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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    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • 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
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/02—Systems containing only non-condensed rings with a three-membered ring
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    • C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
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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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Abstract

The present invention pertains generally to the field of therapeutic compounds, and more specifically to certain aryl-amido-aryl compounds of the following formula (for convenience, collectively referred to herein as “AAA compounds”), which, inter alia, are (selective) retinoic acid receptor α (RARα) agonists. 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 RARα, and in the treatment of diseases and conditions that are mediated by RARα, that are ameliorated by the activation of RARα, 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.

Description

    RELATED APPLICATION
  • This application is related to United Kingdom patent application number 0915196.0 filed 1 Sep. 2009, the contents of which are incorporated herein by reference in their entirety.
    • TECHNICAL FIELD
  • 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 α (RARα) agonists. 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 RARα, and in the treatment of diseases and conditions that are mediated by RARα, that are ameliorated by the activation of RARα, 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.
    • BACKGROUND
  • A number of patents and publications are cited herein in order to more fully describe and disclose the invention and the state of the art to which the invention pertains. Each of these references is incorporated herein by reference in its entirety into the present disclosure, to the same extent as if each individual reference was specifically and individually indicated to be incorporated by reference.
  • Throughout this specification, including the claims which follow, unless the context requires otherwise, the word “comprise,” and variations such as “comprises” and “comprising,” will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.
  • It must be noted that, as used in the specification and the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “a pharmaceutical carrier” includes mixtures of two or more such carriers, and the like.
  • 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.
  • This disclosure includes information that may be useful in understanding the present invention. It is not an admission that any of the information provided herein is prior art or relevant to the presently claimed invention, or that any publication specifically or implicitly referenced is prior art.
    • Alzheimer's Disease
  • The current licensed treatments for Alzheimer's disease (AD) improve the symptoms that people experience but do not alter the progression of the underlying disease changes in the brain. Most of the attempts to develop new treatments have focused on altering deposits of the amyloid protein in the brain, but despite more than a decade of intensive research this has still not yielded any new therapies in the clinic.
  • The only currently approved medications for the treatment of AD are two groups of drugs, acetylcholinesterase inhibitors (e.g., Aricept™) and non-competitive NMDA receptor blockers (e.g., Memantine™), which give significant symptomatic improvement but do not fundamentally prevent or alter disease progression.
  • Recent research has concentrated on the mis-processing of the amyloid precursor protein (APP) and overproduction amyloid β(Aβ), as the central causative substrates in the disease process and the main treatment target. However, despite considerable effort and research over more than a decade, these treatments have not yet translated into treatments in the clinic.
  • The inventors have now determined the importance of RARα signalling in processing the APP into the non-amyloidic pathway, and a key role of this pathway in modulating neuronal survival.
    • Retinoic Acid Receptors
  • The retinoic acid receptor (RAR) is a type of nuclear receptor which is activated by both all-trans retinoic acid and 9-cis retinoic acid. There are three retinoic acid receptors, known as RARα, RARβ, and RARγ.
  • The inventors' studies have highlighted a specific retinoic acid receptor, (RAR)α, as a novel and exciting target for the development of new treatments. This receptor has two potential mechanisms of action; it regulates amyloid deposits in the brain and also plays a key role in the survival of neurons.
  • The pathological hallmarks of Alzheimer's disease (AD) are the presence of senile plaques containing amyloid β(Aβ) peptide and the formation of neuronal tangles in the cerebral cortex. In addition, 90% of AD patients have amyloid β deposits in their cerebral blood vessels (see, e.g., Vinters, 1987). Recently it has been shown that in AD there are genetic linkages to the disease which are close to genes involved in the retinoid signalling pathway (see, e.g., Goodman and Pardee, 2003). This is mediated by retinoic acid receptors (RARs) and retinoid X receptors (RXRs), both of which have three types α, β, and γ and various isoforms (see, e.g., Bastien and Rochette-Egly, 2004). Transcription occurs when the small lipophilic molecule, retinoic acid (RA) binds to an RAR/RXR heterodimer which then binds to retinoic acid response elements (RAREs) located in the regulatory regions of target genes (see, e.g., Bastien and Rochette-Egly, 2004).
  • Vitamin A deficiency in rats leads to Aβ deposits in the brain vasculature and a down-regulation of RARα 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). In addition, 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). Similarly, 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).
  • It has also been shown that the amyloid precursor protein (APP), which gives rise to amyloid β protein, can be differentially spliced depending on the concentration of RA (see, e.g., Pan et al., 1993). The APP can be cleaved into Aβ40 and Aβ42 by β and γ secretases (see, e.g., Selkoe, 2001). Alternatively, APP can be cleaved by α secretases into a soluble neuroprotective fragment (see, e.g., Annaert and De, 2000). Disintegrin-metalloproteinases (ADAMS) have been shown to act as α secretases (see, e.g., Lammich et al., 1999; Endres et al., 2005), and one of these (ADAM10) has been shown to be regulated by RA (see, e.g., Endres et al., 2005) and this appears to be direct as the promoter of this gene contains an RARE (see, e.g., Prinzen et al., 2005).
  • Other consistent aspects of AD are defects in the levels of the neurotransmitter, acetylcholine, which is produced by cholinergic neurons. In AD, there is a loss of the cholinergic markers choline acetyltransferase (chAT), which synthesises acetylcholine and acetylcholinesterase (Ache); Ache breaks down acetylcholine, and subsequently causes the loss of cholinergic neurons themselves (see, e.g., Coyle et al., 1983; Perry et al., 1992; Geula et al., 1998; Ladner and Lee, 1998; Talesa, 2001). It is the loss in cholinergic function that leads to the memory deficits in AD (see, e.g., Collerton, 1986; DeKosky et al., 1992; Bierer et al., 1995; Fischer et al., 1989). RA can also increase chAT expression (see, e.g., Cervini et al., 1994; Berrard et al., 1995; Bejanin et al., 1994).
  • The inventors' have now shown that RARα agonists are likely to be useful in the treatment of AD. They prevent neuronal cell death in the presence of Aβ42; in culture, they up-regulate chAT, down-regulate APP and increase the expression of ADAM10. In vivo, the inventors' have shown that feeding RARα agonists to Tg2576 mice (which overexpresses the Swedish mutation of the human APP leading to amyloid β deposits and cognitive decline) results in a significant reduction in the levels of both Aβ40 and Aβ42. Studies demonstrating these findings are described in more detail in the Examples below.
  • Certain aryl-amido-aryl compounds are known in the art.
  • Teng et al., 1997 (U.S. Pat. No. 5,663,357) describes certain compounds which apparently have retinoid-like biological activity. All of the compounds exemplified therein (see Table 1, spanning column 6 and 7 therein) have the following formula, in which the ring that is opposite the ring bearing the carboxylic acid group has two tert-butyl substituents.
  • Figure US20120149737A1-20120614-C00001
  • Shudo, 1987 (U.S. Pat. No. 4,703,110) describes certain compounds which apparently are useful for diagnosis of leukemia types, the treatment of dermatological disorders, and as differentiation-inducing agents for neoplastic cells. Among the compounds exemplified therein (see Tables 1 and 2 spanning columns 8 to 12 therein) are compounds of the following formula, wherein —X— is an amide linkage (see, e.g., the last few compounds in Table 1, and compounds 15-40, 64, 65, 67, and 68 in Table 2). However, in each case, the substituents R1, R2, R3, R4, and R5, 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.
  • Figure US20120149737A1-20120614-C00002
  • Shudo et al., 1996, (U.S. Pat. No. 5,525,618) describes certain compounds which apparently are useful in osteopathic treatment. The following compounds are shown in Table 1 (see columns 8 to 9 therein).
  • Figure US20120149737A1-20120614-C00003
  • 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.
  • Figure US20120149737A1-20120614-C00004
  • Of the numerous compounds described therein, Compound 132 on page 59 has the structure given below.
  • Figure US20120149737A1-20120614-C00005
  • Mizukoshi et al., 1986 (JP 61-233678 A) describes compounds useful as anti-ulcer agents. Compound 1849-89-4 therein has the structure shown below.
  • Figure US20120149737A1-20120614-C00006
  • Albright et al., 1998 (U.S. Pat. No. 5,849,735) describes tricyclic compounds of the following general formula. These compounds are said to exhibit in vivo vasopressin antagonist activity and antagonist activity at oxytocin receptors, and to be useful in treating conditions where decreased vasopressin levels are desired, such as in congestive heart failure, in disease conditions with excess renal water reabsorption and in conditions with increased vascular resistance and coronary vasoconstriction.
  • Figure US20120149737A1-20120614-C00007
  • Additionally, 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.
  • Figure US20120149737A1-20120614-C00008
  • Schmidt et al., 1975 (GB 1 409 689) describes compounds referred to as “new penicillin compounds”, which are said to be suitable for treating bacterial infections. Additionally, 4-(3,4,5-trimethoxybenzoylamino)-benzoic acid is mentioned as a precursor compound (for compound 22; see page 35 therein). This precursor compound has the structure shown below.
  • Figure US20120149737A1-20120614-C00009
  • Coppola et al., 2005 describes compounds said to have activity as inhibitors of 11β-HSD1, and suggests that the compounds may “serve as useful tools to study the effect of 11β-HSD1 inhibition in animal models of diabetes, dyslipidemia and obesity”. Of the compounds described in the document, compound 9a has the structure shown below.
  • Figure US20120149737A1-20120614-C00010
    • SUMMARY OF THE INVENTION
  • One aspect of the invention pertains to certain aryl-amido-aryl compounds (for convenience, collectively referred to herein as “AAA compounds”), as described herein.
  • Another aspect of the invention pertains to a composition (e.g., a pharmaceutical composition) comprising an AAA compound, as described herein, and a pharmaceutically acceptable carrier or diluent.
  • Another aspect of the invention pertains to method of preparing a composition (e.g., a pharmaceutical 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 α (RARα), in vitro or in vivo, comprising contacting RARα with an effective amount of an AAA compound, as described herein.
  • Another aspect of the present invention pertains to a method of selectively activating retinoic acid receptor α (RARα) (e.g., with respect to RARβ and/or RARγ), in vitro or in vivo, comprising contacting RARα with an effective amount of an AAA compound, as described herein.
  • Another aspect of the present invention pertains to a method of activating retinoic acid receptor α (RARα) in a neuronal cell, in vitro or in vivo, comprising contacting the cell with an effective amount of an AAA compound, as described herein.
  • Another aspect of the present invention pertains to a method of selectively activating retinoic acid receptor α (RARα) (e.g., with respect to RARβ and/or RARγ) in a neuronal cell, in vitro or in vivo, comprising contacting the cell 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, 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 Aβ40 and Aβ42 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 Aβ40 and Aβ42 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.
  • In one embodiment, the treatment is treatment of a disease or condition that is mediated by RARα.
  • In one embodiment, the treatment is treatment of a disease or condition that is ameliorated by the activation of RARα.
  • In one embodiment, the treatment is treatment of a disease or condition that is ameliorated by the selective activation of RARα (e.g., with respect to RARβ and/or RARγ).
  • In one embodiment, 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.
  • In one embodiment, the treatment is treatment of Alzheimer's disease.
  • In one embodiment, the treatment is treatment of early stage Alzheimer's disease.
  • In one embodiment, the treatment is treatment of intermediate stage Alzheimer's disease.
  • In one embodiment, the treatment is treatment of late stage Alzheimer's disease.
  • In one embodiment, the treatment is treatment of cognitive impairment.
  • In one embodiment, the treatment is treatment of mild cognitive impairment.
  • Another aspect of the present invention pertains to a kit 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.
  • As will be appreciated by one of skill in the art, features and preferred embodiments of one aspect of the invention will also pertain to other aspect of the invention.
    • DETAILED DESCRIPTION OF THE INVENTION Compounds
  • One aspect of the present invention relates to certain compounds which are structurally related to the following compounds:
  •
    1
    Figure US20120149737A1-20120614-C00011
         		4-Benzoylamino- benzoic acid
    2
    Figure US20120149737A1-20120614-C00012
         		6-Benzoylamino- nicotinic acid
    3
    Figure US20120149737A1-20120614-C00013
         		5-Benzoylamino- pyridine-2- carboxylic acid
    4
    Figure US20120149737A1-20120614-C00014
         		6-Benzoylamino- pyridazine- 3-carboxylic acid
    5
    Figure US20120149737A1-20120614-C00015
         		N-Phenyl- terephthalamic acid
    6
    Figure US20120149737A1-20120614-C00016
         		5-Phenylcarbamoyl- pyridine-2- carboxylic acid
    7
    Figure US20120149737A1-20120614-C00017
         		6-Phenylcarbamoyl- nicotinic acid
    8
    Figure US20120149737A1-20120614-C00018
         		6-Phenylcarbamoyl- pyridazine-3- carboxylic acid
  • Thus, 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 —R1, —R2, —R3, -J-, —W═, —Y═, —Z═, and —RO are as defined herein (for convenience, collectively referred to herein as “aryl-amido-aryl compounds” or “AAA compounds”):
  • Figure US20120149737A1-20120614-C00019
  • Some embodiments of the invention include the following:
  • (1) A compound selected from compounds of the following formula, and pharmaceutically acceptable salts, hydrates, and solvates thereof:
  • Figure US20120149737A1-20120614-C00020
  • wherein:
      • —R1 is independently —X, —RX, —O—RX, —O—RA, —O—RC, —O-L-RC, —O—RAR, or —O-L-RAR;
      • —R2 is independently —X, —RX, —O—RX, —O—RA, —O—RC, —O-L-RC, —O—RAR, or —O-L-RAR;
      • —R3 is independently —X, —RX, —O—RX, —O—RA, —O—RC, —O-L-RC, —O—RAR, or —O-L-RAR;
        wherein:
      • each —X is independently —F, —Cl, —Br, or —I;
      • each —RA is independently saturated aliphatic C1-6alkyl;
      • each —RX is independently saturated aliphatic C1-6haloalkyl;
      • each —RC is independently saturated C3-7cycloalkyl;
      • each —RAR is independently phenyl or C5-6heteroaryl;
      • each -L- is independently saturated aliphatic C1-3alkylene;
        and wherein:
      • -J- is independently —C(═O)—NRN— or —NRN—C(═O)—;
      • —RN is independently —H or —RNN;
      • —RNN is independently saturated aliphatic C1-4alkyl;
      • ═Y— is ═CRY— and —Z═ is —CRZ═; or
      • ═Y— is ═N— and —Z═ is —CRZ═; or
      • ═Y— is ═CRY— and —Z═ is —N═; or
      • ═Y— is ═N— and —Z═ is —N═;
      • —RY is independently —H or —RYY;
      • —RYY is independently —F, —Cl, —Br, —I, or saturated aliphatic C1-4alkyl;
      • —RZ is independently —H or —RZZ;
      • —RZZ is independently —F, —Cl, —Br, —I, —OH, saturated aliphatic C1-4alkoxy, saturated aliphatic C1-4alkyl, or saturated aliphatic C1-4haloalkyl;
      • ═W— is ═CRW—;
      • —RW is independently —H or —RWW;
      • —R′ is independently —F, —Cl, —Br, —I, —OH, saturated aliphatic C1-4alkoxy, saturated aliphatic C1-4alkyl, or saturated aliphatic C1-4haloalkyl;
      • —RO is independently —OH, —ORE, —NH2, —NHRT1, —NRT1RT1, or —NRT2RT3;
      • —RE is independently saturated aliphatic C1-6alkyl;
      • each —RT1 is independently saturated aliphatic C1-6alkyl;
      • —NRT2RT3 is independently azetidino, pyrrolidino, piperidino, piperizino, N—(C1-3alkyl)piperizino, or morpholino.
  • For the avoidance of doubt, it is not intended that —R1 and —R2 and —R3 are attached to one another other than as shown in the above formula. For example, it is not intended that —R1 and —R2 together form a ring fused to the benzene ring to which they are attached. Similarly, it is not intended that —R2 and —R3 together form a ring fused to the benzene ring to which they are attached. Similarly, it is not intended that —R1 and —R3 together form a ring fused to the benzene ring to which they are attached.
  • For the avoidance of doubt, the term “C1-6haloalkyl” refers to a C1-6alkyl group that has one or more (e.g., 1, 2, 3, etc.) halo substituents, and includes, for example, —CF3, —CH2CF3, —CH2CH2F, etc.
  • For the avoidance of doubt, the term “agonist” is intended to encompass compounds which are partial agonists.
    • Optional Provisos
  • In one or more aspects of the present invention (e.g., compounds, compositions, compounds for use in therapy, use of compounds in the manufacture of a medicament, methods, methods of treatment, etc.), the compounds are optionally as defined herein, but with one or more optional provisos, as defined herein.
  • (2) A compound according to (1), with the proviso that the compound is not a compound selected from: compounds (PP-01), (PP-02), and (PP-03), and salts, hydrates, and solvates thereof.
    (3) A compound according to (1), with the proviso that the compound is not a compound selected from: compounds (PP-01), (PP-02), (PP-03), (PP-04), (PP-05), (PP-06), (PP-07), and (PP-08), and salts, hydrates, and solvates thereof.
  • # Structure Name Registry No.
    PP-01
    Figure US20120149737A1-20120614-C00021
         		4-(3,4,5-triethoxy- benzoylamino)- benzoic acid 926257-87-6
    PP-02
    Figure US20120149737A1-20120614-C00022
         		4-(3,5-Dichloro-4- ethoxy- benzoylamino)- benzoic acid 690982-75-3
    PP-03
    Figure US20120149737A1-20120614-C00023
         		4-(3,5-Dichloro-4- methoxy- benzoylamino)- benzoic acid 832094-08-3
    PP-04
    Figure US20120149737A1-20120614-C00024
         		4-(3,4,5- Trimethoxy- benzoylamino)- benzoic acid methyl ester 303796-30-7
    PP-05
    Figure US20120149737A1-20120614-C00025
         		4-(3,4,5- Trimethoxy- benzoylamino)- benzoic acid ethyl ester  1849-89-4
    PP-06
    Figure US20120149737A1-20120614-C00026
         		6-(3,4,5- Trimethoxy- benzoylamino)- nicotinic acid 180339-52-0
    PP-07
    Figure US20120149737A1-20120614-C00027
         		4-(3,4,5- Trimethoxy- benzoylamino)- benzoic acid  54057-51-1
    PP-08
    Figure US20120149737A1-20120614-C00028
         		3,4,5-Trimethoxy- N-[4-(piperidine-1- carbonyl)-phenyl]- benzamide 901062-25-7
  • It appears that compounds (PP-01), (PP-02), and (PP-03) are commercially available. However, their usefulness (e.g., as RARα agonists, in method of therapy, etc., as described herein) has not yet been published.
  • In one or more aspects of the present invention (e.g., compounds for use in therapy, use of compounds in the manufacture of a medicament, methods of treatment, etc.), the compounds are optionally as defined herein, but without the proviso regarding compounds (PP-01), (PP-02), and (PP-03).
  • In one or more aspects of the present invention (e.g., compounds for use in therapy, use of compounds in the manufacture of a medicament, methods of treatment, etc.), 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).
  • For example, a reference to a particular group of compounds “without the recited proviso regarding compounds (PP-01), (PP-02), and (PP-03)” (e.g., for use in therapy) 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.
  • In one or more aspects of the present invention (e.g., compounds for use in therapy, use of compounds in the manufacture of a medicament, methods of treatment, etc.), the compounds are optionally as defined herein, with the proviso regarding compounds (PP-01), (PP-02), and (PP-03).
  • In one or more aspects of the present invention (e.g., compounds for use in therapy, use of compounds in the manufacture of a medicament, methods of treatment, etc.), 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).
    • The Group —R1
  • (4) A compound according to any one of (1) to (3), wherein:
      • —R1 is independently —X, —RX, —O—RX, —O—RA, —O—RC, —O-L-RC, or —O-L-RAR.
        (5) A compound according to any one of (1) to (3), wherein:
      • —R1 is independently —X, —RX, —O—RX, —O—RA, —O—RC, —O-L-RC.
        (6) A compound according to any one of (1) to (3), wherein:
      • —R1 is independently —X, —RX, —O—RX, —O—RA, or —O—RC.
        (7) A compound according to any one of (1) to (3), wherein:
      • —R1 is independently —X, —RX, —O—RA, or —O—RC.
        (8) A compound according to any one of (1) to (3), wherein:
      • —R1 is independently —X, —RX, or —O—RA.
        (9) A compound according to any one of (1) to (3), wherein:
      • —R1 is independently —X or —RX.
        (10) A compound according to any one of (1) to (3), wherein:
      • —R1 is independently —X.
        (11) A compound according to any one of (1) to (3), wherein:
      • —R1 is independently —RX.
        (12) A compound according to any one of (1) to (3), wherein:
      • —R1 is independently —O—RX.
        (13) A compound according to any one of (1) to (3), wherein:
      • —R1 is independently —O—RA.
        (14) A compound according to any one of (1) to (3), wherein:
      • —R1 is independently —O—RC.
        (15) A compound according to any one of (1) to (3), wherein:
      • —R1 is independently —O-L-RC.
        (16) A compound according to any one of (1) to (3), wherein:
      • —R1 is independently —O—RAR.
        (17) A compound according to any one of (1) to (3), wherein:
      • —R1 is independently —O-L-RAR.
    The Group —R2
  • (18) A compound according to any one of (1) to (17), wherein:
      • —R2 is independently —O—RX, —O—RA, —O—RC, —O-L-RC, —O—RAR, or —O-L-RAR.
        (19) A compound according to any one of (1) to (17), wherein:
      • —R2 is independently —O—RX, —O—RA, —O—RC, —O-L-RC, or —O-L-RAR.
        (20) A compound according to any one of (1) to (17), wherein:
      • —R2 is independently —O—RA, —O—RC, —O-L-RC, or —O-L-RAR.
        (21) A compound according to any one of (1) to (17), wherein:
      • —R2 is independently —O—RA, —O—RC, or —O-L-RC.
        (22) A compound according to any one of (1) to (17), wherein:
      • —R2 is independently —O—RA or —O—RC.
        (23) A compound according to any one of (1) to (17), wherein:
      • —R2 is independently —X or —RX.
        (24) A compound according to any one of (1) to (17), wherein:
      • —R2 is independently —X.
        (25) A compound according to any one of (1) to (17), wherein:
      • —R2 is independently —RX.
        (26) A compound according to any one of (1) to (17), wherein:
      • —R2 is independently —O—RX.
        (27) A compound according to any one of (1) to (17), wherein:
      • —R2 is independently —O—RA.
        (28) A compound according to any one of (1) to (17), wherein:
      • —R2 is independently —O—RC.
        (29) A compound according to any one of (1) to (17), wherein:
      • —R2 is independently —O-L-RC.
        (30) A compound according to any one of (1) to (17), wherein:
      • —R2 is independently —O—RAR.
        (31) A compound according to any one of (1) to (17), wherein:
      • —R2 is independently —O-L-RAR.
    The Group —R3
  • (32) A compound according to any one of (1) to (31), wherein:
      • —R3 is independently —X, —RX, —O—RX, —O—RA, —O—RC, —O-L-RC, or —O-L-RAR.
        (33) A compound according to any one of (1) to (31), wherein:
      • —R3 is independently —X, —RX, —O—RX, —O—RA, —O—RC, —O-L-RC.
        (34) A compound according to any one of (1) to (31), wherein:
      • —R3 is independently —X, —RX, —O—RX, —O—RA, or —O—RC.
        (35) A compound according to any one of (1) to (31), wherein:
      • —R3 is independently —X, —RX, —O—RA, or —O—RC.
        (36) A compound according to any one of (1) to (31), wherein:
      • —R3 is independently —X, —RX, or —O—RA.
        (37) A compound according to any one of (1) to (31), wherein:
      • —R3 is independently —X or —RX.
        (38) A compound according to any one of (1) to (31), wherein:
      • —R3 is independently —X.
        (39) A compound according to any one of (1) to (31), wherein:
      • —R3 is independently —RX.
        (40) A compound according to any one of (1) to (31), wherein:
      • —R3 is independently —O—RX.
        (41) A compound according to any one of (1) to (31), wherein:
      • —R3 is independently —O—RA.
        (42) A compound according to any one of (1) to (31), wherein:
      • —R3 is independently —O—RC.
        (43) A compound according to any one of (1) to (31), wherein:
      • —R3 is independently —O-L-RC.
        (44) A compound according to any one of (1) to (31), wherein:
      • —R3 is independently —O—RAR.
        (45) A compound according to any one of (1) to (31), wherein:
      • —R3 is independently —O-L-RAR.
    Examples of Some Particular Combinations of —R1, —R2, and —R3
  • (46) A compound according to any one of (1) to (3), wherein:
      • —R1 is independently —X, —RX, —O—RX, —O—RA, —O—RC, —O-L-RC, —O—RAR, or —O-L-RAR;
      • —R2 is independently —X, —RX, —O—RX, —O—RA, —O—RC, —O-L-RC, —O—RAR, or —O-L-RAR;
      • —R3 is independently —X, —RX, —O—RX, —O—RA, —O—RC, —O-L-RC, —O—RAR, or —O-L-RAR;
      • with the proviso that —R1, —R2, and —R3 are not all —O-Me; and
      • with the proviso that —R1, —R2, and —R3 are not all —O-Et.
        (47) A compound according to any one of (1) to (3), wherein:
      • —R1 is independently —X, —RX, —O—RX, —O—RA, —O—RC, —O-L-RC, —O—RAR, or —O-L-RAR;
      • —R2 is independently —X, —RX, —O—RX, —O—RA, —O—RC, —O-L-RC, —O—RAR, or —O-L-RAR;
      • —R3 is independently —X, —RX, —O—RX, —O—RA, —O—RC, —O-L-RC, —O—RAR, or —O-L-RAR;
      • with the proviso that if: —R1, —R2, and —R3 are all —O—RA,
      • then: —R1, —R2, and —R3 are not all the same.
        (48) A compound according to any one of (1) to (3), wherein:
      • —R1 is independently —X, —RX, —O—RX, —O—RA, —O—RC, —O-L-RC, —O—RAR, or —O-L-RAR;
      • —R2 is independently —X, —RX, —O—RX, —O—RA, —O—RC, —O-L-RC, —O—RAR, or —O-L-RAR;
      • —R3 is independently —X, —RX, —O—RX, —O—RA, —O—RC, —O-L-RC, —O—RAR, or —O-L-RAR;
      • with the proviso that —R1, —R2, and —R3 are not all —O—RA.
        (49) A compound according to any one of (1) to (3), wherein:
      • —R1 is independently —X, —RX, —O—RX, —O—RA, —O—RC, or —O-L-RC;
      • —R2 is independently —O—RA, —O—RC, or —O-L-RC; and
      • —R3 is independently —X, —RX, —O—RX, —O—RA, —O—RC, or —O-L-RC.
        (50) A compound according to any one of (1) to (3), wherein:
      • —R1 is independently —X, —RX, —O—RX, —O—RA, —O—RC, or —O-L-RC;
      • —R2 is independently —O—RA, —O—RC, or —O-L-RC; and
      • —R3 is independently —X, —RX, —O—RX, —O—RA, —O—RC, or —O-L-RC;
      • with the proviso that —R1, —R2, and —R3 are not all —O-Me; and
      • with the proviso that —R1, —R2, and —R3 are not all —O-Et.
        (51) A compound according to any one of (1) to (3), wherein:
      • —R1 is independently —X, —RX, —O—RX, —O—RA, —O—RC, or —O-L-RC;
      • —R2 is independently —O—RA, —O—RC, or —O-L-RC; and
      • —R3 is independently —X, —RX, —O—RX, —O—RA, —O—RC, or —O-L-RC;
      • with the proviso that if: —R1, —R2, and —R3 are all —O—RA,
      • then: —R1, —R2, and —R3 are not all the same.
        (52) A compound according to any one of (1) to (3), wherein:
      • —R1 is independently —X, —RX, —O—RX, —O—RA, —O—RC, or —O-L-RC;
      • —R2 is independently —O—RA, —O—RC, or —O-L-RC; and
      • —R3 is independently —X, —RX, —O—RX, —O—RA, —O—RC, or —O-L-RC;
      • with the proviso that —R1, —R2, and —R3 are not all —O—RA.
        (53) A compound according to any one of (1) to (3), wherein:
      • —R1 is independently —X, —RX, —O—RA, —O—RC, or —O-L-RC;
      • —R2 is independently —O—RA, —O—RC, or —O-L-RC; and
      • —R3 is independently —X, —RX, —O—RA, —O—RC, or —O-L-RC.
        (54) A compound according to any one of (1) to (3), wherein:
      • —R1 is independently —X, —RX, —O—RA, —O—RC, or —O-L-RC;
      • —R2 is independently —O—RA, —O—RC, or —O-L-RC; and
      • —R3 is independently —X, —RX, —O—RA, —O—RC, or —O-L-RC;
      • with the proviso that —R1, —R2, and —R3 are not all —O-Me; and
      • with the proviso that —R1, —R2, and —R3 are not all —O-Et.
        (55) A compound according to any one of (1) to (3), wherein:
      • —R1 is independently —X, —RX, —O—RA, —O—RC, or —O-L-RC;
      • —R2 is independently —O—RA, —O—RC, or —O-L-RC; and
      • —R3 is independently —X, —RX, —O—RA, —O—RC, or —O-L-RC;
      • with the proviso that if: —R1, —R2, and —R3 are all —O—RA,
      • then: —R1, —R2, and —R3 are not all the same.
        (56) A compound according to any one of (1) to (3), wherein:
      • —R1 is independently —X, —RX, —O—RA, —O—RC, or —O-L-RC;
      • —R2 is independently —O—RA, —O—RC, or —O-L-RC; and
      • —R3 is independently —X, —RX, —O—RA, —O—RC, or —O-L-RC;
      • with the proviso that —R1, —R2, and —R3 are not all —O—RA.
        (57) A compound according to any one of (1) to (3), wherein:
      • —R1 is independently —X or —RX;
      • —R2 is independently —O—RA, —O—RC, or —O-L-RC; and
      • —R3 is independently —X or —RX;
        (58) A compound according to any one of (1) to (3), wherein:
      • —R1 is independently —X;
      • —R2 is independently —O—RA, —O—RC, or —O-L-RC; and
      • —R3 is independently —X.
        (59) A compound according to any one of (1) to (3), wherein:
      • —R1 is independently —X;
      • —R2 is independently —O—RA or —O—RC; and
      • —R3 is independently —X.
        (60) A compound according to any one of (1) to (3), wherein:
      • —R1 is independently —O—RA, —O—RC, or —O-L-RC;
      • —R2 is independently —O—RA, —O—RC, or —O-L-RC; and
      • —R3 is independently —X or —RX;
      • or:
      • —R1 is independently —X or —RX;
      • —R2 is independently —O—RA, —O—RC, or —O-L-RC; and
      • —R3 is independently —O—RA, —O—RC, or —O-L-RC.
        (61) A compound according to any one of (1) to (3), wherein:
      • —R1 is independently —O—RA or —O—RC;
      • —R2 is independently —O—RA or —O—RC; and
      • —R3 is independently —X or —RX;
      • or:
      • —R1 is independently —X or —RX;
      • —R2 is independently —O—RA or —O—RC; and
      • —R3 is independently —O—RA or —O—RC.
        (62) A compound according to any one of (1) to (3), wherein:
      • —R1 is independently —O—RA;
      • —R2 is independently —O—RA; and
      • —R3 is independently —X or —RX;
      • or:
      • —R1 is independently —X or —RX;
      • —R2 is independently —O—RA; and
      • —R3 is independently —O—RA.
        (63) A compound according to any one of (1) to (3), wherein:
      • —R1 is independently —O—RA, —O—RC, or —O-L-RC;
      • —R2 is independently —O—RA, —O—RC, or —O-L-RC; and
      • —R3 is independently —X;
      • or:
      • —R1 is independently —X;
      • —R2 is independently —O—RA, —O—RC, or —O-L-RC; and
      • —R3 is independently —O—RA, —O—RC, or —O-L-RC.
        (64) A compound according to any one of (1) to (3), wherein:
      • —R1 is independently —O—RA or —O—RC;
      • —R2 is independently —O—RA or —O—RC; and
      • —R3 is independently —X;
      • or:
      • —R1 is independently —X;
      • —R2 is independently —O—RA or —O—RC; and
      • —R3 is independently —O—RA or —O—RC.
        (65) A compound according to any one of (1) to (3), wherein:
      • —R1 is independently —O—RA;
      • —R2 is independently —O—RA; and
      • —R3 is independently —X;
      • or:
      • —R1 is independently —X;
      • —R2 is independently —O—RA; and
      • —R3 is independently —O—RA.
        (66) A compound according to any one of (1) to (3), wherein:
      • —R1 is independently —O—RA, —O—RC, or —O-L-RC;
      • —R2 is independently —O—RA, —O—RC, or —O-L-RC; and
      • —R3 is independently —O—RA, —O—RC, or —O-L-RC.
        (67) A compound according to any one of (1) to (3), wherein:
      • —R1 is independently —O—RA, —O—RC, or —O-L-RC;
      • —R2 is independently —O—RA, —O—RC, or —O-L-RC; and
      • —R3 is independently —O—RA, —O—RC, or —O-L-RC;
      • with the proviso that —R1, —R2, and —R3 are not all —O-Me; and
      • with the proviso that —R1, —R2, and —R3 are not all —O-Et.
        (68) A compound according to any one of (1) to (3), wherein:
      • —R1 is independently —O—RA, —O—RC, or —O-L-RC;
      • —R2 is independently —O—RA, —O—RC, or —O-L-RC; and
      • —R3 is independently —O—RA, —O—RC, or —O-L-RC;
      • with the proviso that if: —R1, —R2, and —R3 are all —O—RA,
      • then: —R1, —R2, and —R3 are not all the same.
        (69) A compound according to any one of (1) to (3), wherein:
      • —R1 is independently —O—RA, —O—RC, or —O-L-RC;
      • —R2 is independently —O—RA, —O—RC, or —O-L-RC; and
      • —R3 is independently —O—RA, —O—RC, or —O-L-RC;
      • with the proviso that —R1, —R2, and —R3 are not all —O—RA.
        (70) A compound according to any one of (1) to (3), wherein:
      • —R1 is independently —O—RA or —O—RC;
      • —R2 is independently —O—RA or —O—RC; and
      • —R3 is independently —O—RA or —O—RC.
        (71) A compound according to any one of (1) to (3), wherein:
      • —R1 is independently —O—RA or —O—RC;
      • —R2 is independently —O—RA or —O—RC; and
      • —R3 is independently —O—RA or —O—RC;
      • with the proviso that —R1, —R2, and —R3 are not all —O-Me; and
      • with the proviso that —R1, —R2, and —R3 are not all —O-Et.
        (72) A compound according to any one of (1) to (3), wherein:
      • —R1 is independently —O—RA or —O—RC;
      • —R2 is independently —O—RA or —O—RC; and
      • —R3 is independently —O—RA or —O—RC;
      • with the proviso that if: —R1, —R2, and —R3 are all —O—RA,
      • then: —R1, —R2, and —R3 are not all the same.
        (73) A compound according to any one of (1) to (3), wherein:
      • —R1 is independently —O—RA or —O—RC;
      • —R2 is independently —O—RA or —O—RC; and
      • —R3 is independently —O—RA or —O—RC;
      • with the proviso that —R1, —R2, and —R3 are not all —O—RA.
    The Group —X
  • (74) A compound according to any one of (1) to (73), wherein:
      • each —X, if present, is independently —F, —Cl, or —Br.
        (75) A compound according to any one of (1) to (73), wherein:
      • each —X, if present, is independently —F or —Cl.
        (76) A compound according to any one of (1) to (73), wherein:
      • each —X, if present, is independently —Cl or —Br.
