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US20190010129A1 - Amide derivatives as lysophosphatidic acid receptor antagonists - Google Patents

Amide derivatives as lysophosphatidic acid receptor antagonists Download PDF

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Publication number
US20190010129A1
US20190010129A1 US15/999,570 US201815999570A US2019010129A1 US 20190010129 A1 US20190010129 A1 US 20190010129A1 US 201815999570 A US201815999570 A US 201815999570A US 2019010129 A1 US2019010129 A1 US 2019010129A1
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Prior art keywords
methyl
benzamido
benzoic acid
cyclopropylmethyl
fluorophenoxy
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US15/999,570
Inventor
William BUFFHAM
Hannah CANNING
Richard Davenport
William FARNABY
Stephen MACK
Alka PARMAR
Susanne WRIGHT
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Takeda Pharmaceutical Co Ltd
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Takeda Pharmaceutical Co Ltd
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Priority to US15/999,570 priority Critical patent/US20190010129A1/en
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Abandoned legal-status Critical Current

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    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more 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, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/34—One oxygen atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
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    • A61K31/275—Nitriles; Isonitriles
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
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    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
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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
    • C07C235/46—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 atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
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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
    • C07C235/52—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 an acyclic carbon atom of a hydrocarbon radical substituted by carboxyl groups
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C255/54—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and etherified hydroxy groups bound to the carbon skeleton
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/04—Systems containing only non-condensed rings with a four-membered ring

Definitions

  • the present invention relates to amide derivatives, processes for their preparation, pharmaceutical compositions containing them and their use in therapy, particularly as lysophosphatidic acid receptor antagonists.
  • Lysophosphatidic acid is a bioactive lipid mediator that interacts with G protein-coupled transmembrane LPA receptors to affect fundamental cellular functions including proliferation, differentiation, survival, migration, adhesion, invasion and morphogenesis.
  • LPA low affinity cognate LPA receptors
  • All known LPA receptors are type 1, rhodopsin-like G protein-coupled receptors (GPCRs) that differ in their tissue distribution and downstream signalling pathways.
  • LPAR1 was the first high affinity LPA receptor identified.
  • LPAR 1 is one of the Endothelial Differentiation Gene (EDG) LPA receptors.
  • EDG Endothelial Differentiation Gene
  • the LPAR1 gene is widely expressed in adult mice, with presence demonstrated in brain, uterus, testis, lung, small intestine, heart, stomach, kidney, spleen, thymus, placenta and skeletal muscle. Expression is also widespread in humans.
  • LPAR 1 couples with and activates G ⁇ i/o, G ⁇ q/11 and G ⁇ 12/13 G proteins to induce a range of cellular responses.
  • Studies with mice lacking functional LPA1 receptor alleles have implicated LPAR1 in the development of pulmonary fibrosis and neuropathic pain. Intrathecal injection of LPA causes allodynia, hyperalgesia and demyelination of the dorsal root in a LPAR1-dependent manner.
  • LPAR2 has approximately 60% amino acid homology to LPAR1 and in mouse is expressed in kidney, uterus, testis and lung with lower levels of expression in stomach, spleen, thymus brain and heart. In human tissues high expression is detected in testis and leukocytes and moderate expression in prostate, spleen, thymus and pancreas. LPAR2 couples with G ⁇ i/o, G ⁇ q/11 and G ⁇ 12/13 G proteins with signalling associated with processes such as cell survival and cell migration which makes LPAR2 a potential factor for cancer metastasis. In cancer cells, aberrant expression of LPAR2 has been reported, suggesting a tumour promoting role.
  • LPAR3 has been seen in human heart, testis, prostate, pancreas, lung, ovary and brain and most abundantly in mouse testis, kidney, lung, small intestine, heart, stomach, spleen, brain and thymus. LPAR3 is able to couple with G ⁇ i/o, G ⁇ q/11 to and is also a potential factor for cancer metastasis.
  • LPA receptors 4, 5 and 6 constitute the non-EDG family of LPA receptors.
  • LPAR4 P2Y9/GPR23
  • P2Y9/GPR23 P2Y purinoreceptors.
  • LPAR4 appears to be broadly expressed in humans with particular abundance in ovary, and is present in mouse heart, skin, thymus and ovary. As with other LPA receptors this GPCR can signal via several pathways, namely G ⁇ s, G ⁇ i, G ⁇ q/11 and G ⁇ 12/13.
  • LPAR5 is located on chromosome 12p13.31 and encodes an approximately 41 kDa protein. LPAR5 is broadly expressed in murine tissues such as small intestine, skin, spleen, stomach, thymus, lung, heart, liver, bladder urothelium, dorsal root ganglion and spinal cord. LPA induces neurite retraction and stress fibre formation in LPAR5-expressing cells through coupling to G ⁇ 12/13 and is also able to activate G ⁇ s and G ⁇ q/11.
  • LPAR5 can be activated by ligands other than LPA, namely endogenous by-products of cholesterol synthesis such as farnesyl pyrophosphate (FPP) and N-arachidonylglycine (NAG). Activation of GPR92/LPAR5 by FPP increases inositol phosphate production, cAMP levels, and Ca 2+ levels in a concentration-dependent manner.
  • FPP farnesyl pyrophosphate
  • NAG N-arachidonylglycine
  • LPAR5 knock-out mice display a urological phenotype consistent with changes in sensory signalling.
  • LPA causes aggregation of human platelets at concentrations that are present in atheromatous legions; LPAR5 has been shown to have an intrinsic role in this process.
  • P2Y5 was named as the sixth LPA receptor. This member of the purinergic receptor family is more closely related to LPAR4 and 5 than LPA1-3. This receptor has been identified as a critical mediator of human hair growth.
  • EP-A-1,553,075 discloses LPA receptor antagonists of general formula
  • R represents an aliphatic hydrocarbon group which may be substituted, or a cyclic group which may have a substituent(s);
  • G represents a bond or a spacer having from 1 to 8 atoms in its principle chain;
  • T represents —CH 2 —, or a spacer having one atom in its principle chain, the principle chain containing a hydrogen bond acceptable group which may have a substituent(s);
  • J represents a nitrogen atom or a carbon atom;
  • B represents an aliphatic hydrocarbon group which may be substituted, or a cyclic group which may have a substituent(s);
  • K represents (1) a bond, or (2) a spacer having from 1 to 8 atoms in its principle chain which may form a ring together with a substituent of the cyclic group in R, the ring D or a substituent on the ring D;
  • Q represents (1) a bond, or (2) a spacer having from 1 to 8 atoms in its principle chain which may form a ring together
  • EP-A-2,481,725 discloses LPA receptor antagonists of general formula
  • A is an aryl which may be substituted or a hetero ring group which may be substituted
  • B is a 5-membered aromatic hetero ring group which may be substituted
  • X is a single bond or —(CR X1 R X2 ) n —, n is 1, 2, 3 or 4
  • R X1 and R X2 are the same or different from each other, and are H, halogen, OH, —O-(lower alkyl which may be substituted), or lower alkyl which may be substituted, or R X1 and R X2 are combined with each other to form oxo ( ⁇ O), or R X1 and R X2 are combined with each other to form C 2-5 alkylene which may be substituted, in which when n is 2, 3 or 4, R X1 may be combined with adjacent R X1 to form a new bond, Y 1 , Y 2 , Y 3 , Y 4 and Y 5 are the same as or different from each other, and
  • EP-A-1,229,034 describes certain amide derivatives as PDE4 inhibitors for treating respiratory diseases and US 2004/0176446 describes certain amide derivatives for use in treating cardiovascular disorders.
  • LPA5-antagonist 4 has been published by Sanofi-Aventis (Kozian et al, 2012, Bioorg Med Chem Lett., 22(16):5239-43) and is reported to be of low potency against LPAR5 (0.8 ⁇ M).
  • R 5 and R 6 each independently represent a hydrogen atom or a C 1 -C 6 alkyl group, or
  • R 5 and R 6 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocycle
  • R 7 and R 8 each independently represent a hydrogen atom or a C 1 -C 6 alkyl group, or
  • R 7 and R 8 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocycle
  • R 15 and R 16 each independently represent a hydrogen atom or a C 1 -C 6 alkyl group, or R 15 and R 16 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocycle;
  • the compounds of the invention have been found to possess dual LPAR5/LPAR1 antagonist properties. Such dual antagonist properties would be expected to be particularly beneficial in the treatment of conditions such as fibrosis.
  • an “alkyl” or “alkenyl” substituent group or an “alkyl” or “alkenyl” moiety in a substituent group may be linear or branched.
  • Examples of C 1 -C 8 alkyl groups/moieties include methyl, ethyl, propyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, tert-butyl, n-pentyl
  • C 2 -C 8 alkenyl groups/moieties include ethenyl, propenyl, 1-butenyl, 2-butenyl, 1-pentenyl, 1-hexenyl, 1,3-butadienyl, 1,3-pentadienyl, 1,4-pentadienyl and 1-hexadienyl.
  • a “C 1 -C 6 haloalkyl” or “C 1 -C 6 haloalkoxy” substituent group/moiety will comprise at least one halogen atom, e.g. one, two, three, four or five halogen atoms, examples of which include trifluoromethyl, trifluoromethoxy or pentafluoroethyl.
  • a “C 1 -C 6 hydroxyalkyl” substituent group/moiety will comprise at least one hydroxyl group, e.g. one, two, three or four hydroxyl groups, examples of which include —CH 2 OH, —CH 2 CH 2 OH, —CH 2 CH 2 CH 2 OH, —CH(OH)CH 2 OH, —CH(CH 3 )OH and —CH(CH 2 OH) 2 .
  • a “cycloalkyl” substituent group/moiety is a saturated hydrocarbyl ring containing, for example, from 3 to 8 carbon atoms, examples of which include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • aryl is intended to mean any stable monocyclic or bicyclic aromatic hydrocarbon system containing up to 10 carbon atoms, e.g. from 5 to 10 carbon atoms, such as phenyl or naphthyl.
  • the saturated or unsaturated 5- to 6-membered ring which may comprise at least one ring heteroatom independently selected from nitrogen, oxygen and sulphur may have alicyclic or aromatic properties.
  • An unsaturated ring will be partially or fully unsaturated. Similar comments apply to the saturated or unsaturated 3- to 10-membered ring systems defined in R 3 . In either case, it should be understood that the invention does not encompass any unstable ring structures or any O—O, O—S or S—S bonds and that a substituent, if present, may be attached to any suitable ring atom.
  • R 5 and R 6 , R 7 and R 8 , R 13 and R 14 , R 15 and R 16 or R 18 and R 19 represents a 4- to 7-membered saturated heterocycle
  • the heterocycle may contain one or more further heteroatoms (e.g. nitrogen, oxygen or sulphur atoms) in addition to the nitrogen atom to which R 5 and R 6 , R 7 and R 8 , R 13 and R 14 , R 15 and R 16 or R 18 and R 19 are attached.
  • R 1 represents a C 5 -C 10 or C 5 -C 6 aryl group substituted by at least one substituent, e.g. one, two, three or four substituents, independently selected from
  • the at least one substituent in R 1 is preferably attached in an ortho position relative to the point of attachment of R 1 to X.
  • R 1 is phenyl
  • the preferred carbon atoms to which a substituent is attached are shown by the asterisks in the structure below:
  • R 1 represents a C 5 -C 6 aryl (preferably phenyl) group substituted by at least one substituent, e.g. one, two, three or four substituents, independently selected from
  • R 1 represents a C 5 -C 6 aryl group substituted by one or two substituents independently selected from
  • R 1 represents a phenyl group substituted by one or two substituents independently selected from
  • R 1 represents fluorophenyl (in particular 2-fluorophenyl), chlorophenyl (in particular 2-chlorophenyl or 3-chlorophenyl), difluorophenyl (in particular 2,6-difluorophenyl), chlorofluorophenyl (in particular 2-chloro-6-fluorophenyl), fluoromethylphenyl (in particular 2-fluoro-6-methylphenyl), methylphenyl (in particular 2-methylphenyl), dimethylphenyl (in particular 2,6-dimethylphenyl), cyanophenyl (in particular 2-cyanophenyl), trifluoromethylphenyl (in particular 2-trifluoromethylphenyl), methoxyphenyl (e.g.
  • X represents an oxygen atom or a group —CH 2 —, —OCH 2 — or —CH 2 O—.
  • X represents an oxygen atom or —CH 2 O— (where it will be understood that the oxygen atom is attached to the ring A in formula (I)).
  • X represents an oxygen atom
  • X represents —CH 2 O—.
  • X represents —CH 2 NR 17 —, in particular —CH 2 NH—.
  • each R 2 independently represents a halogen atom (e.g. fluorine, chlorine, bromine or iodine) or a hydroxyl, C 1 -C 6 , or C 1 -C 4 , or C 1 -C 2 alkyl, difluoromethyl, trifluoromethyl, C 1 -C 6 , or C 1 -C 4 , or C 1 -C 2 alkoxy, difluoromethoxy, trifluoromethoxy or NR 15 R 16 group.
  • R 2 represents a halogen atom (particularly fluorine) or a C 1 -C 6 , or C 1 -C 4 , or C 1 -C 2 alkyl (particularly methyl) group.
  • m is 1 and R 2 represents a halogen atom (particularly fluorine).
  • m is 2 and each R 2 independently represents a C 1 -C 6 , or C 1 -C 4 , or C 1 -C 2 alkyl (particularly methyl) group.
  • n is 0 and the ring A has no R 2 substituents.
  • Y represents CH 2 or CH(CH 3 ), preferably CH 2 .
  • R 3 represents C 1 -C 8 , or C 1 -C 6 , or C 1 -C 4 , or C 1 -C 2 alkyl, C 2 -C 8 , or C 2 -C 6 , or
  • C 2 -C 4 alkenyl or a saturated or unsaturated 3- to 10-membered (e.g. 3-, 4-, 5- or 6- to 7-, 8-, 9- or 10-membered) ring system which may comprise at least one ring heteroatom (e.g. one, two, three or four ring heteroatoms) independently selected from nitrogen, oxygen and sulphur, each of the preceding groups being optionally substituted by at least one substituent (e.g. one, two, three or four substituents) independently selected from
  • saturated or unsaturated 3- to 10-membered ring systems which may be monocyclic or polycyclic (e.g. bicyclic) in which the two or more rings may be fused, bridged or Spiro include one or more (in any combination) of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[2.2.1]heptyl, cyclopentenyl, cyclohexenyl, phenyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, oxadiazolyl (e.g.
  • 1,2,4-oxadiazolyl 1,2,4-oxadiazolyl
  • tetrahydrofuranyl diazabicyclo[2.2.1]hept-2-yl
  • naphthyl benzofuranyl, benzothienyl, benzodioxolyl, benzoxazolyl, quinolinyl, oxazolyl, thiadiazolyl
  • 1,2,3-thiadiazolyl 2,3-dihydrobenzofuranyl, tetrahydropyranyl, pyrazolyl, imidazo[1,2-a]pyridinyl, pyrazinyl, thiazolidinyl, indanyl, thienyl, isoxazolyl, pyridazinyl, pyrrolyl, furanyl, thiazolyl, isothiazolyl, indolyl, isoindolyl, imidazolyl, pyrimidinyl, benzimidazolyl, triazolyl, tetrazolyl and pyridinyl.
