido)benzoic acid (XXX-01) (14 mg, 49% for final step) was prepared in essentially the same manner as in Steps (iii) and (iv) for AAA-001, except that 4-ethoxy-3-(trifluoromethyl)benzoic acid (prepared in 2 steps from 4-hydroxy-3-(trifluoromethyl)benzoic acid by sequential treatment with ethyl iodide and base and then lithium hydroxide) was used instead of 3,5-dichloro-4-(cyclopentyloxy)benzoic acid in step (iii): m/z 352 (M ⁇ H) ⁇ (ES ⁇ ).
  • Ethyl 4-amino-2,6-difluorobenzoate (1) (3.26 g, 16.2 mmol) was dissolved in THF (40 mL) and treated with lithium hydroxide (1.94 g, 81 mmol), followed by water (10 mL). The resultant mixture was stirred at RT for 20 h. Methanol (4 mL) was added and the resultant mixture was stirred at RT for 20 h. The solvent was removed in vacuo. The residue was twice dissolved in toluene and the solvent removed in vacuo. The material was divided into three equal portions and each was dissolved in AcOH (5 mL) and then partitioned between EtOAc and water.
  • Benzyl 4-(4-ethoxy-3-(trifluoromethyl)benzamido)-2,6-difluorobenzoate (4) (172 mg, 37%) was prepared from 4-ethoxy-3-(trifluoromethyl)benzoic acid (250 mg, 1.07 mmol) and benzyl 4-amino-2,6-difluorobenzoate (4) (255 mg, 970 ⁇ mol) using a procedure essentially the same as in Step (iii) for AAA-001, except the reaction mixture was stirred at RT for 16 h and then heated at 35° C. for 1 h.
  • the crude product was partially purified by silica gel chromatography (15-20% EtOAc/isohexane) followed by trituration successively with 10% EtOAc/isohexane and then diethyl ether. The filtered solid was dissolved in EtOAc and washed twice with NaHCO 3 , then successively with water and brine. The organic phase was dried over MgSO 4 , filtered and the solvent removed in vacuo. The residue was further purified by silica gel chromatography (50% DCM/isohexane): m/z 477.8 (M ⁇ H) ⁇ (ES ⁇ ).
  • Benzyl 4-(4-ethoxy-3-(trifluoromethyl)benzamido)-2,6-difluorobenzoate (4) (25 mg, 52 ⁇ mol) was dissolved in methanol (10 mL) and was passed through a Thales ‘H-cube’ cartridge (10% Pd/C) at a flow rate of 1 mL/min at 25° C. under H 2 (10 bar). The solvent was removed in vacuo to afford 4-(4-ethoxy-3-(trifluoromethyl)benzamido)-2,6-difluorobenzoic acid (XXX-02) (20 mg, 97%) as a white solid: m/z 388.1 (M ⁇ H) ⁇ (ES ⁇ ).
  • the title compound was obtained from commercial sources.
  • AAA-031 4-(4-(tert-Butoxy)-3,5-dichlorobenzamido)benzoic acid (AAA-031) (39 mg, 51%) was prepared from methyl 4-(4-(tert-butoxy)-3,5-dichlorobenzamido)benzoate (2) (82 mg, 294 ⁇ mol) using a procedure essentially the same as in step (ii) for AAA-001: m/z 380 [M ⁇ H] ⁇ (ES ⁇ ); 1 H NMR (400 MHz, DMSO-d 6 ) ⁇ : 12.79 (1H, s), 10.60 (1H, s), 8.06 (2H, s), 7.94 (2H, d), 7.87 (2H, d), 1.49 (9H, s).
  • AAA-032 4-(3,5-Dichloro-4-isopropoxybenzamido-2-methylbenzoic acid (AAA-032) (30 mg, 41% for final step) was prepared in essentially the same manner as for (AAA-001) except that isopropyl bromide was used instead of cyclopentyl bromide in step (i) and methyl 4-amino-2-methylbenzoate was used instead of methyl 4-aminobenzoate in step (iii): m/z 383 (M+H) + (ES + ); 1 H NMR (400 MHz, DMSO) 12.61 (1H, bs), 10.46 (1H, s), 8.07 (2H, s), 7.86 (1H, m), 7.69 (2H, m), 4.66 (1H, m), 2.53 (3H, s), 1.33 (6H, d).
  • AAA-033 4-(3,5-Dichloro-4-ethoxybenzamido)-2-(trifluoromethyl)benzoic acid (AAA-033) (12 mg, 10% for final step) was prepared in essentially the same manner as for AAA-001 except that ethyl iodide was used instead of cyclopentyl bromide in step (i) and methyl 4-amino-2-(trifluoromethyl)benzoate (prepared from 4-amino-2-(trifluoromethyl)benzoic acid by reaction with MeOH and TMSCl) was used instead of methyl 4-aminobenzoate in step (iii): m/z 422 [M+H] + (ES + ); 420 [M ⁇ H] ⁇ (ES ⁇ ); 1 H NMR (400 MHz, DMSO-d 6 ) ⁇ : 10.77 (1H, s), 8.26 (1H, s), 8.14 (1H, d), 8.10 (2H, s), 7.88 (1H,
  • Methyl 4-(3-chloro-4-hydroxy-5-(trifluoromethyl)benzamido)benzoate (4) (178 mg, 22%) was prepared in essentially the same manner as in step (iii) for AAA-001 except that 3-chloro-4-hydroxy-5-trifluoromethylbenzoic acid was used instead of 3,5-dichloro-4-(cyclopentyloxy)benzoic acid: m/z 374 [M+H] + (ES + ); 1 H NMR (400 MHz, DMSO-d 6 ) ⁇ : 11.43 (1H, br s), 10.50 (1H, s), 8.33 (1H, d), 8.16 (1H, d), 7.97 (2H, m), 7.91 (2H, m), 3.84 (3H, s).
  • Methyl 4-(3-chloro-4-cyclobutoxy-5-(trifluoromethyl)benzamido)benzoate (5) (105 mg, 51%) was prepared in essentially the same manner as in steps (i) for AAA-001 except that cyclobutyl bromide and tetrabutylammonium iodide were used instead of cyclopentylbromide and that the reaction was carried out at 90° C.: m/z 428 [M+H] + (ES + ); 1 H NMR (400 MHz, DMSO-d 6 ) ⁇ : 10.72 (1H, s), 8.40 (1H, d), 8.20 (1H, d), 7.90 (2H, m), 7.97 (2H, m) 4.72 (1H, m), 3.84 (3H, s), 2.36 (2H, m), 2.27 (2H, m), 1.69 (1H, m), 1.44 (1H, m).