        (77) A compound according to any one of (1) to (73), wherein:
      • each —X, if present, is independently —F.
        (78) A compound according to any one of (1) to (73), wherein:
      • each —X, if present, is independently —Cl.
        (79) A compound according to any one of (1) to (73), wherein:
      • each —X, if present, is independently —Br.
    The Group —RA
  • (80) A compound according to any one of (1) to (79), wherein:
      • each —RA, if present, is independently saturated aliphatic C1-4alkyl.
        (81) A compound according to any one of (1) to (79), wherein:
      • each —RA, if present, is independently -Me, -Et, -nPr, or -iPr.
        (82) A compound according to any one of (1) to (79), wherein:
      • each —RA, if present, is independently -Me.
        (83) A compound according to any one of (1) to (79), wherein:
      • each —RA, if present, is independently -Et.
        (84) A compound according to any one of (1) to (79), wherein:
      • each —RA, if present, is independently -iPr.
    The Group —RX
  • (85) A compound according to any one of (1) to (84), wherein:
      • each —RX, if present, is independently saturated aliphatic C1-4haloalkyl.
        (86) A compound according to any one of (1) to (84), wherein:
      • each —RX, if present, is independently —CF3, —CH2CF3, or —CH2CH2F.
        (87) A compound according to any one of (1) to (84), wherein:
      • each —RX, if present, is independently —CF3.
    The Group —RC
  • (88) A compound according to any one of (1) to (87), wherein:
      • each —RC, if present, is independently cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
        (89) A compound according to any one of (1) to (87), wherein:
      • each —RC, if present, is independently cyclopropyl, cyclobutyl, or cyclopentyl.
        (90) A compound according to any one of (1) to (87), wherein:
      • each —RC, if present, is independently cyclopropyl.
        (91) A compound according to any one of (1) to (87), wherein:
      • each —RC, if present, is independently cyclobutyl.
        (92) A compound according to any one of (1) to (87), wherein:
      • each —RC, if present, is independently cyclopentyl.
    The Group —RAR
  • (93) A compound according to any one of (1) to (92), wherein:
      • each —RAR, if present, is independently phenyl or C6heteroaryl.
        (94) A compound according to any one of (1) to (92), wherein:
      • each —RAR, if present, is independently phenyl, pyridinyl, pyrimidinyl, or pyridizinyl.
        (95) A compound according to any one of (1) to (92), wherein:
      • each —RAR, if present, is independently phenyl or pyridinyl.
        (96) A compound according to any one of (1) to (92), wherein:
      • each —RAR, if present, is independently phenyl.
        (97) A compound according to any one of (1) to (92), wherein:
      • each —RAR, if present, is independently pyridinyl.
    The Group -L-
  • (98) A compound according to any one of (1) to (97), wherein:
      • each -L-, if present, is independently —CH2— or —CH2CH2—.
        (99) A compound according to any one of (1) to (97), wherein:
      • each -L-, if present, is independently —CH2—.
    The Groups Y and Z
  • (100) A compound according to any one of (1) to (99), wherein:
      • ═Y— is ═CRY— and —Z═ is —CRZ.
  • Figure US20120149737A1-20120614-C00029
  • (101) A compound according to any one of (1) to (99), wherein:
      • ═Y— is ═N— and —Z═ is —CRZ.
  • Figure US20120149737A1-20120614-C00030
  • (102) A compound according to any one of (1) to (99), wherein:
      • ═Y— is ═CRY— and —Z═ is —N═.
  • Figure US20120149737A1-20120614-C00031
  • (103) A compound according to any one of (1) to (99), wherein:
      • ═Y— is ═N— and —Z═ is —N═.
  • Figure US20120149737A1-20120614-C00032
    • The Groups —RY and —RYY
  • (104) A compound according to any one of (1) to (103), wherein:
      • —RY, if present, is independently —H.
        (105) A compound according to any one of (1) to (103), wherein:
      • —RY, if present, is independently —RYY.
        (106) A compound according to any one of (1) to (105), wherein:
      • —RYY, if present, is independently —F, —Cl, —Br, —I, -Me, or -Et.
        (107) A compound according to any one of (1) to (105), wherein:
      • —RYY, if present, is independently —F, —Cl, or -Me.
        (108) A compound according to any one of (1) to (105), wherein:
      • —RYY, if present, is independently —F or —Cl.
        (109) A compound according to any one of (1) to (105), wherein:
      • —RYY, if present, is independently —F.
        (110) A compound according to any one of (1) to (105), wherein:
      • —RYY, if present, is independently —Cl.
        (111) A compound according to any one of (1) to (105), wherein:
      • —RYY, if present, is independently -Me.
    The Groups —RZ and —RZZ
  • (112) A compound according to any one of (1) to (111), wherein:
      • —RZ, if present, is independently —H.
        (113) A compound according to any one of (1) to (111), wherein:
      • —RZ, if present, is independently —RZZ.
        (114) A compound according to any one of (1) to (113), wherein:
      • —RZZ, if present, is independently —F, —Cl, —Br, —I, —OH, —OMe, —OEt, -Me, -Et, or —CF3.
        (115) A compound according to any one of (1) to (113), wherein:
      • —RZZ, if present, is independently —F, —Cl, —Br, —I, —OH, saturated aliphatic C1-4alkyl.
        (116) A compound according to any one of (1) to (113), wherein:
      • —RZZ, if present, is independently —F, —Cl, —Br, —I, —OH, -Me or -Et.
        (117) A compound according to any one of (1) to (113), wherein:
      • —RZZ, if present, is independently —F, —Cl, —Br, —I, or saturated aliphatic C1-4alkyl.
        (118) A compound according to any one of (1) to (113), wherein:
      • —RZZ, if present, is independently —F, —Cl, —Br, —I, -Me, or -Et.
        (119) A compound according to any one of (1) to (113), wherein:
      • —RZZ, if present, is independently —F, —Cl, -Me, or —OH.
        (120) A compound according to any one of (1) to (113), wherein:
      • —RZZ, if present, is independently —F, -Me, or —OH.
        (121) A compound according to any one of (1) to (113), wherein:
      • —RZZ, if present, is independently —F, —Cl, or -Me.
        (122) A compound according to any one of (1) to (113), wherein:
      • —RZZ, if present, is independently -Me.
        (123) A compound according to any one of (1) to (113), wherein:
      • —RZZ, if present, is independently —F.
        (124) A compound according to any one of (1) to (113), wherein:
      • —RZZ, if present, is independently —OH.
        (125) A compound according to any one of (1) to (113), wherein:
      • —RZZ, if present, is independently —Cl.
    The Groups —RW and —RWW
  • (126) A compound according to any one of (1) to (125), wherein:
      • —RW, if present, is independently —H.
        (127) A compound according to any one of (1) to (125), wherein:
      • —RW, if present, is independently —RWW.
        (128) A compound according to any one of (1) to (127), wherein:
      • —RWW, if present, is independently —F, —Cl, —Br, —I, —OH, —OMe, —OEt, -Me, -Et, or —CF3.
        (129) A compound according to any one of (1) to (127), wherein:
      • —RWW, if present, is independently —F, —Cl, —Br, —I, or saturated aliphatic C1-4alkyl.
        (130) A compound according to any one of (1) to (127), wherein:
      • —RWW, if present, is independently —F, —Cl, —Br, —I, -Me, or -Et.
        (131) A compound according to any one of (1) to (127), wherein:
      • —RWW, if present, is independently —F, —Cl, or -Me.
        (132) A compound according to any one of (1) to (127), wherein:
      • —RWW, if present, is independently —F.
        (133) A compound according to any one of (1) to (127), wherein:
      • —RWW, if present, is independently —Cl.
        (134) A compound according to any one of (1) to (127), wherein:
      • —RWW, if present, is independently -Me.
    The Group -J-
  • (135) A compound according to any one of (1) to (134), wherein:
      • -J- is independently —C(═O)—NRN—.
  • Figure US20120149737A1-20120614-C00033
  • (136) A compound according to any one of (1) to (134), wherein:
      • -J- is independently —NRN—C(═O)—.
  • Figure US20120149737A1-20120614-C00034
    • The Groups —RN and —RNN
  • (137) A compound according to any one of (1) to (136), wherein:
      • —RN is independently —H.
        (138) A compound according to any one of (1) to (136), wherein:
      • —RN is independently —RNN.
        (139) A compound according to any one of (1) to (138), wherein:
      • RNN, if present, is independently -Me or -Et.
        (140) A compound according to any one of (1) to (138), wherein:
      • —RNN, if present, is independently -Me.
    The Group —RO
  • (141) A compound according to any one of (1) to (140), wherein:
      • —RO is independently —OH, —ORE, —NH2, or —NHRT1.
        (142) A compound according to any one of (1) to (140), wherein:
      • —RO is independently —OH or —ORE.
        (143) A compound according to any one of (1) to (140), wherein:
      • —RO is independently —OH.
    The Group —RE
  • (144) A compound according to any one of (1) to (143), wherein:
      • —RE, if present, is independently saturated aliphatic C1-4alkyl.
        (145) A compound according to any one of (1) to (143), wherein:
      • —RE, if present, is independently -Me or -Et.
        (146) A compound according to any one of (1) to (143), wherein:
      • —RE, if present, is independently -Me.
    The Group —RT1
  • (147) A compound according to any one of (1) to (146), wherein:
      • each —RT1, if present, is independently saturated aliphatic C1-4alkyl.
        (148) A compound according to any one of (1) to (146), wherein:
      • each —RT1, if present, is independently -Me or -Et.
        (149) A compound according to any one of (1) to (146), wherein:
      • each —RT1, if present, is independently -Me.
    The Group —NRT2RT3
  • (150) A compound according to any one of (1) to (149), wherein:
      • —NRT2RT3 is independently piperidino, piperizino, N—(C1-3alkyl)piperizino, or morpholine.
    Molecular Weight
  • (151) A compound according to any one of (1) to (150), wherein the compound has a molecular weight of from 295 to 1200.
    (152) A compound according to (151), wherein the bottom of range is 300, 325, 350, or 400.
    (153) A compound according to (151) or (152), wherein the top of range is 1100, 1000, 900, 800, 700, or 600.
    (154) A compound according to any one of (1) to (150), wherein the compound has a molecular weight of range from 325 to 600.
    • Activity and Selectivity
  • (155) A compound according to any one of (1) to (154), wherein the compound has a RARα activity ratio (with respect to atRA) of less than about 200; or less than about 70; or less than about 30; or less than about 10; or less than about 5.
    (156) A compound according to any one of (1) to (155), wherein the compound is selective for RARα, as compared to RARβ.
    (157) A compound according to any one of (1) to (155), wherein the compound is selective for RARα, as compared to RARγ.
    (158) A compound according to any one of (1) to (155), wherein the compound is selective for RARα, as compared to both RARβ and RARγ.
    (159) A compound according to any one of (1) to (158), wherein the compound has a ratio of RARα activity ratio (with respect to atRA) to RARβ activity ratio (with respect to atRA) of at least 10; or at least 20; or at least 50; or at least 100; or at least 200.
    • Specific Compounds
  • (160) A compound according to (1), selected from compounds of the following formulae and pharmaceutically acceptable salts, hydrates, and solvates thereof:
  • Code
    No. Synthesis Structure
    AAA- 001  1
    Figure US20120149737A1-20120614-C00035
    AAA- 002  1
    Figure US20120149737A1-20120614-C00036
    AAA- 003  2
    Figure US20120149737A1-20120614-C00037
    AAA- 004  3
    Figure US20120149737A1-20120614-C00038
    AAA- 005  4
    Figure US20120149737A1-20120614-C00039
    AAA- 006  5
    Figure US20120149737A1-20120614-C00040
    AAA- 007  6
    Figure US20120149737A1-20120614-C00041
    AAA- 008  7
    Figure US20120149737A1-20120614-C00042
    AAA- 009  8
    Figure US20120149737A1-20120614-C00043
    AAA- 010 9
    Figure US20120149737A1-20120614-C00044
    AAA- 011 10
    Figure US20120149737A1-20120614-C00045
    AAA- 012 11
    Figure US20120149737A1-20120614-C00046
    AAA- 013 12
    Figure US20120149737A1-20120614-C00047
    AAA- 014 13
    Figure US20120149737A1-20120614-C00048
    AAA- 015 14
    Figure US20120149737A1-20120614-C00049
    AAA- 016 15
    Figure US20120149737A1-20120614-C00050
    AAA- 017 16
    Figure US20120149737A1-20120614-C00051
    AAA- 018 17
    Figure US20120149737A1-20120614-C00052
    AAA- 0019 18
    Figure US20120149737A1-20120614-C00053
    AAA- 020 19
    Figure US20120149737A1-20120614-C00054
    AAA- 021 20
    Figure US20120149737A1-20120614-C00055
    AAA- 022 21
    Figure US20120149737A1-20120614-C00056
    AAA- 023 22
    Figure US20120149737A1-20120614-C00057
    AAA- 024 23
    Figure US20120149737A1-20120614-C00058
    AAA- 025 24
    Figure US20120149737A1-20120614-C00059
    AAA- 026 25
    Figure US20120149737A1-20120614-C00060
    AAA- 027 26
    Figure US20120149737A1-20120614-C00061
    AAA- 028 (PP-01) 27
    Figure US20120149737A1-20120614-C00062
    AAA- 029 (PP-02) 28
    Figure US20120149737A1-20120614-C00063
    AAA- 030 (PP-03) 29
    Figure US20120149737A1-20120614-C00064

    (161) A compound according to (1), selected from compounds of the following formulae and pharmaceutically acceptable salts, hydrates, and solvates thereof: AAA-001 to AA-027.
    (162) A compound according to (1), selected from compounds of the following formulae and pharmaceutically acceptable salts, hydrates, and solvates thereof:
  • Code
    No. Synthesis Structure
    AAA- 031 33
    Figure US20120149737A1-20120614-C00065
    AAA- 032 34
    Figure US20120149737A1-20120614-C00066
    AAA- 033 35
    Figure US20120149737A1-20120614-C00067
    AAA- 034 36
    Figure US20120149737A1-20120614-C00068
    AAA- 035 37
    Figure US20120149737A1-20120614-C00069
    AAA- 036 38
    Figure US20120149737A1-20120614-C00070
    AAA- 037 39
    Figure US20120149737A1-20120614-C00071
    AAA- 038 40
    Figure US20120149737A1-20120614-C00072
    AAA- 039 41
    Figure US20120149737A1-20120614-C00073
    AAA- 040 42
    Figure US20120149737A1-20120614-C00074
    AAA- 041 43
    Figure US20120149737A1-20120614-C00075
    AAA- 042 44
    Figure US20120149737A1-20120614-C00076
    AAA- 043 45
    Figure US20120149737A1-20120614-C00077
    AAA- 044 46
    Figure US20120149737A1-20120614-C00078
    AAA- 045 47
    Figure US20120149737A1-20120614-C00079
    AAA- 046 48
    Figure US20120149737A1-20120614-C00080
    AAA- 047 49
    Figure US20120149737A1-20120614-C00081
    AAA- 048 50
    Figure US20120149737A1-20120614-C00082
    AAA- 049 51
    Figure US20120149737A1-20120614-C00083
    AAA- 050 52
    Figure US20120149737A1-20120614-C00084
    AAA- 051 53
    Figure US20120149737A1-20120614-C00085
    AAA- 052 54
    Figure US20120149737A1-20120614-C00086
    AAA- 053 55
    Figure US20120149737A1-20120614-C00087
    AAA- 054 56
    Figure US20120149737A1-20120614-C00088
    AAA- 055 57
    Figure US20120149737A1-20120614-C00089
    AAA- 056 58
    Figure US20120149737A1-20120614-C00090
    AAA- 057 59
    Figure US20120149737A1-20120614-C00091
    AAA- 058 60
    Figure US20120149737A1-20120614-C00092
    AAA- 059 61
    Figure US20120149737A1-20120614-C00093
    AAA- 060 62
    Figure US20120149737A1-20120614-C00094
    AAA- 061 63
    Figure US20120149737A1-20120614-C00095
    AAA- 062 64
    Figure US20120149737A1-20120614-C00096
    AAA- 063 65
    Figure US20120149737A1-20120614-C00097
    AAA- 064 66
    Figure US20120149737A1-20120614-C00098
    AAA- 065 67
    Figure US20120149737A1-20120614-C00099
    AAA- 066 68
    Figure US20120149737A1-20120614-C00100
    AAA- 067 69
    Figure US20120149737A1-20120614-C00101
    AAA- 068 70
    Figure US20120149737A1-20120614-C00102
    AAA- 069 71
    Figure US20120149737A1-20120614-C00103
    AAA- 070 72
    Figure US20120149737A1-20120614-C00104
    AAA- 071 73
    Figure US20120149737A1-20120614-C00105
    AAA- 072 74
    Figure US20120149737A1-20120614-C00106
    AAA- 073 75
    Figure US20120149737A1-20120614-C00107
    AAA- 074 76
    Figure US20120149737A1-20120614-C00108
    AAA- 075 77
    Figure US20120149737A1-20120614-C00109
    AAA- 076 78
    Figure US20120149737A1-20120614-C00110
    AAA- 077 79
    Figure US20120149737A1-20120614-C00111
    AAA- 078 80
    Figure US20120149737A1-20120614-C00112
    AAA- 079 81
    Figure US20120149737A1-20120614-C00113
    AAA- 080 82
    Figure US20120149737A1-20120614-C00114
    AAA- 081 83
    Figure US20120149737A1-20120614-C00115
    AAA- 082 84
    Figure US20120149737A1-20120614-C00116
    AAA- 083 85
    Figure US20120149737A1-20120614-C00117
    AAA- 084 86
    Figure US20120149737A1-20120614-C00118
    AAA- 085 87
    Figure US20120149737A1-20120614-C00119
    AAA- 086 88
    Figure US20120149737A1-20120614-C00120
    AAA- 087 89
    Figure US20120149737A1-20120614-C00121
    AAA- 088 90
    Figure US20120149737A1-20120614-C00122
    AAA- 089 91
    Figure US20120149737A1-20120614-C00123
    AAA- 090 92
    Figure US20120149737A1-20120614-C00124
    AAA- 091 93
    Figure US20120149737A1-20120614-C00125
    AAA- 092 94
    Figure US20120149737A1-20120614-C00126
    AAA- 093 95
    Figure US20120149737A1-20120614-C00127
    AAA- 094 96
    Figure US20120149737A1-20120614-C00128
    AAA- 095 97
    Figure US20120149737A1-20120614-C00129
    AAA- 096 98
    Figure US20120149737A1-20120614-C00130
    AAA- 097 99
    Figure US20120149737A1-20120614-C00131
    AAA- 098 100 
    Figure US20120149737A1-20120614-C00132
    AAA- 099 101 
    Figure US20120149737A1-20120614-C00133
    AAA- 100 102 
    Figure US20120149737A1-20120614-C00134
    AAA- 101 103 
    Figure US20120149737A1-20120614-C00135
    AAA- 102 104 
    Figure US20120149737A1-20120614-C00136
    AAA- 103 105 
    Figure US20120149737A1-20120614-C00137
    AAA- 104 106 
    Figure US20120149737A1-20120614-C00138
    AAA- 105 107 
    Figure US20120149737A1-20120614-C00139
    AAA- 106 108 
    Figure US20120149737A1-20120614-C00140
    AAA- 107 109 
    Figure US20120149737A1-20120614-C00141
    AAA- 108 110 
    Figure US20120149737A1-20120614-C00142
    AAA- 109 111 
    Figure US20120149737A1-20120614-C00143
    AAA- 110 112 
    Figure US20120149737A1-20120614-C00144
    AAA- 111 113 
    Figure US20120149737A1-20120614-C00145
    AAA- 112 114 
    Figure US20120149737A1-20120614-C00146
    AAA- 113 115 
    Figure US20120149737A1-20120614-C00147
    AAA- 114 116 
    Figure US20120149737A1-20120614-C00148
    AAA- 115 117 
    Figure US20120149737A1-20120614-C00149
    AAA- 116 118 
    Figure US20120149737A1-20120614-C00150
    AAA- 117 119 
    Figure US20120149737A1-20120614-C00151
    AAA- 118 120 
    Figure US20120149737A1-20120614-C00152
    AAA- 119 121 
    Figure US20120149737A1-20120614-C00153
    AAA- 120 122 
    Figure US20120149737A1-20120614-C00154

    (163) A compound according to (1), selected from compounds of the following formulae and pharmaceutically acceptable salts, hydrates, and solvates thereof: AAA-01 to AA-027 and AA-031 to M-120.
    • Combinations
  • It is appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable sub-combination. All combinations of the embodiments pertaining to the chemical groups represented by the variables (e.g., —R1, —R2, —R3, -J-, —W═, —Y═, —Z═, —RO, —X, —RX, —RA, —RC, -L-, —RN, —RNN, —RW, —RWW, —RY, —RYY, —RZ, —RZZ, —RE, —RT1, —NRT2RT3, etc.) are specifically embraced by the present invention and are disclosed herein just as if each and every combination was individually and explicitly disclosed, to the extent that such combinations embrace compounds that are stable compounds (i.e., compounds that can be isolated, characterised, and tested for biological activity). In addition, all sub-combinations of the chemical groups listed in the embodiments describing such variables are also specifically embraced by the present invention and are disclosed herein just as if each and every such sub-combination of chemical groups was individually and explicitly disclosed herein.
    • Substantially Purified Forms
  • 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.
  • In one embodiment, the compound is in substantially purified form and/or in a form substantially free from contaminants.
  • In one embodiment, 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.
  • Unless specified, the substantially purified form refers to the compound in any stereoisomeric or enantiomeric form. For example, in one embodiment, the substantially purified form refers to a mixture of stereoisomers, i.e., purified with respect to other compounds. In one embodiment, the substantially purified form refers to one stereoisomer, e.g., optically pure stereoisomer. In one embodiment, the substantially purified form refers to a mixture of enantiomers. In one embodiment, the substantially purified form refers to an equimolar mixture of enantiomers (i.e., a racemic mixture, a racemate). In one embodiment, the substantially purified form refers to one enantiomer, e.g., optically pure enantiomer.
  • In one embodiment, 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.
  • Unless specified, 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.
  • In one embodiment, 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%.
    • Isomers
  • 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; α- and β-forms; axial and equatorial forms; boat-, chair-, twist-, envelope-, and halfchair-forms; and combinations thereof, hereinafter collectively referred to as “isomers” (or “isomeric forms”).
  • Note that, except as discussed below for tautomeric forms, specifically excluded from the term “isomers,” as used herein, 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). For example, a reference to a methoxy group, —OCH3, is not to be construed as a reference to its structural isomer, a hydroxymethyl group, —CH2OH. Similarly, a reference to ortho-chlorophenyl is not to be construed as a reference to its structural isomer, meta-chlorophenyl. However, a reference to a class of structures may well include structurally isomeric forms falling within that class (e.g., C1-7alkyl includes n-propyl and iso-propyl; butyl includes n-, iso-, sec-, and tert-butyl; methoxyphenyl includes ortho-, meta-, and para-methoxyphenyl).
  • The above exclusion does not pertain to tautomeric forms, for example, keto-, enol-, and enolate-forms, as in, for example, the following tautomeric pairs: keto/enol (illustrated below), imine/enamine, amide/imino alcohol, amidine/amidine, nitroso/oxime, thioketone/enethiol, N-nitroso/hydroxyazo, and nitro/aci-nitro.
  • Figure US20120149737A1-20120614-C00155
  • Note that specifically included in the term “isomer” are compounds with one or more isotopic substitutions. For example, H may be in any isotopic form, including 1H, 2H (D), and 3H (T); C may be in any isotopic form, including 12C, 13C, and 14C; O may be in any isotopic form, including 16O and 18O; and the like.
  • Unless otherwise specified, 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.
    • Salts
  • It may be convenient or desirable to prepare, purify, and/or handle a corresponding salt of the compound, for example, a pharmaceutically-acceptable salt. Examples of pharmaceutically acceptable salts are discussed in Berge et al., 1977, “Pharmaceutically Acceptable Salts,” J. Pharm. Sci., Vol. 66, pp. 1-19.
  • For example, if the compound is anionic, or has a functional group which may be anionic (e.g., —COOH may be —COO−)), then a salt may be formed with a suitable cation. Examples of suitable inorganic cations include, but are not limited to, alkali metal ions such as Na+ and K+, alkaline earth cations such as Ca2+ and Mg2+, and other cations such as Al3+. Examples of suitable organic cations include, but are not limited to, ammonium ion (i.e., NH4 +) and substituted ammonium ions (e.g., NH3R+, NH2R2 +, NHR3 +, NR4 +). Examples of some 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(CH3)4 +.
  • If the compound is cationic, or has a functional group which may be cationic (e.g., —NH2 may be —NH3 +), then a salt may be formed with a suitable anion. Examples of 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.
  • Examples of 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. Examples of suitable polymeric organic anions include, but are not limited to, those derived from the following polymeric acids: tannic acid, carboxymethyl cellulose.
  • Unless otherwise specified, a reference to a particular compound also includes salt forms thereof.
    • Hydrates and Solvates
  • It may be convenient or desirable to prepare, purify, and/or handle a corresponding solvate of the compound. The term “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.
  • Unless otherwise specified, a reference to a particular compound also includes solvate and hydrate forms thereof.
    • Chemically Protected Forms
  • It may be convenient or desirable to prepare, purify, and/or handle the compound in a chemically protected form. The term “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). In practice, well known chemical methods are employed to reversibly render unreactive a functional group, which otherwise would be reactive, under specified conditions. In a chemically protected form, 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). By protecting a reactive functional group, reactions involving other unprotected reactive functional groups can be performed, without affecting the protected group; the protecting group may be removed, usually in a subsequent step, without substantially affecting the remainder of the molecule. See, for example, Protective Groups in Organic Synthesis (T. Greene and P. Wuts; 4th Edition; John Wiley and Sons, 2006).
  • A wide variety of such “protecting,” “blocking,” or “masking” methods are widely used and well known in organic synthesis. For example, 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. After the desired reaction (involving the other functional group) is complete, the protected group may be “deprotected” to return it to its original functionality.
  • For example, 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)CH3, —OAc).
  • For example, an aldehyde or ketone group may be protected as an acetal (R—CH(OR)2) or ketal (R2C(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.
  • For example, 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—CH3); a benzyloxy amide (—NHCO—OCH2C6H5, —NH-Cbz); as a t-butoxy amide (—NHCO—OC(CH3)3, —NH-Boc); a 2-biphenyl-2-propoxy amide (—NHCO—OC(CH3)2C6H4C6H5, —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), as an allyloxy amide (—NH-Alloc), as a 2(-phenylsulfonyl)ethyloxy amide (—NH-Psec); or, in suitable cases (e.g., cyclic amines), as a nitroxide radical (>N—O).
  • For example, a carboxylic acid group may be protected as an ester for example, as: an C1-7alkyl ester (e.g., a methyl ester; a t-butyl ester); a C1-7haloalkyl ester (e.g., a C1-7trihaloalkyl ester); a triC1-7alkylsilyl-C1-7alkyl ester; or a C5-20aryl-C1-7alkyl ester (e.g., a benzyl ester; a nitrobenzyl ester); or as an amide, for example, as a methyl amide.
  • For example, a thiol group may be protected as a thioether (—SR), for example, as: a benzyl thioether; an acetamidomethyl ether (—S—CH2NHC(═O)CH3).
    • Prodruqs
  • It may be convenient or desirable to prepare, purify, and/or handle the compound in the form of a prodrug. The term “prodrug,” as used herein, pertains to a compound which, when metabolised (e.g., in vivo), yields the desired active compound. Typically, the prodrug is inactive, or less active than the desired active compound, but may provide advantageous handling, administration, or metabolic properties.
  • For example, 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. Such 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.
  • Also, some 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.). For example, the prodrug may be a sugar derivative or other glycoside conjugate, or may be an amino acid ester derivative.
    • Chemical Synthesis
  • Several methods for the chemical synthesis of compounds of the present invention are described herein. These and/or other well known methods may be modified and/or adapted in known ways in order to facilitate the synthesis of additional compounds within the scope of the present invention.
  • In one approach, certain compounds of the invention (where -J- is —C(═O)—NRN—) 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.
  • For example, coupling a suitably substituted benzoic acid (e.g., (1)(i)) with a suitably protected para-amino benzoic acid compound (e.g., (1)(ii), wherein —RP denotes a protecting group, such as -Me), gives the corresponding amide (e.g., (1)(iii)). 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.
  • If necessary or desired, the protecting group can be removed using conventional methods to give the carboxylic acid compound (e.g., (1)(iv)). For example, if the protecting group (e.g., —RP) is alkyl, then hydrolysis can be achieved using lithium hydroxide in a mixture of THF or dioxane and water. If the protecting group (e.g., —RP) is benzyl, it may be removed by hydrogenation, for example by using hydrogen over a metal catalyst.
  • If necessary or desired, the carboxylic acid compound (e.g., (1)(iv)) can be converted to a corresponding amide compound (e.g., (1)(v)), for example, by reaction with a suitable amine.
  • An example of such a method is illustrated in the following scheme.
  • Figure US20120149737A1-20120614-C00156
  • In another approach, certain compounds of the invention (where -J- is —NRN—C(═O)—) 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.
  • For example, coupling a suitably substituted aniline (e.g., (2)(i)) with a suitably protected terephthalic acid compound (e.g., (2)(ii), wherein —RP denotes a protecting group and -LG denotes a leaving group), gives the corresponding amide (e.g., (2)(iii)). An example of a suitable leaving group is halogen (e.g., Cl), and 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. In this case, 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. Another example of a suitable leaving group is —OH. In this case, coupling may be achieved, for example, using oxalyl chloride, HATU, EEDQ, PyBOP, PyBrOP, CDI or EDC under usual conditions.
  • If necessary or desired, the protecting group can be removed using conventional methods to give the carboxylic acid compound (e.g., (2)(iv)). For example, if the protecting group (e.g., —RP) is alkyl, then hydrolysis can be achieved using lithium hydroxide in a mixture of THF or dioxane and water. If the protecting group (e.g., —RP) is benzyl, it may be removed by hydrogenation, for example by using hydrogen over a metal catalyst.
  • If necessary or desired, the carboxylic acid compound (e.g., (2)(iv)) can be converted to a corresponding amide compound (e.g., (2)(v)), for example, by reaction with a suitable amine.
  • An example of such a method is illustrated in the following scheme.
  • Figure US20120149737A1-20120614-C00157
  • The benzoic acids (e.g., (1)(i)) 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. For example, suitably protected hydroxyl-benzoic acids may be alkylated. Deprotection gives the corresponding substituted benzoic acid.
  • For example, suitably protected hydroxyl-benzoic acid (e.g., (3)(i)) 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)). For example, if the protecting group (e.g., —RP) is alkyl, then hydrolysis can be achieved using lithium hydroxide in a mixture of THF or dioxane and water. If the protecting group (e.g., —RP) is benzyl, it may be removed by hydrogenation, for example by using hydrogen over a metal catalyst.
  • An example of such a method is illustrated in the following scheme.
  • Figure US20120149737A1-20120614-C00158
  • The amines (e.g., (1)(ii)) 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. For example, compounds where —RN is other than —H can be prepared by reductive amination of a suitably protected 4-aminobenzoic acid derivative.
  • In another approach, one or more of the groups —R1, —R2, and —R3 may be changed after coupling. For example, debenzylation of a pendant —OCH2Ph group gives a corresponding —OH group, which can then be alkylated.
  • For example, in a method similar to Scheme 1 above, when one of —R1, —R2, and —R3 in the starting material (e.g., (4)(i)) is —OCH2Ph, then, following coupling (e.g., to give (4)(iii)), debenzylation (for example, using boron trichloride) converts this —OCH2Ph group to —OH (e.g., (4)(iv)). 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)).
  • Again, if necessary or desired, the protecting group can be removed using conventional methods to give the carboxylic acid compound (e.g., (4)(iv)). For example, if the protecting group (e.g., —RP) is alkyl, then hydrolysis can be achieved using lithium hydroxide in a mixture of THF or dioxane and water. If the protecting group (e.g., —RP) is benzyl, it may be removed by hydrogenation, for example by using hydrogen over a metal catalyst.
  • Again, if necessary or desired, the carboxylic acid compound (e.g., (4)(vi)) can be converted to a corresponding amide compound (e.g., (4)(vii)), for example, by reaction with a suitable amine.
  • An example of such a method is illustrated in the following scheme.
  • Figure US20120149737A1-20120614-C00159
    Figure US20120149737A1-20120614-C00160
  • In another approach, one or more of the groups —R1, —R2, and —R3 may be changed after coupling. For example, a pendant —OH may be alkylated.
  • For example, in a method similar to that described in Scheme 2 above, one of —R1, —R2, and —R3 in the starting material (e.g., (5)(i)) is —OH. Following coupling (e.g., to give (5)(iii)), 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).
  • Again, if necessary or desired, the protecting group can be removed using conventional methods to give the carboxylic acid compound (e.g., (5)(v)). For example, if the protecting group (e.g., —RP) is alkyl, then hydrolysis can be achieved using lithium hydroxide in a mixture of THF or dioxane and water. If the protecting group (e.g., —RC) is benzyl, it may be removed by hydrogenation, for example by using hydrogen over a metal catalyst.
  • Again, if necessary or desired, the carboxylic acid compound (e.g., (5)(v)) can be converted to a corresponding amide compound (e.g., (5)(vi)), for example, by reaction with a suitable amine.
  • An example of such a method is illustrated in the following scheme.
  • Figure US20120149737A1-20120614-C00161
  • In the above methods, 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., —RYY, —RZZ, —RWW), 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., —RYY, —RZZ, —RWW).
    • Compositions
  • One aspect of the present invention pertains to a composition (e.g., a pharmaceutical composition) comprising an AAA compound, as described herein, and a pharmaceutically acceptable carrier, diluent, or excipient.
  • Another aspect of the present invention pertains to a method of preparing a composition (e.g., a pharmaceutical composition) comprising admixing an AAA compound, as described herein, and a pharmaceutically acceptable carrier, diluent, or excipient.
    • Uses
  • The compounds described herein are useful, for example, in the treatment of diseases and conditions that are ameliorated by the (selective) activation of RARα, such as, for example, Alzheimer's disease.
    • Use in Methods of Activating Retinoic Acid Receptor α (RARα)
  • One aspect of the present invention pertains to a method of activating retinoic acid receptor α (RARα), in vitro or in vivo, comprising contacting RARα with an effective amount of an AAA compound, as described herein.
  • One aspect of the present invention pertains to a method of selectively activating retinoic acid receptor α (RARα) (e.g., with respect to RARβ and/or RARγ), in vitro or in vivo, comprising contacting RARα with an effective amount of an AAA compound, as described herein.
  • In one embodiment, the method is performed in vitro.
  • In one embodiment, the method is performed in vivo.
  • One aspect of the present invention pertains to a method of activating retinoic acid receptor α (RARα) in a neuronal cell, in vitro or in vivo, comprising contacting the cell with an effective amount of an AAA compound, as described herein.
  • One aspect of the present invention pertains to a method of selectively activating retinoic acid receptor α (RARα) (e.g., with respect to RARβ and/or RARγ) in a neuronal cell, in vitro or in vivo, comprising contacting the cell with an effective amount of an AAA compound, as described herein.
  • In one embodiment, the AAA compound is provided in the form of a pharmaceutically acceptable composition.
  • Suitable assays for determining RARα activation are described herein and/or are known in the art.
  • Use in Methods of Up-Regulating chAT, Etc.
  • The 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 Aβ40 and Aβ42 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 Aβ40 and Aβ42 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.
  • In one embodiment, the method is performed in vitro.