  • Preferred ring systems include phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and thienyl.
  • R 3 represents C 1 -C 4 , or C 1 -C 3 , or C 1 -C 2 alkyl
  • C 2 -C 4 alkenyl or a saturated or unsaturated 3-, 4-, 5- or 6-membered ring system which may comprise at least one ring heteroatom (e.g. one, two, three or four ring heteroatoms) independently selected from nitrogen, oxygen and sulphur, each of the preceding groups being optionally substituted by at least one substituent (e.g. one, two, three or four substituents) independently selected from
  • R 3 represents C 1 -C 4 , or C 1 -C 3 , or C 1 -C 2 alkyl, C 2 -C 4 alkenyl, or a saturated or unsaturated 3-, 4-, 5- or 6-membered hydrocarbyl ring system (e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or phenyl), each of the preceding groups being optionally substituted by at least one substituent (e.g. one, two, three or four substituents) independently selected from
  • R 3 represents C 1 -C 4 , or C 1 -C 3 , or C 1 -C 2 alkyl, or a saturated or to unsaturated 3-, 4-, 5- or 6-membered hydrocarbyl ring system (e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or phenyl), each of the preceding groups being optionally substituted by at least one substituent (e.g. one, two, three or four substituents) independently selected from
  • R 3 represents C 1 -C 4 , or C 1 -C 3 , or C 1 -C 2 alkyl, cyclopropyl, cyclobutyl or phenyl, each of the preceding groups being optionally substituted by at least one substituent (e.g. one, two, three or four substituents) independently selected from
  • R 3 represents any one of the following moieties or is selected from a group containing any two or more of such moieties:
  • Z represents CH 2 or CH(CH 3 ), preferably CH 2 .
  • each R 4 independently represents a halogen atom (e.g. fluorine, chlorine, bromine or iodine) or a hydroxyl, C 1 -C 6 , or C 1 -C 4 , or C 1 -C 2 alkyl, difluoromethyl, trifluoromethyl, C 1 -C 6 , or C 1 -C 4 , or C 1 -C 2 alkoxy, difluoromethoxy, trifluoromethoxy or NR 18 R 19 group.
  • halogen atom e.g. fluorine, chlorine, bromine or iodine
  • n is 1 and R 4 represents a halogen atom (particularly fluorine) or a C 1 -C 6 , or C 1 -C 4 , or C 1 -C 2 alkyl (particularly methyl) or a C 1 -C 6 , or C 1 -C 4 , or C 1 -C 2 alkoxy (particularly methoxy) group.
  • R 4 represents a halogen atom (particularly fluorine) or a C 1 -C 6 , or C 1 -C 4 , or C 1 -C 2 alkyl (particularly methyl) or a C 1 -C 6 , or C 1 -C 4 , or C 1 -C 2 alkoxy (particularly methoxy) group.
  • n is 0 and the ring B has no R 4 substituents.
  • R 5 and R 6 each independently represent a hydrogen atom or a C 1 -C 6 , or C 1 -C 4 , or C 1 -C 2 alkyl group, or R 5 and R 6 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocycle (e.g. pyrrolidinyl, morpholinyl, piperazinyl or piperidinyl).
  • a 4- to 7-membered saturated heterocycle e.g. pyrrolidinyl, morpholinyl, piperazinyl or piperidinyl.
  • R 7 and R 8 each independently represent a hydrogen atom or a C 1 -C 6 , or C 1 -C 4 , or C 1 -C 2 alkyl group, or R 7 and R 8 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocycle (e.g. pyrrolidinyl, morpholinyl, piperazinyl or piperidinyl).
  • a 4- to 7-membered saturated heterocycle e.g. pyrrolidinyl, morpholinyl, piperazinyl or piperidinyl.
  • R 13 and R 14 each independently represent a hydrogen atom or a C 1 -C 6 , or C 1 -C 4 , or C 1 -C 2 alkyl group, or R 13 and R 14 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocycle (e.g. pyrrolidinyl, morpholinyl, piperazinyl or piperidinyl).
  • a 4- to 7-membered saturated heterocycle e.g. pyrrolidinyl, morpholinyl, piperazinyl or piperidinyl.
  • R 15 and R 16 each independently represent a hydrogen atom or a C 1 -C 6 , or C 1 -C 4 , or C 1 -C 2 alkyl group, or R 15 and R 16 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocycle (e.g. pyrrolidinyl, morpholinyl, piperazinyl or piperidinyl).
  • a 4- to 7-membered saturated heterocycle e.g. pyrrolidinyl, morpholinyl, piperazinyl or piperidinyl.
  • R 17 represents a hydrogen atom or a C 1 -C 6 , or C 1 -C 4 , or C 1 -C 2 alkyl (particularly methyl or ethyl) group, especially a hydrogen atom.
  • R 18 and R 19 each independently represent a hydrogen atom or a C 1 -C 6 , or C 1 -C 4 , or C 1 -C 2 alkyl group, or R 18 and R 19 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocycle (e.g. pyrrolidinyl, morpholinyl, piperazinyl or piperidinyl).
  • a 4- to 7-membered saturated heterocycle e.g. pyrrolidinyl, morpholinyl, piperazinyl or piperidinyl.
  • Rings A and B each independently represent a saturated or unsaturated 5-, 6-, 7-, 8-, 9- or 10-membered ring system which may comprise at least one ring heteroatom (e.g. one, two, three or four heteroatoms) independently selected from nitrogen, oxygen and sulphur.
  • ring heteroatom e.g. one, two, three or four heteroatoms
  • saturated or unsaturated 5- to 10-membered ring systems which may be monocyclic or polycyclic (e.g. bicyclic) in which the two or more rings are fused include one or more (in any combination) of cyclopentyl, cyclohexyl, cyclopentenyl, cyclohexenyl, phenyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, oxadiazolyl (e.g.
  • 1,2,4-oxadiazolyl 1,2,4-oxadiazolyl
  • tetrahydrofuranyl naphthyl
  • benzofuranyl benzothienyl
  • benzodioxolyl benzoxazolyl
  • quinolinyl oxazolyl
  • thiadiazolyl e.g.
  • 1,2,3-thiadiazolyl 2,3-dihydrobenzofuranyl, tetrahydropyranyl, pyrazolyl, imidazo[1,2-a]pyridinyl, pyrazinyl, thiazolidinyl, indanyl, thienyl, isoxazolyl, pyridazinyl, pyrrolyl, furanyl, thiazolyl, isothiazolyl, indolyl, isoindolyl, imidazolyl, pyrimidinyl, benzimidazolyl, triazolyl, tetrazolyl and pyridinyl.
  • Preferred ring systems include 5- or 6-membered ring systems such as phenyl, pyridinyl, pyrimidinyl, thienyl and cyclohexyl.
  • ring A is selected from phenyl, pyridinyl, pyrimidinyl, thienyl and cyclohexyl. Examples of ring A showing the points of attachment of R 1 —X—, R 2 and C(O) to the ring are shown below:
  • ring B is selected from phenyl, thienyl and cyclohexyl. Examples of ring B showing the points of attachment of Z, R 4 and C(O)OH to the ring are shown below:
  • rings A and B are both phenyl.
  • Examples of compounds of the invention include:
  • the present invention further provides a process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined above which comprises hydrolysing a compound of formula (II)
  • L 1 represents a leaving group (e.g. alkoxy such as methoxy) and R 1 , X, m, R 2 , Y, R 3 , Z, n, R 4 , A and B are as defined in formula (I), in the presence of a suitable base; and optionally thereafter carrying out one or more of the following procedures:
  • the process is conveniently carried out using a base such as lithium hydroxide or sodium hydroxide in a solvent such as 1,4-dioxane or a solvent mixture such as water and tetrahydrofuran, at room temperature or at elevated temperature, e.g. in the range from 20° C. to 100° C.
  • a base such as lithium hydroxide or sodium hydroxide
  • a solvent such as 1,4-dioxane or a solvent mixture such as water and tetrahydrofuran
  • R 1 , X, m, R 2 and A are as defined in formula (II), with a compound of formula (IV), or a salt (e.g. hydrochloride salt) thereof,
  • L 1 , Y, R 3 , Z, n, R 4 and B are as defined in formula (II).
  • the reaction is conveniently carried out in the presence of an organic solvent such as tetrahydrofuran or N,N-dimethylformamide, a base such as diisopropylethylamine and an amide coupling agent such as 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) or O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HBTU).
  • an organic solvent such as tetrahydrofuran or N,N-dimethylformamide
  • a base such as diisopropylethylamine
  • Suitable oxidising agents include sodium chlorite.
  • L 2 represents a leaving group (e.g. a halogen atom such as fluorine) and m, R 2 and A are as defined in formula (V).
  • a leaving group e.g. a halogen atom such as fluorine
  • L 3 represents a leaving group (e.g. a halogen atom such as bromine)
  • P 1 represents a suitable protecting group (e.g. an alkoxy group such as methoxy) and m
  • R 2 and A are as defined in formula (III)
  • R 1 is as defined in formula (III)
  • a suitable palladium catalyst e.g. [1,1′-bis(diphenylphosphino)ferrocene]palladium(11) chloride complex with dichloromethane (see, for example, WO 2012/080221 in the name of Katholieke Universiteit Leuven), followed by ester hydrolysis.
  • Compounds of formula (III) in which X represents —OCH 2 — may be prepared by reacting a compound of formula (VIII) as defined above with a compound of formula (XII), R 1 —X′H, wherein R 1 and X′ are as defined in formula (VI), in the presence of a base such as potassium carbonate and in a solvent such as N,N-dimethylformamide (see, for example, WO 2012/007868 in the name of Pfizer Limited), followed by ester hydrolysis.
  • a base such as potassium carbonate
  • a solvent such as N,N-dimethylformamide
  • Compounds of formula (V) in which X represents —CH 2 NR 17 may be prepared by reacting a compound of formula (VII) as defined above with a compound of formula (XIII), R 1 —CH 2 NR 17 H, in which R 1 and R 17 are as defined in formula (V), in the presence of a suitable copper catalyst such as copper (I) iodide (see, for example, Kwong et al., Organic Letters, 2002, volume 4, pages 581 to 584).
  • a suitable copper catalyst such as copper (I) iodide
  • Compounds of formula (III) in which X represents —NR 17 CH 2 — may be prepared by reacting a compound of formula (VIII) as defined above with a compound of formula (XIV), R 1 —NR 17 H, wherein R 1 and R 17 are as defined in formula (III), in the presence of a base such as calcium carbonate and a solvent such as iosbutyramide (see, for example, WO 2007/120096 in the names of AstraZeneca AB and Astex Therapeutics Limited), followed by ester hydrolysis.
  • a base such as calcium carbonate
  • a solvent such as iosbutyramide
  • R 20 represents hydrogen or methyl
  • L 1 , n, R 4 and B are as defined in formula (IV)
  • a reducing agent such as sodium triacetoxyborohydride
  • the preparation of the compounds of formula (I) may involve, at an appropriate stage, the introduction and/or removal of one or more protecting groups.
  • the compounds of formula (I) above may be converted to a pharmaceutically acceptable salt thereof, preferably an acid addition salt such as a hydrochloride, hydrobromide, benzenesulphonate (besylate), saccharin (e.g. monosaccharin), trifluoroacetate, sulphate, nitrate, phosphate, acetate, fumarate, maleate, tartrate, lactate, citrate, pyruvate, succinate, valerate, propanoate, butanoate, malonate, oxalate, 1-hydroxy-2-napthoate (xinafoate), methanesulphonate or p-toluenesulphonate salt.
  • an acid addition salt such as a hydrochloride, hydrobromide, benzenesulphonate (besylate), saccharin (e.g. monosaccharin), trifluoroacetate, sulphate, nitrate, phosphate, acetate,
  • compounds of formula (I) may bear one or more radiolabels.
  • radiolabels may be introduced by using radiolabel-containing reagents in the synthesis of the compounds of formula (I), or may be introduced by coupling the compounds of formula (I) to chelating moieties capable of binding to a radioactive metal atom.
  • radiolabeled versions of the compounds may be used, for example, in diagnostic imaging studies.
  • any atom specified herein may also be an isotope of said atom.
  • hydrogen encompasses 1 H, 2 H and 3 H.
  • carbon atoms are to be understood to include 12 C, 13 C and 14 C
  • nitrogen atoms are to be understood to include 14 N and 15 N
  • oxygen atoms are to be understood to include 16 O, 17 O and 18 O.
  • compounds of formula (I) may be isotopically labelled.
  • an “isotopically labelled” compound is one in which the abundance of a particular nuclide at a particular atomic position within the molecule is increased above the level at which it occurs in nature.
  • Compounds of formula (I) and their salts may be in the form of hydrates or solvates which form an aspect of the present, invention.
  • Such solvates may be formed with common organic solvents, including but not limited to, alcoholic solvents e.g. methanol, ethanol or isopropanol.
  • Compounds of formula (I) and their salts may be amorphous or in a polymorphic form or a mixture of any of these, each of which forms an aspect of the present invention.
  • the compounds of formula (I) and their pharmaceutically acceptable salts have activity as pharmaceuticals, in particular as modulators (e.g. antagonists) of LPAR5 and, optionally also, as modulators (e.g. antagonists) of LPAR1, and thus may be used in the treatment of: fibrosis of organs such as liver, kidney, skin, lung, heart and the like; liver diseases (acute hepatitis, chronic hepatitis, liver fibrosis, liver cirrhosis, portal hypertension, regenerative failure, non-alcoholic steato hepatitis (NASH), liver hypofunction, hepatic blood flow disorder, and the like); cardiovascular disorders (restenosis, atherosclerosis, heart failure, cardiomyopathy, myocardial infarction, myocardial remodelling, vascular remodelling, hypertension, peripheral arterial occlusive disease, thrombosis, vascular permeability disorders, and the like); cell proliferative disease (cancer (solid tumour, solid tumour metastasis,
  • the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof as hereinbefore defined for use in therapy, in particular for the treatment of conditions whose development or symptoms are linked to LPAR5 or LPAR1 activity.
  • the present invention also provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof as hereinbefore defined for the preparation of a medicament for the treatment of conditions whose development or symptoms are linked to LPAR5 or LPAR1 activity.
  • the terms “therapy” and “treatment” also include “prophylaxis” unless there are specific indications to the contrary.
  • the terms “therapeutic”, “therapeutically” and “treating” should be construed accordingly.
  • Prophylaxis is expected to be particularly relevant to the treatment of persons who have suffered a previous episode of, or are otherwise considered to be at increased risk of, the disorder or condition in question.
  • Persons at risk of developing a particular disorder or condition generally include those having a family history of the disorder or condition, or those who have been identified by genetic testing or screening to be particularly susceptible to developing the disorder or condition or those in the prodromal phase of a disorder.