  • AAA-037 4-(4-(tert-Butoxy)-3-chloro-5-(trifluoromethyl)benzamido)benzoic acid (AAA-037) (27 mg, 39% for final step) was prepared in essentially the same manner as for AAA-031 except that methyl-4-(3-chloro-4-hydroxy-5-(trifluoromethyl)benzamido)benzoate (Synthesis 38 steps (i) and (ii)) was used instead of methyl 4-(3,5-dichloro-4-hydroxybenzamido)benzoate in step (i): m/z 416 [M+H] + (ES + ), 414 [M ⁇ H] ⁇ (ES ⁇ ); 1 H-NMR (400 MHz, DMSO-d 6 ) ⁇ : 12.77 (1H, s), 10.69 (1H, s), 8.40 (1H, d), 8.21 (1H, d), 7.95 (2H, m), 7.88 (2H, m), 1.48 (9H
  • AAA-038 4-(4-(tert-Butoxy)-3-chloro-5-(trifluoromethyl)benzamido)-2-methylbenzoic acid (AAA-038) (10 mg, 32% for final step) was prepared in essentially the same manner as for AAA-031 except that methyl 4-(3-chloro-4-hydroxy-5-(trifluoromethyl)benzamido)-2-methylbenzoate was used instead of methyl 4-(3,5-dichloro-4-hydroxybenzamido)benzoate in step (i).
  • Methyl 4-(3-chloro-4-hydroxy-5-(trifluoromethyl)benzamido)-2-methylbenzoate was prepared essentially as in synthesis 38 steps (i) and (ii) except that and methyl 4-amino-2-methylbenzoate was used instead of methyl 4-aminobenzoate in step (ii): m/z 430 [M+H] + (ES + ), 428 [M ⁇ H] ⁇ (ES ⁇ ); 1 H-NMR (400 MHz, d 4 -MeOH) ⁇ : 8.30 (1H, d), 8.20 (1H, d), 7.95 (1H, d), 7.68-7.65 (2H, m), 2.60 (3H, s), 1.54 (9H, s).
  • AAA-019 4-(3-Chloro-4-ethoxy-5-(trifluoromethyl)benzamido)-2-methylbenzoic acid (AAA-039) (36 mg, 53% for final step) was prepared in essentially the same manner as for AAA-019 except that 3-chloro-4-ethoxy-5-trifluoromethylbenzoic acid was used instead of 3,5-dichloro-4-ethoxybenzoic acid in step (i) and 1,4-dioxane (5 mL) was used instead of THF in step (ii): m/z 402 [M+H] + (ES + ), 400 [M ⁇ H] ⁇ (ES ⁇ ); 1 H-NMR (400 MHz, DMSO-d 6 ) ⁇ : 12.65 (1H, br s), 10.59 (1H, s), 8.42 (1H, d), 8.23 (1H, d), 7.88 (1H, d), 7.74-7.68 (2H, m), 4.20 (2H, q), 2.55 (3
  • AAA-040 4-(3-Chloro-4-isopropoxy-5-(trifluoromethyl)benzamido)-2-methylbenzoic acid (AAA-040) (36 mg, 65% for final step) was prepared in essentially the same manner as for AAA-019 except that 3-chloro-4-isopropoxy-5-trifluoromethylbenzoic acid was used instead of 3,5-dichloro-4-ethoxybenzoic acid in step (i) and 1,4-dioxane (5 mL) was used instead of THF in step (ii): m/z 416 [M+H] + (ES + ), 414 [M ⁇ H] ⁇ (ES ⁇ ); 1 H-NMR (400 MHz, DMSO-d 6 ) ⁇ : 12.57 (1H, br s), 10.56 (1H, s), 8.39 (1H, d), 8.22 (1H, d), 7.88 (1H, d), 7.73-7.67 (2H, m), 5.06 (2H, sep),
  • AAA-041 4-(3-Chloro-4-methoxy-5-(trifluoromethyl)benzamido)-2-methylbenzoic acid (AAA-041) (28 mg, 57% for final step) was prepared in essentially the same manner as for AAA-019 except that 3-chloro-4-methoxy-5-trifluoromethylbenzoic acid was used instead of 3,5-dichloro-4-ethoxybenzoic acid in step (i) and 1,4-dioxane (2.5 mL) was used instead of THF in step (ii): m/z 388 [M+H] + (ES + ), 386 [M ⁇ H] ⁇ (ES ⁇ ); 1 H-NMR (400 MHz, DMSO-d 6 ) ⁇ : 12.62 (1H, br s), 10.59 (1H, s), 8.43 (1H, d), 8.23 (1H, d), 7.88 (1H, d), 7.73-7.67 (2H, m), 3.97 (3H, s), 2.54
  • AAA-042 4-(3-Bromo-4-ethoxy-5-(trifluoromethyl)benzamido)benzoic acid (AAA-042) (35 mg, 60% for final step) was prepared in essentially the same manner as for AAA-019 except that 3-bromo-4-ethoxy-5-trifluoromethylbenzoic acid (prepared in 3 steps from 4-hydroxy-3-(trifluoromethyl)benzoic acid by sequential treatment with bromine in acetic acid, ethyl iodide and base and then lithium hydroxide) was used instead of 3,5-dichloro-4-ethoxybenzoic acid and methyl 4-aminobenzoate was used instead of methyl 4-amino-2-methylbenzoate in step (i) and 1,4-dioxane (2.5 mL) was used instead of THF in step (ii): m/z 434 [M+H] + (ES + ), 432 [M ⁇ H] ⁇ (ES ⁇ ); 1 H-NMR (400 MHz
  • AAA-043 4-(3-Chloro-4-(cyclopentyloxy)-5-(trifluoromethyl)benzamido)benzoic acid (AAA-043) (20 mg, 26% for final step) was prepared in essentially the same manner as for AAA-036 except that cyclopentyl iodide was used instead of cyclobutyl iodide in step (iii): m/z 426 [M ⁇ H] ⁇ (ES ⁇ ); 1 H NMR (400 MHz, DMSO-d 6 ) ⁇ : 12.71 (1H, br s), 10.69 (1H, s), 8.40 (1H, d), 8.22 (1H, d), 7.96 (2H, m), 7.88 (2H, m), 5.27 (1H, q), 1.86 (4H, m), 1.75 (2H, m), 1.59 (2H, m).
  • Tribromoborane (7.86 mL, 82 mmol) was added dropwise to a stirring mixture of 3-chloro-4-hydroxy-5-methoxybenzoic acid (1) (6.61 g, 32.6 mmol) in DCM (50 mL) under nitrogen at 0° C. The resulting orange mixture was stirred at the same temperature for 2 h then poured portionwise onto ice/brine (250 mL). The aqueous phase was extracted with EtOAc (2 ⁇ 150 mL) and the combined organic extracts were dried over MgSO 4 and filtered.