  • In one embodiment, 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 Aβ40 and Aβ42 expression in a cortical neuron in a patient, comprising administering to the patient a therapeutically effective amount of an AAA compound, as described herein.
  • In one embodiment, 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 Aβ40 and Aβ42 expression; are described herein and/or are known in the art.
    • Use in Methods of Preventing Cortical Neuronal Death
  • The 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.
    • Use in Methods of Therapy
  • Another aspect of the present invention pertains to an AAA compound, as described herein, for treatment of the human or animal body by therapy.
    • Use in the Manufacture of Medicaments
  • 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.
  • In one embodiment, the medicament comprises the AAA compound.
    • Methods of Treatment
  • 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.
    • Conditions Treated—Conditions Mediated by RARα
  • In one embodiment (e.g., of use in methods of therapy, of use in the manufacture of medicaments, of methods of treatment), the treatment is treatment of a disease or condition that is mediated by RARα.
    • Conditions Treated—Conditions Ameliorated by the Activation of RARα
  • In one embodiment (e.g., of use in methods of therapy, of use in the manufacture of medicaments, of methods of treatment), the treatment is treatment of: a disease or condition that is ameliorated by the activation of RARα.
  • In one embodiment (e.g., of use in methods of therapy, of use in the manufacture of medicaments, of methods of treatment), the treatment is treatment of: a disease or condition that is ameliorated by the selective activation of RARα (e.g., with respect to RARβ and/or RARγ).
    • Conditions Treated
  • In one embodiment (e.g., of use in methods of therapy, of use in the manufacture of medicaments, of methods of treatment), 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.
  • In one embodiment, the treatment is treatment of Alzheimer's disease.
  • In one embodiment, the treatment is treatment of early stage Alzheimer's disease.
  • In one embodiment, the treatment is treatment of intermediate stage Alzheimer's disease.
  • In one embodiment, the treatment is treatment of late stage Alzheimer's disease.
  • In one embodiment, the treatment is treatment of cognitive impairment.
  • In one embodiment, the treatment is treatment of mild cognitive impairment.
    • Treatment
  • The term “treatment,” as used herein in the context of treating a condition, 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) is also included. For example, use with patients who have not yet developed the condition, but who are at risk of developing the condition, is encompassed by the term “treatment” (that is, treatment of condition encompasses reducing the risk of that condition).
  • For example, treatment includes the prophylaxis of Alzheimer's disease, reducing the risk of Alzheimer's disease, alleviating the symptoms of Alzheimer's disease, etc.
  • The term “therapeutically-effective amount,” as used herein, 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.
    • Combination Therapies
  • The term “treatment” includes combination treatments and therapies, in which two or more treatments or therapies are combined, for example, sequentially or simultaneously.
  • For example, the compounds described herein may also be used in combination therapies, e.g., in conjunction with other agents. Examples of 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.
  • For example, it 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 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 particular combination would be at the discretion of the physician who would select dosages using his common general knowledge and dosing regimens known to a skilled practitioner.
  • The agents (i.e., the compound described herein, plus one or more other agents) may be administered simultaneously or sequentially, and may be administered in individually varying dose schedules and via different routes. For example, when administered sequentially, 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).
  • The agents (i.e., the compound described here, plus one or more other 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.
    • Other Uses
  • The AAA compounds described herein may also be used as cell culture additives to activate RARα, e.g., to up-regulate chAT expression; to down-regulate APP expression; to up-regulate ADAM10 expression; to down-regulate Aβ40 and Aβ42 expression; to prevent, reduce, or slow cortical neuronal death.
  • The 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.
  • The AAA compounds described herein may also be used as a standard, for example, in an assay, in order to identify other compounds, other RARα agonists, etc.
    • Kits
  • One aspect of the invention pertains to a kit 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.
    • Routes of Administration
  • 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, intraarticular, subarachnoid, and intrasternal; by implant of a depot or reservoir, for example, subcutaneously or intramuscularly.
    • The Subject/Patient
  • 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., gorilla, chimpanzee, orangutang, gibbon), or a human.
  • Furthermore, the subject/patient may be any of its forms of development, for example, a foetus.
  • In one preferred embodiment, the subject/patient is a human.
    • Formulations
  • 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.
  • Thus, 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.
  • The term “pharmaceutically acceptable,” as used herein, 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.
  • 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.
  • 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 (e.g., by ingestion) 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.
  • 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.
  • 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 p-hydroxybenzoate, sorbic acid); flavours, flavour enhancing agents, and sweeteners. 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. If desired, 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. Preferably, 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. Together, the emulsifier(s) with or without stabiliser(s) make up the so-called emulsifying wax, and 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. The choice of 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. Thus 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 (e.g., by inhalation or insufflation therapy) 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.
  • 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.
  • 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 (e.g., by injection), 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). 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. Examples of excipients include, for example, water, alcohols, polyols, glycerol, vegetable oils, and the like. Examples of suitable isotonic carriers for use in such formulations include Sodium Chloride Injection, Ringer's Solution, or Lactated Ringer's Injection. Typically, the concentration of the compound in the liquid is from about 1 ng/mL to about 10 μg/mL, for example from about 10 ng/ml to about 1 μg/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. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules, and tablets.
    • Dosage
  • It will be appreciated by one of skill in the art that 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.
  • In general, a suitable dose of the AAA compound is in the range of about 10 μg to about 250 mg (more typically about 100 μg to about 25 mg) per kilogram body weight of the subject per day. Where 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.
    • EXAMPLES
  • The following examples are provided solely to illustrate the present invention and are not intended to limit the scope of the invention, as described herein.
    • Abbreviations
  • AcOH=glacial acetic acid
    aq.=aqueous
    Boc=tert-butoxycarbonyl
    br=broad
    CDI=1,1-carbonyldiimidazole
    d=doublet
    DCM=dichloromethane
    • DIPEA=N,N-diisopropylethylamine DMA=N,N-dimethylacetamide
  • DMAP=4-dimethylaminopyridine
    • DMF=N,N-dimethylformamide
  • DMSO=dimethylsulfoxide
    EDC=1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride
    eq.=no. of molar equivalents
    EtOAc=ethyl acetate
    h=hour(s)
    HATU=2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate
    • HOBt=N-hydroxybenzotriazole
  • HPLC=high performance liquid chromatography
    IPA=isopropanol
    m=multiplet
    MeOH=methanol
    min=minute(s)
    NMR=nuclear magnetic resonance
    PTSA=toluene-4-sulfonic acid
    quin=quintet
    RT=room temperature
    s=singlet
    sat.=saturated
    SAX=solid supported strong anion exchange resin
    SCX=solid supported strong cation exchange resin
    sep=septet
    t=triplet
    T3P=2-propanephosphonic acid anhydride
    TBAF=tetrabutylammonium fluoride
    TEA=triethylamine
    TFA=trifluoroacetic acid
    THF=tetrahydrofuran
    TMSCl=trimethylchlorosilane
    • General Procedures
  • All starting materials and solvents were either obtained from commercial sources or prepared according to literature conditions.
  • 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% NH3 in methanol.
  • Column chromatography was performed on Silicycle pre-packed silica (230-400 mesh, 40-63 μM) cartridges.
    • Analytical Methods Preparative HPLC:
  • The system consisted of a Gilson HPLC and an Agilent 5 μm 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.
    • 1H NMR Spectroscopy:
  • NMR spectra were recorded using a Bruker Avance III™ 400 MHz instrument, using either residual non-deuterated solvent or tetra-methylsilane as reference.
    • Chemical Synthesis Synthesis 1 4-(3,5-dichloro-4-(cyclopentyloxy)benzamido)benzoic acid (AAA-001) and Methyl 4-(3,5-dichloro-4-(cyclopentyloxy)benzamido)benzoate (AAA-002)
  • Figure US20120149737A1-20120614-C00162
    • Step (i): Methyl 3,5-dichloro-4-(cyclopentyloxy)benzoate (2)
  • Figure US20120149737A1-20120614-C00163
  • Methyl 3,5-dichloro-4-hydroxybenzoate (1) (1.00 g, 4.52 mmol) was dissolved in DMF (8 mL) and treated with bromocyclopentane (534 μL, 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 H2O (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 MgSO4 and filtered. The solvent was removed in vacuo to afford methyl 3,5-dichloro-4-(cyclopentyloxy)benzoate (2) (1.10 g, 84%): 1H NMR (400 MHz, CDCl3) δ: 7.97 (2H, s), 5.04 (1H, m), 3.90 (3H, s), 2.04-1.91 (4H, m), 1.82-1.75 (2H, m), 1.69-1.60 (2H, m).
    • Step (ii): 3,5-Dichloro-4-(cyclopentyloxy)benzoic acid (3)
  • Figure US20120149737A1-20120614-C00164
  • 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−).
    • Step (iii): Methyl 4-(3,5-dichloro-4-(cyclopentyloxy)benzamido)benzoate (AAA-002)
  • Figure US20120149737A1-20120614-C00165
  • A solution of 3,5-dichloro-4-(cyclopentyloxy)benzoic acid (3) (100 mg, 363 μmol) in DCM (5 mL), cooled to 0° C., was treated with oxalyl chloride (63.6 μL, 727 μmol), followed by a drop of DMF. The resultant mixture was stirred for 1 h at RT. The solvent was evaporated in vacuo and the residue dissolved in DCM (5 mL), and then treated with a solution of methyl 4-aminobenzoate (54.9 mg, 363 μmol) and DIPEA (190 μL, 1.09 mmol) in DCM (5 mL). The 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 MgSO4, 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−). NMR (400 MHz, CDCl3) δ: 8.06 (2H, d), 7.85 (1H, br s), 7.82 (2H, s), 7.71 (2H, d), 5.05 (1H, m), 3.92 (3H, s), 2.10-1.90 (4H, m), 1.85-1.70 (2H, m), 1.70-1.60 (2H, m).
    • Step (iv): 4-(3,5-Dichloro-4-(cyclopentyloxy)benzamido)benzoic acid (AAA-001)
  • Figure US20120149737A1-20120614-C00166
  • 4-(3,5-Dichloro-4-(cyclopentyloxy)benzamido)benzoic acid (AAA-001) (15.0 mg, 51%) was prepared from methyl 4-(3,5-dichloro-4-(cyclopentyloxy)benzamido)benzoate (AAA-002) (30.0 mg, 74 μmol) using a procedure essentially the same as in Step (ii): m/z 392 (M−H)− (ES−). 1H NMR (400 MHz, DMSO-d6) δ: 12.77 (1H, s), 10.58 (1H, s), 8.07 (2H, s), 7.93 (2H, d), 7.88 (2H, d), 5.02 (1H, m), 1.90-1.60 (8H, m).
    • Synthesis 2 4-(3,5-Dichloro-4-propoxybenzamido)benzoic acid (AAA-003)
  • Figure US20120149737A1-20120614-C00167
  • 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−). 1H NMR (400 MHz, MeOH-d4) δ: 7.99 (4H, s), 7.85 (2H, d), 4.07 (2H, s), 3.89 (3H, s), 1.89 (2H, s), 1.12 (3H, s).
    • Synthesis 3 4-(3,5-Dichloro-4-isopropoxybenzamido)benzoic acid (AAA-004)
  • Figure US20120149737A1-20120614-C00168
  • 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+). 1H NMR (400 MHz, MeOH-d4) δ: 8.03 (4H, m), 7.83 (2H, d), 4.77 (1H, m), 1.38 (6H, s).
    • Synthesis 4 4-(4-(Benzyloxy)-3,5-dichlorobenzamido)benzoic acid (AAA-005)
  • Figure US20120149737A1-20120614-C00169
  • 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−). 1H NMR (400 MHz, MeOH-d4) δ: 8.03 (4H, d), 7.83 (2H, d), 7.53 (2H, d), 7.38 (3H, m), 5.15 (2H, s).
    • Synthesis 5 4-(3-Chloro-4-(cyclopentyloxy)-5-methoxybenzamido)benzoic acid (AAA-006)
  • Figure US20120149737A1-20120614-C00170
  • 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+). 1H NMR (400 MHz, CDCl3) δ: 12.68 (1H, s), 10.41 (1H, s), 7.86 (2H, d), 7.82 (2H, d), 7.63 (1H, d), 7.49 (1H, d), 4.95 (1H, m), 3.85 (3H, s), 1.80-1.47 (8H, m).
    • Synthesis 6 4-(3,5-Dichloro-4-ethoxybenzamido)-2-fluorobenzoic acid (AAA-007)
  • Figure US20120149737A1-20120614-C00171
  • 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+). 1H NMR (400 MHz, MeOH-d4) δ: 8.01 (2H, s), 7.92 (1H, t), 7.79 (1H, d), 7.53 (1H, d), 4.18 (2H, q), 1.46 (3H, t).
    • Synthesis 7 4-(4-Ethoxy-3,5-diisopropoxybenzamido)benzoic acid (AAA-008)
  • Figure US20120149737A1-20120614-C00172
  • 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+). 1H NMR (400 MHz, MeOH-d4) δ: 8.02 (2H, d), 7.85 (2H, d), 7.28 (2H, s), 4.70 (2H, m), 4.10 (2H, q), 1.37 (15H, m).
    • Synthesis 8 4-(3,4-Diethoxy-5-isopropoxybenzamido)benzoic acid (AAA-009)
  • Figure US20120149737A1-20120614-C00173
  • 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+). 1H NMR (400 MHz, CDCl3) δ: 8.12 (2H, d), 7.75 (2H, d), 7.08 (2H, d), 4.63 (1H, m), 4.13 (4H, m), 1.47 (3H, t), 1.40-1.36 (9H, m).
    • Synthesis 9 4-(3,5-Dichloro-4-(cyclopropylmethoxy)benzamido)benzoic acid (AAA-010)
  • Figure US20120149737A1-20120614-C00174
    Figure US20120149737A1-20120614-C00175
    • Step (i): Methyl 4-(benzyloxy)-3,5-dichlorobenzoate (2)
  • Figure US20120149737A1-20120614-C00176
  • Crude methyl 4-(benzyloxy)-3,5-dichlorobenzoate (2) (16.9 g) was prepared from methyl 3,5-dichloro-4-hydroxybenzoate (1) (10 g, 45.2 mmol) and benzyl bromide (15.5 g, 90 mmol) using a procedure essentially the same as in Step (0 for AAA-001, except that the mixture was stirred at RT for 18 h. The crude product was partially purified by silica gel chromatography (330 g, 0-10% EtOAc/isohexane) to afford a white solid. The material was used in the next step without further purification.
    • Step (ii): 4-(Benzyloxy)-3,5-dichlorobenzoic acid (3)
  • Figure US20120149737A1-20120614-C00177
  • 4-(Benzyloxy)-3,5-dichlorobenzoic acid (3) (12.8 g, 96% over 2 steps) was prepared from crude 4-(benzyloxy)-3,5-dichlorobenzoate (2) (16.9 g) using a procedure essentially the same as in Step (iv) for AAA-001: m/z 295 (M−H)− (ES−). 1H NMR (400 MHz, DMSO-d6) δ: 7.88 (2H, s), 7.51 (2H, d), 7.44-7.37 (3H, m), 5.05 (2H, s).
    • Step (iii): Methyl 4-(4-(benzyloxy)-3,5-dichlorobenzamido)benzoate (4)
  • Figure US20120149737A1-20120614-C00178
  • 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−). 1H NMR (400 MHz, CDCl3) δ: 8.07 (2H, d), 7.84 (2H, s), 7.73 (2H, d), 7.54 (2H, d), 7.44-7.36 (3H, m), 5.13 (2H, s), 3.92 (3H, s).
    • Step (iv): Methyl 4-(3,5-dichloro-4-hydroxybenzamido)benzoate (5)
  • Figure US20120149737A1-20120614-C00179
  • A solution of methyl 4-(4-(benzyloxy)-3,5-dichlorobenzamido)benzoate (4) (8.8 g, 20.5 mmol) in DCM (500 mL) was cooled to 0° C. and treated dropwise with boron trichloride (20.5 mL, 20.5 mmol, 1 M in DCM). The mixture was then allowed to stir at RT for 12 h. The mixture was cooled in an ice bath then quenched by addition of water (150 mL). The resultant mixture was partitioned between EtOAc (200 mL) and H2O (100 mL). The aqueous phase was extracted with EtOAc (2×75 mL) and the combined organic phases washed successively with water (50 mL) and brine (50 mL), then dried over MgSO4 and filtered. The solvent was removed in vacuo. The residue was crystallised from isohexane/EtOAc to afford methyl 4-(3,5-dichloro-4-hydroxybenzamido)benzoate (5) (5.81 g, 84%): m/z 338 (M−H)− (ES−). 1H NMR (400 MHz, DMSO-d6) δ: 11.06 (1H, s), 10.52 (1H, s), 8.06 (2H, s), 8.00 (2H, d), 7.95 (2H, d), 3.88 (3H, s).
    • Step (v): Methyl 4-(3,5-dichloro-4-(cyclopropylmethoxy)benzamido)benzoate (6)
  • Figure US20120149737A1-20120614-C00180
  • 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 μmol) and (bromomethyl)cyclopropane (57 μL, 588 μmol) 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−). 1H NMR (400 MHz, DMSO-d6) δ: 7.99 (4H, d), 7.85 (2H, d), 3.99 (2H, d), 3.90 (3H, s), 1.49-1.29 (1H, m), 0.65-0.60 (2H, m), 0.37-0.34 (2H, m).
    • Step (vi): 4-(3,5-Dichloro-4-(cyclopropylmethoxy)benzamido)benzoic acid (AAA-010)
  • Figure US20120149737A1-20120614-C00181
  • 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 μmol) using a procedure essentially the same as in Step (iv) for AAA-001: m/z 378 (M−H)− (ES−). 1H NMR (400 MHz, MeOH-d4) δ: 8.01 (4H, d), 7.83 (2H, d), 3.98 (2H, d), 1.40-1.30 (1H, m), 0.64-0.60 (2H, m), 0.37-0.33 (2H, m).
    • Synthesis 10 4-(3,5-Dichloro-4-cyclobutoxybenzamido)benzoic acid (AAA-011)
  • Figure US20120149737A1-20120614-C00182
  • 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−). 1H NMR (400 MHz, MeOH-d4) δ: 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).
    • Synthesis 11 4-(3,5-Dichloro-4-(pyridin-4-ylmethoxy)benzamido)benzoic acid (AAA-012)
  • Figure US20120149737A1-20120614-C00183
  • 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-d4) δ: 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).
    • Synthesis 12 4-(3,5-Dichloro-4-ethoxyphenylcarbamoyl)benzoic acid (AAA-013)
  • Figure US20120149737A1-20120614-C00184
    • Step (i): 4-(3,5-Dichloro-4-hydroxyphenylcarbamoyl)benzoic acid (4)
  • Figure US20120149737A1-20120614-C00185
  • A mixture of 4-(chlorocarbonyl)benzoic acid methyl ester (1) (600 mg, ca. 3.02 mmol) contaminated with 4-(methoxycarbonyl)benzoic acid was suspended in DCM (5 mL) and cooled to 0° C. The mixture was treated with oxalyl chloride (529 μL, 6.04 mmol) and DMF (1 drop). The resultant mixture was warmed to RT, stirred for 2 h, and then concentrated in vacuo. The residue was dissolved in DCM (3 mL) and a suspension of 4-amino-2,6-dichlorophenol (2) (511 mg, 2.9 mmol) in DCM (18 mL) was added. The resultant suspension was treated with DIPEA (1.58 mL, 9.06 mmol) and was stirred at RT overnight. The solvent was removed in vacuo and the residue partitioned between EtOAc/DCM and aqueous HCl (1 M). The layers were separated and the organic layer was washed with water and brine. The organic layer was dried over MgSO4, filtered and then the solvent evaporated in vacuo to afford a pale brown solid (930 mg), which was triturated in hot acetonitrile/methanol (9:1) and filtered. The precipitate and filtrate were recombined, the solvent was evaporated in vacuo and then the residue was dissolved in THF (40 mL). Water (10 mL) was added and the mixture treated with lithium hydroxide (340 mg, 14.2 mmol). The mixture was stirred overnight and then partitioned between EtOAc and aqueous HCl (1 M). The organic layer was washed successively with water (2×50 mL), brine, dried over MgSO4, filtered and then concentrated in vacuo to afford crude 4-(3,5-dichloro-4-hydroxyphenylcarbamoyl)benzoic acid (3) as a pale brown solid. This material was used in the subsequent reaction step without purification.
    • Step (ii): Ethyl 4-(3,5-dichloro-4-ethoxyphenylcarbamoyl)benzoate (4)
  • Figure US20120149737A1-20120614-C00186
  • Crude 4-(3,5-dichloro-4-hydroxyphenylcarbamoyl)benzoic acid (3) (450 mg) was dissolved in DMF (15 mL) and treated with potassium carbonate (829 mg, 6.00 mmol) and iodoethane (436 μL, 5.4 mmol). The mixture was stirred at 65° C. overnight. Iodoethane (200 μL, 2.48 mmol) was added and the reaction mixture stirred at 70° C. for 3 h. The mixture was partitioned between EtOAc (150 mL) and aqueous HCl (100 mL, 1 M). The layers were separated and the organic layer was washed successively with saturated aqueous NaHCO3 and water. The organic layer was dried over MgSO4, filtered and the solvent evaporated in vacuo. The residue was purified by silica gel chromatography (10-25% EtOAc/isohexane) to afford Ethyl 4-(3,5-dichloro-4-ethoxyphenylcarbamoyl)benzoate (4) (500 mg, 75% over 2 steps) as a pale pink solid: m/z 380 (M−H)+ (ES−).
    • Step (iii): 4-(3,5-Dichloro-4-ethoxyphenylcarbamoyl)benzoic acid (AAA-013)
  • Figure US20120149737A1-20120614-C00187
  • Ethyl 4-(3,5-dichloro-4-ethoxyphenylcarbamoyl)benzoate (6) (109 mg, 285 μmol) in THF (5 mL) was treated with aqueous lithium hydroxide (1.43 mL, 1 M, 1.43 mmol) and the mixture was stirred at RT for 5 h. The reaction mixture was partitioned between EtOAc and aqueous HCl (1 M). The organic layer was separated and washed successively with water and brine. The organic layer was dried over MgSO4, filtered and then concentrated in vacuo to afford 4-(3,5-dichloro-4-ethoxyphenylcarbamoyl)benzoic acid (AAA-013) (89 mg, 88%) as a pale lilac solid: m/z 352 [M−H]− (ES−). 1H NMR (400 MHz, DMSO-d6) δ: 13.30 (1H, s), 10.58 (1H, s), 8.08 (2H, d), 8.03 (2H, d), 7.94 (2H, d), 4.04 (2H, q), 1.37 (3H, t).
    • Synthesis 13 4-(3,5-Dibromo-4-ethoxyphenylcarbamoyl)benzoic acid (AAA-014)
  • Figure US20120149737A1-20120614-C00188
    • Step (i): 3,5-Dibromo-4-ethoxyaniline (2)
  • Figure US20120149737A1-20120614-C00189
  • 4-Amino-2,6-dibromophenol (1) (1.00 g, 3.75 mmol) was dissolved in anhydrous DMF (10 mL) and cooled to 0° C. Sodium hydride (165 mg, 4.12 mmol) was added portionwise. The dark blue solution was stirred for 1 h at RT before iodoethane (318 μL, 3.93 mmol) was added. The mixture was stirred at RT for 3 days and then partitioned between EtOAc and aqueous NaOH (1 M). The organic layer was washed successively with water and brine, then dried over MgSO4 and filtered. The solvent was evaporated in vacuo and the residue purified by silica gel chromatography (10% EtOAc/isohexane) to afford 3,5-dibromo-4-ethoxyaniline (2) (790 mg, 72%) as a dark orange solid: m/z 296 (M+H)+ (ES+). 1H NMR (400 MHz, CDCl3) δ: 6.82 (2H, s), 3.99 (2H, q), 3.58 (2H, s), 1.54 (3H, s), 1.44 (3H, t).
    • Step (ii): Methyl 4-(3,5-dibromo-4-ethoxyphenylcarbamoyl)benzoate (4)
  • Figure US20120149737A1-20120614-C00190
  • 3,5-Dibromo-4-ethoxyaniline (2) (100 mg, 339 μmol) was dissolved in DCM (2.5 mL) and treated with triethylamine (143 μL, 1.02 mmol). 4-(Chlorocarbonyl)benzoic acid methyl ester (3) (135 mg, 678 μmol) 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 NaHCO3, water and brine. The organic layer was then dried over MgSO4, filtered and the solvent evaporated in vacuo. The residue was triturated from Et2O and filtered. The filtered solid was washed with methanol and the washings were concentrated in vacuo to provide methyl 4-(3,5-dibromo-4-ethoxyphenylcarbamoyl)benzoate (4) (141 mg, 73%) as a pale brown solid: m/z 456 [M−H]− (ES−).
    • Step (iii): 4-(3,5-Dibromo-4-ethoxyphenylcarbamoyl)benzoic acid (AAA-014)
  • Figure US20120149737A1-20120614-C00191
  • 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 μmol) 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−). 1H NMR (400 MHz, DMSO-d6) δ: 13.31 (1H, s), 10.59 (1H, s), 8.15 (2H, s), 8.05 (2H, d), 8.03 (2H, d), 4.01 (2H, q), 1.40 (3H, t).
    • Synthesis 14 4-(4-Ethoxy-3,5-bis(trifluoromethyl)phenylcarbamoyl)benzoic acid (AAA-015)
  • Figure US20120149737A1-20120614-C00192
    • Step (i): 2-Ethoxy-5-nitro-1,3-bis(trifluoromethyl)benzene (2)
  • Figure US20120149737A1-20120614-C00193
  • Ethanol (20 mL, 343 mmol) was treated with potassium hydroxide (956 mg, 17.0 mmol) and the mixture was stirred at RT for 1 h. A solution of 2-chloro-5-nitro-1,3-bis(trifluoromethyl)benzene (1) (1.00 g, 3.41 mmol) in DMSO (10 mL) was added drop-wise. The resultant mixture was stirred at RT for 1 h. The mixture was partitioned between EtOAc and water and the aqueous phase was extracted twice with EtOAc. The combined organic phases were washed with brine, dried over MgSO4, filtered and the solvent removed in vacuo to afford 2-ethoxy-5-nitro-1,3-bis(trifluoromethyl)benzene (2) (1.00 g, 93%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ: 8.72 (2H, s), 4.21 (2H, q), 1.41 (3H, t).
    • Step (ii): 4-Ethoxy-3,5-bis(trifluoromethyl)aniline (3)
  • Figure US20120149737A1-20120614-C00194
  • 2-Ethoxy-5-nitro-1,3-bis(trifluoromethyl)benzene (2) (1.00 g, 3.30 mmol) was dissolved in MeOH (150 mL) and passed through a Thales ‘H-cube’ cartridge (10% Pd/C) at a flow rate of 1 mL/min at 30° C. under H2 (full H2 mode). The solvent was removed in vacuo and the residue was dissolved in EtOH (20 mL) and then treated with 10% Pd/C (182 mg, 171 μmol). Hydrogen gas was bubbled through the mixture, with stirring at RT for 2 h. The mixture was then filtered through Celite and concentrated in vacuo. The residue was purified by silica gel chromatography (15% EtOAc in isohexane) to afford 4-ethoxy-3,5-bis(trifluoromethyl)aniline (3) (460 mg, 56%) as a white solid: m/z 273 [M+H]+ (ES+). 1H NMR (400 MHz, DMSO-d6) δ: 7.09 (2H, s), 5.76 (2H, s), 3.87 (2H, q), 1.29 (3H, t).
    • Step (iii): Methyl 4-(4-ethoxy-3,5-bis(trifluoromethyl)phenylcarbamoyl)benzoate (5)
  • Figure US20120149737A1-20120614-C00195
  • 4-(Methoxycarbonyl)benzoic acid (4) (246 mg, 1.37 mmol) was dissolved in DCM (15 mL) and treated with EDC (654 mg, 3.41 mmol) and DMAP (33 mg, 273 μmol). The resultant mixture was stirred at RT for 15 min. 4-Ethoxy-3,5-bis(trifluoromethyl)aniline (3) (360 mg, 1.32 mmol) was added and the resultant mixture was stirred at RT for 20 h. The mixture was diluted with EtOAc and washed three times with 1 M HCl and then three times with NaHCO3 solution. The organic phase was washed with brine, dried over MgSO4, filtered and the solvent removed in vacuo. The residue was purified by silica gel chromatography (10% EtAOc in isohexane) to afford methyl 4-(4-ethoxy-3,5-bis(trifluoromethyl)phenylcarbamoyl)benzoate (5) (150 mg, 28%): m/z 436 [M+H]+ (ES+). 1H NMR (400 MHz, DMSO-d6) δ: 10.88 (1H, s), 8.48 (2H, s), 8.11 (4H, m), 4.04 (2H, q), 3.90 (3H, s), 1.37 (3H, t).
    • Step (iv): 4-(4-Ethoxy-3,5-bis(trifluoromethyl)phenylcarbamoyl)benzoic acid (AAA-015)
  • Figure US20120149737A1-20120614-C00196
  • 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 μmol) using a procedure essentially the same as in Step (vi) for AAA-010: m/z 422 [M+H]+ (ES+). 1H NMR (400 MHz, DMSO-d6) δ: 13.39 (1H, bs), 10.92 (1H, s), 8.55 (2H, s), 8.15 (4H, m), 4.11 (2H, q), 1.44 (3H, t).
    • Synthesis 15 N-(4-Carbamoylphenyl)-3,5-dichloro-4-ethoxybenzamide (AAA-016)
  • Figure US20120149737A1-20120614-C00197
  • 3,5-Dichloro-4-ethoxybenzoic acid (1) (100 mg, 425 μmol) was dissolved in DCM (2 mL) and treated with EDC (204 mg, 1.06 mmol) and DMAP (10 mg, 85 μmol). The resultant mixture was stirred at RT for 30 min. 4-Aminobenzamide (2) (58 mg, 425 μmol) 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+). 1H NMR (400 MHz, DMSO-d6) δ: 10.51 (1H, bs), 8.08 (2H, s), 7.84 (5H, m), 7.27 (1H, bs), 4.14 (2H, q), 1.40 (3H, t).
    • Synthesis 16 Methyl 4-(3,5-dichloro-4-ethoxybenzamido)-2-chlorobenzoate (AAA-017)
  • Figure US20120149737A1-20120614-C00198
  • 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−). 1H NMR (400 MHz, CDCl3) δ: 7.93 (2H, d), 7.85 (1H, s), 7.83 (1H, d), 7.80 (2H, s), 4.18 (2H, q), 3.93 (3H, s), 1.49 (3H, t).
    • Synthesis 17 2-Chloro-4-(3,5-dichloro-4-ethoxybenzamido)benzoic acid (AAA-018)
  • Figure US20120149737A1-20120614-C00199
  • 2-Chloro-4-(3,5-dichloro-4-ethoxybenzamido)benzoic acid (AAA-018) (39 mg, 39% for the 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 was used instead of 3,5-dichloro-4-(cyclopentyloxy)benzoic acid and methyl 4-amino-2-chlorobenzoate was used instead of methyl 4-aminobenzoate in Step (iii): m/z 386 (M−H)− (ES−). 1H NMR (400 MHz, DMSO-d6) δ: 13.18 (1H, s), 10.65 (1H, s), 8.07 (2H, s), 8.00 (1H, d), 7.88 (1H, d), 7.78 (1H, dd), 4.13 (2H, q), 1.39 (3H, t).
    • Synthesis 18 4-(3,5-Dichloro-4-ethoxybenzamido)-2-methylbenzoic acid (AAA-019)
  • Figure US20120149737A1-20120614-C00200
    • Step (i): Methyl 4-(3,5-dichloro-4-ethoxybenzamido)-2-methylbenzoate (3)
  • Figure US20120149737A1-20120614-C00201
  • A solution of 3,5-dichloro-4-ethoxybenzoic acid (1) (285 mg, 1.21 mmol) and DIPEA (1.05 mL, 6.05 mmol) in DMF (2.5 mL) was added to HATU (690 mg, 1.82 mmol) and the orange mixture was stirred for 5 min prior to the addition of methyl 4-amino-2-methylbenzoate (2) (200 mg, 1.21 mmol) in DMF (1 mL). The resulting dark orange solution was stirred overnight for 18 h. 2 M HCl (10 mL) was added and stirring continued for 10 min, and then the mixture was extracted with diethyl ether. The organic layer was washed with water (3×15 mL), dried over MgSO4, filtered and the solvent was evaporated in vacuo. The yellow residue was purified by silica gel chromatography (40 g, 0-100% EtOAc in isohexane) to afford methyl 4-(3,5-dichloro-4-ethoxybenzamido)-2-methylbenzoate (3) (267 mg, 56%): m/z 380 (M−H)− (ES−). 1H NMR (400 MHz, CDCl3) δ: 7.97 (1H, s), 7.80 (3H, m), 7.54 (1H, dd), 7.51 (1H, d), 4.18 (2H, q), 3.89 (3H, s), 2.63 (3H, s), 1.49 (3H, t).
    • Step (ii): 4-(3,5-Dichloro-4-ethoxybenzamido)-2-methylbenzoic acid (AAA-019)
  • Figure US20120149737A1-20120614-C00202
  • Lithium hydroxide (60 mg, 2.51 mmol) in water (1 mL) was added dropwise to a stirring solution of methyl 4-(3,5-dichloro-4-ethoxybenzamido)-2-methylbenzoate (3) (267 mg, 56%) (240 mg, 0.628 mmol) in THF (5 mL) and the resulting yellow solution was stirred for 5 days at RT. The solvent was evaporated in vacuo and dissolved in water (5 mL), then acidified with 2 M HCl. The resultant mixture was extracted with EtOAc. The organic layer was washed with water, dried over MgSO4 and filtered and pre-adsorbed on silica. Silica gel chromatography (40 g, 0-10% IPA in DCM) provided 4-(3,5-dichloro-4-ethoxybenzamido)-2-methylbenzoic acid (AAA-019) (52 mg, 22%): m/z 366 (M−H)− (ES−). 1H NMR (400 MHz, DMSO-d6) δ: 12.66 (1H, s), 10.49 (1H, s), 8.08 (2H, s), 7.87 (1H, d), 7.71 (1H, dd), 7.68 (1H, d), 4.14 (2H, q), 2.54 (3H, s), 1.40 (2H, t).
    • Synthesis 19 6-(3,5-dichloro-4-ethoxyphenylcarbamoyl)nicotinic acid (AAA-020)
  • Figure US20120149737A1-20120614-C00203
    • Step (i): 3,5-Dichloro-4-ethoxyaniline (2)
  • Figure US20120149737A1-20120614-C00204
  • 4-Amino-2,6-dichlorophenol (1) (1.00 g, 5.62 mmol) was dissolved in dry DMF (9 mL) and cooled to 0° C. Sodium hydride (142 mg, 5.90 mmol) was added to the mixture portionwise. The dark purple solution was stirred for 1 h at RT, then iodoethane (468 μL, 5.79 mmol) was added. The reaction mixture was stirred for 3 h and partitioned between EtOAc and aqueous NaOH (1 M). The organic layer was washed successively with water and brine, and then dried over MgSO4, filtered and the solvent evaporated in vacuo. The residue was purified by silica gel chromatography (5% EtOAc/isohexane) to afford 3,5-dichloro-4-ethoxyaniline (2) (460 mg, 40%): m/z 206 [M+H]+ (ES+). 1H NMR (400 MHz, CDCl3) δ: 6.60 (2H, s), 4.01 (2H, q), 3.60 (2H, s), 1.42 (3H, t).