  • the compounds of the invention may be used in the treatment of pain (such as neuropathic pain), atherosclerosis and fibrosis.
  • Pain means the more or less localised sensation of discomfort, distress or agony resulting from the stimulation of specialised nerve endings. There are many types of pain (as illustrated above) and the goal of treatment of pain is to reduce the degree or severity of pain perceived by a treatment subject.
  • the invention also provides a method of treating pain (e.g. neuropathic pain), atherosclerosis or fibrosis which comprises administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof as hereinbefore defined.
  • pain e.g. neuropathic pain
  • atherosclerosis e.g. atherosclerosis or fibrosis
  • the daily dosage of the compound of the invention if inhaled, may be in the range from 0.05 micrograms per kilogram body weight ( ⁇ g/kg) to 100 micrograms per kilogram body weight ( ⁇ g/kg).
  • the daily dosage of the compound of the invention may be in the range from 0.01 micrograms per kilogram body weight ( ⁇ g/kg) to 100 milligrams per kilogram body weight (mg/kg).
  • the compounds of formula (I) and pharmaceutically acceptable salts thereof may be used on their own but will generally be administered in the form of a pharmaceutical composition in which the formula (I) compound/salt (active ingredient) is in association with a pharmaceutically acceptable adjuvant, diluent or carrier.
  • the present invention further provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof as hereinbefore defined, in association with a pharmaceutically acceptable adjuvant, diluent or carrier.
  • the invention still further provides a process for the preparation of a pharmaceutical composition of the invention which comprises mixing a compound of formula (I) or a pharmaceutically acceptable salt thereof as hereinbefore defined with a pharmaceutically acceptable adjuvant, diluent or carrier.
  • compositions of the invention are those conventionally employed in the field of pharmaceutical formulation, and include, but are not limited to, sugars, sugar alcohols, starches, ion exchangers, alumina, aluminium stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycerine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulphate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.
  • compositions of the present invention may be administered orally, topically, parenterally, by inhalation spray, rectally, nasally, buccally, vaginally or via an implanted reservoir. Oral or topical administration is preferred.
  • the pharmaceutical compositions of the invention may contain any conventional non-toxic pharmaceutically acceptable adjuvants, diluents or carriers.
  • parenteral as used herein includes subcutaneous, intracutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques.
  • the pharmaceutical compositions may be in the form of a sterile injectable preparation, for example, as a sterile injectable aqueous or oleaginous suspension.
  • the suspension may be formulated according to techniques known in the art using suitable dispersing or wetting agents (such as, for example, Tween 80) and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol.
  • suitable diluents and solvents that may be employed are mannitol, water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or diglycerides.
  • Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions.
  • These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant.
  • compositions of this invention may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, powders, granules, and aqueous suspensions and solutions. These dosage forms are prepared according to techniques well-known in the art of pharmaceutical formulation. In the case of tablets for oral use, carriers which are commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried corn starch. When aqueous suspensions are administered orally, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening and/or flavouring and/or colouring agents may be added.
  • compositions of the invention may also be administered in the form of suppositories for rectal administration.
  • These compositions can be prepared by mixing the active ingredient with a suitable non-irritating excipient which is solid at room temperature but liquid at the rectal temperature and therefore will melt in the rectum to release the active ingredient.
  • suitable non-irritating excipient include, but are not limited to, cocoa butter, beeswax and polyethylene glycols.
  • compositions of this invention may be administered by nasal aerosol or inhalation.
  • Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other solubilising or dispersing agents known in the art.
  • the pharmaceutical composition will preferably comprise from 0.05 to 99% w (percent by weight), more preferably from 0.05 to 80% w, still more preferably from 0.10 to 70% w, and even more preferably from 0.10 to 50% w, of active ingredient, all percentages by weight being based on total composition.
  • the compounds of the invention may also be administered in conjunction with other compounds used for the treatment of the above conditions.
  • the invention therefore further relates to combination therapies wherein a compound of the invention or a pharmaceutical composition or formulation comprising a compound of the invention is administered concurrently, sequentially or as a combined preparation with another therapeutic agent or agents, for the treatment of one or more of the conditions previously indicated.
  • therapeutic agents may be selected from the following:
  • opioid agonists, partial agonists or antagonists such as, for example, morphine, buprenorphine, alfentanil, fentanyl, pethidine, oxycodone, tramadol and codeine, and equivalents and pharmaceutically active isomer(s) and/or metabolite(s) thereof;
  • antidepressants such as, for example, amitriptyline, amoxapine, bupropion, citalopram, clomipramine, desipramine, doxepin duloxetine, elzasonan, escitalopram, fluvoxamine, fluoxetine, gepirone, imipramine, ipsapirone, maprotiline, nortriptyline, nefazodone, paroxetine, phenelzine, protriptyline, reboxetine, robaizotan, sertraline, sibutramine, thionisoxetine, tranylc
  • Example anxiolytics include adinazolam, alprazolam, balezepam, bentazepam, bromazepam, brotizolam, buspirone, clonazepam, clorazepate, chlordiazepoxide, cyprazepam, diazepam, diphenhydramine; estazolam, fenobam, flunitrazepam, flurazepam, fosazepam, lorazepam, lormetazepam, meprobamate, midazolam, nitrazepam, oxazepam; prazepam, quazepam, reclazepam, tracazolate, trepipam, temazepam, triazolam, uldazepam, and zolazepam; and equivalents and pharmaceutically active isomer(s) and/or metabolite(s) thereof; (iv) anticonvul
  • Such combination products employ the compounds of this invention within the dosage range described herein and the other pharmaceutically active agent within approved dosage ranges.
  • Nuclear magnetic resonance (NMR) spectra were typically recorded at 400 MHz; the chemical shifts ( ⁇ ) are reported in parts per million. Spectra were recorded using a Bruker 400 Avance instrument fitted with a 5 mm BBFO probe or DUL probe. Instrument control was by Bruker TopSpin 2.1 software, unless stated otherwise.
  • Preparative HPLC was typically performed using an Agilent Technologies 1100 Series system or a Waters autopurification LC/MS system typically using Waters 19 mm id ⁇ 100 mm long C18 columns such as XBridge or SunFire 5 ⁇ m materials at room temperature.
  • Mobile phases typically consisted of MeCN or MeOH mixed with water containing either 0.1% formic acid or 0.1% NH 4 OH, unless stated otherwise.
  • Step (i) Potassium carbonate (31.1 g, 225 mmol) was added to a solution of 4-fluorobenzaldehyde (7.96 mL, 75 mmol) and 2-fluorophenol (9 mL, 98 mmol) in DMF (100 mL). The mixture was heated at 100° C. under nitrogen for 24 h. After cooling to RT, the mixture was partitioned between EtOAc (200 mL) and water (150 mL). The aqueous phase was extracted with EtOAc (200 mL). The combined organic phases were washed with brine (3 ⁇ 50 mL), dried and concentrated.
  • Step (ii) 4-(2-Fluorophenoxy)benzaldehyde (crude, 17.7 g) was dissolved in THF (100 mL), tert-butanol (100 mL) and water (50 mL), and the mixture cooled in an ice-water bath.
  • 2-Methyl-2-butene (43.3 mL, 409 mmol), potassium dihydrogen phosphate (27.8 g, 205 mmol) and sodium chlorite (23.12 g, 205 mmol) were added sequentially and the mixture was stirred at KT for 18 h.
  • Step (i) Tripotassium phosphate (9.27 g, 43.7 mmol) and palladium(II) acetate (0.490 g, 2.18 mmol) were added to a solution of ethyl 4-bromobenzoate (5 g, 21.8 mmol) and 2,6-dimethylphenol (3.73 g, 30.6 mmol) in toluene (40 mL). The mixture was degassed for about 5 minutes and purged with nitrogen. A solution of di-tert-butyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (1.390 g, 3.27 mmol) in toluene (5 mL) was added.
  • Step (ii) Ethyl 4-(2,6-dimethylphenoxy)benzoate (crude, 2 g) was dissolved in MeOH (7 mL). NaOH (2 M, 7 mL) was added, and the mixture heated under microwave irradiation at 120° C. for 20 minutes. The mixture was acidified to pH 1 (2 M HCl), diluted with water (50 mL) and extracted with EtOAc (50 mL). The organic phase was dried and concentrated. The residue was dissolved/suspended in EtOAc (50 mL) and the mother liquor concentrated. This process was repeated with Et 2 O:EtOAc (4:1, 20 mL) and then Et 2 O (20 mL) to give the title compound (crude, 800 mg) which was used in the next step without further purification or characterisation.
  • Step (i) 4-(2,6-Difluorophenoxy)benzaldehyde was prepared as described for 4-(2-fluorophenoxy)benzaldehyde (Intermediate A1, step (i)) from 4-fluorobenzaldehyde and 2,6-difluorophenol, except with 2 eq potassium carbonate and 1.2 eq of the phenol.
  • Step (ii) 4-(2,6-Difluorophenoxy)benzaldehyde (0.500 g, 2.14 mmol) was dissolved in tert-butanol (6 mL) and water (3 mL). 2-Methyl-2-butene (2 M in THF, 5.34 mL, 10.67 mmol), potassium dihydrogen phosphate (0.73 g, 5.34 mmol) and sodium chlorite (0.72 g, 2.14 mmol) were added sequentially and the mixture was stirred at RT for 4 h. The mixture was partitioned between water (30 mL) and Et 2 O (30 mL).
  • the aqueous phase was acidified with HCl (2 M, 10 mL) and extracted with Et 2 O (30 mL).
  • the combined organic phases were washed sequentially with saturated sodium thiosulfate solution (15 mL) and brine (15 mL), dried and concentrated. The residue was loaded onto an anion exchange cartridge.
  • Step (i) 4-(2-Fluoro-6-methylphenoxy)benzaldehyde was prepared as described for 4-(2-fluorophenoxy)benzaldehyde (Intermediate A1, step (i)) from 4-fluorobenzaldehyde and 2-fluoro-6-methylphenol, and used in the next step (ii) without further purification or characterisation.
  • Step (ii) The title compound was prepared as described for 4-(2-fluorophenoxy)benzoic acid (Intermediate A1, step (ii)) from 4-(2-fluoro-6-methylphenoxy)benzaldehyde (step (i) above), with recrystallisation of the product from EtOAc/petrol, and used in the next step without further purification or characterisation.
  • Step (i) 4-(2-Chloro-6-fluorophenoxy)benzaldehyde was prepared as described for 4-(2-fluorophenoxy)benzaldehyde (Intermediate A1, step (i)) from 4-fluorobenzaldehyde and 2-chloro-6-fluorophenol.
  • Step (ii) The title compound was prepared as described for 4-(2-fluorophenoxy)benzoic acid (Intermediate A1, step (ii)) from 4-(2-chloro-6-fluorophenoxy)benzaldehyde (step (i) above).
  • Step (i) 2-Fluoro-4-(2-fluorophenoxy)benzaldehyde was prepared as described for 4-(2-fluorophenoxy)benzaldehyde (Intermediate A1, step (i)) from 2,4-difluorobenzaldehyde and 2-fluorophenol, except with 1 eq of the phenol and heating at 80° C.
  • Step (ii) The title compound was prepared as described for 4-(2-fluorophenoxy)benzoic acid (Intermediate A1, step (ii)) from 2-fluoro-4-(2-fluorophenoxy)benzaldehyde (step (i) above).
  • Step (i) Sodium hydride (60% dispersion in mineral oil, 0.177 g, 4.43 mmol) was added to a mixture of 4-fluorobenzaldehyde (0.437 mL, 4.03 mmol) and (2-fluorophenyl)methanol (0.508 g, 4.03 mmol) in DMF (20 mL). The reaction was stirred under nitrogen at room temperature for 18 h. The mixture was diluted with EtOAc and washed with sodium bicarbonate and then brine. The organic phase was dried and concentrated to give 4-((2-fluorobenzyl)oxy)benzaldehyde as a residue which was used in the next step (ii) without further purification or characterisation.
  • Step (ii) The title compound was prepared as described for 4-(2,6-difluorophenoxy)benzoic acid (Intermediate A3, step (ii)) from 4-((2-fluorobenzyl)oxy)benzaldehyde (step (i) above) and used in the next step without further purification or characterisation.
  • Step (i) (S,S)-(+)-N′,N′-Bis(3,5-di-tert-butylsalicylidene)-1,2-cyclohexanediaminocobalt(II) (0.048 g, 0.080 mmol), THF (0.25 mL) and acetic acid (0.018 mL, 0.318 mmol) were added to 2-benzyloxirane (4.27 g, 31.8 mmol). The mixture was cooled in an ice-water bath and water (0.129 mL, 7.16 mmol) was added in one portion.
  • Step (ii) (S)-2-Benzyloxirane (step (i) above) (2.74 g, 20.42 mmol) was added to a solution of methyl 4-(aminomethyl)benzoate hydrochloride (7.41 g, 36.8 mmol) and DIPEA (8.92 mL, 51.1 mmol) in MeOH (300 mL). After stirring for 3 days, the reaction mixture was concentrated. The residue was partitioned between saturated sodium hydrogencarbonate solution (200 mL) and DCM (2 ⁇ 200 mL). The aqueous phase was extracted with DCM (200 mL).
  • Step (i) Prepared as described for (S)-2-benzyloxirane (Intermediate B48, step (i)), except using (R,R)-( ⁇ )-N, N′-bis(3,5-di-tert-butylsalicylidene)-1,2-cyclohexanediaminocobalt(II) to give (R)-2-benzyloxirane which was used in the next step without further purification or characterisation.
  • Step (ii) Prepared as described for (S)-methyl 4-(((2-hydroxy-3-phenylpropyl)amino)methyl)benzoate (Intermediate B20, step (ii)) from (R)-2-benzyloxirane (step (i) above) and methyl 4-(aminomethyl)benzoate hydrochloride to give the title compound as a pale brown gum.
  • Triethylamine (6 mmol), 1-hydroxy-7-azabenzotriazole (2.4 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) (2.4 mmol) were added to a solution/suspension of the relevant amine or amine hydrochloride (2 mmol) and 4-phenoxybenzoic acid (2 mmol) in THF (10 mL). The reaction was stirred at RT for 18 h.
  • EDC 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide
  • HATU 1.1 mmol was added to a solution of the acid (1 mmol) and DIPEA (2.2 mmol) in DMF or THF (2 mL). The mixture was stirred at RT and allowed to stand. After 5 minutes, the relevant amine or amine hydrochloride (1.1 mmol) was added. (In some cases, 0.9 mmol of amine or amine hydrochloride was used.) When the amine hydrochloride was used, DBU (1.5 mmol) was added at this stage. After 10 minutes, the mixture was diluted with EtOAc or DCM (30 mL) and washed with either HCl (1 M, 20 mL) or saturated sodium bicarbonate solution (20 mL) or water (20 mL).
  • the aqueous phase was further extracted with EtOAc or DCM.