  • Methyl 4-(3-chloro-4,5-bis(cyclopentyloxy)benzamido)benzoate (7) was prepared from 3-chloro-4,5-bis(cyclopentyloxy)benzoic acid (5) (200 mg, 0.616 mmol) using a procedure essentially the same as in Step (iii) for AAA-001: m/z 458 [M+H] + (ES + ), 456 [M ⁇ H] ⁇ (ES ⁇ ); 1 H NMR (400 MHz, CDCl 3 ) ⁇ : 8.06 (2H, d), 7.84 (1H, br s), 7.71 (2H, d), 7.38 (2H, d), 5.02 (1H, m), 4.88 (1H, m), 3.92 (3H, s), 1.95-1.63 (16H, m).
  • AAA-045 4-(3,4-bis(Benzyloxy)-5-chlorobenzamido)benzoic acid (AAA-045) (48 mg, 96% for final step) was prepared in essentially the same manner as for AAA-044 except that benzyl bromide was used instead of cyclopentyl iodide in step (iii) and stirring was carried out at 40° C.
  • AAA-046 4-(3-Chloro-4,5-bis(cyclopentyloxy)benzamido)-2-methylbenzoic acid (AAA-046) (65 mg, 85% for final step) was prepared in essentially the same manner as for AAA-044 except that methyl 4-amino-2-methylbenzoate (prepared from 4-amino-2-methylbenzoic acid by reaction with methanol and chlorotrimethylsilane) was used instead of methyl 4-aminobenzoate in Step (v): m/z 456 [M ⁇ H] ⁇ (ES ⁇ ); 1 H NMR (400 MHz, DMSO-d 6 ) ⁇ : 12.63 (1H, br s), 10.33 (1H, s), 7.86 (1H, d), 7.72-7.68 (3H, m), 7.52 (1H, d), 4.98 (2H, m), 2.54 (3H, s), 1.99-1.91 (2H, m), 1.78-1.58 (14H, m).
  • Diisopropylazo dicarboxylate (807 ⁇ L, 4.10 mmol) was added dropwise to a stirring mixture of methyl 4-(benzyloxy)-3-chloro-5-hydroxybenzoate (2) (300 mg, 1.03 mmol), cyclohexanol (434 ⁇ L, 4.10 mmol) and triphenylphosphine (1.08 g, 4.10 mmol) in THF (5 mL) and the mixture was stirred at RT for 20 h. The reaction was quenched with MeOH (10 mL) and the solvent was removed in vacuo.
  • Diisopropylazo dicarboxylate (63 ⁇ L, 0.32 mmol) was added dropwise to a stirring mixture of methyl 4-(3-chloro-5-(cyclohexyloxy)-4-hydroxybenzamido)benzoate (7) (65 mg, 161 ⁇ mol), cyclohexanol (34 ⁇ L, 0.32 mmol) and triphenylphosphine (84 mg, 0.32 mmol) in THF (2 mL) and the resulting yellow mixture was stirred at RT for 20 h. The reaction was quenched with MeOH (5 mL) and the solvent was removed in vacuo.
  • N,N-Dimethylformamide di-tert-butyl acetal (2) (5.92 mL, 24.7 mmol) was added to a solution of methyl 3-chloro-4,5-dihydroxybenzoate (1) (500 mg, 2.47 mmol) in toluene (10 mL) and the reaction mixture was stirred at RT under nitrogen for 21 h. The solvent was removed in vacuo and the residue was purified by silica gel chromatography (40 g, 0-20% EtOAc in iso-hexane) to give the bis-alkylated intermediate, which was dissolved in 1,4-dioxane/water (20 mL, 1:1) and treated with lithium hydroxide (591 mg, 24.7 mmol).
  • Methyl 4-(3,4-di-tert-butoxy-5-chlorobenzamido)benzoate (5) (185 mg, 50%) was prepared from 3,4-di-tert-butoxy-5-chlorobenzoic acid (3) (250 mg, 0.831 mmol) using a procedure essentially the same as in Step (i) for AAA-019 except that methyl 4-aminobenzoate was used instead of methyl 4-amino-2-methylenzoate and TEA (579 ⁇ L, 4.16 mmol) was used as base instead of DIPEA: m/z 432 [M ⁇ H] ⁇ (ES ⁇ ); 1 H NMR (400 MHz, DMSO-d 6 ) ⁇ : 10.54 (1H, s), 7.96 (2H, d), 7.91 (2H, d), 7.86 (1H, d), 7.60 (1H, d), 3.84 (3H, s), 1.41 (9H, s), 1.32 (9H, s).
  • AAA-049 4-(3,4-Di-tert-butoxy-5-chlorobenzamido)-2-methylbenzoic acid (AAA-049) (86 mg, 49% for final step) was prepared in essentially the same manner as for AAA-048 except that methyl 4-amino-2-methylbenzoate was used instead of methyl 4-aminobenzoate in step (ii): m/z 432 [M ⁇ H] ⁇ (ES ⁇ ); 1 H NMR (400 MHz, DMSO-d 6 ) ⁇ : 12.60 (1H, br s), 10.38 (1H, s), 7.86 (2H, m), 7.72 (1H, br d), 7.70 (1H, br s), 7.60 (1H, d), 2.45 (3H, s), 1.41 (9H, s), 1.32 (9H, s).
  • AAA-050 4-(3-Chloro-4,5-diisopropoxybenzamido)benzoic acid (AAA-050) (134 mg, 74% for final step) was prepared in essentially the same manner as AAA-044 except isopropyl bromide was used instead of cyclopentyl iodide and the reaction performed at 80° C.
  • AAA-051 4-(3-Chloro-4,5-diisopropoxybenzamido)benzoic acid (AAA-051) (103 mg, 48% for final step) was prepared in essentially the same manner as AAA-044 except isopropyl bromide was used instead of cyclopentyl iodide and the reaction performed at 80° C.
  • step (iii) methyl 4-amino-2-methylbenzoate was used instead of methyl 4-aminobenzoate in step (v): m/z 404 [M ⁇ H] ⁇ (ES ⁇ ); 1 H NMR (400 MHz, DMSO-d 6 ) ⁇ : 12.62 (1H, br s), 10.34 (1H, s), 7.87 (1H, d), 7.73 (1H, dd), 7.68 (2H, d), 7.54 (1H, d), 4.76 (1H, m), 4.59 (1H, m), 2.54 (3H, s), 1.33 (6H, d), 1.28 (6H, d).