    • Step (ii): Methyl 6-(3,5-dichloro-4-ethoxyphenylcarbamoyl)nicotinate (3)
  • Figure US20120149737A1-20120614-C00205
  • 5-(Methoxycarbonyl)-2-pyridine carboxylic acid (50 mg, 276 μmol) was dissolved in DMF (2 mL) and treated with CDI (60 mg, 370 μmol). The reaction mixture was stirred at RT for 2 h. 3,5-Dichloro-4-ethoxyaniline (2) (57 mg, 276 μmol) and DIPEA (96 μL, 552 μmol) were added sequentially and the reaction mixture was stirred at RT overnight, then at 70° C. for 19 h. The reaction mixture was partitioned between EtOAc and aqueous HCl (1 M). The organic layer was washed successively with water and brine, and then dried over MgSO4, filtered and concentrated in vacuo. The residue was crystallised from methanol to afford methyl 6-(3,5-dichloro-4-ethoxyphenylcarbamoyl)nicotinate (3) (46 mg, 45%) as a white solid: m/z 369 [M+H]+ (ES+). 1H NMR (400 MHz, DMSO-d6) δ: 11.12 (1H, s), 9.18 (1H, dd), 8.55 (1H, dd), 8.29 (1H, dd), 8.13 (2H, s), 4.06 (2H, q), 3.94 (3H, s), 1.37 (3H, t).
    • Step (iii): 6-(3,5-Dichloro-4-ethoxyphenylcarbamoyl)nicotinic acid (AAA-020)
  • Figure US20120149737A1-20120614-C00206
  • 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 μmol) 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−). 1H NMR (400 MHz, DMSO-d6) δ: 11.12 (1H, s), 9.18 (1H, dd), 8.55 (1H, dd), 8.29 (1H, dd), 8.13 (2H, s), 4.06 (2H, q), 1.37 (3H, t).
    • Synthesis 20 4-(4-Ethoxy-3,5-difluorophenylcarbamoyl)benzoic acid (AAA-021)
  • Figure US20120149737A1-20120614-C00207
  • 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 Et2O/EtOAc 8:1 and purification by preparative HPLC (Method 1): m/z 320 [M−H]− (ES−). 1H NMR (400 MHz, MeOD-d4) δ: 8.42 (1H, s), 8.10 (2H, d), 7.94 (2H, d), 7.45 (2H, d), 4.14 (2H, q), 1.35 (3H, t).
    • Synthesis 21 4-(3-Chloro-4-ethoxy-5-(trifluoromethyl)benzamido)-2,6-difluorobenzoic acid (AAA-022)
  • Figure US20120149737A1-20120614-C00208
  • 4-(3-Chloro-4-ethoxy-5-(trifluoromethyl)benzamido)-2,6-difluorobenzoic acid (AAA-022) (5 mg, 7% 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-trifluoromethylbenzoic acid (prepared in 3 steps from 4-hydroxy-3-(trifluoromethyl)benzoic acid by sequential treatment with sulfuryl chloride, ethyl iodide and base and then lithium hydroxide) and ethyl 2,6-difluoro-4-aminobenzoate were used instead of 3,5-dichloro-4-(cyclopentyloxy)benzoic acid and methyl 4-aminobenzoate respectively in step (iii): m/z 422 (M−H)− (ES−). 1H NMR (400 MHz, MeOD) δ: 8.32 (d, 1H), 8.21 (d, 1H), 7.49 (d, 2H), 4.24 (q, 2H), 1.48 (t, 3H).
    • Synthesis 22 4-(3,5-Dibromo-4-ethoxybenzamido)benzoic acid (AAA-023)
  • Figure US20120149737A1-20120614-C00209
  • 4-(3,5-Dibromo-4-ethoxybenzamido)benzoic acid (AAA-023) (42 mg, 87% for final step) was prepared in essentially the same manner as in Steps (iii) and (iv) for AAA-001, except that 3,5-dibromo-4-ethoxybenzoic acid (prepared in 2 steps from methyl 3,5-dibromo-4-hydroxybenzoate 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 442 (M−H)− (ES−). 1H NMR (400 MHz, CDCl3) 10.59 (1H, s), 8.24 (2H, s), 7.94 (2H, d), 7.87 (2H, d), 4.10 (2H, q), 1.43 (3H, t).
    • Synthesis 23 4-(3-Chloro-4-ethoxy-5-methoxybenzamido)benzoic acid (AAA-024)
  • Figure US20120149737A1-20120614-C00210
  • 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−). 1H NMR (400 MHz, DMSO) 12.76 (1H, br s), 10.46 (1H, br s), 7.93 (2H, d), 7.87 (2H, d), 7.69 (1H, d), 7.56 (1H, d), 4.19 (2H, q), 3.85 (3H, s), 1.39 (3H, t).
    • Synthesis 24 4-(3-Chloro-4-ethoxy-5-(trifluoromethyl)benzamido)benzoic acid (AAA-025)
  • Figure US20120149737A1-20120614-C00211
  • 4-(3-Chloro-4-ethoxy-5-(trifluoromethyl)benzamido)benzoic acid (AAA-025) (17 mg, 34% 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-(trifluoromethyl)benzoic acid was used instead of 3,5-dichloro-4-(cyclopentyloxy)benzoic acid in step (iii): m/z 386 (M−H)− ES−. 1H NMR (400 MHz, DMSO) 12.78 (1H, br s), 10.69 (1H, br s), 8.42 (1H, d), 8.22 (1H, d), 7.95 (2H, d), 7.87 (2H, d), 3.37 (2H, q), 1.41 (3H, t).
    • Synthesis 25 5-(3,5-Dichloro-4-ethoxybenzamido)picolinic acid (AAA-026)
  • Figure US20120149737A1-20120614-C00212
  • 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+). 1H NMR 400 MHz, DMSO-d6) δ: 10.9 (1H, s), 9.0 (1H, d), 8.4 (1H, dd), 8.2 (2H, s), 8.1 (1H, d), 4.1 (2H, q), 1.4 (3H, t). (The final compound was isolated as a hydrochloride salt.
    • Synthesis 26 6-(3,5-Dichloro-4-ethoxybenzamido)nicotinic acid (AAA-027)
  • Figure US20120149737A1-20120614-C00213
  • 6-(3,5-Dichloro-4-ethoxybenzamido)nicotinic acid (AAA-027) (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−). 1H NMR (400 MHz, DMSO-d6) δ: 11.3 (1H, s), 8.9 (1H, d), 8.3 (1H, dd), 8.2 (1H, d), 8.1 (2H, s), 4.1 (2H, q), 1.4 (3H, t).
    • Synthesis 27 4-(3,4,5-Triethoxybenzamido)benzoic acid (AAA-028) (PP-01)
  • Figure US20120149737A1-20120614-C00214
  • 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+). 1H NMR (400 MHz, DMSO-d6) δ: 10.3 (1H, s), 7.9 (2H, d), 7.8 (2H, d), 7.2 (2H, s), 4.1 (4H, q), 4.0 (2H, q), 1.4 (6H, t), 1.2 (3H, t).
    • Synthesis 28 4-(3,5-Dichloro-4-ethoxybenzamido)benzoic acid (AAA-029) (PP-02)
  • Figure US20120149737A1-20120614-C00215
  • The title compound was obtained from commercial sources.
    • Synthesis 29 4-(3,5-Dichloro-4-methoxybenzamido)benzoic acid (AAA-030) (PP-03)
  • Figure US20120149737A1-20120614-C00216
  • The title compound was obtained from commercial sources.
    • Synthesis 30 (Comparison Compound) 4-(4-Ethoxy-3-(trifluoromethyl)benzamido)benzoic acid (XXX-01)
  • Figure US20120149737A1-20120614-C00217
  • 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−). 1H NMR (400 MHz, DMSO) 12.75 (1H, br s) 10.54 (1H, br s), 8.26 (1H, d), 8.24 (1H, d), 7.94 (2H, d), 7.88 (2H, d), 7.41 (1H, d), 4.27 (2H, q), 1.36 (3H, t).
    • Synthesis 31 (Comparison Compound) 4-(4-Ethoxy-3-(trifluoromethyl)benzamido)-2,6-difluorobenzoic acid (XXX-02)
  • Figure US20120149737A1-20120614-C00218
    • Step (i): 4-Amino-2,6-difluorobenzoic acid (2)
  • Figure US20120149737A1-20120614-C00219
  • 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. The phases were separated and the organic phase was washed successively with water and brine, then dried over MgSO4, filtered and the solvent removed in vacuo. The residues were combined to afford 4-amino-2,6-difluorobenzoic acid (2) (2.46 g, 88%) as a pale yellow solid: m/z 173 (M−H)− (ES−). 1H NMR (400 MHz, DMSO-d6) a: 12.59 (1H, br s), 6.31 (1H, s), 6.16 (2H, dt).
    • Step (iv): Benzyl 4-amino-2,6-difluorobenzoate (3)
  • Figure US20120149737A1-20120614-C00220
  • 4-Amino-2,6-difluorobenzoic acid (5) (900 mg, 5.20 mmol) was dissolved in DMF (15 mL) and treated with potassium carbonate (790 mg, 5.72 mmol). Benzyl bromide (617 μL, 5.20 mmol) was added over 5 min. The resultant mixture was stirred at RT for 2 h. The mixture was then partitioned between EtOAc (150 mL) and water. The phases were separated and the aqueous phase extracted with EtOAc. The combined organic phases were washed successively with water (4 times) and then brine. The organic phase was then dried over MgSO4, filtered and the solvent removed in vacuo. The residue was purified by silica gel chromatography (100% DCM). The resultant material was dissolved in the minimum volume of EtOAc and added dropwise to isohexane (150 mL). The resultant white precipitate was collected by filtration to afford benzyl 4-amino-2,6-difluorobenzoate (6) (910 mg, 64%) as a white solid: m/z 264 (M+H)+ (ES+). 1H NMR (400 MHz, CDCl3) δ: 7.44 (2H, dd), 7.39-7.29 (3H, m), 6.16 (2H, dt), 5.34 (2H, s), 4.18 (2H, br s).
    • Step (v): Benzyl 4-(4-ethoxy-3-(trifluoromethyl)benzamido)-2,6-difluorobenzoate (4)
  • Figure US20120149737A1-20120614-C00221
  • 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 μmol) 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 NaHCO3, then successively with water and brine. The organic phase was dried over MgSO4, 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−). 1H NMR (400 MHz, MeOD) δ: 8.22 (1H, d), 8.18 (1H, dd), 7.55 (2H, dt), 7.46-7.44 (2H, m), 7.41-7.36 (3H, m), 7.29 (1H, d), 5.37 (2H, s), 4.25 (2H, q), 1.46 (3H, t).
    • Step (vi): 4-(4-Ethoxy-3-(trifluoromethyl)benzamido)-2,6-difluorobenzoic acid (XXX-02)
  • Figure US20120149737A1-20120614-C00222
  • Benzyl 4-(4-ethoxy-3-(trifluoromethyl)benzamido)-2,6-difluorobenzoate (4) (25 mg, 52 μmol) 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 H2 (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−). 1H NMR (400 MHz, MeOD) a: 8.23 (1H, d), 8.19 (1H, dd), 7.53 (2H, dt), 7.30 (1H, d), 4.26 (2H, q), 1.46 (3H, t).
    • Synthesis 32 (Comparison Compound) 4-(3,5-Dichlorobenzamido)benzoic acid (XXX-03)
  • Figure US20120149737A1-20120614-C00223
  • The title compound was obtained from commercial sources.
    • Synthesis 33 4-(4-(tert-Butoxy)-3,5-dichlorobenzamido)benzoic acid (AAA-031)
  • Figure US20120149737A1-20120614-C00224
    • Step (i): Methyl 4-(4-(tert-butoxy)-3,5-dichlorobenzamido)benzoate (2)
  • Figure US20120149737A1-20120614-C00225
  • A stirred suspension of methyl 4-(3,5-dichloro-4-hydroxybenzamido)benzoate (1) (Synthesis 9) (100 mg, 294 μmol) in toluene (2 mL) was heated at 80° C. until homogenous. The resultant solution was treated with 1,1-di-tert-butoxy-N,N-dimethylmethanamine
  • (141 μL, 588 μmol) and the mixture heated at 80° C. for 3 h, and then at RT for 18 h. Additional 1,1-di-tert-butoxy-N,N-dimethylmethanamine (141 μL, 588 μmol) was added and mixture was heated at 80° C. for 5 h. The reaction mixture was cooled to RT and solvent was removed in vacuo. The residue was diluted with water and extracted with Et2O. The organic layer was dried over MgSO4, filtered and concentrated in vacuo. The residue was partially purified by silica gel chromatography (12 g, 0-50% EtOAc in isohexane) to afford methyl 4-(4-(tert-butoxy)-3,5-dichlorobenzamido)benzoate (2) (82 mg, 71%). The material was used in the next step without further purification.
    • Step (ii): 4-(4-(tert-Butoxy)-3,5-dichlorobenzamido)benzoic acid (AAA-031)
  • Figure US20120149737A1-20120614-C00226
  • 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 μmol) using a procedure essentially the same as in step (ii) for AAA-001: m/z 380 [M−H]− (ES−); 1H NMR (400 MHz, DMSO-d6) δ: 12.79 (1H, s), 10.60 (1H, s), 8.06 (2H, s), 7.94 (2H, d), 7.87 (2H, d), 1.49 (9H, s).
    • Synthesis 34 4-(3,5-Dichloro-4-isopropoxybenzamido-2-methylbenzoic acid (AAA-032)
  • Figure US20120149737A1-20120614-C00227
  • 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+); 1H 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).
    • Synthesis 35 4-(3,5-Dichloro-4-ethoxybenzamido)-2-(trifluoromethyl)benzoic acid (AAA-033)
  • Figure US20120149737A1-20120614-C00228
  • 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−); 1H NMR (400 MHz, DMSO-d6) δ: 10.77 (1H, s), 8.26 (1H, s), 8.14 (1H, d), 8.10 (2H, s), 7.88 (1H, d), 7.15 (1H, br s), 4.14 (2H, q), 1.40 (3H, t).
    • Synthesis 36 4-(3-Chloro-4-isopropoxy-5-(trifluoromethyl)benzamido)benzoic acid (AAA-034)
  • Figure US20120149737A1-20120614-C00229
  • 4-(3-Chloro-4-isopropoxy-5-(trifluoromethyl)benzamido)benzoic acid (AAA-034) (35 mg, 38% for final step) was prepared in essentially the same manner as in steps (iii) and (iv) for AAA-001 except that 3-chloro-4-isopropoxy-5-(trifluoromethyl)benzoic acid (prepared in 3 steps from 4-hydroxy-3-(trifluoromethyl)benzoic acid by sequential treatment with sulfuryl chloride, 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−); 1H NMR (400 MHz, DMSO-d6) δ: 12.80 (1H, br s), 10.69 (1H, s), 8.39 (1H, d), 8.22 (1H, d), 7.94 (2H, m), 7.87 (2H, m), 5.06 (1H, m), 1.28 (6H, d).
    • Synthesis 37 4-(3-Chloro-4-methoxy-5-(trifluoromethyl)benzamido)benzoic acid (AAA-035)
  • Figure US20120149737A1-20120614-C00230
  • 4-(3-Chloro-4-methoxy-5-(trifluoromethyl)benzamido)benzoic acid (AAA-035) (5 mg, 73% 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-trifluoromethylbenzoic acid (prepared in 3 steps from 4-hydroxy-3-(trifluoromethyl)benzoic acid by sequential treatment with sulfuryl chloride, methyl iodide and base and then lithium hydroxide) was used instead of 3,5-dichloro-4-(cyclopentyloxy)benzoic acid in step (iii): m/z 374 [M+H]+ (ES+), 372 [M−H]− (ES−); 1H-NMR (400 MHz, DMSO-d6) δ: 12.79 (1H, bs), 10.70 (1H, s), 8.44 (1H, d), 8.23 (1H, d), 7.96 (2H, d), 7.88 (2H, d), 3.98 (3H, s).
    • Synthesis 38 4-(3-Chloro-4-cyclobutoxy-5-(trifluoromethyl)benzamido)benzoic acid (AAA-036)
  • Figure US20120149737A1-20120614-C00231
    • Step (i) 3-Chloro-4-hydroxy-5-(trifluoromethyl)benzoic acid (2)
  • Figure US20120149737A1-20120614-C00232
  • 4-Hydroxy-3-(trifluoromethyl)benzoic acid (1) (2.00 g, 9.70 mmol) was dissolved in AcOH (40 mL) and treated with sulfuryl chloride (2.37 mL, 29.1 mmol). The mixture was stirred at 60° C. for 20 h. The reaction mixture was allowed to cool to RT and then poured into water (100 mL). The product was extracted with EtOAc (75 mL) and the organic solution was washed with water (2×75 mL) and brine (75 mL), then dried over MgSO4 and filtered. The solvent was removed in vacuo and the residue was purified by silica gel chromatography (120 g, 0-100% EtOAc/isohexane) to afford 3-chloro-4-hydroxy-5-(trifluoromethyl)benzoic acid (2) (1.87 g, 80%) as a white solid: m/z 241 [M+H]+ (ES+), 239 [M−H]− (ES−).
    • Step (ii): Methyl 4-(3-chloro-4-hydroxy-5-(trifluoromethyl)benzamido)benzoate (4)
  • Figure US20120149737A1-20120614-C00233
  • 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+); 1H NMR (400 MHz, DMSO-d6) δ: 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).
    • Step (iii): Methyl 4-(3-chloro-4-cyclobutoxy-5-(trifluoromethyl)benzamido)benzoate (5)
  • Figure US20120149737A1-20120614-C00234
  • 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+); 1H NMR (400 MHz, DMSO-d6) δ: 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).
    • Step (iv): 4-(3-Chloro-4-cyclobutoxy-5-(trifluoromethyl)benzamido)benzoic acid (AAA-036)
  • Figure US20120149737A1-20120614-C00235
  • 4-(3-Chloro-4-cyclobutoxy-5-(trifluoromethyl)benzamido)benzoic acid (96 mg, 91%) was prepared in essentially the same manner as in step (ii) for AAA-001 except that 1,4-dioxane was used instead of THF: m/z 412 [M−H]− (ES−); 1H NMR (400 MHz, DMSO-d6) δ: 12.81 (1H, br s), 10.70 (1H, s), 8.41 (1H, d), 8.20 (1H, d), 7.95 (2H, m), 7.88 (2H, m), 4.73 (1H, m), 2.36 (2H, m), 2.27 (2H, m), 1.69 (1H, m), 1.44 (1H, m).
    • Synthesis 39 4-(4-(tert-Butoxy)-3-chloro-5-(trifluoromethyl)benzamido)benzoic acid (AAA-037)
  • Figure US20120149737A1-20120614-C00236
  • 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−); 1H-NMR (400 MHz, DMSO-d6) δ: 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, s).
    • Synthesis 40 4-(4-(tert-Butoxy)-3-chloro-5-(trifluoromethyl)benzamido)-2-methylbenzoic acid (AAA-038)
  • Figure US20120149737A1-20120614-C00237
  • 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−); 1H-NMR (400 MHz, d4-MeOH) δ: 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).
    • Synthesis 41 4-(3-Chloro-4-ethoxy-5-(trifluoromethyl)benzamido)-2-methylbenzoic acid (AAA-039)
  • Figure US20120149737A1-20120614-C00238
  • 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−); 1H-NMR (400 MHz, DMSO-d6) δ: 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 (3H, s), 1.42 (3H, t).
    • Synthesis 42 4-(3-Chloro-4-isopropoxy-5-(trifluoromethyl)benzamido)-2-methylbenzoic acid (AAA-040)
  • Figure US20120149737A1-20120614-C00239
  • 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−); 1H-NMR (400 MHz, DMSO-d6) δ: 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), 2.54 (3H, s), 1.29 (6H, d).
    • Synthesis 43 4-(3-Chloro-4-methoxy-5-(trifluoromethyl)benzamido)-2-methylbenzoic acid (AAA-041)
  • Figure US20120149737A1-20120614-C00240
  • 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−); 1H-NMR (400 MHz, DMSO-d6) δ: 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 (3H, s).
    • Synthesis 44 4-(3-Bromo-4-ethoxy-5-(trifluoromethyl)benzamido)benzoic acid (AAA-042)
  • Figure US20120149737A1-20120614-C00241
  • 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−); 1H-NMR (400 MHz, DMSO-d6) δ: 12.81 (1H, br s), 10.71 (1H, s), 8.56 (1H, d), 8.26 (1H, d), 7.96 (2H, d), 7.88 (2H, d), 4.18 (2H, q), 1.43 (3H, t).
    • Synthesis 45 4-(3-Chloro-4-(cyclopentyloxy)-5-(trifluoromethyl)benzamido)benzoic acid (AAA-043)
  • Figure US20120149737A1-20120614-C00242
  • 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−); 1H NMR (400 MHz, DMSO-d6) δ: 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).
    • Synthesis 46 4-(3-Chloro-4,5-bis(cyclopentyloxy)benzamido)benzoic acid (AAA-044)
  • Figure US20120149737A1-20120614-C00243
    Figure US20120149737A1-20120614-C00244
    • Step (i): 3-Chloro-4,5-dihydroxybenzoic acid (2)
  • Figure US20120149737A1-20120614-C00245
  • 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 MgSO4 and filtered. The solvent was removed in vacuo to give 3-chloro-4,5-dihydroxybenzoic acid (2) (5.11 g, 79%): m/z 187 [M−H]− (ES−); 1H NMR (400 MHz, DMSO-d6) δ: 12.69 (1H, br s), 10.14 (2H, br s), 7.35 (1H, d), 7.32 (1H, d).
    • Step (ii): Methyl 3-chloro-4,5-dihydroxybenzoate (3)
  • Figure US20120149737A1-20120614-C00246
  • A solution of 3-chloro-4,5-dihydroxybenzoic acid (2) (3.16 g, 16.76 mmol) and chlorotrimethylsilane (6.36 mL, 50.3 mmol) in MeOH (50 mL) was stirred at 50° C., under nitrogen overnight. The solvent was removed in vacuo and the residue was partitioned between brine (75 mL) and EtOAc (75 mL). The organic layer was washed with brine (75 mL), dried over MgSO4 and filtered. The solvent was removed in vacuo to give methyl 3-chloro-4,5-dihydroxybenzoate (3) (3.26 g, 13.68 mmol, 82% yield): m/z 201 [M−H]− (ES−); 1H NMR (400 MHz, DMSO-d6) δ: 10.17 (2H, br s), 7.38 (1H, d), 7.35 (1H, d), 3.78 (3H, s).
    • Step (iii): Methyl 3-chloro-4,5-bis(cyclopentyloxy)benzoate (4)
  • Figure US20120149737A1-20120614-C00247
  • A mixture of methyl 3-chloro-4,5-dihydroxybenzoate (3) (300 mg, 1.48 mmol), iodocyclopentane (558 μL, 4.44 mmol) and potassium carbonate (614 mg, 4.44 mmol) in DMF (10 mL) was stirred at 70° C. for 46 h. The reaction mixture was cooled to room temperature and then partitioned between 1M HCl (75 mL) and EtOAc (100 mL). The phases were separated and the organic phase was washed with brine (2×75 mL) then dried over MgSO4 and filtered. The solvent was removed in vacuo and the residue was purified by silica gel chromatography (40 g, 0-100% EtOAc in isohexane) to give methyl 3-chloro-4,5-bis(cyclopentyloxy)benzoate (4) (427 mg, 1.26 mmol, 85% yield): m/z 339 [M+H]+ (ES+); 1H NMR (400 MHz, CDCl3) δ: 7.66 (1H, d), 7.45 (1H, d), 5.05-4.98 (1H, m), 4.87-4.83 (1H, m), 3.89 (3H, s), 1.95-1.55 (16H, m).
    • Step (iv): 3-Chloro-4,5-bis(cyclopentyloxy)benzoic acid (5)
  • Figure US20120149737A1-20120614-C00248
  • 3-Chloro-4,5-bis(cyclopentyloxy)benzoic acid (5) (380 mg, 99%) was prepared from methyl 3-chloro-4,5-bis(cyclopentyloxy)benzoate (4) (400 mg, 1.18 mmol) using a procedure essentially the same as in Step (ii) for AAA-001, except that 1,4-dioxane (10 mL) was used instead of THF: m/z 323 [M−H]− (ES−); 1H NMR (400 MHz, DMSO-d6) δ: 13.07 (1H, br s), 7.52 (1H, d), 7.45 (1H, d), 4.97-4.91 (2H, m), 1.99-1.90 (2H, m), 1.70-1.57 (14H, m).
    • Step (v): Methyl 4-(3-chloro-4,5-bis(cyclopentyloxy)benzamido)benzoate (7)
  • Figure US20120149737A1-20120614-C00249
  • Methyl 4-(3-chloro-4,5-bis(cyclopentyloxy)benzamido)benzoate (7) (155 mg, 49%) 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−); 1H NMR (400 MHz, CDCl3) δ: 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).
    • Step (vi): 4-(3-Chloro-4,5-bis(cyclopentyloxy)benzamido)benzoic acid (AAA-044)
  • Figure US20120149737A1-20120614-C00250
  • 4-(3-Chloro-4,5-bis(cyclopentyloxy)benzamido)benzoic acid (AAA-044) (55 mg, 72%) was prepared from methyl 4-(3-chloro-4,5-bis(cyclopentyloxy)benzamido)benzoate (7) (75 mg, 0.16 mmol) using a procedure essentially the same as in Step (ii) for AAA-001, except that 1,4-dioxane (2.5 mL) was used instead of THF: m/z 442 [M−H]− (ES−); 1H NMR (400 MHz, DMSO-d6) δ: 12.74 (1H, br s), 10.45 (1H, s), 7.94 (2H, d), 7.88 (2H, d), 7.69 (1H, d), 7.52 (1H, d), 4.97 (2H, m), 1.99-1.93 (2H, m), 1.73-1.48 (14H, m).
    • Synthesis 47 4-(3,4-bis(benzyloxy)-5-chlorobenzamido)benzoic acid (AAA-045)
  • Figure US20120149737A1-20120614-C00251
  • 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. in step (v): m/z 486 [M−H]− (ES−); 1H NMR (400 MHz, DMSO-d6) δ: 12.76 (1H, br s), 10.51 (1H, s), 7.95 (2H, m), 7.89 (2H, m), 7.74 (2H, d), 7.52 (2H, d), 7.44-7.32 (8H, m), 5.31 (2H, s), 5.11 (2H, s).
    • Synthesis 48 4-(3-Chloro-4,5-bis(cyclopentyloxy)benzamido)-2-methylbenzoic acid (AAA-046)
  • Figure US20120149737A1-20120614-C00252
  • 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−); 1H NMR (400 MHz, DMSO-d6) δ: 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).
    • Synthesis 49 4-(3-Chloro-4,5-bis(cyclohexyloxy)benzamido)benzoic acid (AAA-047)
  • Figure US20120149737A1-20120614-C00253
    Figure US20120149737A1-20120614-C00254
    • Step (i): Methyl 4-(benzyloxy)-3-chloro-5-hydroxybenzoate (2)
  • Figure US20120149737A1-20120614-C00255
  • (Bromomethyl)benzene (1.41 mL, 11.9 mmol) was added dropwise to a stirring suspension of methyl 3-chloro-4,5-dihydroxybenzoate (1) (product step ii, Synthesis 46 (2.00 g, 9.87 mmol) and potassium carbonate (1.50 g, 10.9 mmol) in DMF (10 mL) at 5-10° C. The resulting mixture was stirred for 2 h at RT and then partitioned between 1M HCl (50 mL) and EtOAc (50 mL). The phases were separated and the organic solution was washed with water (2×40 mL), dried over MgSO4 and filtered. The solvent was removed in vacuo and residue was purified by silica gel chromatography (80 g, 0-50% EtOAc in iso-hexanes) to give methyl 4-(benzyloxy)-3-chloro-5-hydroxybenzoate (2) (1.66 g, 54% yield): m/z 291 [M−H] (ES−); 1H NMR (400 MHz, DMSO-d6) δ: 10.50 (1H, s), 7.49 (2H, m), 7.46 (1H, d), 7.40-7.33 (4H, m), 5.14 (2H, s), 3.82 (3H, s).
    • Step (ii): Methyl 4-(benzyloxy)-3-chloro-5-(cyclohexyloxy)benzoate (2)
  • Figure US20120149737A1-20120614-C00256
  • Diisopropylazo dicarboxylate (807 μL, 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 μL, 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. The residue was purified by silica gel chromatography (80 g, 0-20% EtOAc in iso-hexane) to afford methyl 4-(benzyloxy)-3-chloro-5-(cyclohexyloxy)benzoate (2) (350 mg, 9%): 1H NMR (400 MHz, CDCl3) δ: 7.66 (1H, d), 7.51 (3H, m), 7.38-7.33 (3H, m), 5.14 (2H, s), 4.38 (1H, m) 3.90 (3H, s) 2.01 (2H, m), 1.80 (2H, m), 1.62-1.50 (3H, m), 1.45-1.35 (3H, m).
    • Step (iii): 4-(Benzyloxy)-3-chloro-5-(cyclohexyloxy)benzoic acid (4)
  • Figure US20120149737A1-20120614-C00257
  • 4-(Benzyloxy)-3-chloro-5-(cyclohexyloxy)benzoic acid (4) (329 mg, 97%) was prepared from methyl 4-(benzyloxy)-3-chloro-5-(cyclohexyloxy)benzoate (3) (350 mg, 0.934 mmol) using a procedure essentially the same as in Step (ii) for AAA-001, except that 1,4-dioxane (5 mL) was used instead of THF: m/z 359 [M−H]− (ES−); 1H NMR (400 MHz, DMSO-d6) δ: 13.19 (1H, s), 7.51 (2H, m), 7.48 (2H, m), 7.42-7.33 (3H, m), 5.10 (2H, s), 4.51 (1H, m), 1.94 (2H, m), 1.72 (2H, m), 1.59-1.49 (3H, m), 1.46-1.27 (3H, m).
    • Step (iv): Methyl 4-(4-(benzyloxy)-3-chloro-5-(cyclohexyloxy)benzamido)benzoate (6)
  • Figure US20120149737A1-20120614-C00258
  • Methyl 4-(4-(benzyloxy)-3-chloro-5-(cyclohexyloxy)benzamido)benzoate (6) (323 mg, 70%) was prepared from 4-(benzyloxy)-3-chloro-5-(cyclohexyloxy)benzoic acid (4) (325 mg, 0.901 mmol) using a procedure essentially the same as in Step (iii) for AAA-001: m/z 494 [M+H]+ (ES+); 1H NMR (400-MHz, DMSO-d6) δ: 10.51 (1H, br s), 7.97 (2H, d), 7.91 (2H, d), 7.68 (1H, d), 7.58 (1H, d), 7.50 (2H, m), 7.42-7.36 (3H, m), 5.12 (2H, s), 4.57 (1H, m), 3.84 (3H, s), 1.98 (2H, m), 1.73 (2H, m), 1.62-1.51 (3H, m), 1.47-1.31 (3H, m).
    • Step (v): Methyl 4-(3-chloro-5-(cyclohexyloxy)-4-hydroxybenzamido)benzoate (7)
  • Figure US20120149737A1-20120614-C00259
  • 45% hydrogen bromide in acetic acid (26 μL, 0.20 mmol) was added to a stirring mixture of methyl 4-(4-(benzyloxy)-3-chloro-5-(cyclohexyloxy)benzamido)benzoate (6) (20 mg, 40 μmol) in TFA (3 mL) and the mixture was stirred at RT for 1 h. The mixture was partitioned between water (15 mL) and EtOAc (15 mL) and the phases were separated. The organic solution was washed with water (10 mL), dried over MgSO4 and the solvent was removed in vacuo to give methyl 4-(3-chloro-5-(cyclohexyloxy)-4-hydroxybenzamido)benzoate (7) (16 mg, 92%): m/z 402 [M−H]− (ES−); 1H NMR (400-MHz, DMSO-d6) δ: 10.37 (1H, s), 7.94 (4H, m), 7.68 (1H, d), 7.54 (1H, d), 4.40 (1H, m), 3.84 (3H, s), 1.94 (2H, m), 1.83-1.73 (2H, m), 1.57-1.45 (3H, m), 1.40-1.20 (3H, m).
    • Step (vi): Methyl 4-(3-chloro-4,5-bis(cyclohexyloxy)benzamido)benzoate (8)
  • Figure US20120149737A1-20120614-C00260
  • Diisopropylazo dicarboxylate (63 μL, 0.32 mmol) was added dropwise to a stirring mixture of methyl 4-(3-chloro-5-(cyclohexyloxy)-4-hydroxybenzamido)benzoate (7) (65 mg, 161 μmol), cyclohexanol (34 μL, 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. The residue was purified by silica gel chromatography (40 g, 0-15% EtOAc in iso-hexane) to give the desired methyl 4-(3-chloro-4,5-bis(cyclohexyloxy)benzamido)benzoate (8) (80 mg, 100%): m/z 486 [M+H]+ (ES+); 1H NMR (400-MHz, DMSO-d6) δ: 10.48 (1H, s), 7.97 (2H, d), 7.91 (2H, d), 7.67 (1H, d), 7.53 (1H, d), 4.53 (1H, m), 4.36 (1H, m), 3.84 (3H, m), 1.92 (4H, m), 1.80-1.70 (4H, m), 1.60-1.40 (6H, m), 1.30-1.05 (6H, m).
    • Step (vii): 4-(3-Chloro-4,5-bis(cyclohexyloxy)benzamido)benzoic acid (AAA-047)
  • Figure US20120149737A1-20120614-C00261
  • 4-(3-Chloro-4,5-bis(cyclohexyloxy)benzamido)benzoic acid (AAA-047) (15 mg, 19%) was prepared from methyl 4-(3-chloro-4,5-bis(cyclohexyloxy)benzamido)benzoate (8) (80 mg, 0.17 mmol) using a procedure essentially the same as in Step (ii) for AAA-001, except that 1,4-dioxane (6 mL) was used instead of THF: m/z 470 [M−H]− (ES−); 1H NMR (400 MHz, DMSO-d6) δ: 12.72 (1H, br s), 10.44 (1H, s), 7.94 (2H, d), 7.87 (2H, d), 7.67 (1H, d), 7.53 (1H, d), 4.53 (1H, m), 4.36 (1H, m), 1.98-1.82 (4H, m), 1.80-1.65 (4H, m), 1.58-1.20 (12H, m).
    • Synthesis 50 4-(3,4-Di-tert-butoxy-5-chlorobenzamido)benzoic acid (AAA-048)
  • Figure US20120149737A1-20120614-C00262
    • Step (i): 3,4-Di-tert-butoxy-5-chlorobenzoic acid (3)
  • Figure US20120149737A1-20120614-C00263
  • 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). The mixture was stirred 18 h at RT. The mixture was poured into 10% aqueous citric acid (100 mL) and the precipitate was collected by filtration. The solid was washed with water and dried to give 3,4-di-tert-butoxy-5-chlorobenzoic acid (2) (534 mg, 70%): m/z 299 [M−H]− (ES−); 1H NMR (400 MHz, DMSO-d6) δ: 13.13 (1H, br s), 7.67 (1H, s), 7.53 (1H, s), 1.39 (9H, s), 1.32 (9H, s).
    • Step (ii): Methyl 4-(3,4-di-tert-butoxy-5-chlorobenzamido)benzoate (5)
  • Figure US20120149737A1-20120614-C00264
  • 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 μL, 4.16 mmol) was used as base instead of DIPEA: m/z 432 [M−H]− (ES−); 1H NMR (400 MHz, DMSO-d6) δ: 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).