  • the combined organic phases were washed with water (2 ⁇ 20 mL), dried and concentrated.
  • further purification was carried out, by silica chromatography (typically 0-100% EtOAc/petrol), reverse-phase chromatography on C18 silica (typically eluting with 5-95% MeCN/water) or preparative HPLC.
  • Step (i) Triethylamine (1.351 mL, 9.69 mmol) was added slowly to a mixture of 4-bromobenzoyl chloride (0.851 g, 3.88 mmol) and methyl 4-((phenethylamino)methyl)-benzoate (Intermediate B14) (0.870 g, 3.23 mmol) in DCM (20 mL) at RT under nitrogen and the mixture stirred for 18 h. The mixture was diluted with DCM (30 mL), water (10 mL) and HCl (2 M, 10 mL), and the phases separated. The aqueous phase was extracted with DCM (30 mL) and the combined organic phases washed with water (10 mL), dried and concentrated.
  • Step (ii) Tripotassium phosphate (2 mmol), palladium(II) acetate (0.1 mmol) and di-tert-butyl(2′,4′,6′ triisopiopylbiphenyl-2-yl)phosphine (0.15 mmol) were added to a solution of methyl 4-((4-bromo-N-phenethylbenzamido)methyl)benzoate (step (i) above) (1 mmol) and the relevant phenol (1.2 mmol) in toluene (5 mL). The mixture was degassed for about 5 minutes, purged with nitrogen and heated either thermally or under microwave irradiation at 120° C. for 20 h. The mixture was filtered through diatomaceous earth, washing through with EtOAc. The filtrate was concentrated and purified either by silica chromatography (typically 0-100% EtOAc/petrol) or preparative HPLC.
  • silica chromatography typically 0-10
  • Step (i) Prepared using the HATU coupling procedure described in Method E4 above from 3-methoxycyclobutanecarboxylic acid (500 mg, 3.84 mmol) and (4-bromophenyl)methanamine hydrochloride (940 mg, 4.23 mmol) to give N-(4-bromobenzyl)-3-methoxycyclobutanecarboxamide (mixture of cis and trans ring isomers) (880 mg, 77%).
  • Step (ii) Lithium aluminium hydride (1 M solution in THF, 2.62 mL, 2.62 mmol) was added to a solution of N-(4-bromobenzyl)-3-methoxycyclobutanecarboxamide from step (i) above (780 mg, 2.62 mmol) in THF (20 mL) at RT. After stirring for 18 h, the mixture was quenched with saturated sodium sulfate dodecahydrate solution (5 mL), filtered and concentrated. The residue was dissolved in DCM (50 mL) and washed with NaOH (2 M, 50 mL).
  • Step (iii) Prepared using the HATU coupling procedure described in Method E4 above from 4-(2-fluorophenoxy)benzoic acid (Intermediate A1) (310 mg, 1.337 mmol) and N-(4-bromobenzyl)-1-(3-methoxycyclobutyl)methanamine from step (ii) above (380 mg, 1.337 mmol) to give the desired compound, N-(4-bromobenzyl)-4-(2-fluorophenoxy)-N-((3-methoxycyclobutyl)methyl)benzamide (mixture of cis and trans ring isomers), along with the corresponding des-bromo analogue N-benzyl-4-(2-fluorophenoxy)-N-((3-methoxycyclobutyl)methyl)benzamide (also a mixture of cis and trans ring isomers).
  • This material (approximately 1:1 mixture of bromo:des-bromo compound, 6
  • Step (iv) A solution of palladium(II) acetate (27.0 mg, 0.120 mmol), 1,3-bis(diphenylphosphino)propane (49.7 mg, 0.120 mmol), and N-(4-bromobenzyl)-4-(2-fluorophenoxy)-N-((3-methoxycyclobutyl)methyl)benzamide from step (iii) above (300 mg, 0.602 mmol) in MeOH (5 mL) and DMF (3 mL) was degassed and purged with nitrogen. Triethylamine (0.168 mL, 1.204 mmol) was added, the reaction mixture was evacuated and carbon monoxide passed through the solution.
  • Step (i) 4-Toluenesulfonyl chloride (18.29 g, 96 mmol) was added in several portions to a solution of ethyl 4-hydroxycyclohexanecarboxylate (ca. 1:1 mixture of cis and trans ring isomers) (29.5 g, 90 mmol) in pyridine (100 mL) in an ice-water bath, and the mixture stirred, allowing to warm to RT. After the solid had dissolved, the mixture was allowed to stand. After 24 h, the mixture was concentrated and the residue partitioned between water and EtOAc (100 mL each).
  • ethyl 4-hydroxycyclohexanecarboxylate ca. 1:1 mixture of cis and trans ring isomers
  • Step (ii) 2-Fluorophenol (2.145 mL, 23.25 mmol) was added to a solution/suspension of ethyl 4-(tosyloxy)cyclohexanecarboxylate from step (i) above and cesium carbonate (7.58 g, 23.25 mmol) in DMF (100 mL) and the mixture stirred for 18 h at 80° C. After cooling, the mixture was diluted with EtOAc (200 mL) and washed with saturated sodium hydrogencarbonate solution (100 mL) and brine (100 mL).
  • Step (iii) Lithium hydroxide (0.307 g, 12.80 mmol) was added to a solution of ethyl 4-(2-fluorophenoxy)cyclohexanecarboxylate from step (ii) above (crude, 3.41 g) in 1,4-dioxane (30 mL) and water (30 mL), and the mixture heated under microwave irradiation at 100° C. for 15 minutes. The mixture was concentrated. The residue was loaded onto an anion exchange cartridge. After washing with MeCN, the product was eluted with 2 M HCl/MeCN and concentrated to give 4-(2-fluorophenoxy)cyclohexanecarboxylic acid (ca. 1:1 mixture of cis and trans ring isomers) (crude, 1.0 g) as a pale yellow solid which was used in the next step without further purification.
  • 4-(2-fluorophenoxy)cyclohexanecarboxylic acid ca. 1:1 mixture of cis and trans ring
  • Step (iv) The title compound was prepared using the HATU coupling procedure described in Method E4 above, from 4-(2-fluorophenoxy)cyclohexanecarboxylic acid from step (iii) above and methyl 4-((benzylamino)methyl)benzoate hydrochloride (Intermediate B10).
  • Step (i) A solution of ethyl 4-hydroxycyclohexanecarboxylate (ca. 1:1 mixture of cis and trans ring isomers) (5 g, 29 mmol), 2-methoxyphenol (3.96 g, 31.9 mmol), triphenylphosphine (8.38 g, 31.9 mmol) and trans-diisopropyl diazene-1,2-dicarboxylate (DIAD) (6.21 mL, 31.9 mmol) in THF (150 mL) was stirred at RT. The mixture was diluted with EtOAc (100 mL) and washed with saturated sodium hydrogencarbonate solution (50 mL) and brine (50 mL).
  • EtOAc 100 mL
  • saturated sodium hydrogencarbonate solution 50 mL
  • brine 50 mL
  • Step (ii) 4-(2-Methoxyphenoxy)cyclohexanecarboxylic acid was prepared as described for 4-(2-fluorophenoxy)cyclohexanecarboxylic acid (Intermediate C60, step (iii)) using ethyl 4-(2-methoxyphenoxy)cyclohexanecarboxylate from step (i) above.
  • Step (iii) The title compound was prepared using the HATU coupling procedure described in Method E4 above from 4-(2-methoxyphenoxy)cyclohexanecarboxylic acid (step (ii) above) and methyl 4-((benzylamino)methyl)benzoate hydrochloride (Intermediate B10).
  • Step (i) Potassium carbonate (3.70 g, 26.7 mmol) was added to a solution of 4-cyano-2-fluorobenzoic acid (4 g, 24.3 mmol) in DMF (350 mL). After stirring at RT for 15 minutes, iodomethane (1.66 mL, 26.7 mmol) was added. The flask was stoppered, and the mixture stirred at 40° C. for 2 h. The mixture was concentrated under reduced pressure and the residue partitioned between DCM (50 mL) and brine (50 mL). The organic phase was passed through silica and concentrated to give methyl 4-cyano-2-fluorobenzoate (4.1 g, 94%).
  • Step (ii) Raney nickel (2.0 g) was added to a solution of methyl 4-cyano-2-fluorobenzoate (obtained as described in step (i) above) (10.1 g, 61.6 mmol) in acetic acid (200 mL) and water (100 mL). The mixture was stirred at RT under argon at 20 bar. After 18 h the mixture was filtered through diatomaceous earth, washing through with water (1000 mL). The filtrate was extracted with EtOAc (3 ⁇ 300 mL).
  • Step (iii) Methyl 2-fluoro-4-(hydroxymethyl)benzoate (step (ii) above) (1 g, 5.4 mmol) was dissolved in chloroform (40 mL) and THF (5 mL). Manganese(IV) oxide (2.36 g, 27 mmol) was added and the mixture stirred at RT for 2 h and then at 60° C. for 1 h. Further manganese(IV) oxide (2.36 g, 27 mmol) was added and heating was continued at 60° C. After 18 h the mixture was filtered through diatomaceous earth to give methyl 2-fluoro-4-formylbenzoate which was used without further purification.
  • Step (iv) Methyl 2-fluoro-4-(((3-methoxybenzyl)amino)methyl)benzoate was prepared using the reductive amination procedure described in Method R3 above from (3-methoxyphenyl)methanamine and methyl 2-fluoro-4-formylbenzoate (step (iii) above).
  • Step (v) Oxalyl chloride (0.30 mL, 3.51 mmol) was added to a solution of 4-(2-fluorophenoxy)benzoic acid (Intermediate A1) (746 mg, 2.34 mmol) in DCM (10 mL) at RT. DMF (1 drop) was added, and the mixture stirred, allowing to warm to RT. After 2 h, the mixture was concentrated. The residue was dissolved in DCM (5 mL) and added to a solution of methyl 2-fluoro-4-(((3-methoxybenzyl)amino)methyl)benzoate (step (iv) above) (708 mg, 23.4 mmol) and triethylamine (0.49 mL, 3.51 mmol).
  • Step (i) Sodium hydride (60% dispersion in mineral oil, 0.258 g, 6.42 mmol) was added to a solution of 2-fluorophenol (0.492 mL, 5.34 mmol) in pyridine (15 mL) in an ice-water bath. Copper(I) bromide was added, and the mixture heated at 100° C. for 5 h. The mixture was concentrated and the residue triturated with EtOAc and purified by silica chromatography (20% EtOAc/heptane) to give 5-(2-fluorophenoxy)pyrimidine-2-carbonitrile (555 mg, 47%).
  • Step (ii) 5-(2-Fluorophenoxy)pyrimidine-2-carbonitrile, NaOH (2 M, 10 mL) and IMS (2 mL) were combined and heated at 70° C. for 18 h. After concentration to remove IMS, HCl (2 M) was added until the pH was 3, and the mixture was extracted with DCM (50 mL). The organic phase was dried and concentrated to give 5-(2-fluorophenoxy)pyrimidine-2-carboxylic acid (250 mg, 48%) as a white solid, which was used in the next step without further purification or characterisation.
  • Step (i) Prepared as for step (i) of Intermediate C70 to give 5-(2-methoxyphenoxy)pyrimidine-2-carbonitrile (555 mg, 47%).
  • Step (ii) Prepared as for step (ii) of Intermediate C70, from 5-(2-methoxyphenoxy)pyrimidine-2-carbonitrile, to give 5-(2-methoxyphenoxy)pyrimidine-2-carboxylic acid.
  • Lithium hydroxide or lithium hydroxide monohydrate (5 mmol) was added to a solution of the relevant ester (1 mmol) in water (2 mL) and either THF or 1,4-dioxane (4 mL). In some cases, MeOH was added in addition to THF. The mixture was stirred, typically at RT for 18 h, 50° C. for 4 h or 100° C. for 20 minutes. In some cases the reaction was diluted with NaOH (2 M) and extracted with EtOAc or DCM, and the resulting aqueous phase acidified with HCl (2 M) and extracted with EtOAc. In other cases the crude mixture was partitioned between HCl (2 M) and EtOAc.
  • the combined organic phases from the extraction of the acidic aqueous phase were dried and concentrated. In some cases the residue was loaded onto an anion exchange cartridge. After washing with MeCN, the product was eluted with 1 M HCl/MeCN then concentrated. In some cases the material obtained was purified by reverse-phase chromatography on C18 silica (typically eluted with 5-95% MeOH/H 2 O with 0.1% NH 4 OH). In some cases the crude product was heated under reflux in HCl (4 M), allowed to cool and filtered. In some cases the final product was recrystallised, typically using one or more of the following: water, EtOH, EtOAc, methyl acetate, methyl tert-butyl ether, pentane, heptane.
  • LPA5 receptor Engagement of the LPA5 receptor by its ligand, oleoyl-L- ⁇ -lysophosphatidic acid (LPA), leads to the release of intracellular stores of calcium into the cytoplasm mediated through a Gq-driven increase in inositol triphosphate (IP3) levels.
  • IP3 inositol triphosphate
  • Gq is a heterotrimeric G protein subunit that activates phospholipase C.
  • test compounds to prevent LPA-driven intracellular release of stored calcium from RH7777 cells expressing human LPA5 receptors was assayed by stimulating the cells with LPA in the presence of various test compounds to measure the test compounds' antagonism, i.e. activity in vitro.
  • test compounds at a final concentration range between 0.32 nM-10 ⁇ M were added to the assay wells and allowed to incubate for fifteen minutes. After incubation with test compounds the assay plate was placed in a FLIPR Tetra system (Molecular Devices) and LPA (diluted in assay buffer) was added to give a final concentration equivalent to its determined EC 90 against LPA5 receptor.
  • Ligand-dependent changes in intracellular calcium levels were determined by measuring changes in fluorescence of the dye over 515-575 nM following excitation over 470-495 nM. Readings from control wells that did not contain test compounds enabled percentage inhibition curves to be plotted using a 4-parameter curve fit algorithm and IC 50 values to be calculated for each compound.
  • Example No. Mean IC 50 (nM) Example No. Mean IC 50 (nM) 1 840 2 690 3 43 4 63 5 16 6 24 7 31 8 32 9 15 10 48 11 6 12 9 13 3 14 2 15 120 16 1 17 1 18 2 19 9 20 40 21 11 22 24 23 44 24 7 25 29 26 260 27 200 28 45 29 43 30 12 31 5 32 0.4 33 0.4 34 460 35 7 36 24 37 28 38 140 39 11 40 31 41 89 42 17 43 58 44 11 45 99 46 17 47 11 48 3300 49 4600 50 3600 51 53 52 370 53 58 54 26 55 690 56 180 57 410 58 32 59 6 60 60 61 8 62 9 63 10 64 7 65 4 66 5 67 5 68 10 69 8 70 140 71 83 72 42 73 890 74 98 75 22 76 140 77 74 78 170 79 68 80 45 83 350 84 91 85 120
  • Farnesyl pyrophosphate is an endogenous ligand for the LPA5 receptor, with a reported in-vitro EC 50 of 49 nM and 3-fold selectivity over other LPA receptors (Williams et al. (2009), ‘Unique Ligand Selectivity of the GPR92/LPA5 Lysophosphatidate Receptor Indicates Role in Human Platelet Activation’, J Biol. Chem., 284(25):17304-17319).