  • AAA-052 4-(3,5-Dibromo-4-isopropoxybenzamido)-2-methylbenzoic acid (AAA-052) (166 mg, 56% for final step) was prepared in essentially the same manner as for AAA-019 except that 3,5-dibromo-4-isopropoxybenzoic acid (prepared in 2 steps from 3,5-dibromo-4-hydroxybenzoic acid by sequential treatment with isopropyl bromide and base followed by lithium hydroxide) was used instead of 3,5-dichloro-4-ethoxybenzoic acid in step (i): m/z 470 [M ⁇ H] ⁇ (ES ⁇ ); 1 H NMR (400 MHz, DMSO-d 6 ) ⁇ : 12.61 (1H, br s), 10.47 (1H, s), 8.25 (2H, s), 7.87 (1H, m), 7.71 (1H, m), 7.68 (1H, m), 4.75 (1H, m), 2.54 (3H, s), 1.35 (6
  • AAA-053 4-(3,5-Dibromo-4-ethoxybenzamido)-2-methylbenzoic acid (AAA-053) (57 mg, 64% for final step) was prepared in essentially the same manner as for AAA-019 except that 3,5-dibromo-4-ethoxybenzoic acid (prepared in 2 steps from 3,5-dibromo-4-hydroxybenzoic acid by sequential treatment with ethyl iodide and base followed by lithium hydroxide) was used instead of 3,5-dichloro-4-ethoxybenzoic acid in step (i) m/z 456 [M ⁇ H] ⁇ (ES ⁇ ); 1 H NMR (400 MHz, DMSO-d 6 ) ⁇ : 12.64 (1H, br s), 10.48 (1H, s), 8.25 (2H, s), 7.87 (1H, m), 7.71 (1H, m), 7.67 (1H, m), 4.10 (2H, q), 2.54 (3H, s), 1.43 (3H
  • AAA-054 4-(3,5-Dichloro-4-(cyclopentyloxy)benzamido)-2-methylbenzoic acid (AAA-054) (137 mg, 46% for final step) was prepared in essentially the same manner as AAA-001 except that methyl 4-amino-2-methylbenzoate, HATU and DIPEA were used instead of methyl 4-aminobenzoate, oxalyl chloride, DIPEA and DMF in step (iii): m/z 406 [M ⁇ H] ⁇ (ES ⁇ ); 1 H NMR (400 MHz, DMSO-d 6 ) ⁇ : 12.63 (1H, br s), 10.46 (1H, s), 8.07 (2H, s), 7.87 (1H, m), 7.72-7.68 (2H, m), 5.02 (1H, m), 2.54 (3H, s), 1.91-1.78 (6H, m), 1.63-1.60 (2H, m).
  • AAA-055 4-(3,5-Dichloro-4-methoxybenzamido)-2-methylbenzoic acid (AAA-055) (53 mg, 18% for final step) was prepared in essentially the same manner as AAA-001 except that methyl iodide was used instead of cyclopentyl bromide in step (i) and methyl 4-amino-2-methylbenzoate, HATU and DIPEA were used instead of methyl 4-aminobenzoate, oxalyl chloride, DIPEA and DMF in step (iii): m/z 352 [M ⁇ H] ⁇ (ES ⁇ ), 354 [M+H] + (ES + ); 1 H NMR (400 MHz, DMSO-d 6 ) ⁇ : 12.65 (1H, br s), 10.48 (1H, s), 8.09 (2H, s), 7.87 (1H, m), 7.73-7.68 (2H, m), 3.91 (3H, s), 2.89 (3H,
  • AAA-046 4-(4-tert-Butoxy-3,5-dichlorobenzamido)-2-methylbenzoic acid (AAA-056) (73 mg, 24% for final step) was prepared in essentially the same manner as AAA-048 except that 5 eq.
  • step (i) m/z 394 [M ⁇ H] ⁇ (ES ⁇ ), 396 [M+H] + (ES + ); 1 H NMR (400 MHz, DMSO-d 6 ) ⁇ : 12.64 (1H, br s), 10.48 (1H, s), 8.07 (2H, s), 7.87 (1H, m), 7.72-7.68 (2H, m), 2.54 (3H, s), 1.50 (9H, s).
  • 1,1-di-tert-Butoxy-N,N-dimethylmethanamine (608 ⁇ L, 2.54 mmol) was added dropwise to a solution of 2-methoxy-4-nitrobenzoic acid (1) (250 mg, 1.27 mmol) in toluene (7.5 mL) at 80° C.
  • the reaction mixture was heated at 80° C. for 3 h, then a further quantity of 1,1-di-tert-butoxy-N,N-dimethylmethanamine (608 ⁇ L, 2.54 mmol) was added.
  • the reaction mixture was heated at 80° C. for 16 h, then diluted with water (10 mL) and extracted with Et 2 O (3 ⁇ 10 mL).
  • tert-Butyl 2-methoxy-4-nitrobenzoate (2) (271 mg, 1.07 mmol) was dissolved in MeOH (270 mL) and passed through a Thales ‘H-cube’ cartridge (10% Pd/C) at a flow rate of 1 mL/min at 25° C. under full H 2 mode.
  • AAA-060 4-(3,4,5-Tri-tert-butoxybenzamido)benzoic acid (AAA-060) (53 mg, 84% for final step) was prepared in essentially the same manner as in Steps (iii) and (iv) for AAA-001 except that 3,4,5-tri-tert-butoxybenzoic acid (prepared in 2 steps from methyl 3,4,5-trihydroxybenzoate by sequential reaction with 1,1-di-tert-butoxy-N,N-dimethylmethanamine and then lithium hydroxide) was used instead of 3,5-dichloro-4-(cyclopentyloxy)benzoic acid in step (iii): m/z 458 [M+H] + (ES + ), 456 [M ⁇ H] ⁇ (ES ⁇ ); 1 H NMR (400 MHz, CDCl 3 ) ⁇ : 8.12 (2H, d), 7.84 (1H, s), 7.75 (2H, d), 7.30 (2H, s), 1.38 (27H,
  • AAA-061 4-(4-Ethoxy-3,5-diisopropoxybenzamido)-2-methylbenzoic acid (AAA-061) (30 mg, 31% for final step) was prepared in essentially the same manner as in steps (iii) and (iv) for AAA-001 except that 4-ethoxy-3,5-diisopropoxybenzoic acid was used instead of 3,5-dichloro-4-(cyclopentyloxy)benzoic acid and methyl 4-amino-2-methylbenzoate was used instead of methyl 4-aminobenzoate in step (iii): m/z 416 (M+H) + (ES + ); 1 H NMR (400 MHz, DMSO) 12.60 (1H, bs), 10.19 (1H, s), 7.86 (1H, d), 7.70 (1H, dd), 7.66 (1H, d), 7.23 (2H, s), 4.67-4.61 (2H, m), 3.99 (2H, q), 2.53 (3
  • AAA-062 4-(3,5-Diisopropoxy-4-methoxybenzamido)benzoic acid (AAA-062) (223 mg, 77% for final step) was prepared in essentially the same manner as for AAA-019 except that 3,5-diisopropoxy-4-methoxybenzoic acid (prepared in 3 steps from methyl 3,4,5-trihydroxybenzoate by sequential treatment with methyl iodide and base, isopropyl bromide and base and then lithium hydroxide) was used instead of 3,5-dichloro-4-ethoxybenzoic acid and methyl 4-aminobenzoate was used instead of methyl 4-amino-2-methylbenzoate in step (i): m/z 388 [M+H] + (ES + ), 386 [M ⁇ H] ⁇ (ES ⁇ ).