    • Step (iii): 4-(3,4-Di-tert-butoxy-5-chlorobenzamido)benzoic acid (AAA-048)
  • Figure US20120149737A1-20120614-C00265
  • 4-(3,4-Di-tert-butoxy-5-chlorobenzamido)benzoic acid (AAA-048) (110 mg, 64%) was prepared from methyl 4-(3,4-di-tert-butoxy-5-chlorobenzamido)benzoate (5) (175 mg, 0.403 mmol) using a procedure essentially the same as in Step (ii) for AAA-001, except that 1,4-dioxane (6 mL) was used instead of THF: m/z 418 [M−H]− (ES−); 1H NMR (400 MHz, DMSO-d6) δ: 12.78 (1H, br s). 10.49 (1H, s), 7.93 (2H, d), 7.87 (2H, d), 7.85 (1H, d), 7.59 (1H, d), 1.40 (9H, s), 1.34 (9H, s).
    • Synthesis 51 4-(3,4-Di-tert-butoxy-5-chlorobenzamido)-2-methylbenzoic acid (AAA-049)
  • Figure US20120149737A1-20120614-C00266
  • 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−); 1H NMR (400 MHz, DMSO-d6) δ: 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).
    • Synthesis 52 4-(3-Chloro-4,5-diisopropoxybenzamido)benzoic acid (AAA-050)
  • Figure US20120149737A1-20120614-C00267
  • 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. in step (iii): m/z 390 [M−H]− (ES−); 1H NMR (400 MHz, DMSO-d6) δ: 12.78 (1H, br s), 10.46 (1H, s), 7.94 (2H, d), 7.87 (2H, d), 7.68 (1H, d), 7.54 (1H, d), 4.76 (1H, m), 4.59 (1H, m), 1.33 (6H, d), 1.28 (6H, d).
    • Synthesis 53 4-(3-Chloro-4,5-diisopropoxybenzamido)-2-methylbenzoic acid (AAA-051)
  • Figure US20120149737A1-20120614-C00268
  • 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. in step (iii) and that methyl 4-amino-2-methylbenzoate was used instead of methyl 4-aminobenzoate in step (v): m/z 404 [M−H]− (ES−); 1H NMR (400 MHz, DMSO-d6) δ: 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).
    • Synthesis 54 4-(3,5-Dibromo-4-isopropoxybenzamido)-2-methylbenzoic acid (AAA-052)
  • Figure US20120149737A1-20120614-C00269
  • 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−); 1H NMR (400 MHz, DMSO-d6) δ: 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 (6H, d).
    • Synthesis 55 4-(3,5-Dibromo-4-ethoxybenzamido)-2-methylbenzoic acid (AAA-053)
  • Figure US20120149737A1-20120614-C00270
  • 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−); 1H NMR (400 MHz, DMSO-d6) δ: 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, t).
    • Synthesis 56 4-(3,5-Dichloro-4-(cyclopentyloxy)benzamido)-2-methylbenzoic acid (AAA-054)
  • Figure US20120149737A1-20120614-C00271
  • 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−); 1H NMR (400 MHz, DMSO-d6) δ: 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).
    • Synthesis 57 4-(3,5-Dichloro-4-methoxybenzamido)-2-methylbenzoic acid (AAA-055)
  • Figure US20120149737A1-20120614-C00272
  • 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+); 1H NMR (400 MHz, DMSO-d6) δ: 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, s).
    • Synthesis 58 4-(4-tert-Butoxy-3,5-dichlorobenzamido)-2-methylbenzoic acid (AAA-056)
  • Figure US20120149737A1-20120614-C00273
  • 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. of N,N-dimethylformamide di-tert-butyl acetal was reacted with methyl 3,5-dichloro-4-hydroxybenzoate in step (i) and the product reacted with methyl 4-amino-2-methylbenzoate instead of methyl 4-aminobenzoate in step (ii): m/z 394 [M−H]− (ES−), 396 [M+H]+ (ES+); 1H NMR (400 MHz, DMSO-d6) δ: 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).
    • Synthesis 59 4-(3,5-Dichloro-4-ethoxybenzamido)-2-hydroxybenzoic acid (AAA-057)
  • Figure US20120149737A1-20120614-C00274
    • Step (i): tert-Butyl 2-methoxy-4-nitrobenzoate (2)
  • Figure US20120149737A1-20120614-C00275
  • 1,1-di-tert-Butoxy-N,N-dimethylmethanamine (608 μL, 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 μL, 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 Et2O (3×10 mL). The combined organic phases were washed with brine (30 mL), dried over MgSO4, filtered and then concentrated in vacuo to afford tert-butyl 2-methoxy-4-nitrobenzoate (2) (271 mg, 78%) as a pale yellow solid. The material was used in the next step without further purification.
    • Step (ii): tert-Butyl 4-amino-2-methoxybenzoate (3)
  • Figure US20120149737A1-20120614-C00276
  • 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 H2 mode. The solvent was removed in vacuo to afford tert-butyl 4-amino-2-methoxybenzoate (3) (234 mg, 92%) as a pale yellow solid: m/z 222 [M−H]− (ES−); 1H-NMR (400 MHz, DMSO-d6) δ: 7.41 (1H, d), 6.16 (1H, d), 6.09 (1H, dd), 5.82 (2H, br s), 3.68 (3H, s), 1.45 (9H, s).
    • Step (iii): tert-Butyl 4-(3,5-dichloro-4-ethoxybenzamido)-2-methoxybenzoate (5)
  • Figure US20120149737A1-20120614-C00277
  • 3,5-Dichloro-4-ethoxybenzoic acid (4) (75 mg, 0.32 mmol) in DCM (5 mL) was treated with oxalyl chloride (56 μL, 0.64 mmol) dropwise, followed by a drop of DMF. The reaction mixture was stirred at RT for 1 h, and then the solvent was removed in vacuo. The residue was dissolved in DCM (5 mL) and TEA (133 μL, 957 μmol) was added. The mixture was added to tert-butyl 4-amino-2-methoxybenzoate (3) (71 mg, 0.32 mmol) and stirred at RT for 16 h. The mixture was sequentially washed with sat. aq. NaHCO3 (5 mL) and 1 M HCl (5 mL), and the organic phase was concentrated in vacuo. The residue was purified by silica gel chromatography (12 g, 0-100% EtOAc in isohexane) to afford tert-butyl 4-(3,5-dichloro-4-ethoxybenzamido)-2-methoxybenzoate (5) (59 mg, 42%) as a white solid: m/z 384 [M-tBu+2H]+ (ES+); 1H-NMR (400 MHz, DMSO-d6) δ: 10.51 (1H, s), 8.09 (2H, s), 7.63 (1H, d), 7.60 (1H, d), 7.43 (1H, dd), 4.15 (2H, q), 3.81 (3H, s), 1.51 (9H, s), 1.41 (3H, t).
    • Step (iv): 4-(3,5-Dichloro-4-ethoxybenzamido)-2-hydroxybenzoic acid (AAA-057)
  • Figure US20120149737A1-20120614-C00278
  • A solution of tert-butyl 4-(3,5-dichloro-4-ethoxybenzamido)-2-methoxybenzoate (5) (55 mg, 0.13 mmol) in DCM (5 mL) was cooled to 0° C. and treated dropwise with a solution of 1 M boron trichloride in DCM (349 μL, 349 μmol). The reaction mixture was stirred at 0° C. for 1 h and then at RT for 2 h. The reaction mixture was cooled to 0° C. and water (0.5 mL) and sat. aq. NaHCO3 (2 mL) were added. The resulting white precipitate was collected by filtration and washed with water (2 mL). The solid was dried, then purified by capture and release on SAX, eluting with 5% AcOH in THF to afford 4-(3,5-dichloro-4-ethoxybenzamido)-2-hydroxybenzoic acid (AAA-057) (11 mg, 24%) as a white solid: m/z 370 [M+H]+ (ES+), 368 [M−H]− (ES−); 1H-NMR (400 MHz, DMSO-d6) δ: 10.51 (1H, s), 8.06 (2H, s), 7.76 (1H, d), 7.48 (1H, d), 7.28 (1H, dd), 4.14 (2H, q), 1.91 (1H, s), 1.40 (3H, t), 1.35 (1H, s).
    • Synthesis 60 4-(3,5-Bis(cyclopentyloxy)-4-ethoxybenzamido)benzoic acid (AAA-058)
  • Figure US20120149737A1-20120614-C00279
  • 4-(3,5-Bis(cyclopentyloxy)-4-ethoxybenzamido)benzoic acid (AAA-058) (75 mg, 55% for final step) was prepared in essentially the same manner as in Steps (iii) and (iv) for AAA-001 except that 3,5-bis(cyclopentyloxy)-4-ethoxybenzoic acid (prepared in 3 steps from methyl 3,4,5-trihydroxybenzoate by sequential reaction with ethyl iodide and base, cyclopentyl bromide and base and then lithium hydroxide) was used instead of 3,5-dichloro-4-(cyclopentyloxy)benzoic acid in step m/z 454 [M+H]+ (ES+), 452 [M−H]− (ES−); 1H NMR (400 MHz, CDCl3) δ: 8.12 (2H, d), 7.83 (1H, s), 7.75 (2H, d), 7.04 (2H, s), 4.87 (2H, m), 4.06 (2H, q), 2.00-1.50 (16H, m), 1.35 (3H, t).
    • Synthesis 61 4-(3,4,5-Triisopropoxybenzamido)benzoic acid (AAA-059)
  • Figure US20120149737A1-20120614-C00280
  • 4-(3,4,5-Triisopropoxybenzamido)benzoic acid (AAA-059) (194 mg, 91% for final step) was prepared in essentially the same manner as in Steps (iii) and (iv) for AAA-001 except that 3,4,5-triisopropoxybenzoic acid (prepared in 2 steps from methyl 3,4,5-trihydroxybenzoate by sequential reaction with 2-bromopropane and base and then lithium hydroxide) was used instead of 3,5-dichloro-4-(cyclopentyloxy)benzoic acid in step (110: m/z 416 [M+H]+ (ES+), 414 [M−H]− (ES−); 1H NMR (400 MHz, CDCl3) δ: 8.13 (2H, d), 7.87 (1H, s), 7.75 (2H, d), 7.08 (2H, s), 4.64 (2H, heptet), 4.46 (1H, heptet), 1.36 (12H, d), 1.32 (6H, d).
    • Synthesis 62 4-(3,4,5-Tri-tert-butoxybenzamido)benzoic acid (AAA-060)
  • Figure US20120149737A1-20120614-C00281
  • 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−); 1H NMR (400 MHz, CDCl3) δ: 8.12 (2H, d), 7.84 (1H, s), 7.75 (2H, d), 7.30 (2H, s), 1.38 (27H, s).
    • Synthesis 63 4-(4-Ethoxy-3,5-diisopropoxybenzamido)-2-methylbenzoic acid (AAA-061)
  • Figure US20120149737A1-20120614-C00282
  • 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+); 1H 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 (3H, s), 1.29 (12H, d), 1.25 (3H, t).
    • Synthesis 64 4-(3,5-Diisopropoxy-4-methoxybenzamido)benzoic acid (AAA-062)
  • Figure US20120149737A1-20120614-C00283
  • 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−). 1H-NMR (400 MHz, DMSO-d6) δ: 12.77 (1H, br s), 10.32 (1H, s), 7.92 (2H, d), 7.87 (2H, d), 7.24 (2H, s), 7.88 (2H, d), 4.66 (2H, sep), 3.73 (3H, s), 1.30 (12H, d).
    • Synthesis 65 4-(3,5-Diisopropoxy-4-methoxybenzamido)-2-methylbenzoic acid (AAA-063)
  • Figure US20120149737A1-20120614-C00284
  • 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−). 1H-NMR (400 MHz, DMSO-d6) δ: 12.62 (1H, br s), 10.21 (1H, s), 7.86 (1H, d), 7.73-7.66 (2H, m), 7.25 (2H, s), 4.66 (2H, sep), 3.74 (3H, s), 2.54 (3H, s), 1.30 (12H, d).
    • Synthesis 66 4-(3,5-Diisopropoxy-4-ethoxybenzamido)-2-fluorobenzoic acid (AAA-064)
  • Figure US20120149737A1-20120614-C00285
    • Step (i): Methyl 4-(3,5-diisopropoxy-4-ethoxybenzamido)-2-fluorobenzoate
  • Figure US20120149737A1-20120614-C00286
  • A mixture of 3,5-diisopropoxy-4-ethoxybenzoic acid (1) (300 mg, 1.06 mmol), methyl 4-amino-2-fluorobenzoate (2) (189 mg, 1.12 mmol) and TEA (149 μL, 1.06 mmol) in EtOAc (2.5 mL) was treated with T3P (50% wt. in EtOAc, 1.69 mL, 2.66 mmol). The reaction mixture was stirred at 60° C. for 1 h, and then allowed to cool to RT. The mixture was diluted with DCM (5 mL) and washed sequentially with 1M HCl (5 mL) and satd. NaHCO3 (5 mL). The solvent was removed in vacuo and the residue was purified by silica gel chromatography (12 g, 0-30% EtOAc in isohexane) to afford methyl 4-(3,5-diisopropoxy-4-ethoxybenzamido)-2-fluorobenzoate (3) (326 mg, 56%): m/z 434 [M+H]+ (ES+), 432 [M−H]− (ES−). 1H-NMR (400 MHz, DMSO-d6) δ: 7.93 (1H, t), 7.82 (1H, br s), 7.73 (1H, dd), 7.27 (1H, dd), 7.04 (2H, s), 4.60 (2H, sep), 4.09 (2H, q), 3.91 (3H, s), 1.39-1.34 (15H, m).
    • Step (ii) 4-(3,5-Diisopropoxy-4-ethoxybenzamido)-2-fluorobenzoic acid (AAA-064)
  • Figure US20120149737A1-20120614-C00287
  • 2 M Lithium hydroxide (554 μL, 1.11 mmol) was added to a solution of 4-(3,5-diisopropoxy-4-ethoxybenzamido)-2-fluorobenzoate (3) (320 mg, 0.740 mmol) in THF (5 mL) and the mixture was stirred at RT for 20 h. The mixture was partitioned between 1M HCl (5 mL) and DCM (10 mL) and the phases were separated. The organic solvent was removed in vacuo and the residue was purified by silica gel chromatography (40 g, 0-20% IPA in isohexane) to afford 4-(3,5-diisopropoxy-4-ethoxybenzamido)-2-fluorobenzoic acid (AAA-064) as a white solid (176 mg, 56%): m/z 420 [M+H]+ (ES+), 418 [M−H]− (ES−). 1H-NMR (400 MHz, DMSO-d6) δ: 13.03 (1H, br s), 10.45 (1H, s), 7.88 (1H, t), 7.81 (1H, dd), 7.61 (1H, dd), 7.22 (2H, s), 4.65 (2H, sep), 4.00 (2H, q), 1.29 (12H, d), 1.26 (3H, t).
    • Synthesis 67 6-(3-Chloro-4-methoxy-5-(trifluoromethyl)benzamido)nicotinic acid (AAA-065)
  • Figure US20120149737A1-20120614-C00288
  • 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−). 1H NMR (400 MHz, DMSO-d6) δ: 13.24 (1H, br s), 11.54 (1H, s), 8.90 (1H, dd), 8.48 (1H, d), 8.39-8.24 (3H, m), 3.97 (3H, s).
    • Synthesis 68 4-(3-Chloro-4-methoxy-5-(trifluoromethyl)benzamido)-2-fluorobenzoic acid (AAA-066)
  • Figure US20120149737A1-20120614-C00289
  • 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−). 1H NMR (400 MHz, DMSO-d6) δ: 13.11 (1H, br s), 10.85 (1H, s), 8.43 (1H, d), 8.22 (1H, d), 7.89 (1H, t), 7.79 (1H, dd), 7.61 (1H, dd), 3.98 (3H, s).
    • Synthesis 69 4-(3-Chloro-4-methoxy-5-(trifluoromethyl)benzamido)-3-fluorobenzoic acid (AAA-067)
  • Figure US20120149737A1-20120614-C00290
  • 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−). 1H NMR (400 MHz, DMSO-d6) δ: 13.35 (1H, br s), 10.62 (1H, s), 8.42 (1H, d), 8.24 (1H, d), 7.83-7.73 (3H, m), 3.98 (3H, s).
    • Synthesis 70 4-(3-Chloro-4-ethoxy-5-(trifluoromethyl)benzamido)-2-fluorobenzoic acid (AAA-068)
  • Figure US20120149737A1-20120614-C00291
  • 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−). 1H NMR (400 MHz, DMSO-d6) δ: 13.06 (1H, br s), 10.83 (1H, s), 8.41 (1H, d), 8.21 (1H, d), 7.90 (1H, t), 7.80 (1H, dd), 7.61 (1H, dd), 4.20 (2H, q), 1.41 (3H, t).
    • Synthesis 71 4-(3-Chloro-4-isopropoxy-5-(trifluoromethyl)benzamido)-2-fluorobenzoic acid (AAA-069)
  • Figure US20120149737A1-20120614-C00292
  • 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−). 1H NMR (400 MHz, DMSO-d6) δ: 13.02 (1H, br s), 10.81 (1H, s), 8.38 (1H, d), 8.21 (1H, d), 7.90 (1H, t), 7.80 (1H, dd), 7.61 (1H, dd), 5.06 (1H, sep), 1.28 (6H, d).
    • Synthesis 72 4-(3-Chloro-4-methoxy-5-(trifluoromethyl)benzamido)-2-hydroxybenzoic acid (AAA-070)
  • Figure US20120149737A1-20120614-C00293
  • 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 H2SO4 and MeOH) was used instead of methyl 4-amino-2-fluorobenzoate in step (i): m/z 388 [M−H]− (ES−). 1H NMR (400 MHz, DMSO-d6) δ: 13.77 (1H, br s), 11.39 (1H, br s), 10.65 (1H, s), 8.43 (1H, d), 8.22 (1H, d), 7.80 (1H, d), 7.51 (1H, d), 7.31 (1H, dd), 3.99 (3H, s).
    • Synthesis 73 4-(3-Bromo-4-ethoxy-5-(trifluoromethyl)benzamido)-2-methylbenzoic acid (AAA-071)
  • Figure US20120149737A1-20120614-C00294
  • 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−). 1H-NMR (400 MHz, DMSO-d6) δ: 12.66 (1H, br s), 10.60 (1H, s), 8.56 (1H, d), 8.26 (1H, d), 7.88 (1H, d), 7.73 (1H, dd), 7.68 (1H, d) 4.17 (2H, q), 2.55 (3H, s) 1.43 (3H, t).
    • Synthesis 74 4-(3-Bromo-4-ethoxy-5-(trifluoromethyl)benzamido)-2-fluorobenzoic acid (AAA-072)
  • Figure US20120149737A1-20120614-C00295
  • 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−). 1H-NMR (400 MHz, DMSO-d6) δ: 13.08 (1H, br s), 10.85 (1H, s), 8.56 (1H, d), 8.26 (1H, d), 7.92 (1H, t), 7.82 (1H, dd), 7.63 (1H, dd), 4.18 (2H, q1.44 (3H, t).
    • Synthesis 75 4-(4-Ethoxy-3,5-difluorobenzamido)benzoic acid (AAA-073)
  • Figure US20120149737A1-20120614-C00296
  • 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 BBr3, 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)−. 1H NMR (400 MHz, DMSO-d6) δ: 12.82 (1H, br s), 10.53 (1H, s), 7.98-7.93 (2H, m), 7.92-7.87 (2H, m), 7.84-7.76 (2H, m), 4.30 (2H, q), 1.34 (3H, t).
    • Synthesis 76 4-(3-Chloro-5-fluoro-4-isopropoxybenzamido)-2-methylbenzoic acid (AAA-074)
  • Figure US20120149737A1-20120614-C00297
  • 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 BBr3, 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)−. 1H NMR (400 MHz, DMSO-d6) δ: 12.75 (1H, br s), 10.44 (1H, s), 7.99-7.96 (1H, m), 7.91-7.83 (2H, m), 7.69 (2H, m), 4.58 (1H, sep), 2.52 (3H, s), 1.33 (6H, d).
    • Synthesis 77 4-(3-Chloro-5-isopropoxy-4-methoxybenzamido)-2-methylbenzoic acid (AAA-075)
  • Figure US20120149737A1-20120614-C00298
    Figure US20120149737A1-20120614-C00299
    • Step (i): Methyl 4-(benzyloxy)-3-chloro-5-isopropoxybenzoate (2)
  • Figure US20120149737A1-20120614-C00300
  • 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+). 1H NMR (400 MHz, CDCl3) δ: 7.68 (1H, d), 7.56-7.47 (3H, m), 7.43-7.28 (3H, m), 5.12 (2H, s), 4.66 (1H, sep), 3.90 (3H, s), 1.38 (6H, d).
    • Step (ii): Methyl 3-chloro-4-hydroxy-5-isopropoxybenzoate (3)
  • Figure US20120149737A1-20120614-C00301
  • 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 H2 (full H2 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−).
    • Step (iii): Methyl 3-chloro-5-isopropoxy-4-methoxybenzoate (4)
  • Figure US20120149737A1-20120614-C00302
  • 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.
    • Step (iv): 3-Chloro-5-isopropoxy-4-methoxybenzoic acid (5)
  • Figure US20120149737A1-20120614-C00303
  • 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−).
    • Step (v): Methyl 4-(3-chloro-5-isopropoxy-4-methoxybenzamido)-2-methylbenzoate (7)
  • Figure US20120149737A1-20120614-C00304
  • A mixture of 3-chloro-5-isopropoxy-4-methoxybenzoic acid (5) (250 mg, 1.02 mmol), methyl 4-amino-2-methylbenzoate (6) (177 mg, 1.07 mmol) and TEA (150 μL, 1.07 mmol) in EtOAc (2.5 mL) was treated with T3P (50% in EtOAc) (1.63 mL, 2.55 mmol) and the mixture was heated at 60° C. for 5 h. The mixture was diluted with DCM (5 mL) and washed with 1M HCl (5 mL) followed by satd. NaHCO3 solution (5 mL). The organic solvents were removed in vacuo and the residue purified by silica gel chromatography (12 g, 0-100% EtOAc in isohexane to yield methyl 4-(3-chloro-5-isopropoxy-4-methoxybenzamido)-2-methylbenzoate (7) (167 mg, 40%): m/z 392 [M+H]+ (ES+), 390 [M−H]− (ES−). 1H NMR (400 MHz, CDCl3) δ: 7.98 (1H, d), 7.78 (1H, s), 7.59-7.50 (2H, m), 7.40 (2H, dd), 4.67 (1H, sep), 3.94 (3H, s), 3.89 (3H, s), 2.62 (3H, s), 1.40 (6H, d).
    • Step (vi): 4-(3-Chloro-5-isopropoxy-4-methoxybenzamido)-2-methylbenzoic acid (AAA-075)
  • Figure US20120149737A1-20120614-C00305
  • 4-(3-Chloro-5-isopropoxy-4-methoxybenzamido)-2-methylbenzoic acid (AAA-075) (94 mg, 57%) was prepared from methyl 4-(3-chloro-5-isopropoxy-4-methoxybenzamido)-2-methylbenzoate (7) (167 mg, 4.10 mmol) using a procedure essentially the same as in step (ii) for AAA-001 except that MeOH was added dropwise until a solution formed and the mixture was stirred at 40° C. for 18 h: m/z 378 [M+H]+ (ES+), 376 [M−H]− (ES−). 1H NMR (400 MHz, DMSO-d6) δ: 12.63 (1H, br s), 10.34 (1H, s), 7.86 (1H, d), 7.75-7.63 (3H, m), 7.57 (1H, d), 4.77 (1H, sep), 3.83 (3H, s), 2.53 (3H, s), 1.34 (6H, d).
    • Synthesis 78 4-(3-Chloro-5-isopropoxy-4-methoxybenzamido)benzoic acid (AAA-076)
  • Figure US20120149737A1-20120614-C00306
  • 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−). 1H NMR (400 MHz, DMSO-d6) δ: 12.78 (1H, br s), 10.47 (1H, s), 7.94 (2H, d), 7.88 (2H, d), 7.69 (1H, d), 7.58 (1H, d), 4.78 (1H, sep), 3.83 (3H, s), 1.33 (6H, d).
    • Synthesis 79 4-(3-Chloro-5-isopropoxy-4-methoxybenzamido)-2-fluorobenzoic acid (AAA-077)
  • Figure US20120149737A1-20120614-C00307
  • 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−). 1H NMR (400 MHz, DMSO-d6) δ: 13.03 (1H, br s), 10.60 (1H, s), 7.90 (1H, t), 7.82 (1H, dd), 7.69 (1H, d), 7.63 (1H, dd), 7.57 (1H, d), 4.78 (1H, sep), 3.85 (3H, s), 1.35 (6H, d).
    • Synthesis 80 4-(3-Chloro-4-ethoxy-5-isopropoxybenzamido)benzoic acid (AAA-078)
  • Figure US20120149737A1-20120614-C00308
  • 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−). 1H NMR (400 MHz, DMSO-d6) δ: 12.77 (1H, br s), 10.46 (1H, s), 7.97-7.90 (2H, m), 7.90-7.84 (2H, m), 7.68 (1H, d), 7.55 (1H, d), 4.75 (1H, sep), 4.11 (2H, q), 1.35-1.28 (9H, m).
    • Synthesis 81 4-(3-Chloro-4-ethoxy-5-isopropoxybenzamido)-2-fluorobenzoic acid (AAA-079)
  • Figure US20120149737A1-20120614-C00309
  • 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−). 1H NMR (400 MHz, DMSO-d6) δ: 13.02 (1H, br s), 10.60 (1H, s), 7.90 (1H, t), 7.82 (1H, dd), 7.69 (1H, d), 7.63 (1H, dd), 7.55 (1H, d), 4.76 (1H, sep), 4.13 (2H, q), 1.38-1.27 (9H, m).
    • Synthesis 82 4-(3-Chloro-4-ethoxy-5-isopropoxybenzamido)-2-methylbenzoic acid (AAA-080)
  • Figure US20120149737A1-20120614-C00310
  • 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−). 1H NMR (400 MHz, DMSO-d6) δ: 12.64 (1H, br s), 10.34 (1H, s), 7.86 (1H, d), 7.74-7.63 (3H, m), 7.55 (1H, d), 4.75 (1H, sep), 4.10 (2H, q), 2.52 (3H, s), 1.37-1.26 (9H, m).
    • Synthesis 83 4-(3-Chloro-4-ethoxy-5-isopropoxybenzamido)-2-hydroxybenzoic acid (AAA-081)
  • Figure US20120149737A1-20120614-C00311
  • 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−). 1H NMR (400 MHz, DMSO-d6) δ: 13.78 (1H, br s), 11.40 (1H, br s), 10.40 (1H, s), 7.77 (1H, d), 7.67 (1H, d), 7.52 (2H, dd), 7.30 (1H, dd), 4.77 (1H, sep), 4.12 (2H, q), 1.37-1.28 (9H, m).
    • Synthesis 84 6-(3-Chloro-4-ethoxy-5-isopropoxybenzamido)pyridazine-3-carboxylic acid (AAA-082)
  • Figure US20120149737A1-20120614-C00312
  • 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−). 1H NMR (400 MHz, DMSO-d6) δ: 13.73 (1H, br s), 11.91 (1H, s), 8.55 (1H, d), 8.26 (1H, d), 7.79 (2H, dd), 4.85 (1H, sep), 4.14 (2H, q), 1.42-1.27 (9H, m).
    • Synthesis 85 4-(3-Chloro-4-isopropoxy-5-methoxybenzamido)benzoic acid (AAA-083)
  • Figure US20120149737A1-20120614-C00313
  • 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−). 1H NMR (400 MHz, DMSO-d6) δ: 12.76 (1H, br s), 10.50 (1H, s), 8.03-7.80 (4H, m), 7.70 (1H, d), 7.56 (1H, d), 4.59 (1H, sep), 3.92 (3H, s), 1.27 (6H, d).
    • Synthesis 86 4-(3-Chloro-4-ethoxy-5-methoxybenzamido)benzoic acid (AAA-084)
  • Figure US20120149737A1-20120614-C00314
  • 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−). 1H NMR (400 MHz, DMSO-d6) δ: 12.75 (1H, br s), 10.48 (1H, s), 7.91 (4H, dd), 7.70 (1H, d), 7.57 (1H, d), 4.09 (2H, q), 3.92 (3H, s), 1.31 (3H, t).
    • Synthesis 87 4-(3-Chloro-4-ethoxy-5-methoxybenzamido)-2-methylbenzoic acid (AAA-085)
  • Figure US20120149737A1-20120614-C00315
  • 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−). 1H NMR (400 MHz, DMSO-d6) δ: 12.65 (1H, br s), 10.39 (1H, s), 7.88 (1H, d), 7.76-7.66 (3H, m), 7.58 (1H, d), 4.10 (2H, q), 3.93 (3H, s), 2.55 (3H, s), 1.32 (3H, t).
    • Synthesis 88 4-(3-Chloro-5-ethoxy-4-isopropoxybenzamido)benzoic acid (AAA-086)
  • Figure US20120149737A1-20120614-C00316
  • 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−). 1H NMR (400 MHz, DMSO-d6) δ: 12.70 (1H, br s), 10.39 (1H, s), 7.93-7.73 (4H, m), 7.61 (1H, d), 7.47 (1H, d), 4.51 (1H, sep), 4.09 (2H, q), 1.31 (3H, t), 1.20 (6H, d).
    • Synthesis 89 4-(3-Chloro-5-ethoxy-4-isopropoxybenzamido)-2-methylbenzoic acid (AAA-087)
  • Figure US20120149737A1-20120614-C00317
  • 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−). 1H NMR (400 MHz, DMSO-d6) δ: 12.68 (1H, s), 10.40 (1H, s), 7.92 (1H, d), 7.81-7.69 (3H, m), 7.59 (1H, d), 4.64 (1H, sep), 4.21 (2H, q), 2.58 (3H, s), 1.45 (3H, t), 1.33 (6H, d).
    • Synthesis 90 4-(3-Chloro-5-(cyclobutoxy)-4-ethoxybenzamido)benzoic acid (AAA-088)
  • Figure US20120149737A1-20120614-C00318
  • 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−). 1H NMR (400 MHz, DMSO-d6) δ: 12.75 (1H, br s), 10.46 (1H, s), 7.95-7.86 (4H, m), 7.71 (1H, d), 7.37 (1H, d), 4.85 (1H, quin), 4.14 (2H, q), 2.49-2.42 (2H, m), 2.19-2.01 (2H, m), 1.92-1.58 (2H, m), 1.33 (3H, t).
    • Synthesis 91 4-(3-Chloro-5-(cyclopropylmethoxy)-4-ethoxybenzamido)benzoic acid (AAA-089)
  • Figure US20120149737A1-20120614-C00319
  • 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−). 1H NMR (400 MHz, DMSO-d6) δ: 12.76 (1H br s), 10.46 (1H, s), 7.92 (4H, dd), 7.70 (1H, d), 7.55 (1H, d), 4.17 (2H, q), 4.00 (2H, d), 1.34 (3H, t), 1.31-1.24 (1H, m), 0.66-0.55 (2H, m), 0.42-0.31 (2H, m).
    • Synthesis 92 4-(3-Chloro-5-(cyclopropylmethoxy)-4-ethoxybenzamido)-2-hydroxybenzoic acid (AAA-090)
  • Figure US20120149737A1-20120614-C00320
  • 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−). 1H NMR (400 MHz, DMSO-d6) δ: 13.72 (1H, br s), 11.40 (1H, br s), 10.39 (1H, s), 7.77 (1H, d), 7.68 (1H, d), 7.52 (2H, dd), 7.30 (1H, dd), 4.17 (2H, q), 4.00 (2H, d), 1.34 (3H, t), 1.31-1.24 (1H, m), 0.68-0.54 (2H, m), 0.44-0.31 (2H, m).
    • Synthesis 93 4-(3-Chloro-4,5-diisopropoxybenzamido)-2-hydroxybenzoic acid (AAA-091)
  • Figure US20120149737A1-20120614-C00321
  • 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−). 1H NMR (400 MHz, DMSO-d6) δ: 13.75 (1H, br s), 11.40 (1H, br s), 10.39 (1H, s), 7.77 (1H, d), 7.67 (1H, d), 7.52 (2H, dd), 7.30 (1H, dd), 4.77 (1H, sep), 4.60 (1H, sep), 1.33 (6H, d), 1.28 (6H, d).
    • Synthesis 94 4-(3-Chloro-4,5-di(cyclobutyloxy)benzamido)benzoic acid (AAA-092)
  • Figure US20120149737A1-20120614-C00322
  • 4-(3-Chloro-4,5-di(cyclobutyloxy)benzamido)benzoic acid (AAA-092) (137 mg, 54% 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-di(cyclobutyloxy)benzoic acid (prepared in 4 steps from 3-chloro-4-hydroxy-5-methoxybenzoic acid by sequential treatment with BBr3, TMSCl and MeOH, cyclobutyl bromide and base and then lithium hydroxide) was used instead of 3-chloro-5-isopropoxy-4-methoxybenzoic acid and methyl 4-aminobenzoate was used instead of methyl 4-amino-2-methylbenzoate in step (v): m/z 414 [M−H]− (ES−). 1H NMR (400 MHz, DMSO-d6) δ: 12.76 (1H, br s), 10.46 (1H, s), 7.98-7.83 (4H, m), 7.70 (1H, d), 7.34 (1H, d), 4.83 (1H, quin), 4.71 (1H, quin), 2.49-2.42 (2H, m), 2.36-2.01 (6H, m), 1.92-1.61 (3H, m), 1.57-1.37 (1H, m).
    • Synthesis 95 4-(3-Chloro-4,5-di(cyclobutyloxy)benzamido)-2-methylbenzoic acid (AAA-093)
  • Figure US20120149737A1-20120614-C00323
  • 4-(3-Chloro-4,5-di(cyclobutyloxy)benzamido)-2-methylbenzoic acid (AAA-093) (83 mg, 99% 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-di(cyclobutyloxy)benzoic acid (Synthesis 94) was used instead of 3-chloro-5-isopropoxy-4-methoxybenzoic in step (v): m/z 428 [M−H]− (ES−). 1H NMR (400 MHz, DMSO-d6) δ: 12.62 (1H, br s), 10.35 (1H, s), 7.87 (1H, d), 7.73-7.66 (3H, m), 7.35 (1H, d), 4.84 (1H, quin), 4.72 (1H, quin), 2.55 (3H, s), 2.49-2.41 (2H, m), 2.22-2.06 (6H, m), 1.84-1.65 (3H, m), 1.54-1.42 (1H, m).
    • Synthesis 96 4-(3-Chloro-4,5-di(cyclobutyloxy)benzamido)-2-hydroxybenzoic acid (AAA-094)
  • Figure US20120149737A1-20120614-C00324
  • 4-(3-Chloro-4,5-di(cyclobutyloxy)benzamido)-2-hydroxybenzoic acid (AAA-094) (33 mg, 75% 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-di(cyclobutyloxy)benzoic acid (Synthesis 94) 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 432 [M+H]+ (ES+), 430 [M−H]− (ES−). 1H NMR (400 MHz, DMSO-d6) δ: 10.39 (1H, s), 7.76 (1H, d), 7.69 (1H, d), 7.49 (1H, d), 7.35-7.25 (2H, m), 4.88-4.80 (1H, m), 4.76-4.67 (1H, m), 2.48-2.43 (2H, m), 2.29-2.05 (6H, m), 1.87-1.81 (1H, m), 1.76-1.65 (2H, m), 1.53-1.44 (1H, m).