  • the FPP-induced hyperalgesia model is a pharmacodynamic rat model which involves inducing pain by injecting FPP, an agonist of LPA5 receptor, into the plantar surface of the hindpaw. Pre-treatment with a LPA5 receptor antagonist prevents the hyperalgesia induced by FPP.
  • LPA oleoyl-L- ⁇ -lysophosphatidic acid
  • IP3 inositol triphosphate
  • test compounds to prevent LPA-driven intracellular release of stored calcium from RH7777 cells expressing human LPA1 receptors was assayed by stimulating the cells with LPA in the presence of various test compounds to measure the test compounds' antagonism, i.e. activity in vitro.
  • test compounds at a final concentration range between 0.32 nM-10 ⁇ M were added to the assay wells and allowed to incubate for twenty five minutes. After incubation with test compounds the assay plate was placed in a FLIPR Tetra system (Molecular Devices) and LPA (diluted in assay buffer) was added to give a final concentration equivalent to its determined EC 80 against LPA1 receptor.
  • Ligand-dependent changes in intracellular calcium levels were determined by measuring changes in fluorescence of the dye over 515-575 nM following excitation over 470-495 nM. Readings from control wells that did not contain test compounds enabled percentage inhibition curves to be plotted using a 4-parameter curve fit algorithm and IC 50 values to be calculated for each compound.
  • Example No. Mean IC 50 (nM) Example No. Mean IC 50 (nM) 3 35 4 49 5 46 8 46 11 6 13 4 14 2 17 0.4 18 1 19 7 20 12 22 30 24 11 25 14 28 46 29 34 30 12 31 4 32 2 33 0.3 36 24 37 25 38 36 40 160 45 75 46 19 47 22 54 27 58 17 60 33 61 4 62 5 63 7 64 9 65 5 66 7 67 7 68 13 69 12 70 47 71 59 72 29 73 120 74 40 75 31 76 130 77 86 78 390 79 94 80 110 83 540 84 170 85 180
  • mice Male male C57BL/6 mice, aged 8-10 weeks, were assigned to groups and allowed to acclimatise for a week. On Day ⁇ 1, the back skin of the animals was shaved. From Day 0, animals were administered with 100 ⁇ l of a 1 mg/ml solution of bleomycin sulphate in phosphate buffered saline (PBS) by intradermal injection in the shaved skin. Injections were repeated in a one square centimeter area every other day for four weeks. A group of ten animals (Control group) was injected with an identical volume of PBS. Treatments were given according to the administration schedule shown in the table below. Animals were weighed at the beginning of the experiment on Day 0 and then twice weekly throughout the study.
  • PBS phosphate buffered saline
  • Bodyweights were graphed along with the standard error of the mean (SEM); Skin samples (two punch biopsies per animal, 4 mm in diameter each) samples were hydrolyzed and hydroxyproline content of the samples was determined from analysis in a semi-automated process using a continuous flow analyzer. Auto analysesr readings were calibrated against hydroxyproline standards and collagen content calculated.
  • the bodyweight loss observed in the Example 5 compound-treated groups did not differ from the bodyweight loss observed in the vehicle-treated group. Some weight loss ⁇ 10% was observed with bleomycin treatment. Bleomycin administration induced a highly significant increase in skin collagen content when compared to the control, saline-injected, group (p ⁇ 0.01).
  • Imatinib and Betamethasone 0.1% induced a non-significant reduction in skin collagen content when compared to the vehicle-treated group.
  • the Example 5 compound administered from Day 0 and from Day 14 induced a significant reduction in skin collagen content when compared to the vehicle-treated group (p ⁇ 0.05).
  • Protopic 0.1% induced a highly significant reduction in skin collagen content when compared to the vehicle-treated group (p ⁇ 0.001).
  • the compound of Example 5 demonstrated an anti-fibrotic effect in an in vivo bleomycin-induced scleroderma model as measured by collagen skin content.

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Abstract

The present invention provides compounds of formula (I) and pharmaceutically acceptable salts thereof, formula (I) wherein R1, X, m, R2, Y, R3, Z, n, R4, A and B are as defined in the specification, processes for their preparation, pharmaceutical compositions containing them and their use in therapy.
Figure US20190010129A1-20190110-C00001

Description

  • The present invention relates to amide derivatives, processes for their preparation, pharmaceutical compositions containing them and their use in therapy, particularly as lysophosphatidic acid receptor antagonists.
  • Lysophosphatidic acid (LPA) is a bioactive lipid mediator that interacts with G protein-coupled transmembrane LPA receptors to affect fundamental cellular functions including proliferation, differentiation, survival, migration, adhesion, invasion and morphogenesis. The effects of LPA at physiological concentrations are mediated by six high affinity cognate LPA receptors (LPA1-6) and potentially at least three additional putative LPA receptors. All known LPA receptors are type 1, rhodopsin-like G protein-coupled receptors (GPCRs) that differ in their tissue distribution and downstream signalling pathways.
  • LPAR1 was the first high affinity LPA receptor identified. Along with LPAR2 and 3, LPAR 1 is one of the Endothelial Differentiation Gene (EDG) LPA receptors. The LPAR1 gene is widely expressed in adult mice, with presence demonstrated in brain, uterus, testis, lung, small intestine, heart, stomach, kidney, spleen, thymus, placenta and skeletal muscle. Expression is also widespread in humans. LPAR 1 couples with and activates Gαi/o, Gαq/11 and Gα12/13 G proteins to induce a range of cellular responses. Studies with mice lacking functional LPA1 receptor alleles have implicated LPAR1 in the development of pulmonary fibrosis and neuropathic pain. Intrathecal injection of LPA causes allodynia, hyperalgesia and demyelination of the dorsal root in a LPAR1-dependent manner.
  • LPAR2 has approximately 60% amino acid homology to LPAR1 and in mouse is expressed in kidney, uterus, testis and lung with lower levels of expression in stomach, spleen, thymus brain and heart. In human tissues high expression is detected in testis and leukocytes and moderate expression in prostate, spleen, thymus and pancreas. LPAR2 couples with Gαi/o, Gαq/11 and Gα12/13 G proteins with signalling associated with processes such as cell survival and cell migration which makes LPAR2 a potential factor for cancer metastasis. In cancer cells, aberrant expression of LPAR2 has been reported, suggesting a tumour promoting role.
  • Expression of LPAR3 has been seen in human heart, testis, prostate, pancreas, lung, ovary and brain and most abundantly in mouse testis, kidney, lung, small intestine, heart, stomach, spleen, brain and thymus. LPAR3 is able to couple with Gαi/o, Gαq/11 to and is also a potential factor for cancer metastasis.
  • LPA receptors 4, 5 and 6 constitute the non-EDG family of LPA receptors. LPAR4 (P2Y9/GPR23) is more closely related to P2Y purinoreceptors. LPAR4 appears to be broadly expressed in humans with particular abundance in ovary, and is present in mouse heart, skin, thymus and ovary. As with other LPA receptors this GPCR can signal via several pathways, namely Gαs, Gαi, Gαq/11 and Gα12/13.
  • Formerly an orphan GPCR, GPR92 was identified at the fifth LPA receptor and renamed LPAR5. Human LPAR5 is located on chromosome 12p13.31 and encodes an approximately 41 kDa protein. LPAR5 is broadly expressed in murine tissues such as small intestine, skin, spleen, stomach, thymus, lung, heart, liver, bladder urothelium, dorsal root ganglion and spinal cord. LPA induces neurite retraction and stress fibre formation in LPAR5-expressing cells through coupling to Gα12/13 and is also able to activate Gαs and Gαq/11. It has been shown that LPAR5 can be activated by ligands other than LPA, namely endogenous by-products of cholesterol synthesis such as farnesyl pyrophosphate (FPP) and N-arachidonylglycine (NAG). Activation of GPR92/LPAR5 by FPP increases inositol phosphate production, cAMP levels, and Ca2+ levels in a concentration-dependent manner. There is evidence of a role for LPAR5 in pain since it is highly expressed in and largely co-localized with TRPV1 in mouse and human dorsal root ganglion, as well as the fact that FPP induces calcium influx in DRG neurons in a LPAR5-specific manner. The targeted deletion of LPAR5 in mice produces an analgesic phenotype, with LPAR5 homozygotic mice being less sensitive to touch and pain stimuli in a number of tests and also resistant to development of neuropathic pain. Additionally, LPAR5 knock-out mice display a urological phenotype consistent with changes in sensory signalling. LPA causes aggregation of human platelets at concentrations that are present in atheromatous legions; LPAR5 has been shown to have an intrinsic role in this process.
  • Most recently, P2Y5 was named as the sixth LPA receptor. This member of the purinergic receptor family is more closely related to LPAR4 and 5 than LPA1-3. This receptor has been identified as a critical mediator of human hair growth.
  • EP-A-1,553,075 (Ono Pharmaceutical Co., Ltd.) discloses LPA receptor antagonists of general formula
  • Figure US20190010129A1-20190110-C00002
  • wherein R represents an aliphatic hydrocarbon group which may be substituted, or a cyclic group which may have a substituent(s);
    G represents a bond or a spacer having from 1 to 8 atoms in its principle chain;
    T represents —CH2—, or a spacer having one atom in its principle chain, the principle chain containing a hydrogen bond acceptable group which may have a substituent(s);
    J represents a nitrogen atom or a carbon atom;
    B represents an aliphatic hydrocarbon group which may be substituted, or a cyclic group which may have a substituent(s);
    K represents (1) a bond, or (2) a spacer having from 1 to 8 atoms in its principle chain which may form a ring together with a substituent of the cyclic group in R, the ring D or a substituent on the ring D;
    Q represents (1) a bond, or (2) a spacer having from 1 to 8 atoms in its principle chain which may form a ring together with the cyclic group in R, a substituent of the cyclic group in R or K;
    ring D represents a cyclic group which may have an additional substituent(s);
    L represents a bond, or a spacer having from 1 to 3 atoms in its principle chain;
    ring E represents a cyclic group which may have an additional substituent(s);
    M represents a bond, or a spacer having from 1 to 8 atoms in its principle chain;
    Z represents an acidic group; and
    t represents 0 or 1, or a salt thereof.
  • EP-A-2,481,725 (Astellas Pharma Inc.) discloses LPA receptor antagonists of general formula
  • Figure US20190010129A1-20190110-C00003
  • wherein A is an aryl which may be substituted or a hetero ring group which may be substituted,
    B is a 5-membered aromatic hetero ring group which may be substituted,
    X is a single bond or —(CRX1RX2)n—,
    n is 1, 2, 3 or 4,
    RX1 and RX2 are the same or different from each other, and are H, halogen, OH, —O-(lower alkyl which may be substituted), or lower alkyl which may be substituted, or
    RX1 and RX2 are combined with each other to form oxo (═O), or
    RX1 and RX2 are combined with each other to form C2-5 alkylene which may be substituted, in which when n is 2, 3 or 4, RX1 may be combined with adjacent RX1 to form a new bond,
    Y1, Y2, Y3, Y4 and Y5 are the same as or different from each other, and are CRY or N,
    RY's are the same as or different from each other, and are H, OH, halogen, —O-(lower alkyl which may be substituted), —S-(lower alkyl which may be substituted), lower alkyl which may be substituted, lower alkenyl which may be substituted, or cycloalkyl which may be substituted,
    m is 1, 2 or 3,
    R3 is H, or lower alkyl which may be substituted,
    R4 is lower alkyl which may be substituted, lower alkenyl which may be substituted, cycloalkyl which may be substituted, aryl which may be substituted, a hetero ring group which may be substituted, or NR101R102, or
    R3 and R4 may be combined with each other to form C2-5 alkylene which may be substituted, and
    R101 and R102 are the same as or different from each other, and are H, OH, —O-(lower alkyl which may be substituted), —C(═O)-(lower alkyl which may be substituted), —C(═O)—O-(lower alkyl which may be substituted), —NH—C(═O)-(lower alkyl which may be substituted), lower alkyl which may be substituted, lower alkenyl which may be substituted, cycloalkyl which may be substituted, aryl which may be substituted, or a hetero ring group which may be substituted, or R101 and R102 may be combined with nitrogen atoms to which they are bonded to form a nitrogen-containing monocyclic saturated hetero ring group,
    in which when R4 is NR101R102, at least one of R3, R101 and R102 is H.
  • In addition EP-A-1,229,034 describes certain amide derivatives as PDE4 inhibitors for treating respiratory diseases and US 2004/0176446 describes certain amide derivatives for use in treating cardiovascular disorders.
  • There are currently very few potent LPAR5-selective antagonists. ‘LPA5-antagonist 4’ has been published by Sanofi-Aventis (Kozian et al, 2012, Bioorg Med Chem Lett., 22(16):5239-43) and is reported to be of low potency against LPAR5 (0.8 μM).
  • It would be desirable to develop compounds that are potent against LPAR5 and/or LPAR1 for use in treating pain disorders and diseases such as atherosclerosis in which these receptors are believed to play a role.