  • AAA-063 4-(3,5-Diisopropoxy-4-methoxybenzamido)-2-methylbenzoic acid (AAA-063) (207 mg, 69% for final step) was prepared in essentially the same manner as for AAA-019 except that 3,5-diisopropoxy-4-methoxybenzoic acid was used instead of 3,5-dichloro-4-ethoxybenzoic acid in step (i): m/z 402 [M+H] + (ES + ), 400 [M ⁇ H] ⁇ (ES ⁇ ).
  • 6-(3-Chloro-4-methoxy-5-(trifluoromethyl)benzamido)nicotinic acid (AAA-065) (65 mg, 48% for final step) was prepared in essentially the same manner as in steps (iii) and (iv) for AAA-001 except that 3-chloro-4-methoxy-5-(trifluoromethyl)benzoic acid was used instead of 3,5-dichloro-4-(cyclopentyloxy)benzoic acid, methyl 6-aminonicotinate was used instead of methyl 4-aminobenzoate and pyridine was used instead of TEA in step (iii) and 1,4-dioxane was used instead of THF in step (iv): m/z 375 [M+H] + (ES + ), 373 [M ⁇ H] ⁇ (ES ⁇ ).
  • AAA-066 4-(3-Chloro-4-methoxy-5-(trifluoromethyl)benzamido)-2-fluorobenzoic acid (AAA-066) (30 mg, 42% for final step) was prepared in essentially the same manner as for AAA-019 except that 3-chloro-4-methoxy-5-(trifluoromethyl)benzoic acid was used instead of 3,5-dichloro-4-ethoxybenzoic acid, methyl 4-amino-2-fluorobenzoate was used instead of methyl 4-amino-2-methylbenzoate and TEA was used instead of DIPEA in step (i): m/z 392 [M+H] + (ES + ), 390 [M ⁇ H] ⁇ (ES ⁇ ).
  • AAA-067 4-(3-Chloro-4-methoxy-5-(trifluoromethyl)benzamido)-3-fluorobenzoic acid (AAA-067) (11 mg, 31% for final step) was prepared in essentially the same manner as for AAA-019 except that 3-chloro-4-methoxy-5-(trifluoromethyl)benzoic acid was used instead of 3,5-dichloro-4-ethoxybenzoic acid, methyl 4-amino-3-fluorobenzoate was used instead of methyl 4-amino-2-methylbenzoate and TEA was used instead of DIPEA in step (i): m/z 392 [M+H] + (ES + ), 390 [M ⁇ H] ⁇ (ES ⁇ ).
  • AAA-068 4-(3-Chloro-4-ethoxy-5-(trifluoromethyl)benzamido)-2-fluorobenzoic acid (AAA-068) (11 mg, 31% for final step) was prepared in essentially the same manner as for AAA-064 except that 3-chloro-4-ethoxy-5-(trifluoromethyl)benzoic acid was used instead of 3,5-diisopropoxy-4-ethoxybenzoic acid in step (i): m/z 404 [M ⁇ H] ⁇ (ES ⁇ ).
  • AAA-069 4-(3-Chloro-4-isopropoxy-5-(trifluoromethyl)benzamido)-2-fluorobenzoic acid (AAA-069) (155 mg, 67% for final step) was prepared in essentially the same manner as for AAA-064 except that 3-chloro-4-isopropoxy-5-(trifluoromethyl)benzoic acid was used instead of 3,5-diisopropoxy-4-ethoxybenzoic acid in step (i): m/z 418 [M ⁇ H] ⁇ (ES ⁇ ).
  • AAA-070 4-(3-Chloro-4-methoxy-5-(trifluoromethyl)benzamido)-2-hydroxybenzoic acid (AAA-070) (73 mg, 58% for final step) was prepared in essentially the same manner as for AAA-064 except that 3-chloro-4-methoxy-5-(trifluoromethyl)benzoic acid was used instead of 3,5-diisopropoxy-4-ethoxybenzoic acid and methyl 4-amino-2-hydroxybenzoate (prepared from methyl 4-amino-2-hydroxybenzoic acid by treatment with H 2 SO 4 and MeOH) was used instead of methyl 4-amino-2-fluorobenzoate in step (i): m/z 388 [M ⁇ H] ⁇ (ES ⁇ ).
  • AAA-011 4-(3-Bromo-4-ethoxy-5-(trifluoromethyl)benzamido)-2-methylbenzoic acid (AAA-071) (20 mg, 52% for final step) was prepared in essentially the same manner as for AAA-019 except that 3-bromo-4-ethoxy-5-trifluoromethylbenzoic acid was used instead of 3,5-dichloro-4-ethoxybenzoic acid in step (i): m/z 446 and 448 [M+H] + (ES + ), 444 and 446 [M ⁇ H] ⁇ (ES ⁇ ).
  • AAA-072 4-(3-Bromo-4-ethoxy-5-(trifluoromethyl)benzamido)-2-fluorobenzoic acid (AAA-072) (95 mg, 64% for final step) was prepared in essentially the same manner as for AAA-019 except that 3-bromo-4-ethoxy-5-trifluoromethylbenzoic acid was used instead of 3,5-dichloro-4-ethoxybenzoic acid and methyl 4-amino-2-fluorobenzoate was used instead of methyl 4-amino-2-methylbenzoate in step (i): m/z 451 [M+H] + (ES + ), 449 [M ⁇ H] ⁇ (ES ⁇ ).
  • 4-(4-Ethoxy-3,5-difluorobenzamido)benzoic acid (AAA-073) (74 mg, 80% for final step) was prepared in essentially the same manner as for AAA-019 except that 4-ethoxy-3,5-difluorobenzoic acid (prepared in 3 steps from 3,5-difluoro-4-methoxybenzoic acid by sequential treatment with BBr 3 , ethyl iodide and base and then lithium hydroxide) was used instead of 3,5-dichloro-4-ethoxybenzoic acid, methyl 4-aminobenzoate was used instead of methyl 4-amino-2-methylbenzoate and TEA was used instead of DIPEA in step (i): m/z 322 [M+H] + (ES + ), 320 [M ⁇ H] ⁇ (ES) ⁇ .