    • Synthesis 97 4-(3-Chloro-4,5-diisopropoxybenzamido)-2-fluorobenzoic acid (AAA-095)
  • Figure US20120149737A1-20120614-C00325
  • 4-(3-Chloro-4,5-diisopropoxybenzamido)-2-fluorobenzoic acid (AAA-095) (207 mg, 93% 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-fluorobenzoate was used instead of methyl 4-amino-2-methylbenzoate in step (v): m/z 410 [M+H]+ (ES+), 408 [M−H]− (ES−). 1H NMR (400 MHz, DMSO-d6) δ: 13.05 (1H, br s), 10.61 (1H, s), 7.90 (1H, t), 7.82 (1H, dd), 7.69 (1H, d), 7.63 (1H, dd), 7.54 (1H, d), 4.77 (1H, sep), 4.61 (1H, sep), 1.34 (6H, d), 1.28 (6H, d).
    • Synthesis 98 4-(3-Chloro-5-(cyclobutoxy)-4-ethoxybenzamido)-2-methylbenzoic acid (AAA-096)
  • Figure US20120149737A1-20120614-C00326
  • 4-(3-Chloro-5-(cyclobutoxy)-4-ethoxybenzamido)-2-methylbenzoic acid (AAA-096) (127 mg, 69% 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) and ethyl iodide was used instead of methyl iodide in step (iii): m/z 402 [M−H]− (ES−). 1H NMR (400 MHz, DMSO-d6) δ: 12.62 (1H, br s), 10.35 (1H, s), 7.87 (1H, d), 7.76-7.66 (3H, m), 7.38 (1H, d), 4.86 (1H, quin), 4.14 (2H, q), 2.53 (3H, s), 2.50-2.43 (2H, m), 2.19-2.03 (2H, m), 1.84 (1H, q), 1.69 (1H, dq), 1.34 (3H, t).
    • Synthesis 99 4-(3-Chloro-5-(cyclopropylmethoxy)-4-ethoxybenzamido)-2-methylbenzoic acid (AAA-097)
  • Figure US20120149737A1-20120614-C00327
  • 4-(3-Chloro-5-(cyclopropylmethoxy)-4-ethoxybenzamido)-2-methylbenzoic acid (AAA-097) (105 mg, 56% 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) and ethyl iodide was used instead of methyl iodide in step (iii): m/z 402 [M−H]− (ES−). 1H NMR (400 MHz, DMSO-d6) δ: 12.65 (1H, br s), 10.35 (1H, s), 7.88 (1H, d), 7.75-7.65 (3H, m), 7.55 (1H, d), 4.17 (2H, q), 4.00 (2H, d), 2.54 (3H, s), 1.34 (3H, t), 1.31-1.25 (1H, m), 0.65-0.58 (2H, m), 0.43-0.35 (2H, m).
    • Synthesis 100 4-(3-Chloro-5-cyclobutoxy-4-methoxybenzamido)benzoic acid (AAA-098)
  • Figure US20120149737A1-20120614-C00328
  • 4-(3-Chloro-5-cyclobutoxy-4-methoxybenzamido)benzoic acid (AAA-098) (232 mg, 78% 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) and methyl 4-aminobenzoate was used instead of methyl 4-amino-2-methylbenzoate in step (v): m/z 374 [M−H]− (ES−). 1H NMR (400 MHz, DMSO-d6) δ: 12.79 (1H, br s), 10.49 (1H, s), 8.11-7.82 (4H, m), 7.73 (1H, d), 7.39 (1H, d), 4.87 (1H, quin), 3.87 (3H, s), 2.49-2.43 (2H, m), 2.30-1.97 (2H, m), 1.83 (1H, q), 1.69 (1H, dq).
    • Synthesis 101 4-(3-Chloro-5-cyclobutoxy-4-methoxybenzamido)-2-methylbenzoic acid (AAA-099)
  • Figure US20120149737A1-20120614-C00329
  • 4-(3-Chloro-5-cyclobutoxy-4-methoxybenzamido)-2-methylbenzoic acid (AAA-099) (170 mg, 75% 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): m/z 388 [M−H]− (ES−). 1H NMR (400 MHz, DMSO-d6) δ: 12.64 (1H, br s), 10.37 (1H, s), 7.88 (1H, d), 7.75-7.66 (3H, m), 7.39 (1H, d), 4.87 (1H, quin), 3.87 (3H, s), 2.53 (3H, s), 2.50-2.43 (2H, m), 2.19-2.05 (2H, m), 1.83 (1H, q), 1.76-1.62 (1H, m).
    • Synthesis 102 4-(3-Chloro-5-cyclobutoxy-4-methoxybenzamido)-2-fluorobenzoic acid (AAA-100)
  • Figure US20120149737A1-20120614-C00330
  • 4-(3-Chloro-5-cyclobutoxy-4-methoxybenzamido)-2-fluorobenzoic acid (AAA-100) (274 mg, 84% 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) and methyl 4-amino-2-fluorobenzoate was used instead of methyl 4-amino-2-methylbenzoate in step (v): m/z 392 [M−H]− (ES−). 1H NMR (400 MHz, DMSO-d6) δ: 13.06 (1H, br s), 10.62 (1H, s), 7.90 (1H, t), 7.82 (1H, dd), 7.73 (1H, d), 7.63 (1H, dd), 7.38 (1H, d), 4.87 (1H, quin), 3.87 (3H, s), 2.50-2.42 (2H, m), 2.20-2.05 (2H, m), 1.83 (1H, q), 1.69 (1H, dq).
    • Synthesis 103 4-(3-Chloro-4-methoxy-5-(pentan-3-yloxy)benzamido)benzoic acid (AAA-101)
  • Figure US20120149737A1-20120614-C00331
  • 4-(3-Chloro-4-methoxy-5-(pentan-3-yloxy)benzamido)benzoic acid (AAA-101) (232 mg, 97% for final step) was prepared in essentially the same manner as AAA-075 except that 3-bromopentane was used instead of isopropyl bromide in step (i) and methyl 4-aminobenzoate was used instead of methyl 4-amino-2-methylbenzoate in step (v): m/z 390 [M−H]− (ES−). 1H NMR (400 MHz, DMSO-d6) δ: 12.80 (1H, br s), 10.49 (1H, s), 8.01-7.84 (4H, m), 7.69 (1H, d), 7.55 (1H, d), 4.45 (1H, quin), 3.85 (3H, s), 1.79-1.61 (4H, m), 0.95 (6H, t).
    • Synthesis 104 4-(3-Chloro-4-methoxy-5-(pentan-3-yloxy)benzamido)-2-methylbenzoic acid (AAA-102)
  • Figure US20120149737A1-20120614-C00332
  • 4-(3-Chloro-4-methoxy-5-(pentan-3-yloxy)benzamido)-2-methylbenzoic acid (AAA-102) (156 mg, 60% for final step) was prepared in essentially the same manner as AAA-075 except that 3-bromopentane was used instead of isopropyl bromide in step (i): m/z 404 [M−H]− (ES−). 1H NMR (400 MHz, DMSO-d6) δ: 12.63 (1H, br s), 10.36 (1H, s), 7.87 (1H, d), 7.75-7.65 (3H, m), 7.54 (1H, d), 4.43 (1H, quin), 3.85 (3H, s), 2.54 (3H, s), 1.76-1.62 (4H, m), 0.94 (6H, t).
    • Synthesis 105 4-(3-Chloro-4-methoxy-5-(pentan-3-yloxy)benzamido)-2-fluorobenzoic acid (AAA-103)
  • Figure US20120149737A1-20120614-C00333
  • 4-(3-Chloro-4-methoxy-5-(pentan-3-yloxy)benzamido)-2-fluorobenzoic acid (AAA-103) (253 mg, 90% for final step) was prepared in essentially the same manner as AAA-075 except that 3-bromopentane was used instead of isopropyl bromide in step (i) and methyl 4-amino-2-fluorobenzoate was used instead of methyl 4-amino-2-methylbenzoate in step (v): m/z 410 [M+H]+ (ES+), 408 [M−H]− (ES−). 1H NMR (400 MHz, DMSO-d6) δ: 13.03 (1H, br s), 10.61 (1H, s), 7.89 (1H, t), 7.81 (1H, dd), 7.68 (1H, d), 7.62 (1H, dd), 7.53 (1H, d), 4.44 (1H, quin), 3.85 (3H, s), 1.77-1.60 (4H, m), 0.94 (6H, t).
    • Synthesis 106 4-(3-Chloro-4-methoxy-5-(2-methoxyethoxy)benzamido)-2-fluorobenzoic acid (AAA-104)
  • Figure US20120149737A1-20120614-C00334
  • 4-(3-Chloro-4-methoxy-5-(2-methoxyethoxy)benzamido)-2-fluorobenzoic acid (AAA-104) (18 mg, 14% for final step) was prepared in essentially the same manner as AAA-075 except that 2-methoxyethyl bromide was used instead of isopropyl bromide in step (i) and methyl 4-amino-2-fluorobenzoate was used instead of methyl 4-amino-2-methylbenzoate in step (v): m/z 398 [M+H]+ (ES+), 396 [M−H]− (ES−). 1H NMR (400 MHz, DMSO-d6) δ: 12.97 (1H, br s), 10.62 (1H, s), 7.89 (1H, t), 7.81 (1H, dd), 7.70 (1H, d), 7.62 (1H, dd), 7.59 (1H, d), 4.33-4.23 (2H, m), 3.87 (3H, s), 3.78-3.69 (2H, m), 3.34 (3H, s).
    • Synthesis 107 4-(3-Chloro-4-methoxy-5-(neopentyloxy)benzamido)benzoic acid (AAA-105)
  • Figure US20120149737A1-20120614-C00335
  • 4-(3-Chloro-4-methoxy-5-(neopentyloxy)benzamido)benzoic acid (AAA-105) (83 mg, 45% for final step) was prepared in essentially the same manner as AAA-075 except that neopentyl bromide, Cs2CO3 and NMP at (130° C., microwave, 20 min) were used instead of isopropyl bromide, K2CO3 and DMF in step (i) and methyl 4-aminobenzoate was used instead of methyl 4-amino-2-methylbenzoate in step (v): m/z 390 [M−H]− (ES−). 1H NMR (400 MHz, DMSO-d6) δ: 10.45 (1H, s), 7.90 (4H, m), 7.71 (1H, d), 7.58 (1H, d), 3.91 (3H, s), 3.81 (2H, s), 1.06 (9H, s).
    • Synthesis 108 4-(4-Bromo-3,5-diethoxybenzamido)benzoic acid (AAA-106)
  • Figure US20120149737A1-20120614-C00336
  • 4-(4-Bromo-3,5-diethoxybenzamido)benzoic acid (AAA-106) (300 mg, 62% for final step) was prepared in essentially the same manner as in steps (v) and (vi) for AAA-075 except that 4-bromo-3,5-diethoxybenzoic acid (prepared in 2 steps from 4-bromo-3,5-dihydroxybenzoic acid by sequential treatment with ethyl iodide and base and then lithium hydroxide) was used instead of 3-chloro-5-isopropoxy-4-methoxybenzoic acid and methyl 4-aminobenzoate was used instead of methyl 4-amino-2-methylbenzoate in step (v): m/z 408 [M+H]+ (ES+), 406 [M−H]− (ES−). 1H NMR (400 MHz, DMSO-d6) δ: 12.61 (1H, br s), 10.29 (1H, s), 7.80-7.71 (2H, m), 7.71-7.63 (2H, m), 7.05 (2H, s), 4.01 (4H, q), 1.20 (6H, t).
    • Synthesis 109 4-(4-Bromo-3,5-diisopropoxybenzamido)benzoic acid (AAA-107)
  • Figure US20120149737A1-20120614-C00337
  • 4-(4-Bromo-3,5-diisopropoxybenzamido)benzoic acid (AAA-107) (338 mg, 63% for final step) was prepared in essentially the same manner as in steps (v) and (vi) for AAA-075 except that 4-bromo-3,5-diisopropoxybenzoic acid (prepared in 2 steps from 4-bromo-3,5-dihydroxybenzoic acid by sequential treatment with isopropyl iodide and base and then lithium hydroxide) was used instead of 3-chloro-5-isopropoxy-4-methoxybenzoic acid and methyl 4-aminobenzoate was used instead of methyl 4-amino-2-methylbenzoate in step (v): m/z 436 [M+H]+ (ES+), 434 [M−H]− (ES−). 1H NMR (400 MHz, DMSO-d6) δ: 12.67 (1H, br s), 10.33 (1H, s), 7.83 (2H, d), 7.75 (2H, d), 7.12 (2H, s), 4.65 (2H, sep), 1.20 (12H, d).
    • Synthesis 110 4-(4-Bromo-3,5-diisopropoxybenzamido)-2-fluorobenzoic acid (AAA-108)
  • Figure US20120149737A1-20120614-C00338
  • 4-(4-Bromo-3,5-diisopropoxybenzamido)-2-fluorobenzoic acid (AAA-108) (51 mg, 37% for final step) was prepared in essentially the same manner as in steps (v) and (vi) for AAA-075 except that 4-bromo-3,5-diisopropoxybenzoic acid (prepared in 2 steps from 4-bromo-3,5-dihydroxybenzoic acid by sequential treatment with isopropyl iodide and base and then lithium hydroxide) was used instead of 3-chloro-5-isopropoxy-4-methoxybenzoic acid and methyl 4-amino-2-fluorobenzoate was used instead of methyl 4-amino-2-methylbenzoate in step (v): m/z 452 and 454 [M−H]− (ES−). 1H NMR (400 MHz, DMSO-d6) δ: 13.05 (1H, br s), 10.59 (1H, s), 7.91 (1H, t), 7.82 (1H, dd), 7.62 (1H, dd), 7.24 (2H, s), 4.78 (2H, sep), 1.34 (12H, d).
    • Synthesis 111 4-(4-Bromo-3,5-diisopropoxybenzamido)-2-hydroxybenzoic acid (AAA-109)
  • Figure US20120149737A1-20120614-C00339
  • 4-(4-Bromo-3,5-diisopropoxybenzamido)-2-hydroxybenzoic acid (AAA-109) (68 mg, 55% for final step) was prepared in essentially the same manner as in steps (v) and (vi) for AAA-075 except that 4-bromo-3,5-diisopropoxybenzoic acid (prepared in 2 steps from 4-bromo-3,5-dihydroxybenzoic acid by sequential treatment with isopropyl iodide and base and then lithium hydroxide) 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 452 [M+H]+ (ES+), 450 [M−H]− (ES−). 1H NMR (400 MHz, DMSO-d6) δ: 1H NMR (400 MHz, DMSO-d6) δ: 13.75 (1H, br s), 11.40 (1H, br s), 10.38 (1H, s), 7.79 (1H, d), 7.51 (1H, d), 7.30 (1H, dd), 7.23 (2H, s), 4.78 (2H, sep), 1.34 (12H, d).
    • Synthesis 112 4-(4-Bromo-3,5-diethoxybenzamido)-2-methylbenzoic acid (AAA-110)
  • Figure US20120149737A1-20120614-C00340
  • 4-(4-Bromo-3,5-diethoxybenzamido)-2-methylbenzoic acid (AAA-110) (275 mg, 56% for final step) was prepared in essentially the same manner as in steps (v) and (vi) for AAA-075 except that 4-bromo-3,5-diethoxybenzoic acid (prepared in 2 steps from 4-bromo-3,5-dihydroxybenzoic acid by sequential treatment with ethyl iodide and base and then lithium hydroxide) was used instead of 3-chloro-5-isopropoxy-4-methoxybenzoic acid in step (v): m/z 422 [M+H]+ (ES+), 420 [M−H]− (ES−). 1H NMR (400 MHz, DMSO-d6) δ: 12.45 (1H, br s), 10.18 (1H, s), 7.69 (1H, d), 7.56-7.50 (1H, m), 7.47 (1H, d), 7.06 (2H, s), 4.01 (4H, q), 2.35 (3H, s), 1.20 (6H, t).
    • Synthesis 113 4-(4-Bromo-3,5-diisopropoxybenzamido)-2-methylbenzoic acid (AAA-111)
  • Figure US20120149737A1-20120614-C00341
  • 4-(4-Bromo-3,5-diisopropoxybenzamido)-2-methylbenzoic acid (AAA-111) (306 mg, 52% for final step) was prepared in essentially the same manner as in steps (v) and (vi) for AAA-075 except that 4-bromo-3,5-diisopropoxybenzoic acid (prepared in 2 steps from 4-bromo-3,5-dihydroxybenzoic acid by sequential treatment with isopropyl iodide and base and then lithium hydroxide) was used instead of 3-chloro-5-isopropoxy-4-methoxybenzoic acid in step (v): m/z 450 [M+H]+ (ES+), 448 [M−H]− (ES−). 1H NMR (400 MHz, DMSO-d6) δ: 12.64 (1H, br s), 10.34 (1H, s), 7.88 (1H, d), 7.71 (1H, dd), 7.66 (1H, d), 7.24 (2H, s), 4.77 (2H, sep), 2.54 (3H, s), 1.32 (12H, d).
    • Synthesis 114 4-(4-Chloro-3,5-diisopropoxybenzamido)benzoic acid (AAA-112)
  • Figure US20120149737A1-20120614-C00342
    Figure US20120149737A1-20120614-C00343
    • Step (i): Methyl 3,5-dihydroxy-4-nitrobenzoate (2)
  • Figure US20120149737A1-20120614-C00344
  • Tetrabutylammonium nitrate (10.9 g, 35.7 mmol) was dissolved in DCM (125 mL) and treated with TFAA (5.04 mL, 35.7 mmol). The resultant solution was added dropwise to an ice cooled solution of methyl 3,5-dihydroxybenzoate (1) (6.0 g, 36 mmol) in DCM (100 mL), keeping the temperature below 5° C. The resultant mixture was allowed to warm to RT and stirred for 18 h. The mixture was filtered through silica, washing through with 20% EtOAc in DCM (500 mL). The solvent was removed in vacuo and the residue was purified by silica gel chromatography (120 g, 0-5% EtOAc in DCM) to afford methyl 3,5-dihydroxy-4-nitrobenzoate (2) (0.36 g, 5% yield) as a bright orange solid: m/z 212 [M−H]− (ES−).
    • Step (ii): Methyl 3,5-diisopropoxy-4-nitrobenzoate (3)
  • Figure US20120149737A1-20120614-C00345
  • Methyl 3,5-diisopropoxy-4-nitrobenzoate (3) (610 mg, 97%) was prepared from methyl 3,5-dihydroxy-4-nitrobenzoate (2) (430 mg, 2.02 mmol) using a procedure essentially the same as in step (i) for AAA-001 except that isopropyl bromide was used instead of cyclopentyl bromide: 1H NMR (400 MHz, CDCl3) δ: 7.25 (2H, s), 4.66 (2H, sep), 3.92 (3H, s), 1.32 (12H, d).
    • Step (iii): Methyl 4-amino-3,5-diisopropoxybenzoate (4)
  • Figure US20120149737A1-20120614-C00346
  • Methyl 3,5-diisopropoxy-4-nitrobenzoate (3) (594 mg, 2.00 mmol) was dissolved in a mixture of MeOH (40 mL) and formic acid (5 mL) and was passed through a Thales ‘H-cube’ cartridge (10% Pd/C) at a flow rate of 1 mL/min at 40° C. under H2 (full H2 mode). The solvents were removed in vacuo to yield methyl 4-amino-3,5-diisopropoxybenzoate (4) (398 mg, 72%) as a pale yellow oil: 1H NMR (400 MHz, CDCl3) δ: 7.20 (2H, s), 4.59 (2H, sep), 4.23 (2H, br s), 3.83 (3H, s), 1.33 (12H, d).
    • Step (iv): Methyl 4-chloro-3,5-diisopropoxybenzoate (5)
  • Figure US20120149737A1-20120614-C00347
  • A suspension of copper (I) chloride (129 mg, 1.31 mmol) and tert-butyl nitrite (155 μL, 1.31 mmol) in anhydrous MeCN (2 mL) was stirred at 65° C. A solution of methyl 4-amino-3,5-diisopropoxybenzoate (4) (233 mg, 0.872 mmol) in anhydrous MeCN (1 mL) was added dropwise. Once the addition was complete the mixture was allowed to cool to RT and poured on to 20% HCl (5 mL). The mixture was partitioned between DCM (10 mL) and aq. ammonia (35%, 5 mL), the phases were separated and the organic solution was further washed with ammonia solution (17.5%, 10 mL), and brine (2×20 mL). The solvent was removed in vacuo and the residue was purified by silica gel chromatography (40 g, 0-100% EtOAc in isohexane) to afford methyl 4-chloro-3,5-diisopropoxybenzoate (93 mg, 36% yield) as a colourless oil: m/z 287 [M+H]+ (ES+).
    • Step (v): 4-Chloro-3,5-diisopropoxybenzoic acid (6)
  • Figure US20120149737A1-20120614-C00348
  • Methyl 4-chloro-3,5-diisopropoxybenzoate (5) (93 mg, 0.32 mmol) was suspended in 2M sodium hydroxide (1.6 mL, 3.2 mmol) and stirred at 100° C. for 3 h. After cooling to RT the mixture was acidified by the addition of 1M HCl. The resulting precipitate was collected by filtration and dried in vacuo to afford 4-chloro-3,5-diisopropoxybenzoic acid (6) (60 mg, 66% yield) as a white solid. This material was used in the subsequent reaction step without purification.
    • Step (vi): Methyl 4-(4-chloro-3,5-diisopropoxybenzamido)benzoate (8)
  • Figure US20120149737A1-20120614-C00349
  • Methyl 4-(4-chloro-3,5-diisopropoxybenzamido)benzoate (8) (86 mg, 96%) was prepared from 4-chloro-3,5-diisopropoxybenzoic acid (6) (60 mg, 0.22 mmol) using a procedure essentially the same as in step (i) for AAA-064 except that DIPEA was used instead of TEA, and methyl 4-aminobenzoate was used instead of methyl 4-amino-2-fluorobenzoate: m/z 406 [M+H]+ (ES)+, 404 [M−H]− (ES)−.
    • Step (vii): 4-(4-Chloro-3,5-diisopropoxybenzamido)benzoic acid (AAA-112)
  • Figure US20120149737A1-20120614-C00350
  • 4-(4-Chloro-3,5-diisopropoxybenzamido)benzoic acid (AAA-112) (40 mg, 46%) was prepared from methyl 4-(4-chloro-3,5-diisopropoxybenzamido)benzoate (8) (86 mg, 0.21 mmol) using a procedure essentially the same as in step (ii) for AAA-001 except that MeOH was added dropwise to obtain a solution and the mixture was heated at 50° C. for 2 h then at RT for 15 h: m/z 390 [M−H]− (ES−), 1H NMR (400 MHz, DMSO-d6) δ: 12.74 (1H, br s), 10.44 (1H, s), 8.01-7.84 (4H, m), 7.29 (2H, s), 4.78 (2H, sep), 1.33 (12H, d).
    • Synthesis 115 4-(3,4-Dichloro-5-isopropoxybenzamido)-2-methylbenzoic acid (AAA-113)
  • Figure US20120149737A1-20120614-C00351
    Figure US20120149737A1-20120614-C00352
    • Step (i) Methyl 4-hydroxy-3-methoxy-5-nitrobenzoate (2)
  • Figure US20120149737A1-20120614-C00353
  • A solution of methyl 4-hydroxy-3-methoxybenzoate (1) (10 g, 55 mmol) in DCM (100 mL) was cooled to −60° C. and fuming nitric acid (24.5 mL, 549 mmol) was added dropwise over 30 min. The reaction mixture was stirred at −60° C. for 2 h then added slowly to iced water (200 mL) with stirring. The precipitate was collected, washed with ice cold water and dried under suction to afford methyl 4-hydroxy-3-methoxy-5-nitrobenzoate (2) (4.4 g, 35% yield) as a bright yellow solid: 1H NMR (400 MHz, CDCl3) δ: 11.08 (1H, d), 8.45 (1H, d), 7.77 (1H, d), 4.01 (3H, s), 3.95 (3H, s).
    • Step (ii): Methyl 4-chloro-3-methoxy-5-nitrobenzoate (3)
  • Figure US20120149737A1-20120614-C00354
  • A solution of methyl 4-hydroxy-3-methoxy-5-nitrobenzoate (2) (4.4 g, 19 mmol) in DMF (30 mL) at 0° C. was treated with oxalyl chloride (5.09 mL, 58.1 mmol) dropwise. The mixture was then stirred at 80° C. for 3 h under a CaCl2 drying tube. The mixture was allowed to cool to RT, poured in to iced water (100 mL) and stirred for 15 min. The precipitate was collected by filtration and washed with water and MeOH to afford methyl 4-chloro-3-methoxy-5-nitrobenzoate (3) (3.2 g, 65% yield) as a yellow solid: 1H NMR (400 MHz, CDCl3) δ: 8.04 (1H, d), 7.77 (1H, d), 4.04 (3H, s), 3.97 (3H, s).
    • Step (iii) Methyl 3-amino-4-chloro-5-methoxybenzoate (4)
  • Figure US20120149737A1-20120614-C00355
  • A suspension of methyl 4-chloro-3-methoxy-5-nitrobenzoate (3) (900 mg, 3.66 mmol) and iron powder (614 mg, 11.0 mmol) in a mixture of EtOH (15 mL) and water (15 mL) was heated to 70° C. and degassed with nitrogen for 20 min. Conc. HCl (44.5 μL, 1.47 mmol) was added and the reaction mixture was stirred at 70° C. for 3 h. Celite (1 g) was added and the suspension stirred for 10 min then filtered through a celite pad. The solvent was removed in vacuo and the residue was partitioned between EtOAc (15 mL) and water (15 mL). The phases were separated and the organic solution was washed with brine (2×15 mL). The solvent was removed in vacuo to afford methyl 3-amino-4-chloro-5-methoxybenzoate (0.82 g, 100% yield) as a yellow solid: 1H NMR (400 MHz, DMSO-d6) δ: 7.10 (1H, d), 6.78 (1H, d), 5.68 (2H, s), 3.81 (6H, m).
    • Step (iv): Methyl 3,4-dichloro-5-methoxybenzoate (5)
  • Figure US20120149737A1-20120614-C00356
  • A suspension of copper (II) chloride (0.97 g, 7.2 mmol) and tert-butyl nitrite (1.07 mL, 9.04 mmol) in anhydrous MeCN (5 mL) was warmed to 65° C. A solution of methyl 3-amino-4-chloro-5-methoxybenzoate (4) (1.3 g, 6.0 mmol) in anhydrous MeCN (3 mL) was added dropwise. Once the addition was complete the mixture was allowed to cool to RT and poured on to 1M HCl (15 mL). The acidic mixture was neutralized with satd. NaHCO3 solution and aq. ammonia (35%, 5 mL) was added. The product was extracted with DCM (25 mL) and then washed with aq. ammonia (17.5%, 20 mL) and brine (2×20 mL). The solvent was removed in vacuo and the residue was triturated with 10% EtOAc in isohexane to afford methyl 3,4-dichloro-5-methoxybenzoate (5) (1.17 g, 79% yield) as a brown solid: 1H NMR (400 MHz, DMSO-d6) δ: 7.72 (1H, d), 7.57 (1H, d), 3.98 (3H, s), 3.89 (3H, s).
    • Step (v): 3,4-Dichloro-5-hydroxybenzoic acid (6)
  • Figure US20120149737A1-20120614-C00357
  • Methyl 3,4-dichloro-5-methoxybenzoate (5) (518 mg, 2.34 mmol) was suspended in DCM (10 mL) under a reflux condenser fitted with a CaCl2 drying tube. BBr3 (554 μL, 5.86 mmol) was added and the reaction mixture was stirred at RT for 15 h. The reaction mixture was cautiously poured in to iced water (20 mL) and the mixture stirred for 10 min. The product was extracted with EtOAc (50 mL), then the organic solution was washed with brine (2×50 mL) and dried over MgSO4 and filtered. The solvent was removed in vacuo and the residue purified by silica gel chromatography (40 g, 0-100% EtOAc in isohexane) to afford 3,4-dichloro-5-hydroxybenzoic acid (6) (260 mg, 51% yield) as a white solid: m/z 205 [M−H]− (ES−).
    • Step (vi): Isopropyl 3,4-dichloro-5-isopropoxybenzoate (7)
  • Figure US20120149737A1-20120614-C00358
  • Isopropyl 3,4-dichloro-5-isopropoxybenzoate (7) (342 mg, 87%) was prepared from 3,4-dichloro-5-hydroxybenzoic acid (6) (260 mg, 1.26 mmol) using a procedure essentially the same as in step (i) for AAA-001 except that isopropyl bromide was used instead of cyclopentyl bromide.
    • Step (vii): 3,4-Dichloro-5-isopropoxybenzoic acid (8)
  • Figure US20120149737A1-20120614-C00359
  • 3,4-Dichloro-5-isopropoxybenzoic acid (8) (199 mg, 63%) was prepared from isopropyl 3,4-dichloro-5-isopropoxybenzoate (7) (340 mg, 1.17 mmol) using a procedure essentially the same as in step (v) for AAA-112 except that the reaction was stirred for 15 h: m/z 247 [M−H]− (ES−).
    • Step (viii): Methyl 4-(3,4-dichloro-5-isopropoxybenzamido)-2-methylbenzoate (10)
  • Figure US20120149737A1-20120614-C00360
  • Methyl 4-(3,4-dichloro-5-isopropoxybenzamido)-2-methylbenzoate (10) (237 mg, 68%) was prepared from 3,4-dichloro-5-isopropoxybenzoic acid (8) (200 mg, 800 μmol) using a procedure essentially the same as in step (i) for AAA-064 except that DIPEA was used instead of TEA, and methyl 4-amino-2-methylbenzoate (9) was used instead of methyl 4-amino-2-fluorobenzoate: m/z 396 [M+H]+ (ES+), 394 [M−H]− (ES−), 1H NMR (400 MHz, DMSO-d6) δ: 10.51 (1H, s), 7.89 (1H, d), 7.81 (1H, d), 7.77-7.72 (2H, m), 7.64 (1H, d), 4.85 (1H, sep), 3.81 (3H, s), 2.54 (3H, s), 1.35 (6H, d).
    • Step (ix): 4-(3,4-Dichloro-5-isopropoxybenzamido)-2-methylbenzoic acid (AAA-113)
  • Figure US20120149737A1-20120614-C00361
  • 4-(3,4-Dichloro-5-isopropoxybenzamido)-2-methylbenzoic acid (AAA-113) (85 mg, 41%) was prepared from methyl 4-(3,4-dichloro-5-isopropoxybenzamido)-2-methylbenzoate (10) (210 mg, 0.530 mmol) using a procedure essentially the same as in step (ii) for AAA-001 except that MeOH was added dropwise to obtain a solution and the mixture was stirred at 40° C. for 20 h: m/z 380 [M−H]− (ES−), 1H NMR (400 MHz, DMSO-d6) δ: 12.66 (1H, br s), 10.48 (1H, s), 7.88 (1H, d), 7.81 (1H, d), 7.75-7.66 (2H, m), 7.64 (1H, d), 4.86 (1H, sep), 2.54 (3H, s), 1.35 (6H, d).
    • Synthesis 116 4-(4-Chloro-3-ethoxy-5-(pentan-3-yloxy)benzamido)benzoic acid (AAA-114)
  • Figure US20120149737A1-20120614-C00362
    Figure US20120149737A1-20120614-C00363
    • Step (i): 4-Chloro-3,5-dimethoxyaniline (2)
  • Figure US20120149737A1-20120614-C00364
  • N-Chlorosuccinimide (15.7 g, 118 mmol) was added to a solution of 3,5-dimethoxyaniline (1) (20.0 g, 131 mmol) in AcOH (150 mL) and the reaction mixture was left to stir at RT for 3 h. The reaction mixture was diluted with water (200 mL) and EtOAc (200 mL). The phases were separated and the organic solution was washed with brine (200 mL). The solvent was removed in vacuo and the residue was purified by silica gel chromatography (120 g, 0-70% EtOAc in isohexanes) to afford 4-chloro-3,5-dimethoxyaniline (2) (6.61 g, 26%) as a colourless solid: m/z 188 [M+H]+ (ES+).
    • Step (ii): 2-Chloro-5-iodo-1,3-dimethoxybenzene (3)
  • Figure US20120149737A1-20120614-C00365
  • 4-Chloro-3,5-dimethoxyaniline (2) (6.61 g, 35.2 mmol) was added to a mixture of sulfuric acid (9.39 mL, 176 mmol) and H2O (100 mL) at 0° C. Sodium nitrite (3.16 g, 45.8 mmol) was added and the reaction mixture was stirred at 0° C. for 30 min. The mixture was added to a pre-warmed mixture of sodium iodide (21.1 g, 141 mmol), iodine (4.47 g, 17.6 mmol), sulphuric acid (8 mL) and H2O (100 mL) at 80° C. and the resulting mixture was heated at reflux for 30 min. The mixture was allowed to cool to RT and then 40% sodium thiosulfate solution (200 mL) was added. The product was extracted with EtOAc (300 mL), the solvent was removed in vacuo and the residue was purified by silica gel chromatography (120 g, 0-50% EtOAc in isohexanes) to afford 2-chloro-5-iodo-1,3-dimethoxybenzene (3) (7.16 g, 67% yield).
    • Step (iii): 2-Chloro-5-iodobenzene-1,3-diol (4)
  • Figure US20120149737A1-20120614-C00366
  • A solution of 2-chloro-5-iodo-1,3-dimethoxybenzene (3) (7.15 g, 23.9 mmol) in DCM (20 mL) was cooled to 0° C. Boron tribromide (11.3 mL, 120 mmol) was added dropwise over 30 min and the reaction mixture was allowed to slowly warm to RT and stirred for 20 h. The reaction mixture was cautiously added to iced water (30 mL) with stirring. The phases were separated and the organic solution was washed with brine (3×30 mL). The solvent was removed in vacuo to afford 2-chloro-5-iodobenzene-1,3-diol (4) (4.17 g, 64% yield) as a white solid: m/z 269 [M−H]− (ES−).
    • Step (iv): 2-Chloro-5-iodo-1,3-phenylene diacetate (5)
  • Figure US20120149737A1-20120614-C00367
  • A solution of 2-chloro-5-iodobenzene-1,3-diol (4) (4.12 g, 15.2 mmol) and DIPEA (7.98 mL, 45.7 mmol) in anhydrous DCM (15 mL) was cooled to 0° C. before acetyl chloride (2.28 mL, 32.0 mmol) was added dropwise. The reaction mixture was allowed to slowly warm to RT and stirred for 20 h. The reaction mixture was diluted with DCM (15 mL), washed sequentially with water (20 mL), 1M HCl (20 mL) and brine (3×20 mL) and then dried over MgSO4. The solvent was removed in vacuo to afford 2-chloro-5-iodo-1,3-phenylene diacetate (5) (5.16 g, 96% yield) as a white solid: m/z 372 [M+H2O]+ (ES+).
    • Step (v): 2-Chloro-3-hydroxy-5-iodophenyl acetate (6)
  • Figure US20120149737A1-20120614-C00368
  • A mixture of 2-chloro-5-iodo-1,3-phenylene diacetate (5) (5.16 g, 14.5 mmol) and 1M lithium hydroxide (29.1 mL, 29.1 mmol) in H2O (5 mL) and dioxane (20 mL) was stirred at 60° C. for 4 h then at RT for 20 h. The reaction mixture was acidified by the addition of 1M HCl and the product was extracted with EtOAc (150 mL). The organic solution was dried over MgSO4 and the solvent was removed in vacuo. The resulting oil was slurried with 1:1 DCM: isohexanes and the solvents were removed in vacuo to yield 2-chloro-3-hydroxy-5-iodophenyl acetate (6) (4.88 g, 86%) as a brown solid: m/z 311 [M−H]− (ES−).