  • In accordance with the present invention, there is therefore provided a compound of formula (I)
  • Figure US20190010129A1-20190110-C00004
  • wherein
      • R1 represents a C5-C10 aryl group substituted by at least one substituent independently selected from halogen, cyano, nitro, carboxyl, hydroxyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkoxycarbonylamino, C1-C6 haloalkoxy, —NR5R6, C3-C6 cycloalkylamino, C1-C6 alkylthio, C1-C6 alkylcarbonyl, C1-C6 alkylcarbonyloxy, C1-C6 alkylcarbonylamino, sulphonamido (—SO2NH2), C1-C6 alkylsulphonyl,
        C1-C6 alkylsulphonylamino, —C(O)NR7R8, C1-C6 alkyl which alkyl group may in turn be optionally substituted by at least one halogen, hydroxyl, carboxyl or C1-C6 alkoxycarbonyl group, and a saturated or unsaturated 5- to 6-membered ring which may comprise at least one ring heteroatom independently selected from nitrogen, oxygen and sulphur, the ring itself being optionally substituted by at least one substituent independently selected from halogen, hydroxyl, oxo (═O), carboxyl, cyano, C1-C6 alkyl, C1-C6 alkoxycarbonyl and C1-C6 hydroxyalkyl;
      • X represents an oxygen atom or a group —CH2—, —OCH2—, —CH2O—, —CH2CH2—, —CH2NR17—, —NR17CH2—, —CHF— or —CF2—;
      • m is 0, 1 or 2;
      • each R2 independently represents a halogen atom or a hydroxyl, C1-C6 alkyl, difluoromethyl, trifluoromethyl, C1-C6 alkoxy, difluoromethoxy; trifluoromethoxy or NR15R16 group;
      • Y represents CR9R10 in which R9 and R10 each independently represent a hydrogen atom or a methyl group;
      • R3 represents C1-C8 alkyl, C2-C8 alkenyl, or a saturated or unsaturated 3- to 10-membered ring system which may comprise at least one ring heteroatom independently selected from nitrogen, oxygen and sulphur, each of the preceding groups being optionally substituted by at least one substituent independently selected from halogen, cyano, hydroxyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C5-C6 aryloxy, C5-C6arylC1-C6alkyloxy, C1-C6 alkoxycarbonyl, C1-C6 alkoxycarbonylamino, C1-C6 alkoxycarbonyloxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, —NR13R14, C3-C6 cycloalkylamino, C1-C6 alkylthio, C1-C6 alkylcarbonyl, C1-C6 alkylcarbonyloxy, C1-C6 alkylcarbonylamino, sulphonamido (—SO2NH2), C1-C6 alkylsulphonyl, C1-C6 alkylsulphonylamino, C1-C6 alkyl, and a saturated or unsaturated 3- to 10-membered ring system which may comprise at least one ring heteroatom independently selected from nitrogen, oxygen and sulphur, the ring system itself being optionally substituted by least one substituent independently selected from halogen, hydroxyl, oxo (═O), carboxyl, cyano, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkoxycarbonyl and C1-C6 hydroxyalkyl;
      • Z represents CR11R12 in which R11 and R12 each independently represent a hydrogen atom or a methyl group but cannot both simultaneously represent a methyl group;
      • n is 0, 1 or 2;
      • each R4 independently represents a halogen atom or a hydroxyl, C1-C6 alkyl, difluoromethyl, trifluoromethyl, C1-C6 alkoxy, difluoromethoxy, trifluoromethoxy or NR18R19 group;
  • R5 and R6 each independently represent a hydrogen atom or a C1-C6 alkyl group, or
  • R5 and R6 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocycle;
  • R7 and R8 each independently represent a hydrogen atom or a C1-C6 alkyl group, or
  • R7 and R8 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocycle;
      • R13 and R14 each independently represent a hydrogen atom or a C1-C6 alkyl group, or R13 and R14 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocycle;
  • R15 and R16 each independently represent a hydrogen atom or a C1-C6 alkyl group, or R15 and R16 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocycle;
      • R17 represents a hydrogen atom or a C1-C6 alkyl group;
      • R18 and R19 each independently represent a hydrogen atom or a C1-C6 alkyl group, or
      • R18 and R19 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocycle; and
      • rings A and B each independently represent a saturated or unsaturated 5- to 10-membered ring system which may comprise at least one ring heteroatom independently selected from nitrogen, oxygen and sulphur;
        or a pharmaceutically acceptable salt thereof.
  • Without being bound to any particular theory, the compounds of the invention have been found to possess dual LPAR5/LPAR1 antagonist properties. Such dual antagonist properties would be expected to be particularly beneficial in the treatment of conditions such as fibrosis.
  • In the context of the present specification, unless otherwise stated, an “alkyl” or “alkenyl” substituent group or an “alkyl” or “alkenyl” moiety in a substituent group may be linear or branched. Examples of C1-C8 alkyl groups/moieties include methyl, ethyl, propyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, n-heptyl and n-octyl. Examples of C2-C8 alkenyl groups/moieties include ethenyl, propenyl, 1-butenyl, 2-butenyl, 1-pentenyl, 1-hexenyl, 1,3-butadienyl, 1,3-pentadienyl, 1,4-pentadienyl and 1-hexadienyl.
  • A “C1-C6 haloalkyl” or “C1-C6 haloalkoxy” substituent group/moiety will comprise at least one halogen atom, e.g. one, two, three, four or five halogen atoms, examples of which include trifluoromethyl, trifluoromethoxy or pentafluoroethyl.
  • A “C1-C6 hydroxyalkyl” substituent group/moiety will comprise at least one hydroxyl group, e.g. one, two, three or four hydroxyl groups, examples of which include —CH2OH, —CH2CH2OH, —CH2CH2CH2OH, —CH(OH)CH2OH, —CH(CH3)OH and —CH(CH2OH)2.
  • A “cycloalkyl” substituent group/moiety is a saturated hydrocarbyl ring containing, for example, from 3 to 8 carbon atoms, examples of which include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • As used herein, “aryl” is intended to mean any stable monocyclic or bicyclic aromatic hydrocarbon system containing up to 10 carbon atoms, e.g. from 5 to 10 carbon atoms, such as phenyl or naphthyl.
  • In the definition of R1, the saturated or unsaturated 5- to 6-membered ring which may comprise at least one ring heteroatom independently selected from nitrogen, oxygen and sulphur may have alicyclic or aromatic properties. An unsaturated ring will be partially or fully unsaturated. Similar comments apply to the saturated or unsaturated 3- to 10-membered ring systems defined in R3. In either case, it should be understood that the invention does not encompass any unstable ring structures or any O—O, O—S or S—S bonds and that a substituent, if present, may be attached to any suitable ring atom.
  • When any of R5 and R6, R7 and R8, R13 and R14, R15 and R16 or R18 and R19 represents a 4- to 7-membered saturated heterocycle, it should be understood that the heterocycle may contain one or more further heteroatoms (e.g. nitrogen, oxygen or sulphur atoms) in addition to the nitrogen atom to which R5 and R6, R7 and R8, R13 and R14, R15 and R16 or R18 and R19 are attached.
  • When any chemical moiety or group in formula (I) is described as being optionally substituted, it will be appreciated that the moiety or group may be either unsubstituted or substituted by one or more of the specified substituents. It will be appreciated that the number and nature of substituents will be selected so as to avoid sterically undesirable combinations.
  • R1 represents a C5-C10 or C5-C6 aryl group substituted by at least one substituent, e.g. one, two, three or four substituents, independently selected from
      • (i) halogen (e.g. fluorine, chlorine, bromine or iodine),
      • (ii) cyano,
      • (iii) nitro,
      • (iv) carboxyl,
      • (v) hydroxyl,
      • (vi) C3-C6 or C5-C6 cycloalkyl,
      • (vii) C1-C6, or C1-C4, or C1-C2 alkoxy,
      • (viii) C1-C6, or C1-C4, or C1-C2 alkoxycarbonyl,
      • (ix) C1-C6, or C1-C4, or C1-C2 alkoxycarbonylamino,
      • (x) C1-C6, or C1-C4, or C1-C2 haloalkoxy,
      • (xi) —NR5R6,
      • (xii) C3-C6 or C5-C6 cycloalkylamino,
      • (xiii) C1-C6, or C1-C4, or C1-C2 alkylthio,
      • (xiv) C1-C6, or C1-C4, or C1-C2 alkylcarbonyl,
      • (xv) C1-C6, or C1-C4, or C1-C2 alkylcarbonyloxy,
      • (xvi) C1-C6, or C1-C4, or C1-C2 alkylcarbonylamino,
      • (xvii) sulphonamido,
      • (xviii) C1-C6, or C1-C4, or C1-C2 alkylsulphonyl,
      • (xix) C1-C6, or C1-C4, or C1-C2 alkylsulphonylamino,
      • (xx) —C(O)NR7R8,
      • (xxi) C1-C6, or C1-C4, or C1-C2 alkyl which alkyl group may in turn be optionally substituted by at least one substituent, e.g. one, two, three or four substituents, independently selected from halogen (e.g. fluorine, chlorine, bromine or iodine), hydroxyl, carboxyl and C1-C6, or C1-C4, or C1-C2 alkoxycarbonyl, and
      • (xxii) a saturated or unsaturated 5- to 6-membered ring which may comprise at least one ring heteroatom, e.g one, two, three or four ring heteroatoms, independently selected from nitrogen, oxygen and sulphur (preferably nitrogen or oxygen), the ring itself being optionally substituted by at least one substituent, e.g. one, two, three or four substituents, independently selected from halogen (e.g. fluorine, chlorine, bromine or iodine), hydroxyl, oxo, carboxyl, cyano, C1-C6, or C1-C4, or C1-C2 alkyl, C1-C6, or C1-C4, or C1-C2 alkoxycarbonyl and C1-C6, or C1-C4, or C1-C2 hydroxyalkyl. Examples of saturated or unsaturated 5- to 6-membered rings include hydrocarbyl rings such as phenyl and heterocyclic rings such as pyrrolidinyl, piperidinyl, morpholinyl, tetrahydropyranyl, oxadiazolyl, pyrrolyl, imidazolyl, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, thienyl and furanyl.
  • The at least one substituent in R1 is preferably attached in an ortho position relative to the point of attachment of R1 to X. For example, if R1 is phenyl, then the preferred carbon atoms to which a substituent is attached are shown by the asterisks in the structure below:
  • Figure US20190010129A1-20190110-C00005
  • In an embodiment of the invention, R1 represents a C5-C6 aryl (preferably phenyl) group substituted by at least one substituent, e.g. one, two, three or four substituents, independently selected from
      • (i) halogen (e.g. fluorine, chlorine, bromine or iodine),
      • (ii) cyano.
      • (iii) nitro,
      • (iv) carboxyl,
      • (v) hydroxyl,
      • (vi) C1-C6, or C1-C4, or C1-C2 alkoxy,
      • (vii) C1-C6, or C1-C4, or C1-C2 alkoxycarbonyl,
      • (viii) C1-C6, or C1-C4, or C1-C2 alkoxycarbonylamino,
      • (ix) C1-C6, or C1-C4, or C1-C2 haloalkoxy,
      • (x) —NR5R6,
      • (xi) C3-C6 or C5-C6 cycloalkylamino,
      • (xii) C1-C6, or C1-C4, or C1-C2 alkylthio,
      • (xiii) C1-C6, or C1-C4, or C1-C2 alkylcarbonyl,
      • (xiv) C1-C6, or C1-C4, or C1-C2 alkylcarbonyloxy,
      • (xv) C1-C6, or C1-C4, or C1-C2 alkylcarbonylamino,
      • (xvi) C1-C6, or C1-C4, or C1-C2 alkylsulphonyl,
      • (xvii) C1-C6, or C1-C4, or C1-C2 alkylsulphonylamino,
      • (xviii) —C(O)NR7R8,
      • (xix) C1-C6, or C1-C4, or C1-C2 alkyl which alkyl group may in turn be optionally substituted by at least one substituent, e.g. one, two, three or four substituents, independently selected from halogen (e.g. fluorine, chlorine, bromine or iodine), hydroxyl, carboxyl and C1-C6, or C1-C4, or C1-C2 alkoxycarbonyl, and
      • (xx) a saturated or unsaturated 5- to 6-membered ring which may comprise at least one ring heteroatom, e.g one, two, three or four ring heteroatoms, independently selected from nitrogen, oxygen and sulphur (preferably nitrogen or oxygen), the ring itself being optionally substituted by at least one substituent, e.g. one, two, three or four substituents, independently selected from halogen (e.g. fluorine, chlorine, bromine or iodine), hydroxyl, oxo, carboxyl, cyano, C1-C6, or C1-C4, or C1-C2 alkyl, C1-C6, or C1-C4, or C1-C2 alkoxycarbonyl and C1-C6, or C1-C4, or C1-C2 hydroxyalkyl.
  • In another embodiment of the invention, R1 represents a C5-C6 aryl group substituted by one or two substituents independently selected from
      • (i) halogen (e.g. fluorine, chlorine, bromine or iodine),
      • (ii) cyano,
      • (iii) nitro,
      • (iv) carboxyl,
      • (v) hydroxyl,
      • (vi) C1-C2 alkoxy,
      • (vii) C1-C2 alkoxycarbonyl,
      • (viii) C1-C2 alkoxycarbonylamino,
      • (ix) C1-C2 haloalkoxy,
      • (x) —NR5R6,
      • (xi) C5-C6 cycloalkylamino,
      • (xii) C1-C2 alkylthio,
      • (xiii) C1-C2 alkylcarbonyl,
      • (xiv) C1-C2 alkylcarbonyloxy,
      • (xv) C1-C2 alkylcarbonylamino,
      • (xvi) C1-C2 alkylsulphonyl,
      • (xvii) C1-C2 alkylsulphonylamino,
      • (xviii) —C(O)NR7R8,
      • (xix) C1-C2 alkyl which alkyl group may in turn be optionally substituted by at least one halogen atom, preferably from 1 to 3 halogen atoms (particularly fluorine atoms), and
      • (xx) a saturated or unsaturated 5- to 6-membered ring which may comprise at least one ring heteroatom, e.g one, two, three or four ring heteroatoms, independently selected from nitrogen, oxygen and sulphur (preferably nitrogen or oxygen), the ring itself being optionally substituted by at least one substituent, e.g. one, two, three or four substituents, independently selected from halogen (e.g. fluorine, chlorine, bromine or iodine), hydroxyl, oxo, carboxyl, cyano, C1-C2 alkyl, C1-C2 alkoxycarbonyl and C1-C2 hydroxyalkyl.
  • In still another embodiment of the invention, R1 represents a phenyl group substituted by one or two substituents independently selected from
      • (i) halogen (e.g. fluorine or chlorine),
      • (ii) cyano,
      • (iii) C1-C2 alkoxy (particularly methoxy), and
      • (iv) C1-C2 alkyl which alkyl group may in turn be optionally substituted by at least one halogen atom, preferably from 1 to 3 halogen atoms (particularly fluorine atoms).
  • In yet another embodiment, R1 represents fluorophenyl (in particular 2-fluorophenyl), chlorophenyl (in particular 2-chlorophenyl or 3-chlorophenyl), difluorophenyl (in particular 2,6-difluorophenyl), chlorofluorophenyl (in particular 2-chloro-6-fluorophenyl), fluoromethylphenyl (in particular 2-fluoro-6-methylphenyl), methylphenyl (in particular 2-methylphenyl), dimethylphenyl (in particular 2,6-dimethylphenyl), cyanophenyl (in particular 2-cyanophenyl), trifluoromethylphenyl (in particular 2-trifluoromethylphenyl), methoxyphenyl (e.g. 2-methoxyphenyl, 3-methoxyphenyl or 4-methoxyphenyl), ethoxyphenyl (in particular 2-ethoxyphenyl), 2-fluoro-6-methoxyphenyl, 3-fluoro-2-methoxyphenyl, 4-fluoro-2-methoxyphenyl or 5-fluoro-2-methoxyphenyl.
  • In an embodiment of the invention, X represents an oxygen atom or a group —CH2—, —OCH2— or —CH2O—.
  • In another embodiment, X represents an oxygen atom or —CH2O— (where it will be understood that the oxygen atom is attached to the ring A in formula (I)).
  • In yet another embodiment, X represents an oxygen atom.
  • In a further embodiment, X represents —CH2O—.
  • In a still further embodiment, X represents —CH2NR17—, in particular —CH2NH—.