  • AAA-074 4-(3-Chloro-5-fluoro-4-isopropoxybenzamido)-2-methylbenzoic acid (AAA-074) (52 mg, 12% for final step) was prepared in essentially the same manner as for AAA-019 except that 4-(3-chloro-5-fluoro-4-isopropoxybenzoic acid (prepared in 3 steps from 3-chloro-5-fluoro-4-methoxybenzoic acid by sequential treatment with BBr 3 , isopropyl bromide and base and then lithium hydroxide) was used instead of 3,5-dichloro-4-ethoxybenzoic acid and TEA was used instead of DIPEA in step (i): m/z 366 [M+H] + (ES + ), 364 [M ⁇ H] ⁇ (ES) ⁇ .
  • Methyl 4-(benzyloxy)-3-chloro-5-isopropoxybenzoate (2) (3.00 g, 94%) was prepared from methyl 4-(benzyloxy)-3-chloro-5-hydroxybenzoate (1) (Synthesis 49 (2.73 g, 9.33 mmol) using a procedure essentially the same as in step (i) for AAA-001 except that isopropyl bromide was used instead of cyclopentyl bromide: m/z 335 [M+H] + (ES + ).
  • Methyl 4-(benzyloxy)-3-chloro-5-isopropoxybenzoate (2) (3.00 g, 8.96 mmol) was dissolved in a mixture of MeOH (100 mL), DCM (10 mL) and AcOH (0.1 mL) and the solution was passed through a Thales ‘H-cube’ cartridge (10% Pd/C) at a flow rate of 1 mL/min at 25° C. under H 2 (full H 2 mode). The solvents were removed in vacuo to afford methyl 3-chloro-4-hydroxy-5-isopropoxybenzoate (3) (2.03 g, 89%): m/z 245 [M+H] + (ES + ), 243 [M ⁇ H] ⁇ (ES ⁇ ).
  • Methyl 3-chloro-5-isopropoxy-4-methoxybenzoate (4) (1.06 g, 95%) was prepared from methyl 3-chloro-4-hydroxy-5-isopropoxybenzoate (3) (1.00 g, 4.09 mmol) using a procedure essentially the same as in step (i) for AAA-001 except that methyl iodide was used instead of cyclopentyl bromide and the mixture was stirred at RT for 18 h.
  • 3-Chloro-5-isopropoxy-4-methoxybenzoic acid (5) (0.93 g, 89%) was prepared from methyl 3-chloro-5-isopropoxy-4-methoxybenzoate (4) (1.06 g, 4.10 mmol) using a procedure essentially the same as in step (ii) for AAA-001 except that MeOH instead of water was added dropwise until a solution formed: m/z 243 [M ⁇ H] ⁇ (ES ⁇ ).
  • AAA-076 4-(3-Chloro-5-isopropoxy-4-methoxybenzamido)benzoic acid (AAA-076) (47 mg, 56% for final step) was prepared in essentially the same manner as AAA-075 except that methyl 4-aminobenzoate was used instead of methyl 4-amino-2-methylbenzoate in step (v): m/z 364 [M+H] + (ES + ), 362 [M ⁇ H] ⁇ (ES ⁇ ).
  • AAA-077 4-(3-Chloro-5-isopropoxy-4-methoxybenzamido)-2-fluorobenzoic acid (AAA-077) (116 mg, 76% for final step) was prepared in essentially the same manner as AAA-075 except that methyl 4-amino-2-fluorobenzoate was used instead of methyl 4-amino-2-methylbenzoate in step (v): m/z 380 [M ⁇ H] ⁇ (ES ⁇ ).
  • AAA-078 4-(3-Chloro-4-ethoxy-5-isopropoxybenzamido)benzoic acid (AAA-078) (145 mg, 80% for final step) was prepared in essentially the same manner as AAA-075 except that ethyl iodide was used instead of methyl iodide in step (iii) and methyl 4-aminobenzoate was used instead of methyl 4-amino-2-methylbenzoate in step (v): m/z 378 [M+H] + (ES + ), 376 [M ⁇ H] ⁇ (ES ⁇ ).
  • AAA-079 4-(3-Chloro-4-ethoxy-5-isopropoxybenzamido)-2-fluorobenzoic acid (AAA-079) (120 mg, 78% for final step) was prepared in essentially the same manner as AAA-075 except that ethyl iodide was used instead of methyl iodide in step (iii) and methyl 4-amino-2-fluorobenzoate was used instead of methyl 4-amino-2-methylbenzoate in step (v): m/z 394 [M ⁇ H] ⁇ (ES ⁇ ).
  • AAA-080 4-(3-Chloro-4-ethoxy-5-isopropoxybenzamido)-2-methylbenzoic acid (AAA-080) (155 mg, 74% for final step) was prepared in essentially the same manner as AAA-075 except that ethyl iodide was used instead of methyl iodide in step (iii): m/z 392 [M+H] + (ES + ), 390 [M ⁇ H] ⁇ (ES ⁇ ).
  • AAA-081 4-(3-Chloro-4-ethoxy-5-isopropoxybenzamido)-2-hydroxybenzoic acid (AAA-081) (29 mg, 37% for final step) was prepared in essentially the same manner as AAA-075 except that ethyl iodide was used instead of methyl iodide in step (iii) and methyl 4-amino-2-hydroxybenzoate was used instead of methyl 4-amino-2-methylbenzoate in step (v): m/z 394 [M+H] + (ES + ), 392 [M ⁇ H] ⁇ (ES ⁇ ).
  • 6-(3-Chloro-4-ethoxy-5-isopropoxybenzamido)pyridazine-3-carboxylic acid (AAA-082) (25 mg, 43% for final step) was prepared in essentially the same manner as AAA-075 except that ethyl iodide was used instead of methyl iodide in step (iii) and methyl 6-aminopyridazine-3-carboxylate was used instead of methyl 4-amino-2-methylbenzoate in step (v): m/z 380 [M+H] + (ES + ), 378 [M ⁇ H] ⁇ (ES ⁇ ).
  • AAA-083 4-(3-Chloro-4-isopropoxy-5-methoxybenzamido)benzoic acid (AAA-083) (116 mg, 55% for final step) was prepared in essentially the same manner as AAA-075 except that methyl iodide at RT was used instead of isopropyl bromide in step (i), isopropyl bromide at 60° C. was used instead of methyl iodide in step (iii) and methyl 4-aminobenzoate was used instead of methyl 4-amino-2-methylbenzoate in step (v): m/z 364 [M+H] + (ES + ), 362 [M ⁇ H] ⁇ (ES ⁇ ).