    • Step (vi): 2-Chloro-3-ethoxy-5-iodophenol (7)
  • Figure US20120149737A1-20120614-C00369
  • Iodoethane (0.78 mL, 9.6 mmol) and K2CO3 (1.3 g, 9.6 mmol) were added to a solution of 2-chloro-3-hydroxy-5-iodophenyl acetate (6) (2.0 g, 6.4 mmol) in DMF (5 mL) and the mixture was stirred at 60° C. for 1 h. The reaction mixture was cooled to RT, diluted with diethyl ether (100 mL) and washed with brine (3×100 mL). The solvent was removed in vacuo and the residue was dissolved in MeOH (20 mL). K2CO3 (1.0 g, 7.2 mmol) was added and the mixture was stirred at RT for 20 h. The solvent was removed in vacuo and the residue was partitioned between EtOAc (100 mL) and water (100 mL). The organic layer was washed with water (100 mL) and evaporated in vacuo. The residue was purified by silica gel chromatography (40 g, 0-30% EtOAc in isohexane) to afford 2-chloro-3-ethoxy-5-iodophenol (7) (1.1 g, 58% yield) as a colourless solid: m/z 297 [M−H]− (ES−); 1H NMR (400 MHz, DMSO-d6) δ: 10.45 (1H, s), 6.89 (2H, d), 4.04 (2H, br s), 1.32 (3H, br s).
    • Step (vii): 2-Chloro-1-ethoxy-5-iodo-3-(pentan-3-yloxy)benzene (8)
  • Figure US20120149737A1-20120614-C00370
  • 2-Chloro-1-ethoxy-5-iodo-3-(pentan-3-yloxy)benzene (8) (1.2 g, 79%) was prepared from 2-chloro-3-ethoxy-5-iodophenol (7) (1.1 g, 3.7 mmol) using a procedure essentially the same as in step (i) for AAA-001 except that 3-bromopentane was used instead of cyclopentyl bromide.
    • Step (viii): 4-Chloro-3-ethoxy-5-(pentan-3-yloxy)benzoic acid
  • Figure US20120149737A1-20120614-C00371
  • n-Butyllithium (1.3 mL, 3.3 mmol) was slowly added to a stirred solution of 2-chloro-1-ethoxy-5-iodo-3-(pentan-3-yloxy)benzene (8) (1.2 g, 3.3 mmol) in anhydrous THF at −78° C. After 5 min CO2 gas was bubbled through the mixture via a CaCl2 drying tube. The solution was allowed to warm to RT under a constant stream of CO2 gas. 1M NaOH, followed by diethyl ether (50 mL) were added to the mixture and the phases were separated. The organic phase was retained. The aqueous phase was acidified by the addition of 1M HCl and then shaken with EtOAc (50 mL). The phases were separated and the organic phase was evaporated to give 100 mg of the desired acid. The organic solution retained from the initial separated mixture was diluted further with diethyl ether and shaken with 1M HCl and the phases were separated. The organic solution was dried over MgSO4 and the solvent was removed in vacuo, the solid obtained was combined with the 100 mg obtained previously to give 4-chloro-3-ethoxy-5-(pentan-3-yloxy)benzoic acid (9) (0.76 g, 76%) as a white solid: m/z 285 [M−H]− (ES−).
    • Step (ix): Methyl 4-(4-chloro-3-ethoxy-5-(pentan-3-yloxy)benzamido)benzoate (11)
  • Figure US20120149737A1-20120614-C00372
  • Methyl 4-(4-chloro-3-ethoxy-5-(pentan-3-yloxy)benzamido)benzoate (11) (76 mg, 51%) was prepared from 4-chloro-3-ethoxy-5-(pentan-3-yloxy)benzoic acid (9) (100 mg, 0.349 mmol) using a procedure essentially the same as in step (iii) for AAA-001: m/z 420 [M+H]+ (ES+), 418 [M−H]− (ES−).
    • Step (x): 4-(4-Chloro-3-ethoxy-5-(pentan-3-yloxy)benzamido)benzoic acid (AAA-114)
  • Figure US20120149737A1-20120614-C00373
  • 4-(4-Chloro-3-ethoxy-5-(pentan-3-yloxy)benzamido)benzoic acid (AAA-114) (50 mg, 65%) was prepared from methyl 4-(4-chloro-3-ethoxy-5-(pentan-3-yloxy)benzamido)benzoate (11) (76 mg, 0.18 mmol) using a procedure essentially the same as in step (ii) for AAA-001 except that dioxane (2 mL) was used instead of THF and the mixture was stirred at 50° C. for 2 h: m/z 406 [M+H]+ (ES+), 404 [M−H]− (ES−); 1H NMR (400 MHz, DMSO-d6) δ: 12.79 (1H, br s), 10.46 (1H, s), 7.99-7.93 (2H, m), 7.91-7.82 (2H, m), 7.27 (2H, dd), 4.46 (1H, quin), 4.20 (2H, q), 1.71-1.64 (4H, m), 1.39 (3H, t), 0.93 (6H, t).
    • Synthesis 117 4-(4-Chloro-3-ethoxy-5-(pentan-3-yloxy)benzamido)-2-methylbenzoic acid (AAA-115)
  • Figure US20120149737A1-20120614-C00374
  • 4-(4-Chloro-3-ethoxy-5-(pentan-3-yloxy)benzamido)-2-methylbenzoic acid (AAA-115) (57 mg, 78% for final step) was prepared in essentially the same manner as AAA-114 except that methyl 4-amino-2-methylbenzoate was used instead of methyl 4-aminobenzoate in step (ix): m/z 420 [M+H]+ (ES+), 418 [M−H]− (ES−); 1H NMR (400 MHz, DMSO-d6) δ: 12.62 (1H, br s), 10.35 (1H, s), 7.88 (1H, d), 7.72 (1H, dd), 7.66 (1H, d), 7.32-7.24 (2H, m), 4.45 (1H, quin), 4.20 (2H, q), 2.55 (3H, s), 1.73-1.61 (4H, m), 1.39 (3H, t), 0.93 (6H, t).
    • Synthesis 118 4-(4-Chloro-3-ethoxy-5-(pentan-3-yloxy)benzamido)-2-fluorobenzoic acid (AAA-116)
  • Figure US20120149737A1-20120614-C00375
  • 4-(4-Chloro-3-ethoxy-5-(pentan-3-yloxy)benzamido)-2-fluorobenzoic acid (AAA-116) (44 mg, 81% for final step) was prepared in essentially the same manner as AAA-114 except that methyl 4-amino-2-fluorobenzoate was used instead of methyl 4-aminobenzoate in step (ix): m/z 424 [M+H]+ (ES+), 422 [M−H]− (ES−); 1H NMR (400 MHz, DMSO-d6) δ: 13.05 (1H, br s), 10.60 (1H, s), 7.91 (1H, t), 7.82 (1H, dd), 7.61 (1H, dd), 7.26 (2H, dd), 4.46 (1H, quin), 4.20 (2H, q), 1.73-1.61 (4H, m), 1.39 (3H, t), 0.92 (6H, t).
    • Synthesis 119 4-(4-Chloro-3,5-diisopropoxybenzamido)-2-methylbenzoic acid (AAA-117)
  • Figure US20120149737A1-20120614-C00376
    Figure US20120149737A1-20120614-C00377
    • Step (i): Ethyl 4-chloro-3,5-dimethoxybenzoate (2)
  • Figure US20120149737A1-20120614-C00378
  • A solution of 2-chloro-5-iodo-1,3-dimethoxybenzene (1) (3.4 g, 11 mmol) in anhydrous THF (100 mL) was cooled to −70° C. and treated with n-butyllithium (5.5 mL, 12 mmol). The reaction mixture was stirred at −70° C. for 45 min then ethyl chloroformate (1.6 mL, 17 mmol) was added dropwise and the reaction mixture was allowed to warm to RT and stirred for 20 h. The reaction mixture was poured on to ice (100 mL) and the product was extracted with EtOAc (2×100 mL). The organic solution was washed with brine (3×100 mL) and the solvent was removed in vacuo. The residue was purified by silica gel chromatography (120 g, 0-50% EtOAc in isohexane) to afford ethyl 4-chloro-3,5-dimethoxybenzoate (2) (0.12 g, 4%): 1H NMR (400 MHz, CDCl3) δ: 7.30 (2H, s), 4.40 (2H, q), 3.96 (6H, s), 1.42 (3H, t).
    • Step (ii): 4-Chloro-3,5-dihydroxybenzoic acid (3)
  • Figure US20120149737A1-20120614-C00379
  • Tribromoborane (318 μL, 3.29 mmol) was added dropwise to a solution of ethyl 4-chloro-3,5-dimethoxybenzoate (2) (115 mg, 0.470 mmol) in DCM (1.5 mL) at 0° C. and the mixture was stirred at the same temperature for 4 h. The reaction mixture was allowed to warm to RT and then poured cautiously in to iced water (5 mL). The mixture was extracted with EtOAc (3×5 mL), and the combined organic extracts were washed with brine (2×5 mL), dried over MgSO4 and evaporated in vacuo to give 4-chloro-3,5-dihydroxybenzoic acid (3) (72 mg, 78%) as a brown solid: m/z 187 [M−H]− (ES−).
    • Step (iii): Isopropyl 4-chloro-3,5-diisopropoxybenzoate (4)
  • Figure US20120149737A1-20120614-C00380
  • Isopropyl 4-chloro-3,5-diisopropoxybenzoate (4) (43 mg, 0.12 mmol) was prepared from 4-chloro-3,5-dihydroxybenzoic acid (3) (72 mg, 0.38 mmol) using a procedure essentially the same as in step (i) for AAA-001 except that isopropyl bromide (8 eq.) was used instead of cyclopentyl bromide and the mixture was stirred at 50° C. for 20 h: 1H NMR (400 MHz, CDCl3) δ: 7.25 (2H, s), 5.23 (1H, sep), 4.63 (2H, sep), 1.38 (18H, m).
    • Step (iv): 4-Chloro-3,5-diisopropoxybenzoic acid (5)
  • Figure US20120149737A1-20120614-C00381
  • 4-Chloro-3,5-diisopropoxybenzoic acid (5) (36 mg, 95%) was prepared from isopropyl 4-chloro-3,5-diisopropoxybenzoate (4) (43 mg, 0.14 mmol) using a procedure essentially the same as in step (ii) for AAA-001 except that the mixture was stirred at 40° C. for 20 h: m/z 271 [M−H]− (ES−).
    • Step (v): Methyl 4-(4-chloro-3,5-diisopropoxybenzamido)-2-methylbenzoate (7)
  • Figure US20120149737A1-20120614-C00382
  • Methyl 4-(4-chloro-3,5-diisopropoxybenzamido)-2-methylbenzoate (7) (29 mg, 52%) was prepared from 4-chloro-3,5-diisopropoxybenzoic acid (5) (36 mg, 0.13 mmol) using a procedure essentially the same as in step (v) for AAA-075 except that the mixture was stirred at 60° C. for 90 min: m/z 420 [M+H]+ (ES+), 418 [M−H]− (ES−); 1H NMR (400 MHz, CDCl3) δ: 7.98 (1H, d), 7.88 (1H, br s), 7.61-7.52 (2H, m), 7.06 (2H, s), 4.71-4.59 (2H, m), 3.89 (3H, s), 2.64 (3H, s), 1.41 (12H, d).
    • Step (vi): 4-(4-Chloro-3,5-diisopropoxybenzamido)-2-methylbenzoic acid (AAA-117)
  • Figure US20120149737A1-20120614-C00383
  • 4-(4-Chloro-3,5-diisopropoxybenzamido)-2-methylbenzoic acid (AAA-117) (21 mg, 83%) was prepared from methyl 4-(4-chloro-3,5-diisopropoxybenzamido)-2-methylbenzoate (7) (25 mg, 60 μmol) using a procedure essentially the same as in step (ii) for AAA-001 except that the mixture was stirred at 40° C. for 20 h: m/z 404 [M−H]− (ES−); 1H NMR (400 MHz, DMSO-d6) δ: 12.61 (1H, br s), 10.33 (1H, s), 7.88 (1H, d), 7.71 (2H, dd), 7.26 (2H, d), 4.78 (2H, sep), 2.55 (3H, s), 1.33 (12H, d).
    • Synthesis 120 4-(4-Chloro-3-isopropoxy-5-methoxybenzamido)benzoic acid (AAA-118)
  • Figure US20120149737A1-20120614-C00384
    • Step (i): 2-Chloro-5-iodo-3-methoxyphenol (2)
  • Figure US20120149737A1-20120614-C00385
  • Tribromoborane (156 μL, 1.65 mmol) was added to a solution of 2-chloro-5-iodo-1,3-dimethoxybenzene (1) (380 mg, 1.27 mmol) in DCM (5 mL) and the mixture was stirred at RT for 1 h. The mixture was poured into iced water (20 mL) and made basic by the addition of 2M NaOH (50 mL). The aqueous mixture was washed with DCM (50 mL) and then acidified by the addition of 4M HCl. The product was then extracted into DCM (50 mL), the organic solution was dried over MgSO4 and the solvent was removed in vacuo to give 2-chloro-5-iodo-3-methoxyphenol (2) (290 mg, 78%) as a colourless oil: m/z 283 [M−H]− (ES−).
    • Step (ii): 2-Chloro-5-iodo-1-isopropoxy-3-methoxybenzene (3)
  • Figure US20120149737A1-20120614-C00386
  • 2-Chloro-5-iodo-1-isopropoxy-3-methoxybenzene (3) (270 mg, 77%) was prepared from 2-chloro-5-iodo-3-methoxyphenol (2) (290 mg, 1.02 mmol) using a procedure essentially the same as in step (i) for AAA-001 except that isopropyl bromide was used instead of cyclopentyl bromide.
    • Step (iii) Methyl 4-(4-chloro-3-isopropoxy-5-methoxybenzamido)benzoate (5)
  • Figure US20120149737A1-20120614-C00387
  • n-Butyllithium (364 μl, 0.909 mmol) was slowly added to a solution of 2-chloro-5-iodo-1-isopropoxy-3-methoxybenzene (3) (270 mg, 0.827 mmol) in anhydrous THF (5 mL) at −78° C. After stirring for 15 min at this temperature a solution of methyl 4-isocyanatobenzoate (176 mg, 0.992 mmol) in anhydrous THF (5 mL) was added dropwise. The solution was allowed to warm to RT and stirred for a further 20 h. The reaction mixture was partitioned between DCM (40 mL) and brine (100 mL). The phases were separated and the organic solution was dried over MgSO4, filtered and the solvent was removed in vacuo. The residue was purified by silica gel chromatography (40 g, 0-40% EtOAc in isohexane) to afford methyl 4-(4-chloro-3-isopropoxy-5-methoxybenzamido)benzoate (5) (20 mg, 6%) as a colourless oil: m/z 376 [M−H]− (ES−).
    • Step (iv): 4-(4-Chloro-3-isopropoxy-5-methoxybenzamido)benzoic acid (AAA-118)
  • Figure US20120149737A1-20120614-C00388
  • 4-(4-Chloro-3-isopropoxy-5-methoxybenzamido)benzoic acid (AAA-118) (10 mg, 55%) was prepared from methyl 4-(4-chloro-3-isopropoxy-5-methoxybenzamido)benzoate (5) (20 mg, 48 μmol) using a procedure essentially the same as in step (ii) for AAA-001 except that dioxane (3 mL) was used instead of THF: m/z 362 [M−H]− (ES−); 1H NMR (400 MHz, DMSO-d6) δ: 12.80 (1H, br s), 10.47 (1H, s), 7.99-7.92 (2H, m), 7.90-7.83 (2H, m), 7.31 (2H, dd), 4.79 (1H, sep), 3.94 (3H, s), 1.33 (6H, d).
    • Synthesis 121 4-(4-Fluoro-3,5-diisopropoxybenzamido)benzoic acid (AAA-119)
  • Figure US20120149737A1-20120614-C00389
    Figure US20120149737A1-20120614-C00390
  • Step (i): tert-Butyl(4-fluorobenzyloxy)dimethylsilane (2)
  • Figure US20120149737A1-20120614-C00391
  • A solution of (4-fluorophenyl)methanol (1) (8.6 mL, 79 mmol) in anhydrous DMF (40 mL) was cooled to 0° C. before imidazole (5.9 g, 87 mmol) was added portionwise, followed by tert-butylchlorodimethylsilane (13 g, 87 mmol). The reaction mixture was allowed to warm to RT and stirred for 20 h. The reaction mixture was diluted with EtOAc (200 mL) and the organic solution was washed with satd NaHCO3 (3×200 mL) and then brine (4×300 mL). The organic solution was dried over MgSO4 and the solvent was removed in vacuo. The residue was purified by silica gel chromatography (120 g, 0-10% EtOAc in isohexane) to afford tert-butyl(4-fluorobenzyloxy)dimethylsilane (2) (15.4 g, 81%) as a clear oil: 1H NMR (400 MHz, DMSO-d6) δ: 7.38-7.28 (2H, m), 7.16 (2H, dd), 4.68 (2H, s), 0.89 (9H, s), 0.07 (6H, s).
    • Step (ii): 5-((tert-Butyldimethylsilyloxy)methyl)-2-fluorophenol (3)
  • Figure US20120149737A1-20120614-C00392
  • sec-Butyllithium (20.7 mL, 29.0 mmol) was added dropwise to a solution of tert-butyl(4-fluorobenzyloxy)dimethylsilane (2) (6.33 g, 26.3 mmol) in THF (30 mL) over 30 min, at −78° C. Trimethyl borate (2.99 mL, 26.3 mmol) was added dropwise over 30 min while the temperature was maintained at −78° C. The reaction mixture was allowed to warm to 0° C. and AcOH (2.26 mL, 39.5 mmol) was added dropwise, followed by hydrogen peroxide (2.48 mL, 29.0 mmol). The mixture was stirred at 0° C. for 30 min then allowed to warm to RT and stirred for 1 h. The reaction mixture was diluted with diethyl ether (100 mL) and washed with 2M NaOH (100 mL) and brine (100 mL). The organic solution was dried over MgSO4, filtered and the solvent was removed in vacuo to give 5-((tert-butyldimethylsilyloxy)methyl)-2-fluorophenol (3) (4.0 g, 50%) as a colourless oil: m/z 255 [M−H]− (ES−).
    • Step (iii): tert-Butyl(3-(tert-butyldimethylsilyloxy)-4-fluorobenzyloxy)dimethylsilane (4)
  • Figure US20120149737A1-20120614-C00393
  • tert-Butyl(3-(tert-butyldimethylsilyloxy)-4-fluorobenzyloxy)dimethylsilane (4) (4.9 g, 81%) was prepared from 5-(tert-butyldimethylsilyloxy)methyl)-2-fluorophenol (3) (4.00 g, 15.6 mmol) using a procedure essentially the same as in step (i).
    • Step (iv): 3-(tert-Butyldimethylsilyloxy)-5-((tert-butyldimethylsilyloxy)methyl)-2-fluorophenol (5)
  • Figure US20120149737A1-20120614-C00394
  • 3-(tert-Butyldimethylsilyloxy)-5-((tert-butyldimethylsilyloxy)methyl)-2-fluorophenol (5) (2.1 g, 80%) was prepared from tert-butyl(3-(tert-butyldimethylsilyloxy)-4-fluorobenzyloxy)-dimethylsilane (4) (2.0 g, 5.4 mmol) using a procedure essentially the same as in step (ii): m/z 385 [M−H]− (ES−).
    • Step (v): tent-Butyl(4-fluoro-3,5-diisopropoxybenzyloxy)dimethylsilane (6)
  • Figure US20120149737A1-20120614-C00395
  • 2-Bromopropane (0.90 mL, 9.5 mmol) and K2CO3 (1.49 g, 10.8 mmol) were added to a stirred solution of 3-(tert-butyldimethylsilyloxy)-5-((tert-butyldimethylsilyloxy)methyl)-2-fluorophenol (5) (2.08 g, 4.30 mmol) in DMF (3 mL) and the mixture was stirred at 60° C. for 2 h. The reaction mixture was allowed to cool to RT and diluted with diethyl ether (50 mL). The organic solution was washed with brine (3×50 mL), dried over MgSO4, filtered and the solvent was removed in vacuo to afford tert-butyl(4-fluoro-3,5-diisopropoxybenzyloxy)dimethylsilane (6) (0.6 g, 31%). This material was used in the subsequent reaction step without purification.
    • Step (vi): (4-Fluoro-3,5-diisopropoxyphenyl)methanol (7)
  • Figure US20120149737A1-20120614-C00396
  • TBAF (1 M in THF) (1.35 mL, 1.35 mmol) was added to a solution of tert-butyl(4-fluoro-3,5-diisopropoxybenzyloxy)dimethylsilane (6) (600 mg, 1.35 mmol) in THF at 0° C. and the mixture was stirred at this temperature for 1 h. The mixture was partitioned between NH4Cl (satd. aq.) (50 mL) and EtOAc (100 mL). The phases were separated and the organic solution was washed with brine (50 mL), then dried over MgSO4 and filtered. The solvent was removed in vacuo and the residue was purified by silica gel chromatography (40 g, 0-50% EtOAc in isohexane) to afford (4-fluoro-3,5-diisopropoxyphenyl)methanol (7) (382 mg, 100%) as a colourless oil.
    • Step (vii): 4-Fluoro-3,5-diisopropoxybenzoic acid (8)
  • Figure US20120149737A1-20120614-C00397
  • TEMPO (12 mg, 79 μmol) was added to (4-fluoro-3,5-diisopropoxyphenyl)methanol (7) (382 mg, 1.58 mmol) in a mixture of MeCN (10 mL) and sodium phosphate buffer at 35° C. Sodium chlorite (285 mg, 3.15 mmol) in water (5 mL) and sodium hypochlorite (97 μl, 1.6 mmol) were added cautiously (portionwise, 20% of one then the other every 10 min until the addition was complete). Once the reaction was complete the mixture was basified to pH 9 by the addition of NaOH (15 mL). Sodium sulfite (aq., 20 mL) was added and the aqueous mixture was washed with diethyl ether (50 mL). The aqueous layer was acidified by the addition of 4M HCl and the product was extracted into EtOAc (50 mL). The organic solution was dried over MgSO4, filtered and the solvent was removed in vacuo. The residue was purified by silica gel chromatography (12 g, 0-40% EtOAc in isohexane) to afford 4-fluoro-3,5-diisopropoxybenzoic acid (8) (50 mg, 12%) as a white solid: m/z 255 [M−H]− (ES−).
    • Step (viii): Methyl 4-(4-fluoro-3,5-diisopropoxybenzamido)benzoate (10)
  • Figure US20120149737A1-20120614-C00398
  • A mixture of 4-fluoro-3,5-diisopropoxybenzoic acid (8) (54 mg, 0.21 mmol), DIPEA (110 μL, 0.632 mmol) and T3P (50% solution in EtOAc) (310 μL, 0.527 mmol) in EtOAc (1 mL) was stirred at RT for 10 min before a solution of methyl 4-aminobenzoate (9) (35 mg, 0.23 mmol) in EtOAc (1 mL) was added dropwise and the mixture was stirred at 40° C. for 20 h. The reaction mixture was adsorbed on to silica and purified by silica gel chromatography (4 g, 0-100% EtOAc in isohexane), then (4 g, 0-10% MeOH in DCM) to afford methyl 4-(4-fluoro-3,5-diisopropoxybenzamido)benzoate (10) (32 mg, 51% purity). The material was taken on in the subsequent reaction step without further purification.
    • Step (ix): 4-(4-Fluoro-3,5-diisopropoxybenzamido)benzoic acid (AAA-119)
  • Figure US20120149737A1-20120614-C00399
  • A suspension of methyl 4-(4-fluoro-3,5-diisopropoxybenzamido)benzoate (10) (32 mg, 51% purity, 82 μmol) in THF (1 mL) and 2M LiOH (0.16 mL, 0.33 mmol) was stirred at RT for 20 h, then at 45° C. for 2 h. The mixture was allowed to cool to RT and was acidified by the addition of 1M HCl. The mixture was partitioned between EtOAc (10 mL) and water (10 mL) and the phases were separated. The organic solution was washed with brine (3×10 mL), then dried over MgSO4 and filtered. The solvent was removed in vacuo and the residue was purified by reverse phase HPLC to afford 4-(4-fluoro-3,5-diisopropoxybenzamido)benzoic acid (AAA-119) (8 mg, 38%) as a white solid: m/z 376 [M+H]+ (ES+), 374 [M−H]− (ES−); 1H NMR (400 MHz, DMSO-d6) δ: 10.37 (1H, s), 7.93 (2H, d), 7.83 (2H, d), 7.35 (2H, d), 4.73 (2H, sep), 1.32 (12H, d). NB acid proton not visible.
    • Synthesis 122 4-(3,4-Diisopropoxy-5-(trifluoromethyl)benzamido)benzoic acid (AAA-120)
  • Figure US20120149737A1-20120614-C00400
    Figure US20120149737A1-20120614-C00401
    • Step (i): 2-Methoxy-6-(trifluoromethyl)phenol (2)
  • Figure US20120149737A1-20120614-C00402
  • A solution of n-butyllithium (20.4 mL, 51.1 mmol) and TMEDA (9.00 mL, 59.6 mmol) in anhydrous THF (50 mL) was cooled to −78° C. 1-Methoxy-3-(trifluoromethyl)benzene (1) (10 g, 57 mmol) was added dropwise and the reaction mixture was stirred at −78° C. for 15 min then allowed to warm to RT and stirred for 10 min. The reaction mixture was cooled to −78° C. and trimethyl borate (16.1 mL, 142 mmol) was added slowly, dropwise, and the reaction mixture was stirred at −78° C. for 15 min then allowed to warm to RT and stirred for 20 h. 7N NH3/MeOH (20 mL) was added and the solvent was removed in vacuo. The residue was dissolved in formic acid (20 mL) and cooled to 0° C. before hydrogen peroxide (6.00 mL, 68.5 mmol) was added and the solution was allowed to warm to RT and stirred for 2 h. The product was extracted with EtOAc (3×50 mL), and then the combined organics were shaken with NaOH (2×50 mL). The aq phase was acidified with 1M HCl and the product was extracted with DCM (2×30 mL). The organic solution was washed with brine (2×30 mL), dried over MgSO4 and filtered. The solvent was removed in vacuo and the residue was purified by silica gel chromatography (120 g, 0-5% MeOH in DCM) to afford 2-methoxy-6-(trifluoromethyl)phenol (2) (4.95 g, 45%) as a colourless oil: m/z 191 [M−H]− (ES−); 1H NMR (400 MHz, CDCl3) δ: 7.15-7.09 (1H, m), 7.04-6.98 (1H, m), 6.89 (1H, td), 6.14 (1H, br s), 3.91 (3H, s).
    • Step (ii): 4-Hydroxy-3-methoxy-5-(trifluoromethyl)benzaldehyde (3)
  • Figure US20120149737A1-20120614-C00403
  • A mixture of 2-methoxy-6-(trifluoromethyl)phenol (2) (2.5 g, 13 mmol) and hexamethylenetetramine (1.8 g, 13 mmol) in TFA (40 mL) was stirred under reflux for 3 h. The solvent was removed in vacuo and the residue was dissolved in 1M HCl (20 mL). The product was extracted with DCM (3×20 mL), the combined organics were washed with brine (2×20 mL) and then the solvent was removed in vacuo. The residue was purified by silica gel chromatography (80 g, 0-100% EtOAc in isohexane) to afford 4-hydroxy-3-methoxy-5-(trifluoromethyl)benzaldehyde (3) (1.03 g, 34%) as a white solid: m/z 219 [M−H]− (ES−).
    • Step (iii): 4-Hydroxy-3-methoxy-5-(trifluoromethyl)benzoic acid (4)
  • Figure US20120149737A1-20120614-C00404
  • A suspension of 4-hydroxy-3-methoxy-5-(trifluoromethyl)benzaldehyde (1.03 g, 4.68 mmol) and Oxone™ (3.45 g, 5.61 mmol) in DMF (10 mL) was stirred at RT for 2 h. The reaction mixture was diluted with EtOAc (40 mL) and the solution was washed sequentially with 1M HCl (40 mL) and brine (4×40 mL). The solvent was removed in vacuo and the residue was purified by silica gel chromatography (80 g, 0-10% MeOH in DCM) to afford 4-hydroxy-3-methoxy-5-(trifluoromethyl)benzoic acid (4) (392 mg, 35%) as a white solid: m/z 235 [M−H]− (ES−); 1H NMR (400 MHz, DMSO-d6) δ: 13.01 (1H, br s), 10.74 (1H, br s), 7.68 (2H, dd), 3.92 (3H, s).
    • Step (iv): 3,4-Dihydroxy-5-(trifluoromethyl)benzoic acid (5)
  • Figure US20120149737A1-20120614-C00405
  • Boron tribromide (392 μL, 4.15 mmol) was added to a suspension of 4-hydroxy-3-methoxy-5-(trifluoromethyl)benzoic acid (4) (392 mg, 1.66 mmol) in DCM (10 mL) at 0° C. The reaction mixture was allowed to warm to RT and stirred for 70 h. The reaction mixture was cautiously added to stirring iced water (50 mL) and stirred for 10 min. The product was extracted with DCM (2×20 mL), and then the combined organic extracts were washed with brine (2×20 mL). The solvent was removed in vacuo and the residue was purified by silica chromatography (12 g, 0-10% MeOH in DCM) to afford 3,4-dihydroxy-5-(trifluoromethyl)benzoic acid (5) (257 mg, 68%) as a white solid: m/z 221 [M−H]− (ES−); 1H NMR (400 MHz, DMSO-d6) δ: 12.83 (1H, br s), 10.45 (2H, br d), 7.56 (2H, dd).
    • Step (v): 3,4-Diisopropoxy-5-(trifluoromethyl)benzoic acid (6)
  • Figure US20120149737A1-20120614-C00406
  • 2-Bromopropane (380 μL, 4.05 mmol) was added to a suspension of 3,4-dihydroxy-5-(trifluoromethyl)benzoic acid (5) (257 mg, 1.16 mmol) and K2CO3 (560 mg, 4.05 mmol) in DMF (10 mL) and the reaction mixture was stirred at 80° C. for 20 h. The reaction mixture was diluted with EtOAc (30 mL) and washed sequentially with 1M HCl (30 mL) and brine (5×30 mL), and then the solvent was removed in vacuo. The residue was suspended in 2M sodium hydroxide (5.8 mL, 12 mmol) and the mixture was stirred at 80° C. for 4 h. Dioxane (10 mL) was added and the mixture continued to stir at 80° C. for a further 20 h. The solvents were removed in vacuo and the residue was partitioned between EtOAc (50 mL) and 1M HCl (50 mL). The phases were separated and the organic solution was washed with brine (3×40 mL), and then dried over MgSO4, and filtered. The solvent was removed in vacuo and the residue was purified by silica chromatography (40 g, 0-15% MeOH in DCM) to afford 3,4-diisopropoxy-5-(trifluoromethyl)benzoic acid (6) (118 mg, 33%) as a yellow solid.
    • Step (vi): Methyl 4-(3,4-diisopropoxy-5-(trifluoromethyl)benzamido)benzoate (8)
  • Figure US20120149737A1-20120614-C00407
  • Methyl 4-(3,4-diisopropoxy-5-(trifluoromethyl)benzamido)benzoate (8) (11 mg, 19%) was prepared from 3,4-diisopropoxy-5-(trifluoromethyl)benzoic acid (6) (40 mg, 0.13 μmol) using a procedure essentially the same as in step (i) for AAA-064 except that methyl 4-aminobenzoate (7) was used instead of methyl 4-amino-2-fluorobenzoate: 1H NMR (400 MHz, DMSO-d6) δ: 10.59 (1H, s), 8.02-7.88 (4H, m), 7.87-7.80 (2H, m), 5.12-5.01 (1H, m), 4.90-4.78 (1H, m), 3.85 (3H, s), 1.37 (6H, d), 1.24 (7H, d).
    • Step (vii): 4-(3,4-Diisopropoxy-5-(trifluoromethyl)benzamido)benzoic acid (AAA-120)
  • Figure US20120149737A1-20120614-C00408
  • 4-(3,4-Diisopropoxy-5-(trifluoromethyl)benzamido)benzoic acid (AAA-120) (8 mg, 71%) was prepared from methyl 4-(3,4-diisopropoxy-5-(trifluoromethyl)benzamido)benzoate (8) (11 mg, 25 μmol) using a procedure essentially the same as in step (ii) for AAA-001 except the mixture was stirred at 40° C. for 20 h: m/z 424 [M−H]− (ES−); 1H NMR (400 MHz, DMSO-d6) δ: 12.79 (1H, br s), 10.55 (1H, s), 7.95 (2H, d), 7.87-7.82 (4H, m), 5.07 (1H, m), 4.85 (1H, m), 1.37 (6H, d), 1.24 (6H, d).
    • Biological Methods Studies of Retinoic Acid Receptors
  • The inventors' have shown that RARα agonists are likely to be useful in the treatment of AD. They prevent neuronal cell death in the presence of Aβ42; in culture, they up-regulate choline acetyltransferase (chAT), down-regulate amyloid precursor protein (APP), and increase the expression of disintegrin-metalloproteinases 10 (ADAM10). In vivo, the inventors' have shown that feeding RARα agonists to Tg2576 mice (which overexpresses the Swedish mutation of the human APP leading to amyloid β deposits and cognitive decline) results in a significant reduction in the levels of both Aβ40 and Aβ42, as well as positive behavioural changes.
    • Materials and Methods: Culture of Cortical Neurons and Survival Assays:
  • Neuronal cultures were prepared from embryonic E19 mouse embryos. Fetal brain cortices were dissected and freed from meninges. The cortices were placed in ice cold PBS containing 0.25% glucose and triturated with fire polished Pasteur pipettes. Cortical cells (1×105) were plated onto poly-L-lysine (10 μg/mL) coated glass coverslips in 24-well tissue culture plates. They were cultured in Neurobasal medium containing B27 supplement, 2 mM glutamine, 20 μg/mL penicillin stepromycin, and 0.25% glucose. They were maintained for 7 days before been treated. For each treatment, 3 coverslips were used and the experiment was repeated 3 times.
  • Treatments consisted of 10 μM Aβ42 in the presence of increasing dose of agonist: all-trans retinoic acid (atRA), BMS 194753 (RARα), AM 580 (RARα), CD 2019 (RARβ), or CD 437 (RARγ).
  • TABLE 1
    RAR Agonists
    Figure US20120149737A1-20120614-C00409
    Figure US20120149737A1-20120614-C00410
    Figure US20120149737A1-20120614-C00411
    Figure US20120149737A1-20120614-C00412
    Figure US20120149737A1-20120614-C00413
  • After 3 days of culture, media was removed and Hoechst 33342 (10 μM) and propidium iodide (10 μM) in PBS was added to the wells for 15 minutes. Only neurons positive for Hoechst 33342 but negative for propidium iodide were counted as surviving neurons.
  • In addition, cortical cultures were treated with agonist alone (0.1 μM) and assayed for chAT, APP, and ADAM10. The antibodies used were a chAT (1:200, Chemicon™), α APP (1:100, Chemicon™) and a ADAM10 (1:200, Chemicon™). Secondary antibody used was anti-rabbit Cy3 or Cy5 conjugated (Jackson™, used at 1:1000). The nuclear marker DAPI (1 μg/mL) was used to stain all cells. Cell counts were carried out in 31 mm2 areas per coverslip by an investigator who did not know the treatments.
    • Animal Treatments:
  • Twenty seven 3 month old Tg2576 mice (Taconic™) were split into 3 groups of 9. One group was fed normal chow, the other groups were fed with 1 mg/Kg RARα agonist, either AM580 or BMS194753. Animals were analysed at 6 and 9 months of age.