  • When m is 1 or 2, each R2 independently represents a halogen atom (e.g. fluorine, chlorine, bromine or iodine) or a hydroxyl, C1-C6, or C1-C4, or C1-C2 alkyl, difluoromethyl, trifluoromethyl, C1-C6, or C1-C4, or C1-C2 alkoxy, difluoromethoxy, trifluoromethoxy or NR15R16 group. Preferably, R2 represents a halogen atom (particularly fluorine) or a C1-C6, or C1-C4, or C1-C2 alkyl (particularly methyl) group.
  • In one embodiment of the invention, m is 1 and R2 represents a halogen atom (particularly fluorine).
  • In a further embodiment, m is 2 and each R2 independently represents a C1-C6, or C1-C4, or C1-C2 alkyl (particularly methyl) group.
  • In a still further embodiment, m is 0 and the ring A has no R2 substituents.
  • In one aspect, Y represents CH2 or CH(CH3), preferably CH2.
  • R3 represents C1-C8, or C1-C6, or C1-C4, or C1-C2 alkyl, C2-C8, or C2-C6, or
  • C2-C4 alkenyl, or a saturated or unsaturated 3- to 10-membered (e.g. 3-, 4-, 5- or 6- to 7-, 8-, 9- or 10-membered) ring system which may comprise at least one ring heteroatom (e.g. one, two, three or four ring heteroatoms) independently selected from nitrogen, oxygen and sulphur, each of the preceding groups being optionally substituted by at least one substituent (e.g. one, two, three or four substituents) independently selected from
      • (i) halogen (e.g. fluorine, chlorine, bromine or iodine),
      • (ii) cyano,
      • (iii) hydroxyl,
      • (iv) C3-C6 or C5-C6 cycloalkyl,
      • (v) C1-C6, or C1-C4, or C1-C2 alkoxy,
      • (vi) C5-C6 aryloxy,
      • (vii) C5-C6arylC1-C6, or C1-C4, or C1-C2 alkyloxy,
      • (viii) C1-C6, or C1-C4, or C1-C2 alkoxycarbonyl,
      • (ix) C1-C6, or C1-C4, or C1-C2 alkoxycarbonylamino,
      • (x) C1-C6, or C1-C4, or C1-C2 alkoxycarbonyloxy,
      • (xi) C1-C6, or C1-C4, or C1-C2 haloalkyl,
      • (xii) C1-C6, or C1-C4, or C1-C2 haloalkoxy,
      • (xiii) —NR13R14,
      • (xiv) C3-C6 or C5-C6 cycloalkylamino,
      • (xv) C1-C6, or C1-C4, or C1-C2 alkylthio,
      • (xvi) C1-C6, or C1-C4, or C1-C2 alkylcarbonyl,
      • (xvii) C1-C6, or C1-C4, or C1-C2 alkylcarbonyloxy,
      • (xviii) C1-C6, or C1-C4, or C1-C2 alkylcarbonylamino,
      • (xix) sulphonamido,
      • (xx) C1-C6, or C1-C4, or C1-C2 alkylsulphonyl,
      • (xxi) C1-C6, or C1-C4, or C1-C2 alkylsulphonylamino,
      • (xxii) C1-C6, or C1-C4, or C1-C2 alkyl, and
      • (xxiii) a saturated or unsaturated 3- to 10-membered (e.g. 3-, 4-, 5- or 6- to 7-, 8-, 9- or 10-membered) ring system which may comprise at least one ring heteroatom (e.g. one, two, three or four ring heteroatoms) independently selected from nitrogen, oxygen and sulphur, the ring system itself being optionally substituted by least one substituent (e.g. one, two, three or lour substituents) independently selected from halogen (e.g. fluorine, chlorine, bromine or iodine), hydroxyl, oxo, carboxyl, cyano, C1-C6, or C1-C4, or C1-C2 alkyl, C1-C6, or C1-C4, or C1-C2 alkoxy, C1-C6, or C1-C4, or C1-C2 alkoxycarbonyl and C1-C6, or C1-C4, or C1-C2 hydroxyalkyl.
  • Examples of saturated or unsaturated 3- to 10-membered ring systems that may be used, which may be monocyclic or polycyclic (e.g. bicyclic) in which the two or more rings may be fused, bridged or Spiro include one or more (in any combination) of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[2.2.1]heptyl, cyclopentenyl, cyclohexenyl, phenyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, oxadiazolyl (e.g. 1,2,4-oxadiazolyl), tetrahydrofuranyl, diazabicyclo[2.2.1]hept-2-yl; naphthyl, benzofuranyl, benzothienyl, benzodioxolyl, benzoxazolyl, quinolinyl, oxazolyl, thiadiazolyl (e.g. 1,2,3-thiadiazolyl), 2,3-dihydrobenzofuranyl, tetrahydropyranyl, pyrazolyl, imidazo[1,2-a]pyridinyl, pyrazinyl, thiazolidinyl, indanyl, thienyl, isoxazolyl, pyridazinyl, pyrrolyl, furanyl, thiazolyl, isothiazolyl, indolyl, isoindolyl, imidazolyl, pyrimidinyl, benzimidazolyl, triazolyl, tetrazolyl and pyridinyl.
  • Preferred ring systems include phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and thienyl.
  • In one aspect of the invention, R3 represents C1-C4, or C1-C3, or C1-C2 alkyl,
  • C2-C4 alkenyl, or a saturated or unsaturated 3-, 4-, 5- or 6-membered ring system which may comprise at least one ring heteroatom (e.g. one, two, three or four ring heteroatoms) independently selected from nitrogen, oxygen and sulphur, each of the preceding groups being optionally substituted by at least one substituent (e.g. one, two, three or four substituents) independently selected from
      • (i) halogen (e.g. fluorine, chlorine, bromine or iodine),
      • (ii) cyano,
      • (iii) hydroxyl,
      • (iv) C3-C6 or C5-C6 cycloalkyl,
      • (v) C1-C2 alkoxy,
      • (vi) C5-C6 aryloxy,
      • (vii) C5-C6arylC1-C2 alkyloxy,
      • (viii) C1-C2 alkoxycarbonyl,
      • (ix) C1-C2 alkoxycarbonylamino,
      • (x) C1-C2 alkoxycarbonyloxy,
      • (xi) C1-C2 haloalkyl,
      • (xii) C1-C2 haloalkoxy,
      • (xiii) —NR13R14,
      • (xiv) C3-C6 or C5-C6 cycloalkylamino,
      • (xv) C1-C2 alkylthio,
      • (xvi) C1-C2 alkylcarbonyl,
      • (xvii) C1-C2 alkylcarbonyloxy,
      • (xviii) C1-C2 alkylcarbonylamino,
      • (xix) sulphonamido,
      • (xx) C1-C2 alkylsulphonyl,
      • (xxi) C1-C2 alkylsulphonylamino,
      • (xxii) C1-C2 alkyl, and
      • (xxiii) a saturated or unsaturated 3-, 4-, 5- or 6-membered ring system which may comprise at least one ring heteroatom (e.g. one, two, three or four ring heteroatoms) independently selected from nitrogen, oxygen and sulphur, the ring system itself being optionally substituted by least one substituent (e.g. one, two, three or four substituents) independently selected from halogen (e.g. fluorine, chlorine, bromine or iodine), hydroxyl, oxo, carboxyl, cyano, C1-C2 alkyl, C1-C2 alkoxy, C1-C2 alkoxycarbonyl and C1-C2 hydroxyalkyl.
  • In a further aspect of the invention, R3 represents C1-C4, or C1-C3, or C1-C2 alkyl, C2-C4 alkenyl, or a saturated or unsaturated 3-, 4-, 5- or 6-membered hydrocarbyl ring system (e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or phenyl), each of the preceding groups being optionally substituted by at least one substituent (e.g. one, two, three or four substituents) independently selected from
      • (i) halogen (e.g. fluorine or chlorine),
      • (ii) hydroxyl,
      • (iii) C3-C6 cycloalkyl,
      • (iv) C1-C2 alkoxy,
      • (v) C5-C6 aryloxy,
      • (vi) C5-C6arylC1-C2 alkyloxy,
      • (vii) C1-C2 haloalkyl,
      • (viii) C1-C2 alkyl, and
      • (ix) a saturated or unsaturated 3-, 4-, 5- or 6-membered ring system which may comprise at least one ring heteroatom (e.g. one or two ring heteroatoms) independently selected from nitrogen, oxygen and sulphur (e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl and thienyl), the ring system itself being optionally substituted by least one substituent (e.g. one, two, three or four substituents) independently selected from halogen (e.g. fluorine or chlorine), C1-C2 alkyl and C1-C2 alkoxy.
  • In a still further aspect, R3 represents C1-C4, or C1-C3, or C1-C2 alkyl, or a saturated or to unsaturated 3-, 4-, 5- or 6-membered hydrocarbyl ring system (e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or phenyl), each of the preceding groups being optionally substituted by at least one substituent (e.g. one, two, three or four substituents) independently selected from
      • (i) fluorine
      • (ii) chlorine,
      • (iii) hydroxyl,
      • (iv) C3-C6 cycloalkyl,
      • (v) C1-C2 alkoxy,
      • (vi) phenoxy,
      • (vii) benzyloxy,
      • (viii) trifluoromethyl,
      • (ix) C1-C2 alkyl, and
      • (x) a saturated or unsaturated 3-, 4-, 5- or 6-membered ring system which may comprise at least one ring heteroatom (e.g. one or two ring heteroatoms) independently selected from nitrogen, oxygen and sulphur (e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl and thienyl), the ring system itself being optionally substituted by least one substituent (e.g. one, two, three or four substituents) independently selected from halogen (e.g. fluorine or chlorine), C1-C2 alkyl and C1-C2 alkoxy.
  • In still another aspect, R3 represents C1-C4, or C1-C3, or C1-C2 alkyl, cyclopropyl, cyclobutyl or phenyl, each of the preceding groups being optionally substituted by at least one substituent (e.g. one, two, three or four substituents) independently selected from
      • (i) fluorine,
      • (ii) hydroxyl,
      • (iii) methoxy,
      • (iv) cyclopropyl,
      • (v) cyclobutyl, and
      • (vi) phenyl optionally substituted by least one halogen (e.g. fluorine or chlorine) atom.
  • In a particular embodiment of the invention, R3 represents any one of the following moieties or is selected from a group containing any two or more of such moieties:
      • (i) methyl,
      • (ii) difluoromethyl,
      • (iii) trifluoromethyl,
      • (iv) ethyl,
      • (v) difluoroethyl (e.g. 1,1-difluoroethyl),
      • (vi)trifluoroethyl (e.g. 2,2,2,-trifluoroethyl),
      • (vii) —CH2CH2CH3,
      • (viii) —CH(CH3)2,
      • (ix) —CH2CH(CH3)2,
      • (x) cyclopropyl,
      • (xi) cyclopropylmethyl,
      • (xii) cyclobutyl,
      • (xiii) cyclobutylmethyl,
      • (xiv) 3-methoxycyclobutyl,
      • (xv) phenyl,
      • (xvi) 2-fluorophenyl,
      • (xvii) 3-methoxyphenyl,
      • (xviii) 4-methoxyphenyl,
      • (xix) benzyl,
      • (xx) phenylethyl,
      • (xxi)(2-fluorophenyl)ethyl,
      • (xxii) (3-fluorophenyl)ethyl,
      • (xxiii) phenylpropyl,
      • (xxiv) phenylcyclopropyl,
      • (xxv) —CH(OH)CH2-phenyl.
  • Z represents CH2 or CH(CH3), preferably CH2.
  • When n is 1 or 2, each R4 independently represents a halogen atom (e.g. fluorine, chlorine, bromine or iodine) or a hydroxyl, C1-C6, or C1-C4, or C1-C2 alkyl, difluoromethyl, trifluoromethyl, C1-C6, or C1-C4, or C1-C2 alkoxy, difluoromethoxy, trifluoromethoxy or NR18R19 group.
  • In one embodiment, n is 1 and R4 represents a halogen atom (particularly fluorine) or a C1-C6, or C1-C4, or C1-C2 alkyl (particularly methyl) or a C1-C6, or C1-C4, or C1-C2 alkoxy (particularly methoxy) group.
  • In another embodiment, n is 0 and the ring B has no R4 substituents.
  • R5 and R6 each independently represent a hydrogen atom or a C1-C6, or C1-C4, or C1-C2 alkyl group, or R5 and R6 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocycle (e.g. pyrrolidinyl, morpholinyl, piperazinyl or piperidinyl).
  • R7 and R8 each independently represent a hydrogen atom or a C1-C6, or C1-C4, or C1-C2 alkyl group, or R7 and R8 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocycle (e.g. pyrrolidinyl, morpholinyl, piperazinyl or piperidinyl).
  • R13 and R14 each independently represent a hydrogen atom or a C1-C6, or C1-C4, or C1-C2 alkyl group, or R13 and R14 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocycle (e.g. pyrrolidinyl, morpholinyl, piperazinyl or piperidinyl).
  • R15 and R16 each independently represent a hydrogen atom or a C1-C6, or C1-C4, or C1-C2 alkyl group, or R15 and R16 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocycle (e.g. pyrrolidinyl, morpholinyl, piperazinyl or piperidinyl).
  • R17 represents a hydrogen atom or a C1-C6, or C1-C4, or C1-C2 alkyl (particularly methyl or ethyl) group, especially a hydrogen atom.
  • R18 and R19 each independently represent a hydrogen atom or a C1-C6, or C1-C4, or C1-C2 alkyl group, or R18 and R19 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocycle (e.g. pyrrolidinyl, morpholinyl, piperazinyl or piperidinyl).
  • Rings A and B each independently represent a saturated or unsaturated 5-, 6-, 7-, 8-, 9- or 10-membered ring system which may comprise at least one ring heteroatom (e.g. one, two, three or four heteroatoms) independently selected from nitrogen, oxygen and sulphur.
  • Examples of saturated or unsaturated 5- to 10-membered ring systems that may be used, which may be monocyclic or polycyclic (e.g. bicyclic) in which the two or more rings are fused include one or more (in any combination) of cyclopentyl, cyclohexyl, cyclopentenyl, cyclohexenyl, phenyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, oxadiazolyl (e.g. 1,2,4-oxadiazolyl), tetrahydrofuranyl, naphthyl, benzofuranyl, benzothienyl, benzodioxolyl, benzoxazolyl, quinolinyl, oxazolyl, thiadiazolyl (e.g. 1,2,3-thiadiazolyl), 2,3-dihydrobenzofuranyl, tetrahydropyranyl, pyrazolyl, imidazo[1,2-a]pyridinyl, pyrazinyl, thiazolidinyl, indanyl, thienyl, isoxazolyl, pyridazinyl, pyrrolyl, furanyl, thiazolyl, isothiazolyl, indolyl, isoindolyl, imidazolyl, pyrimidinyl, benzimidazolyl, triazolyl, tetrazolyl and pyridinyl. Preferred ring systems include 5- or 6-membered ring systems such as phenyl, pyridinyl, pyrimidinyl, thienyl and cyclohexyl.