  • AAA-084 4-(3-Chloro-4-ethoxy-5-methoxybenzamido)benzoic acid (AAA-084) (16 mg, 46% for final step) was prepared in essentially the same manner as AAA-019 except that 3-chloro-4-ethoxy-5-methoxybenzoic acid (prepared in 3 steps from methyl 4-hydroxy-3-methoxybenzoate by sequential treatment with sulfuryl chloride, ethyl iodide and base and then lithium hydroxide) was used instead of 3,5-dichloro-4-ethoxybenzoic acid and methyl 4-aminobenzoate was used instead of methyl 4-amino-2-methylbenzoate in step (i): m/z 350 [M+H] + (ES + ), 348 [M ⁇ H] ⁇ (ES ⁇ ).
  • AAA-019 4-(3-Chloro-4-ethoxy-5-methoxybenzamido)-2-methylbenzoic acid (AAA-085) (97 mg, 52% for final step) was prepared in essentially the same manner as AAA-019 except that 3-chloro-4-ethoxy-5-methoxybenzoic acid (prepared in 3 steps from methyl 4-hydroxy-3-methoxybenzoate by sequential treatment with sulfuryl chloride, ethyl iodide and base and then lithium hydroxide) was used instead of 3,5-dichloro-4-ethoxybenzoic acid in step (i): m/z 364 [M+H] + (ES + ), 362 [M ⁇ H] ⁇ (ES ⁇ ).
  • AAA-086 4-(3-Chloro-5-ethoxy-4-isopropoxybenzamido)benzoic acid (AAA-086) (10 mg, 4% for final step) was prepared in essentially the same manner as AAA-075 except that ethyl iodide at RT was used instead of isopropyl bromide in step (i), isopropyl bromide at 60° C. was used instead of methyl iodide in step (iii) and methyl 4-aminobenzoate was used instead of methyl 4-amino-2-methylbenzoate in step (v): m/z 378 [M+H] + (ES + ), 376 [M ⁇ H] ⁇ (ES ⁇ ).
  • AAA-087 4-(3-Chloro-5-ethoxy-4-isopropoxybenzamido)-2-methylbenzoic acid (AAA-087) (129 mg, 56% for final step) was prepared in essentially the same manner as AAA-075 except that ethyl iodide at RT was used instead of isopropyl bromide in step (i) and isopropyl bromide at 60° C. was used instead of methyl iodide in step (iii): m/z 390 [M ⁇ H] ⁇ (ES ⁇ ).
  • AAA-0808 4-(3-Chloro-5-(cyclobutoxy)-4-ethoxybenzamido)benzoic acid (AAA-088) (112 mg, 41% for final step) was prepared in essentially the same manner as AAA-075 except that cyclobutyl bromide was used instead of isopropyl bromide in step (i), ethyl iodide was used instead of methyl iodide in step (iii) and methyl 4-aminobenzoate was used instead of methyl 4-amino-2-methylbenzoate in step (v): m/z 388 [M ⁇ H] ⁇ (ES ⁇ ).
  • AAA-089 4-(3-Chloro-5-(cyclopropylmethoxy)-4-ethoxybenzamido)benzoic acid (AAA-089) (255 mg, 90% for final step) was prepared in essentially the same manner as AAA-075 except that bromomethylcyclopropane was used instead of isopropyl bromide in step (i), ethyl iodide was used instead of methyl iodide in step (iii) and methyl 4-aminobenzoate was used instead of methyl 4-amino-2-methylbenzoate in step (v): m/z 388 [M ⁇ H] ⁇ (ES ⁇ ).
  • AAA-090 4-(3-Chloro-5-(cyclopropylmethoxy)-4-ethoxybenzamido)-2-hydroxybenzoic acid (AAA-090) (76 mg, 90% for final step) was prepared in essentially the same manner as AAA-075 except that bromomethylcyclopropane was used instead of isopropyl bromide in step (i), ethyl iodide was used instead of methyl iodide in step (iii) and methyl 4-amino-2-hydroxybenzoate was used instead of methyl 4-amino-2-methylbenzoate in step (v): m/z 406 [M+H] + (ES + ), 404 [M ⁇ H] ⁇ (ES ⁇ ).
  • AAA-091 4-(3-Chloro-4,5-diisopropoxybenzamido)-2-hydroxybenzoic acid (AAA-091) (43 mg, 63% for final step) was prepared in essentially the same manner as in steps (v) and (vi) for AAA-075 except that 3-chloro-4,5-diisopropoxybenzoic acid (Synthesis 52) was used instead of 3-chloro-5-isopropoxy-4-methoxybenzoic acid and methyl 4-amino-2-hydroxybenzoate was used instead of methyl 4-amino-2-methylbenzoate in step (v): m/z 408 [M+H] + (ES + ), 406 [M ⁇ H] ⁇ (ES ⁇ ).

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9447028B2 (en) 2009-09-01 2016-09-20 King's College London Therapeutic aryl-amido-aryl compounds and their use
GB201900687D0 (en) 2019-01-17 2019-03-06 King S College London Immunotherapeutic methods and compositions
WO2020128478A1 (en) 2018-12-19 2020-06-25 King's College London Immunotherapeutic methods and compositions
US10738016B2 (en) 2015-10-13 2020-08-11 H. Lee Moffitt Cancer Center And Research Institute, Inc. BRD4-kinase inhibitors as cancer therapeutics
WO2020263960A1 (en) * 2019-06-28 2020-12-30 Carl Wagner Compositions comprising a retinoid x receptor (rxr) agonist, a retinoic acid receptor (rar) agonist, or a dual rxr/rar agonist

Families Citing this family (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012125749A2 (en) * 2011-03-14 2012-09-20 Io Therapeutics, Inc. INFLAMMATION AND AUTOIMMUNE DISORDER TREATMENT USING RARα SELECTIVE AGONISTS
CN102727475B (zh) * 2012-06-14 2014-05-07 合肥博太医药生物技术发展有限公司 视黄酸及其衍生物在制备防治老年痴呆药物中的应用
JP6596090B2 (ja) * 2014-12-17 2019-10-23 キングス カレッジ ロンドン レチノイン酸受容体ベータ（ＲＡＲβ）アゴニストとしてのビシクロヘテロアリール−ヘテロアリール−安息香酸化合物
EP3267969A1 (en) * 2015-03-09 2018-01-17 King's College London Combination therapy with rar alpha agonists for enhancing th1 response
WO2017174999A1 (en) * 2016-04-07 2017-10-12 High Force Research Limited Synthetic retinoids for use in rar mediated conditions
CN107459519A (zh) 2016-06-06 2017-12-12 上海艾力斯医药科技有限公司 稠合嘧啶哌啶环衍生物及其制备方法和应用
CA3128032A1 (en) 2019-01-29 2020-08-06 The Johns Hopkins University Small molecule neutral sphingomyelinase 2 (nsmase2) inhibitors
JP2026500298A (ja) 2022-12-15 2026-01-06 シンジェンタ クロップ プロテクション アクチェンゲゼルシャフト 殺有害生物剤として有用である新規な二環式カルボキサミド化合物

Family Cites Families (29)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2260118C2 (de) 1972-12-08 1982-06-03 Bayer Ag, 5090 Leverkusen Penicilline sowie ihre Verwendung als Arzneimittel
DE3580134D1 (de) 1984-07-07 1990-11-22 Shudo Koichi Prof Dr Chem Benzoesaeurederivate.