    • Tissue Preparation:
  • Animals were perfused with PBS. The brain was dissected and one hemisegment was fixed in 4% PFA overnight, 20% sucrose for 3 days, embedded in OCT compound and stored frozen. The cortex was removed form the other hemisegment and the protein extracted.
    • Aβ Levels:
  • To measure Aβ40 and Aβ42 levels, a sandwich ELISA assay kit (Biosource™) was used according to the manufactures instructions. A 1:5000 of the guanidine-soluble extracts were made with TBS containing 5% BSA and 1× protease inhibitor (Calbiochem™) and centrifuged at 16000×g for 20 minutes at 4° C. Samples were diluted 1:10000 in sample diluent provided by the manufacturer. Samples were loaded in triplicate (100 mL) and the plate read at 420 nm, by an investigator who did not know the treatments.
    • Graphs and Statistics:
  • Graphs were plotted using Sigma Plot™. Data were expressed as mean+/−S.E.M and statistical analysis was carried out using student's t test.
    • Results:
  • RARα signalling prevents neuronal death in the presence of Aβ42:
  • Cortical cultures were treated after 7 days with 10 μM Aβ42 and supplemented with 0.01-1 μM of agonist. After 3 days, the number of surviving cells was determined. In the presence of atRA, there was an increase in cell survival with increasing dose of atRA as compared to the control cultures (treated only with Aβ42). As atRA is a weak pan-agonist of all the RARs, it was decided to identify the specific receptor involved in this process using RAR specific agonists. Neuronal survival was notably better for each of two RARαselective agonists (AM 580 and BMS 194753) but notably worse for RARβ and RARγ selective agonists (CD 2019 and CD 437, respectively). The data are summarised in the following table. This suggests that it is RARα signalling that is required for neuronal survival in the presence of Aβ42.
  • TABLE 2
    Effect of Increasing Dose of RAR Agonists on Survival of
    Cortical Neurons in the Presence of 10 μM Aβ42
    % Surviving Neurons
    0.01 μM 0.1 μM 1.0 μM
    Agonist agonist agonist agonist
    atRA (pan-RAR) 53 ± 4 69 ± 4 82 ± 4
    AM 580 (RARα) 52 ± 7 70 ± 6 99 ± 9
    BMS 194753 (RARα) 57 ± 7 69 ± 3 88 ± 4
    CD 2019 (RARβ) 52 ± 3 58 ± 5 60 ± 5
    CD 437 (RARγ) 53 ± 3  30 ± 11  26 ± 10
    Control 1 (no Aβ42) 100 ± 6 
    Control 2 (Aβ42; 52 ± 7
    no agonist)
    • RARα Signalling Up-Regulates Chat Expression in Cultures of E17 Cortical Neurons:
  • Cortical cultures were treated after 7 days with 0.1 μM of agonist, and analysed 3 days later. Only in the presence of RARα agonist was there a significant increase in choline acetyltransferase (chAT) expression (and so an increase in the number of chAT expressing neurons). The data are summarised in the following table.
  • TABLE 3
    Effect of Agonists on chAT Expression in Cortical Neurons
    Agonist (0.01 μM) Number of chAT Neurons
    Control (no agonist) 5 ± 1
    atRA 16 ± 2 
    BMS 194753 (RARα) 37 ± 3 
    CD 2019 (RARβ) 8 ± 1
    CD 437 (RARγ) 2 ± 1
    • RARα Signalling Down-Regulates App Expression in Cultures of E17 Cortical Neurons:
  • Cortical cultures were treated after 7 days with 0.1 μM of agonist, and analysed 3 days later. Only in the presence of the RARα agonist was there a significant decrease in amyloid precursor protein (APP) expression (and so a decrease in the number of APP expressing neurons). The data are summarised in the following table.
  • TABLE 4
    Effect of Agonists on APP Expression in Cortical Neurons
    Agonist (0.01 μM) Number of APP Neurons
    Control (no agonist) 27 ± 2
    atRA 15 ± 2
    BMS 194753 (RARα) 10 ± 2
    AM 580 (RARα) 11 ± 2
    CD 2019 (RARβ) 23 ± 2
    CD 437 (RARγ) 22 ± 3

    RARα signalling up-regulates ADAM10 expression in cultures of E17 cortical neurons:
  • Cortical cultures were treated after 7 days with 0.1 μM of agonist, and analysed 3 days later. Only in the presence of the RARα agonist was there a significant increase in disintegrin-metalloproteinases 10 (ADAM10) expression (and so an increase in the number of ADAM10 expressing neurons). The data are summarised in the following table.
  • TABLE 5
    Effect of Agonists on APP Expression in Cortical Neurons
    Agonist (0.01 μM) Number of APP Neurons
    Control (no agonist) 2 ± 0.5
    atRA 11 ± 1.5 
    BMS 194753 (RARα) 20 ± 2  
    AM 580 (RARα) 19 ± 3  
    CD 2019 (RARβ) 1 ± 0.5
    CD 437 (RARγ)  2 ± 0.75
    • Oral Dosing of RARα Agonist Down-Regulates Aβ40 and Aβ42 Expression in the Tg2576 Mouse:
  • The above data taken together suggest that RARα signalling as opposed to RARβ and RARγ signalling regulates a number of genes involve in AD. In order to demonstrate the usefulness of a RARα agonists in vivo, a mouse model was employed which shows many aspects of AD. These are Tg2576 mice, which over-express the Swedish mutation of APP. These mice overproduce Aβ40 and Aβ42. Three month old mice were fed for 3 months with normal chow or chow supplemented with 1 mg/kg of agonist. At six months of age, there is a dramatic decrease in both Aβ40 and Aβ42 levels in the mice fed with the RARα agonist, as compared to the normal fed mice.
  • TABLE 6
    Effect of Oral RARα Agonist on Aβ40 and Aβ42 in Tg2576 Mice
    Agonist % of Aβ40 % of Aβ42
    Control (no agonist) 100 ± 2  100 ± 4 
    AM 580 (RARα) 4 ± 1 8 ± 1
    BMS 194753 (RARα)  3 ± 0.5 7 ± 1
    • Behavioural Outcomes:
  • It is well known in the field that the Tg2576 mice become very aggressive with age and that this is one of the symptoms of AD. It was noted in the above studies, that while it was necessary to cage the control mice individually during the course of the experiment due to their aggression, the mice treated with RARα agonist displayed little or no aggression such that they could be caged together and displayed increased sexual activity. These data suggest that orally administered RARα agonist is of therapeutic value in the treatment of AD.
    • Transactivation Assays for RARα, RARβ, and RARγ Receptors
  • Transcriptional transactivation assays were performed with gal4 fusion receptor constructs, created using each of the RAR ligand binding domains, co-transfected with the pFR-luc (Stratagene™) reporter construct in COS-7 cells. Thus, transfected cells will constitutively express the gal4-RAR fusion protein which in turn may be transactivated by all trans retinoic acid (atRA) to induce the expression of the luciferase that is driven by a gal4UAS.
  • Briefly, on day 1, 96 well plates were seeded with 8000 cells per well then left to recover overnight. On day 2, the cells were co-transfected with 100 ng of reporter plasmid and 10 ng of the appropriate receptor plasmid per well using lipofectamine (Invitrogen™). On day 3, the lipofectamine containing media was replaced by a DMEM without phenol red, followed by the addition of test compound dissolved in 1 μL of DMSO to each well's 100 μL total volume. Finally, on day 4, the cells were lysed and their luciferase substrate was provided by the BrightGlo™ reagent (Promega™), the plates were then read on the MicroBeta TriLux™ (Perkin Elmer™)
  • On each plate, an 8 point dose-response curve of atRA was run in duplicate and dose-response curves of test compounds were also generated in duplicate.
  • EC50 data both for test compounds and atRA was generated by fitting dose-response curves using GraphPad Prism™. Data for test compounds are quoted as a ratio of the test compound EC50 to that of atRA obtained on the same plate. Where replicate data has been generated, the data are quoted as a ratio of the mean EC50 from the separate experiments.
    • Biological Data
  • A number of compounds of the invention were examined using the transactivation assay for RAR alpha, the transactivation assay for RAR beta, and the transactivation assay for RAR gamma, as described above.
  • For comparison purposes, data for several reference compounds, XXX-01, XXX-02, and XXX-03, were also obtained. A key structural feature of the compounds of the present invention is the presence of particular subsituents (i.e., —R1, —R2, and —R3) at the positions meta, para, and meta to the amide linkage (i.e., -J-). The comparison compounds described herein were selected because they are structurally similar to the compounds of the present invention, but lack one of these three substituents.
  • Comparison Compounds
    Code
    Number Structure
    XXX-01
    Figure US20120149737A1-20120614-C00414
    XXX-02
    Figure US20120149737A1-20120614-C00415
    XXX-03
    Figure US20120149737A1-20120614-C00416

    The data are summarised in the following table.
  • RARα RARβ RARα/ RARγ
    Code activity activity RARβ activity
    Number ratio ratio ratio (*) ratio
    atRA 1 1 1 1
    XXX-01 327 2570 7.9 inactive
    XXX-02 2242 — — —
    XXX-03 90 642 7.1 inactive
    AAA-001 11 342 31.1 4700
    AAA-002 50 2900 58.0 inactive
    AAA-003 15 139 9.3 1200
    AAA-004 7 1420 202.9 820
    AAA-005 68 3570 52.5 3770
    AAA-006 14 1054 75.3 5840
    AAA-007 25 2010 80.4 inactive
    AAA-008 26 4560 175.4 56900
    AAA-009 29 2450 84.5 960
    AAA-010 102 2530 24.8 inactive
    AAA-011 34 2960 87.1 21800
    AAA-012 533 1300 2.4 inactive
    AAA-013 30 355 11.8 inactive
    AAA-014 58 1350 23.3 inactive
    AAA-015 20 540 27.0 inactive
    AAA-016 500 — —
    AAA-017 140 inactive >500 —
    AAA-018 151 9660 64.0 inactive
    AAA-019 0.9 74 82.2 136
    AAA-020 108 214 2.0 inactive
    AAA-021 760 — —
    AAA-022 448 inactive >50 inactive
    AAA-023 5 404 80.8 62370
    AAA-024 66 805 12.2 27200
    AAA-025 5 131 26.2 inactive
    AAA-026 180 4920 27.3 inactive
    AAA-027 260 inactive >5 —
    AAA-028 370 64000 173.0 inactive
    (PP-01)
    AAA-029 24 1920 80 inactive
    (PP-02)
    AAA-030 29 9525 328 5850
    (PP-03)
    AAA-031 7 2930 420 6250
    AAA-032 61 2700 44 16875
    AAA-033 13 19 1.5 148
    AAA-034 2 244 122 1250
    AAA-035 0.30 2620 8700 87000
    AAA-036 7.0 215 31 2438
    AAA-037 0.25 324 1300 >2600
    AAA-038 0.50 49 98 0.36
    AAA-039 3.0 177 59 2985
    AAA-040 1.1 60 55 194
    AAA-041 5.4 238 44 31340
    AAA-042 5.4 369 68 6000
    AAA-043 2 53 27 688
    AAA-044 1.7 55 32 571
    AAA-045 7.3 283 39 3651
    AAA-046 2.8 121 43 698
    AAA-047 11 22 2 270
    AAA-048 0.86 38 44 162
    AAA-049 0.64 8460 13200 82
    AAA-050 1.7 89 52 1386
    AAA-051 0.97 43 45 2859
    AAA-052 0.25 21 84 1923
    AAA-053 4.2 1410 336 414
    AAA-054 0.59 21 36 51
    AAA-055 18 1926 107 69000
    AAA-056 3.1 >770 >250 22
    AAA-057 33 1226 37 4920
    AAA-058 29 4200 145 550
    AAA-059 27 2600 96 225
    AAA-060 45 2267 50 30
    AAA-061 44 5200 118 1531
    AAA-062 85 714 8 5328
    AAA-063 76 1686 22 6429
    AAA-064 81 >3500 >40 1977
    AAA-065 15 140 9 3521
    AAA-066 32 7558 236
    AAA-067 50 279 6 6047
    AAA-068 7 976 140 60833
    AAA-069 1.2 505 421 3380
    AAA-070 3.4 2386 701 >62500
    AAA-071 5.2 160 31 13333
    AAA-072 9.4 2333 248 29474
    AAA-073 19 117 6 220
    AAA-074 154 32400 210 14500
    AAA-075 4.7 1134 241 2394
    AAA-076 5.3 1500 283 10833
    AAA-077 6.7 4082 609 117857
    AAA-078 0.7 103 147 8083
    AAA-079 1.1 536 487 6786
    AAA-080 1.6 318 200 17460
    AAA-081 9.0 1453 161 >27000
    AAA-082 25 6885 275 >56000
    AAA-083 9 90 10 4390
    AAA-084 26 6087 234 >1400
    AAA-085 33 6923 210 >8300
    AAA-086 2.1 7 3.1 1203
    AAA-087 7 2000 286 11725
    AAA-088 1.0 115 115 1706
    AAA-089 1.3 510 392 2647
    AAA-090 5.0 1250 250 367000
    AAA-091 1.6 216 135 75000
    AAA-092 2 53 27 1059
    AAA-093 2.0 92 46 10833
    AAA-094 0.23 656 2852 20000
    AAA-095 2.7 92 34 812
    AAA-096 3.2 215 67 7895
    AAA-097 2.6 151 58 100000
    AAA-098 12 433 36 2955
    AAA-099 11 655 59 89
    AAA-100 33 3273 99 11818
    AAA-101 1.7 39 23 375
    AAA-102 2.2 73 33 833
    AAA-103 2.6 57 21 583
    AAA-104 19 10164 535 5000
    AAA-105 0.66 8.4 13 941
    AAA-106 66 2245 34 2326
    AAA-107 4.8 647 135 2833
    AAA-108 5.1 1727 338 32500
    AAA-109 4 1583 396 792000
    AAA-110 16 1921 120 >12000
    AAA-111 10 712 71 50000
    AAA-112 2 2464 1212 1268
    AAA-113 3.9 900 231 11093
    AAA-114 4.4 100 23 22759
    AAA-115 2.6 150 58 25172
    AAA-116 4.5 208 46 55172
    AAA-117 4 273 68 29730
    AAA-118 36 1700 47 933333
    AAA-119 26 5000 192 >42000
    AAA-120 0.89 142 157 2162
    (*) The ratio of the “RARα activity ratio” to the “RARβ activity ratio” is referred to as “RARα/RARβ ratio” and reflects the fold-selectivitity for RARα over RARβ.
    (In the above table, “inactive” means that no agonist action was seen at the highest concentration tested.)
  • All of the above AAA compounds were found to be agonists of RARα. Most of the AAA compounds have a RARα activity ratio (with respect to atRA) of less than about 200. Many of the AAA compounds have a RARα activity ratio of less than about 70. Many of the AAA compounds have a RARα activity ratio of less than about 30. Many of the AAA compounds have a RARα activity ratio of less than about 10. Many of the AAA compounds have a RARα activity ratio of less than about 5.
  • In addition, all of the above AAA compounds were found to be selective for RARα as compared to RARβ. For most of the AAA compounds, the selectivity for RARα as compared to RARβ is by a factor or at least about 10 (e.g., the ratio of the RARα activity ratio to the RARβ activity ratio is at least about 10). For many of the AAA compounds, the selectivity for RARα as compared to RARβ is by a factor of at least about 20. For many of the AAA compounds, the selectivity for RARα as compared to RARβ is by a factor of at least about 50. For many of the AAA compounds, the selectivity for RARα as compared to RARβ is by a factor of at least about 100. For many of the AAA compounds, the selectivity for RARα as compared to RARβ is by a factor of at least about 200.
  • Indeed, many of the AAA compounds (e.g., AAA-001, AAA-004, AAA-006, AAA-007, AAA-008, AAA-009, AAA-015, AAA-019, AAA-023, AAA-025) provide at least a 3-fold increase in activity towards RARα (i.e., a RARα activity ratio of less than about 30), as compared to the three reference compounds, while simultaneously providing at least a 3-fold increase in RARα versus RARβ selectivity (i.e., a RARα/RARβ ratio greater than about 25) as compared to the three reference compounds.
  • In a comparison with compound XXX-01, compound AAA-025 provides a 65-fold increase in RARα activity (i.e., 5 versus 327) while simultaneously providing a 3-fold increase in RARα versus RARβ selectivity (i.e., 26.2 versus 7.9).
  • RARα RARβ RARα/
    Code activity activity RARβ
    Number ratio ratio ratio (*)
    XXX-01 327 2570 7.9
    AAA-025 5 131 26.2
    (*) The ratio of the “RARα activity ratio” to the “RARβ activity ratio” is referred to as “RARα/RARβ ratio” and reflects the fold-selectivitity for RARα over RARβ.
  • Code
    Number Structure
    XXX-01
    Figure US20120149737A1-20120614-C00417
    AAA-025
    Figure US20120149737A1-20120614-C00418
  • Similarly, in a comparison with compound XXX-02, compound AAA-022 provides a 5-fold increase in RARα activity (i.e., 448 versus 2242) while simultaneously providing a very high selectivity for RARα as compared to RARβ selectivity (i.e., >50).
  • RARα RARβ RARα/
    Code activity activity RARβ
    Number ratio ratio ratio (*)
    XXX-02 2242 — —
    AAA-022 448 inactive >50
    (*) The ratio of the “RARα activity ratio” to the “RARβ activity ratio” is referred to as “RARα/RARβ ratio” and reflects the fold-selectivitity for RARα over RARβ.
  • Code
    Number Structure
    XXX-02
    Figure US20120149737A1-20120614-C00419
    AAA-022
    Figure US20120149737A1-20120614-C00420
  • Similarly, in a comparison with compound XXX-03, each of compounds AAA-001, AM-003, AAA-004, AAA-005, AAA-010, AAA-011, AAA-019, AAA-029 (PP-02), and AAA-030 (PP-03) provides a comparable or improved activity towards RARα (i.e., from 0.9 to 102, versus 90), while simultaneously providing improved RARα versus RARβ selectivity (i.e., from 9.3 to 328, versus 7.1).
  • RARα RARβ RARα/
    Code activity activity RARβ
    Number ratio Improvement ratio ratio (*) Improvement
    XXX-03 90 — 642 7.1 —
    AAA-001 11 ~8.2-fold 342 31.1 ~4.4-fold 
    AAA-003 15 ~6.0-fold 139 9.3 ~1.3-fold 
    AAA-004 7  ~13-fold 1420 203 ~29-fold
    AAA-005 68 ~1.3-fold 3570 52.5 ~7.4-fold 
    AAA-010 102 ~0.9-fold 2530 24.8 ~3.5-fold 
    AAA-011 34 ~2.6-fold 2960 87.1 ~12-fold
    AAA-019 0.9 ~100-fold  74 82.2 ~12-fold
    AAA-029 24 ~3.8-fold 1920 80.0 ~11-fold
    (PP-02)
    AAA-030 29 ~3.1-fold 9525 328 ~46-fold
    (PP-03)
    (*) The ratio of the “RARα activity ratio” to the “RARβ activity ratio” is referred to as “RARα/RARβ ratio” and reflects the fold-selectivitity for RARα over RARβ.
  • It may be noted that some of the compounds (e.g., AAA-001, AAA-004, AAA-011, AAA-029, and AAA-030) provide both substantially improved activity towards RARα (i.e., from 7 to 34, versus 90), while simultaneously providing substantially improved RARα versus RARβ selectivity (i.e., from 31 to 328, versus 7.1).
  • Code
    Number Structure
    XXX- 003
    Figure US20120149737A1-20120614-C00421
    AAA- 001
    Figure US20120149737A1-20120614-C00422
    AAA- 003
    Figure US20120149737A1-20120614-C00423
    AAA- 004
    Figure US20120149737A1-20120614-C00424
    AAA- 005
    Figure US20120149737A1-20120614-C00425
    AAA- 010
    Figure US20120149737A1-20120614-C00426
    AAA- 011
    Figure US20120149737A1-20120614-C00427
    AAA- 019
    Figure US20120149737A1-20120614-C00428
    AAA- 029 (PP-02)
    Figure US20120149737A1-20120614-C00429
    AAA- 030 (PP-03)
    Figure US20120149737A1-20120614-C00430
  • And so, for example, one preferred group of compounds (e.g., compounds for use in therapy, use of compounds in the manufacture of a medicament, methods of treatment, etc.) are selected from compounds of the following formula, and pharmaceutically acceptable salts, hydrates, and solvates thereof:
  • Figure US20120149737A1-20120614-C00431
  • wherein:
      • —R1 is independently —X or —RX;
      • —R2 is independently —O—RA or —O—RC;
      • —R3 is independently —X or —RX;
        wherein:
      • —Z═ is —CRZ═;
      • —RZZ is independently —H or —RZZ;
      • —RZZ is independently saturated aliphatic C1-4alkyl, —OH, or —F;
        wherein:
      • each —X is independently —Cl or —Br;
      • each —RX is independently saturated aliphatic C1-6haloalkyl;
      • each —RA is independently saturated aliphatic C1-6alkyl;
      • each —RC is independently saturated C3-7cycloalkyl.
  • In a further embodiment of the above, —RZZ is independently saturated aliphatic C1-4alkyl.
  • Similarly, for example, one preferred group of compounds (e.g., compounds for use in therapy, use of compounds in the manufacture of a medicament, methods of treatment, etc.) are selected from compounds of the following formula, and pharmaceutically acceptable salts, hydrates, and solvates thereof:
  • Figure US20120149737A1-20120614-C00432
  • wherein:
      • —R1 is independently —X;
      • —R2 is independently —O—RA or —O—RC;
      • —R3 is independently —X;
        wherein:
      • —Z═ is —CRZ═;
      • —RZ is independently —H or —RZZ;
      • —RZZ is independently saturated aliphatic C1-4alkyl, —OH, or —F;
        wherein:
      • each —X is independently —Cl or —Br;
      • each —RA is independently saturated aliphatic C1-6alkyl;
      • each —RC is independently saturated C3-7cycloalkyl.
  • In a further embodiment of the above, —RZZ is independently saturated aliphatic C1-4alkyl.
  • Similarly, for example, one preferred group of compounds (e.g., compounds for use in therapy, use of compounds in the manufacture of a medicament, methods of treatment, etc.) are selected from compounds of the following formula, and pharmaceutically acceptable salts, hydrates, and solvates thereof:
  • Figure US20120149737A1-20120614-C00433
  • wherein:
      • —R1 is independently —X;
      • —R2 is independently —O—RA or —O—RC;
      • —R3 is independently —X;
        wherein:
      • each —X is independently —Cl or —Br;
      • each —RA is independently saturated aliphatic C1-6alkyl;
      • each —RC is independently saturated C3-7cycloalkyl.
  • It may be noted that some of the compounds (e.g., AAA-050, AAA-051, AAA-080) provide both substantially improved activity towards RARα (i.e., from 0.97 to 1.7, versus 90), while simultaneously providing substantially improved RARα versus RARβ selectivity (i.e., from 45 to 200, versus 7.1).
  •
    AAA-050
    Figure US20120149737A1-20120614-C00434
    AAA-051
    Figure US20120149737A1-20120614-C00435
    AAA-080
    Figure US20120149737A1-20120614-C00436
  • And so, for example, one preferred group of compounds (e.g., compounds for use in therapy, use of compounds in the manufacture of a medicament, methods of treatment, etc.) are selected from compounds of the following formula, and pharmaceutically acceptable salts, hydrates, and solvates thereof:
  • Figure US20120149737A1-20120614-C00437
  • wherein:
      • —R1 is independently —O—RA or —O—RC;
      • —R2 is independently —O—RA or —O—RC;
      • —R3 is independently —X;
      • or:
      • —R1 is independently —X;
      • —R2 is independently —O—RA or —O—RC;
      • —R3 is independently —O—RA or —O—RC;
        wherein:
      • —Z═ is —CRZ═;
      • —RZ is independently —H or —RZZ;
      • —RZZ is independently saturated aliphatic C1-4alkyl, —OH, or —F;
        wherein:
      • each —X is independently —Cl or —Br;
      • each —RA is independently saturated aliphatic C1-6alkyl; and
      • each —RC is independently saturated C3-7cycloalkyl.
  • In a further embodiment of the above, —RZZ is independently saturated aliphatic C1-4alkyl.
  • Similarly, for example, one preferred group of compounds (e.g., compounds for use in therapy, use of compounds in the manufacture of a medicament, methods of treatment, etc.) are selected from compounds of the following formula, and pharmaceutically acceptable salts, hydrates, and solvates thereof:
  • Figure US20120149737A1-20120614-C00438
  • wherein:
      • —R1 is independently —O—RA;
      • —R2 is independently —O—RA;
      • —R3 is independently —X;
      • or:
      • —R1 is independently —X;
      • —R2 is independently —O—RA;
      • —R3 is independently —O—RA;
        wherein:
      • —Z═ is —CRZ═;
      • —RZ is independently —H or —RZZ;
      • —RZZ is independently saturated aliphatic C1-4alkyl, —OH, or —F;
        wherein:
      • each —X is independently —Cl or —Br; and
      • each —RA is independently saturated aliphatic C1-6alkyl.
  • In a further embodiment of the above, —RZZ is independently saturated aliphatic C1-4alkyl.
  • Similarly, for example, one preferred group of compounds (e.g., compounds for use in therapy, use of compounds in the manufacture of a medicament, methods of treatment, etc.) are selected from compounds of the following formula, and pharmaceutically acceptable salts, hydrates, and solvates thereof:
  • Figure US20120149737A1-20120614-C00439
  • wherein:
      • —R1 is independently —O—RA;
      • —R2 is independently —O—RA;
      • —R3 is independently —X;
      • or:
      • —R1 is independently —X;
      • —R2 is independently —O—RA;
      • —R3 is independently —O—RA;
        wherein:
      • —Z═ is —CRZ═;
      • —RZ is independently —H or —RZZ;
      • —RZZ is independently -Me, —OH, or —F;
        wherein:
      • each —X is independently —Cl; and
      • each —RA is independently saturated aliphatic C1-4alkyl.
  • In a further embodiment of the above, —RZZ is independently -Me.
  • The foregoing has described the principles, preferred embodiments, and modes of operation of the present invention. However, the invention should not be construed as limited to the particular embodiments discussed. Instead, the above-described embodiments should be regarded as illustrative rather than restrictive, and it should be appreciated that variations may be made in those embodiments by workers skilled in the art without departing from the scope of the present invention.
    • REFERENCES
  • A number of patents and publications are cited herein in order to more fully describe and disclose the invention and the state of the art to which the invention pertains. Full citations for these references are provided below. Each of these references is incorporated herein by reference in its entirety into the present disclosure, to the same extent as if each individual reference was specifically and individually indicated to be incorporated by reference.
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Claims (31)

1-154. (canceled)
155. A compound of the following formula, or a pharmaceutically acceptable salt thereof:
Figure US20120149737A1-20120614-C00440
wherein:
—R1 is independently —X, —RX, —O—RX, —O—RA, —O—RC, —O-L-RC, —O—RAR, or —O-L-RAR;
—R2 is independently —X, —RX, —O—RX, —O—RA, —O—RC, —O-L-RC, —O—RAR, or —O-L-RAR;
—R3 is independently —X, —RX, —O—RX, —O—RA, —O—RC, —O-L-RC, —O—RAR, or —O-L-RAR;
with the proviso that —R1, —R2, and —R3 are not all —O—RA;
wherein:
each —X is independently —F, —Cl, —Br, or —I;
each —RA is saturated aliphatic C1-6alkyl;
each —RX is saturated aliphatic C1-6haloalkyl;
each —RC is saturated C3-7cycloalkyl;
each —RAR is phenyl or C5-6heteroaryl;
each -L- is saturated aliphatic C1-3alkylene;
and wherein:
-J- is —C(═O)—NRN—;
—RN is independently —H or —H or —RNN;
—RNN is saturated aliphatic C1-4alkyl;
═Y— is ═CRY— and —Z═ is —CRZ═;
—RY is —H;
—RZ is independently —H or —RZZ;
—RZZ is independently —F, —Cl, —Br, —I, —OH, saturated aliphatic C1-4alkoxy, saturated aliphatic C1-4alkyl, or saturated aliphatic C1-4haloalkyl;
═W— is ═CRW—;
—RW is —H;
—RO is independently —OH, —ORE, —NH2, —NHRT1, —NRT1RT1 or —NRT2RT3;
—RE is saturated aliphatic C1-6alkyl;
each —RT1 is saturated aliphatic C1-6alkyl;
—NRT2RT3 is independently azetidino, pyrrolidino, piperidino, piperizino, N—(C1-3alkyl) piperizino, or morpholino;
with the proviso that the compound is not a compound selected from the following compounds, and salts, hydrates, and solvates thereof:
4-(3,5-dichloro-4-ethoxy-benzoylamino)-benzoic acid (PP-02); and
4-(3,5-dichloro-4-methoxy-benzoylamino)-benzoic acid (PP-03).
156. A compound according to claim 155, wherein:
—R1 is independently —X, —RX, —O—RX, —O—RA, —O—RC, or —O-L-RC;
—R2 is independently —O—RA, —O—RC, or —O-L-RC; and
—R3 is independently —X, —RX, —O—RX, —O—RA, —O—RC, or —O-L-RC;
with the proviso that —R1, —R2, and —R3 are not all —O—RA.
157. A compound according to claim 155, wherein:
—R1 is independently —X, —RX, —O—RA, —O—RC, or —O-L-RC;
—R2 is independently —O—RA, —O—RC, or —O-L-RC; and
—R3 is independently —X, —RX, —O—RA, —O—RC, or —O-L-RC;
with the proviso that —R1, —R2, and —R3 are not all —O—RA.
158. A compound according to claim 155, wherein:
—R1 is independently —X or —RX;
—R2 is independently —O—RA, —O—RC, or —O-L-RC; and
—R3 is independently —X or —RX.
159. A compound according to claim 155, wherein:
—R1 is —X;
—R2 is independently —O—RA, —O—RC, or —O-L-RC; and
—R3 is —X.
160. A compound according to claim 155, wherein:
—R1 is —X;
—R2 is independently —O—RA or —O—RC; and
—R3 is —X.
161. A compound according to claim 155, wherein:
—R1 is independently —O—RA, —O—RC, or —O-L-RC;
—R2 is independently —O—RA, —O—RC, or —O-L-RC; and
—R3 is independently —X or —RX;
or:
—R1 is independently —X or —RX;
—R2 is independently —O—RA, —O—RC, or —O-L-RC; and
—R3 is independently —O—RA, —O—RC, or —O-L-RC.
162. A compound according to claim 155, wherein:
—R1 is independently —O—RA or —O—RC;
—R2 is independently —O—RA or —O—RC; and
—R3 is independently —X or —RX;
or:
—R1 is independently —X or —RX;
—R2 is independently —O—RA or —O—RC; and
—R3 is independently —O—RA or —O—RC.
163. A compound according to claim 155, wherein:
—R1 is —O—RA;
—R2 is —O—RA; and
—R3 is independently —X or —RX;
or:
—R1 is independently —X or —RX;
—R2 is —O—RA; and
—R3 is —O—RA.
164. A compound according to claim 155, wherein:
—R1 is independently —O—RA, —O—RC, or —O-L-RC;
—R2 is independently —O—RA, —O—RC, or —O-L-RC; and
—R3 is —X;
or:
—R1 is —X;
—R2 is independently —O—RA, —O—RC, or —O-L-RC; and
—R3 is independently —O—RA, —O—RC, or —O-L-RC.
165. A compound according to claim 155, wherein:
—R1 is independently —O—RA or —O—RC;
—R2 is independently —O—RA or —O—RC; and
—R3 is —X;
or:
—R1 is —X;
—R2 is independently —O—RA or —O—RC; and
—R3 is independently —O—RA or —O—RC.
166. A compound according to claim 155, wherein:
—R1 is independently —O—RA;
—R2 is independently —O—RA; and
—R3 is —X;
or:
—R1 is —X;
—R2 is independently —O—RA; and
—R3 is independently —O—RA.
167. A compound according to claim 155, wherein:
each —X is independently —F, —Cl, or —Br;
each —RA is saturated aliphatic C1-4alkyl;
each —RX is —CF3;
each —RC is independently cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl;
each —RAR is independently phenyl, pyridinyl, pyrimidinyl, or pyridizinyl; and
each -L- is independently —CH2— or —CH2CH2—.
168. A compound according to claim 155, wherein:
—RZZ is independently —F, —Cl, —OH, or -Me;
—RN is —H; and
—RO is —OH.
169. A compound according to claim 156, wherein:
—RZZ is independently —F, —Cl, —OH, or -Me;
—RN is —H; and
—RO is —OH.
170. A compound according to claim 157, wherein:
—RZZ is independently —F, —Cl, —OH, or -Me;
—RN is —H; and
—RO is —OH.
171. A compound according to claim 158, wherein:
—RZZ is independently —F, —Cl, —OH, or -Me;
—RN is —H; and
—RO is —OH.
172. A compound according to claim 159, wherein:
—RZZ is independently —F, —Cl, —OH, or -Me;
—RN is —H; and
—RO is —OH.
173. A compound according to claim 160, wherein:
—RZZ is independently —F, —Cl, —OH, or -Me;
—RN is —H; and
—RO is —OH.
174. A compound according to claim 161, wherein:
—RZZ is independently —F, —Cl, —OH, or -Me;
—RN is —H; and
—RO is —OH.
175. A compound according to claim 162, wherein:
—RZZ is independently —F, —Cl, —OH, or -Me;
—RN is —H; and
—RO is —OH.
176. A compound according to claim 163, wherein:
—RZZ is independently —F, —Cl, —OH, or -Me;
—RN is —H; and
—RO is —OH.
177. A compound according to claim 164, wherein:
—RZZ is independently —F, —Cl, —OH, or -Me;
—RN is —H; and
—RO is —OH.
178. A compound according to claim 165, wherein:
—RZZ is independently —F, —Cl, —OH, or -Me;
—RN is —H; and
—RO is —OH.
179. A compound according to claim 166, wherein:
—RZZ is independently —F, —Cl, —OH, or -Me;
—RN is —H; and
—RO is —OH.
180. A compound according to claim 167, wherein:
—RZZ is independently —F, —Cl, —OH, or -Me;
—RN is —H; and
—RO is —OH.
181. A compound according to claim 155, which is selected from the following compounds, or a pharmaceutically acceptable salt thereof:
Figure US20120149737A1-20120614-C00441
Figure US20120149737A1-20120614-C00442
Figure US20120149737A1-20120614-C00443
Figure US20120149737A1-20120614-C00444
Figure US20120149737A1-20120614-C00445
Figure US20120149737A1-20120614-C00446
Figure US20120149737A1-20120614-C00447
Figure US20120149737A1-20120614-C00448
Figure US20120149737A1-20120614-C00449
Figure US20120149737A1-20120614-C00450
Figure US20120149737A1-20120614-C00451
Figure US20120149737A1-20120614-C00452
Figure US20120149737A1-20120614-C00453
Figure US20120149737A1-20120614-C00454
Figure US20120149737A1-20120614-C00455
Figure US20120149737A1-20120614-C00456
182. A composition comprising a compound according to claim 155, and a pharmaceutically acceptable carrier, diluent, or excipient.
183. A method of preparing a composition comprising admixing a compound according to claim 155 and a pharmaceutically acceptable carrier, diluent, or excipient.
184. A method of 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 comprising administering to a subject in need of treatment a therapeutically-effective amount of a compound according to claim 155.
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US20160039747A1 (en) 2016-02-11
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AU2010291056A1 (en) 2012-03-15
IL218137A (en) 2016-06-30
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JP2013503819A (en) 2013-02-04
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IL218137A0 (en) 2012-06-28
SG178480A1 (en) 2012-04-27

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