JPS61233678A (ja) 1985-04-09 1986-10-17 Maruko Seiyaku Kk ベンジルピペラジン誘導体
JPS62215581A (ja) 1986-03-18 1987-09-22 Koichi Shiyudo フラボンカルボン酸誘導体
US4808631A (en) 1986-11-07 1989-02-28 Hoffmann-La Roche Inc. Aromatic acid derivatives
US4992468A (en) 1989-07-26 1991-02-12 Allergan, Inc. Phenylethenyl compounds having retinoid-like activity
ZA911101B (en) * 1990-02-14 1991-11-27 Chugai Pharmaceutical Co Ltd Inhibition of modified ldl products
FR2663850B1 (fr) 1990-07-02 1994-01-14 Gird Galderma Composition pharmaceutique ou cosmetique contenant en association un retinouide et un sterol.
EP0619116A3 (en) 1993-04-05 1994-11-23 Hoechst Japan Use of synthetic retinoids for osteopathy.
US5648385A (en) 1994-01-03 1997-07-15 Bristol-Myers Squibb Co. Retinoid-like compounds
US5849735A (en) 1995-01-17 1998-12-15 American Cyanamid Company Tricyclic benzazepine vasopressin antagonists
US5559248A (en) 1995-04-05 1996-09-24 Bristol-Myers Squibb Co. Retinoid-like heterocycles
ES2180751T3 (es) 1995-04-10 2003-02-16 Taiho Pharmaceutical Co Ltd Inhibidor de metastasis de cancer.
JP3964478B2 (ja) 1995-06-30 2007-08-22 エーザイ・アール・アンド・ディー・マネジメント株式会社 ヘテロ環含有カルボン酸誘導体及びそれを含有する医薬
FR2739777B1 (fr) 1995-10-11 1997-11-14 Cird Galderma Ligand antagoniste rar-gamma ou agoniste rar-alpha en tant qu'inhibiteur d'apoptose
US5663357A (en) * 1995-11-22 1997-09-02 Allergan Substituted heteroarylamides having retinoid-like biological activity
HUP0102470A3 (en) 1998-07-01 2002-05-28 Takeda Chemical Industries Ltd 1,3-azole derivatives as retinoid-associated receptor regulators and their use
US6245884B1 (en) 1998-10-16 2001-06-12 Vivian Y. H. Hook Secretases related to alzheimer's dementia
PL198852B1 (pl) 1998-10-22 2008-07-31 Neurosearch As Podstawione pochodne fenylu, kompozycja farmaceutyczna je zawierająca oraz ich zastosowanie
TW400614B (en) 1998-11-06 2000-08-01 United Microelectronics Corp The manufacture method of Shallow Trench Isolation(STI)
US6897304B2 (en) 2000-09-22 2005-05-24 Zenyaku Kogyo Kabushiki Kaisha Cephem compounds and ESBL-detecting reagents containing the same
CA2432825A1 (en) 2000-12-15 2002-06-20 Emory University Nonpeptide agonists and antagonists of vasopressin receptors
GB0103998D0 (en) 2001-02-19 2001-04-04 King S College London Method
US7105566B2 (en) * 2002-10-22 2006-09-12 Allergan, Inc. Methods of treatment during vascular procedures
US8367822B2 (en) 2003-09-22 2013-02-05 Enzo Therapeutics, Inc. Compositions and methods for bone formation and remodeling
KR100921173B1 (ko) * 2007-11-14 2009-10-13 (주)아모레퍼시픽 피부 내에서 히알루론산 생합성을 촉진시키는3,4,5-트리메톡시벤즈 아미드 유도체 화합물, 그 제조방법및 이를 함유하는 화장료 조성물
EP2415755A4 (en) 2009-03-31 2012-09-19 Renascience Co Ltd INHIBITOR AGENT OF PLASMINOGEN ACTIVATOR INHIBITOR 1
GB0915196D0 (en) 2009-09-01 2009-10-07 King S College London Therapeutic compounds and their use
WO2012058378A1 (en) 2010-10-29 2012-05-03 Romark Laboratories L.C. Pharmaceutical compositions and methods of use of salicylanilides for treatment of hepatitis viruses

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
Benzoylamino Benzoic Acid CAS ENtry Dates *
Elected Compound CAS Entry date *
Entry Date forCAS Registry Number 690982-75-3 corresponding compound example AAA-007 in claim 181 *

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9447028B2 (en) 2009-09-01 2016-09-20 King's College London Therapeutic aryl-amido-aryl compounds and their use
US10738016B2 (en) 2015-10-13 2020-08-11 H. Lee Moffitt Cancer Center And Research Institute, Inc. BRD4-kinase inhibitors as cancer therapeutics
US11643396B2 (en) 2015-10-13 2023-05-09 H. Lee Moffitt Cancer Center And Research Institute, Inc. BRD4-kinase inhibitors as cancer therapeutics
WO2020128478A1 (en) 2018-12-19 2020-06-25 King's College London Immunotherapeutic methods and compositions
US20220062340A1 (en) * 2018-12-19 2022-03-03 King's College London Immunotherapeutic methods and compositions
GB201900687D0 (en) 2019-01-17 2019-03-06 King S College London Immunotherapeutic methods and compositions
WO2020263960A1 (en) * 2019-06-28 2020-12-30 Carl Wagner Compositions comprising a retinoid x receptor (rxr) agonist, a retinoic acid receptor (rar) agonist, or a dual rxr/rar agonist
US12540121B2 (en) 2019-06-28 2026-02-03 Arizona Board Of Regents On Behalf Of Arizona State University Compositions comprising a retinoid X receptor (RXR) agonist, a retinoic acid receptor (RAR) agonist, or a dual RXR/RAR agonist

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EP2473479A1 (en) 2012-07-11
CN102639487A (zh) 2012-08-15
RU2012108173A (ru) 2013-10-10
SG178480A1 (en) 2012-04-27
WO2011027106A1 (en) 2011-03-10
MX2012002481A (es) 2012-03-26
JP2013503819A (ja) 2013-02-04
JP5778675B2 (ja) 2015-09-16
US9447028B2 (en) 2016-09-20
AU2010291056B2 (en) 2016-01-28
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US20160039747A1 (en) 2016-02-11

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