  • In an embodiment of the invention, ring A is selected from phenyl, pyridinyl, pyrimidinyl, thienyl and cyclohexyl. Examples of ring A showing the points of attachment of R1—X—, R2 and C(O) to the ring are shown below:
  • Figure US20190010129A1-20190110-C00006
  • In another embodiment of the invention, ring B is selected from phenyl, thienyl and cyclohexyl. Examples of ring B showing the points of attachment of Z, R4 and C(O)OH to the ring are shown below:
  • Figure US20190010129A1-20190110-C00007
  • In a further embodiment, rings A and B are both phenyl.
  • In a preferred embodiment of the invention:
      • R1 represents a phenyl group substituted by one or two substituents independently selected from halogen, cyano, C1-C2 alkoxy, and C1-C2 alkyl which alkyl group may in turn be optionally substituted by at least one halogen atom;
      • X represents an oxygen atom or —CH2O—;
      • m is 0 or 1;
      • if present, R2 represents a halogen atom;
      • Y represents CH2;
      • R3 represents C1-C4 alkyl, or a saturated or unsaturated 3-, 4-, 5- or 6-membered hydrocarbyl ring system, each of the preceding groups being optionally substituted by at least one substituent independently selected from fluorine, hydroxyl, C1-C2 alkoxy, and a saturated or unsaturated 3-, 4-, 5- or 6-membered ring system which may comprise at least one ring heteroatom independently selected from nitrogen, oxygen and sulphur, the ring system itself being optionally substituted by least one substituent independently selected from halogen atoms;
      • Z represents CH2;
      • n is 0 or 1;
      • If present, R4 represents a halogen atom, and
      • rings A and B each independently represent a saturated or unsaturated 5- or 6-membered ring system which may comprise at least one ring heteroatom independently selected from nitrogen, oxygen and sulphur.
  • Examples of compounds of the invention include:
    • 4-((N-Ethyl-4-(2-fluorophenoxy)benzamido)methyl)benzoic acid,
    • 4-((N-(2,2-Difluoroethyl)-4-(2-fluorophenoxy)benzamido)methyl)benzoic acid,
    • 4-((4-(2-Fluorophenoxy)-N-(2,2,2-trifluoroethyl)benzamido)methyl)benzoic acid,
    • 4-((4-(2-Fluorophenoxy)-N-isobutylbenzamido)methyl)benzoic acid,
    • 4-((N-(Cyclopropylmethyl)-4-(2-fluorophenoxy)benzamido)methyl)benzoic acid,
    • 4-((N-(Cyclobutylmethyl)-4-(2-fluorophenoxy)benzamido)methyl)benzoic acid,
    • 4-((4-(2-Fluorophenoxy)-N-((3-methoxycyclobutyl)methyl)benzamido)-methyl)benzoic acid,
    • 4-((4-(2-Fluorophenoxy)-N-isopentylbenzamido)methyl)benzoic acid,
    • 4-((N-(2-Cyclopropylethyl)-4-(2-fluorophenoxy)benzamido)methyl)benzoic acid,
    • 4-((N-(2-Cyclobutylethyl)-4-(2-fluorophenoxy)benzamido)methyl)benzoic acid,
    • 4-((N-Benzyl-4-(2-fluorophenoxy)benzamido)methyl)benzoic acid,
    • 4-((N-(2-Fluorobenzyl)-4-(2-fluorophenoxy)benzamido)methyl)benzoic acid,
    • 4-((4-(2-Fluorophenoxy)-N-(3-methoxybenzyl)benzamido)methyl)benzoic acid,
    • 4-((4-(2-Fluorophenoxy)-N-(4-methoxybenzyl)benzamido)methyl)benzoic acid,
    • 4-((4-(2-Fluorophenoxy)-N-phenethylbenzamido)methyl)benzoic acid,
    • 4-((4-(2-Fluorophenoxy)-N-(3-(2-fluorophenyl)propyl)benzamido)methyl)benzoic acid,
    • 4-((4-(2-Fluorophenoxy)-N-(3-(3-fluorophenyl)propyl)benzamido)methyl)benzoic acid,
    • 4-((4-(2-Fluorophenoxy)-N-((trans-2-phenylcyclopropyl)methyl)benzamido)-methyl)benzoic acid,
    • (S)-4-((4-(2-Fluorophenoxy)-N-(2-hydroxy-3-phenylpropyl)-benzamido)methyl)benzoic acid,
    • (R)-4-((4-(2-Fluorophenoxy)-N-(2-hydroxy-3-phenylpropyl)benzamido)-methyl)benzoic acid,
    • 4-((4-(2-Fluorophenoxy)-N-(4-phenylbutyl)benzamido)methyl)benzoic acid,
    • 4-((N-(Cyclopropylmethyl)-4-(o-tolyloxy)benzamido)methyl)benzoic acid,
    • 4-((N-(Cyclobutylmethyl)-4-(o-tolyloxy)benzamido)methyl)benzoic acid,
    • 4-((N-Benzyl-4-(o-tolyloxy)benzamido)methyl)benzoic acid,
    • 4-((N-Phenethyl-4-(o-tolyloxy)benzamido)methyl)benzoic acid,
    • 4-((N-Phenethyl-4-(2-(trifluoromethyl)phenoxy)benzamido)methyl)benzoic acid,
    • 4-((N-Benzyl-4-(2-cyanophenoxy)benzamido)methyl)benzoic acid,
    • 4-((N-Ethyl-4-(2-methoxyphenoxy)benzamido)methyl)benzoic acid,
    • 4-((N-(2,2-Difluoroethyl)-4-(2-methoxyphenoxy)benzamido)methyl)benzoic acid,
    • 4-((N-Isobutyl-4-(2-methoxyphenoxy)benzamido)methyl)benzoic acid,
    • 4-((N-(Cyclopropylmethyl)-4-(2-methoxyphenoxy)benzamido)methyl)benzoic acid,
    • 4-((4-(2-Methoxyphenoxy)-N-(3-phenylpropyl)benzamido)methyl)benzoic acid,
    • 4-((N-(3-(3-Fluorophenyl)propyl)-4-(2-methoxyphenoxy)benzamido)-methyl)benzoic acid,
    • 4-((N-(Cyclopropylmethyl)-4-(2-ethoxyphenoxy)benzamido)methyl)benzoic acid,
    • 4-((4-(2-Chlorophenoxy)-N-(cyclopropylmethyl)benzamido)methyl)benzoic acid,
    • 4-((N-(Cyclopropylmethyl)-4-(2,6-difluorophenoxy)benzamido)methyl)benzoic acid,
    • 4-((N-(2-Cyclopropylethyl)-4-(2,6-difluorophenoxy)benzamido)methyl)benzoic acid,
    • 4-((N-Benzyl-4-(2,6-difluorophenoxy)benzamido)methyl)benzoic acid,
    • 4-((N-(Cyclopropylmethyl)-4-(2-fluoro-6-methylphenoxy)benzamido)-methyl)benzoic acid,
    • 4-((N-(Cyclobutylmethyl)-4-(2-fluoro-6-methylphenoxy)benzamido)-methyl)benzoic acid,
    • 4-((4-(2-Chloro-6-fluorophenoxy)-N-(cyclopropylmethyl)benzamido-methyl)benzoic acid,
    • 4-((4-(2-Chloro-6-fluorophenoxy)-N-(2-cyclopropylethyl)benzamido)-methyl)benzoic acid,
    • 4-((N-Benzyl-4-(2-chloro-6-fluorophenoxy)benzamido)methyl)benzoic acid,
    • 4-((4-(2,6-Dimethylphenoxy)-N-isopentylbenzamido)methyl)benzoic acid,
    • 4-((N-Benzyl-4-(2,6-dimethylphenoxy)benzamido)methyl)benzoic acid,
    • 4-((4-(2,6-Dimethylphenoxy)-N-phenethylbenzamido)methyl)benzoic acid,
    • 4-((4-(3-Methoxyphenoxy)-N-phenethylbenzamido)methyl)benzoic acid,
    • 4-((4-(4-Methoxyphenoxy)-N-phenethylbenzamido)methyl)benzoic acid,
    • 4-((4-(3-Chlorophenoxy)-N-phenethylbenzamido)methyl)benzoic acid,
    • 4-((N-(Cyclopropylmethyl)-4-((2-fluorobenzyl)oxy)benzamido)methyl)benzoic acid,
    • 4-((N-(Cyclobutylmethyl)-4-((2-fluorobenzyl)oxy)benzamido)methyl)benzoic acid,
    • 4-((N-Benzyl-4-((2-fluorobenzyl)oxy)benzamido)methyl)benzoic acid,
    • 4-((N-(Cyclopropylmethyl)-2-fluoro-4-(2-fluorophenoxy)-benzamido)methyl)benzoic acid,
    • 4-((N-Benzyl-4-(2-fluorophenoxy)cyclohexanecarboxamido)methyl)benzoic acid,
    • trans-4-((N-Benzyl-4-(2-methoxyphenoxy)cyclohexanecarboxamido)-methyl)benzoic acid,
    • cis-4-((N-(3-(3-Fluorophenyl)propyl)-4-(2-methoxyphenoxy)cyclohexanecarboxamido)methyl)benzoic acid,
    • trans-4-((N-(3-(3-Fluorophenyl)propyl)-4-(2-methoxyphenoxy)cyclohexanecarboxamido)methyl)benzoic acid
    • 2-Fluoro-4-((4-(2-fluorophenoxy)-N-(3-methoxybenzyl)benzamido)methyl)benzoic acid,
    • 4-((4-(2-Fluorophenoxy)-N-propylbenzamido)methyl)benzoic acid,
    • 4-((4-(2-Methoxyphenoxy)-N-(2,2,2-trifluoroethyl)benzamido)methyl)benzoic acid,
    • 4-((4-(2-methoxyphenoxy)-N-propylbenzamido)methyl)benzoic acid,
    • 4-((N-(2,2-difluoropropyl)-4-(2-methoxyphenoxy)-benzamido)methyl)benzoic acid,
    • 4-((4-(2-methoxyphenoxy)-N-(3,3,3-trifluoropropyl)-benzamido)methyl)benzoic acid,
    • 4-((N-butyl-4-(2-methoxyphenoxy)benzamido)methyl)benzoic acid,
    • 4-((N-(cyclopropylmethyl)-2-fluoro-4-(2-methoxyphenoxy)-benzamido)methyl)benzoic acid,
    • 4-((N-(cyclopropylmethyl)-4-(2-fluoro-6-methoxyphenoxy)-benzamido)methyl)benzoic acid,
    • 4-((N-(cyclopropylmethyl)-4-(4-fluoro-2-methoxyphenoxy)-benzamido)methyl)benzoic acid,
    • 4-((N-(cyclopropylmethyl)-5-(2-methoxyphenoxy)-picolinamido)methyl)benzoic acid,
    • 4-((4-(o-Tolyloxy)-N-(2,2,2-trifluoroethyl)benzamido)methyl)benzoic acid,
    • 4-((4-(2-Fluorophenoxy)-N-(3,3,3-trifluoropropyl)benzamido)methyl)benzoic acid,
    • 4-((4-(2-Chlorophenoxy)-N-(2,2,2-trifluoroethyl)benzamido)methyl)benzoic acid,
    • 4-((N-Ethyl-4-(o-tolyloxy)benzamido)methyl)benzoic acid,
    • 4-((N-(2,2-Difluoropropyl)-4-(2-fluorophenoxy)benzamido)methyl)benzoic acid,
    • 4-((N-Butyl-4-(2-fluorophenoxy)benzamido)methyl)benzoic acid,
    • 4-((4-(2-Chlorophenoxy)-N-ethylbenzamido)methyl)benzoic acid,
    • 4-((N-(Cyclopropylmethyl)-5-(2-fluorophenoxy)picolinamido)methyl)benzoic acid,
    • 4-((4-(2-Chlorophenoxy)-N-(2,2-difluoroethyl)benzamido)methyl)benzoic acid,
    • 4-((N-(Cyclopropylmethyl)-4-(5-fluoro-2-methoxyphenoxy)-benzamido)methyl)benzoic acid,
    • 4-((4-(4-Fluoro-2-methoxyphenoxy)-N-propylbenzamido)methyl)benzoic acid,
    • 4-((4-(5-Fluoro-2-methoxyphenoxy)-N-propylbenzamido)methyl)benzoic acid,
    • 4-((N-(Cyclopropylmethyl)-4-(3-fluoro-2-methoxyphenoxy)benzamido)methyl)benzoic acid,
    • 4-((N-(Cyclopropylmethyl)-5-(2-fluorophenoxy)pyrimidine-2-carboxamido)methyl)benzoic acid,
    • 4-((N-(Cyclopropylmethyl)-5-(2-methoxyphenoxy)pyrimidine-2-carboxamido)methyl)benzoic acid.
    • 4-((5-(2-Methoxyphenoxy)-N-propylpyrimidine-2-carboxamido)methyl)benzoic acid,
      and pharmaceutically acceptable salts of any one thereof.
  • It should be noted that each of the chemical compounds listed above represents a particular and independent aspect of the invention.
  • The present invention further provides a process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined above which comprises hydrolysing a compound of formula (II)
  • Figure US20190010129A1-20190110-C00008
  • wherein L1 represents a leaving group (e.g. alkoxy such as methoxy) and R1, X, m, R2, Y, R3, Z, n, R4, A and B are as defined in formula (I), in the presence of a suitable base;
    and optionally thereafter carrying out one or more of the following procedures:
      • converting a compound of formula (I) into another compound of formula (I)
      • removing any protecting groups
      • forming a pharmaceutically acceptable salt.
  • The process is conveniently carried out using a base such as lithium hydroxide or sodium hydroxide in a solvent such as 1,4-dioxane or a solvent mixture such as water and tetrahydrofuran, at room temperature or at elevated temperature, e.g. in the range from 20° C. to 100° C.
  • Compounds of formula (II) may be prepared by reacting a compound of formula (III)
  • Figure US20190010129A1-20190110-C00009
  • wherein R1, X, m, R2 and A are as defined in formula (II), with a compound of formula (IV), or a salt (e.g. hydrochloride salt) thereof,
  • Figure US20190010129A1-20190110-C00010
  • wherein L1, Y, R3, Z, n, R4 and B are as defined in formula (II). The reaction is conveniently carried out in the presence of an organic solvent such as tetrahydrofuran or N,N-dimethylformamide, a base such as diisopropylethylamine and an amide coupling agent such as 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) or O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HBTU).
  • Compounds of formula (III) may be prepared by oxidising the corresponding aldehyde of formula (V)
  • Figure US20190010129A1-20190110-C00011
  • wherein R1, X, m, R2 and A are as defined in formula (III). Suitable oxidising agents include sodium chlorite.
  • Compounds of formula (V) in which X represents an oxygen atom or —CH2O— may be prepared by reacting a compound of formula (VI), R1—(CH2)pX′H, in which p is 0 or 1, X′ is oxygen and R1 is as defined in formula (V) with a compound of formula (VII)
  • Figure US20190010129A1-20190110-C00012
  • in which L2 represents a leaving group (e.g. a halogen atom such as fluorine) and m, R2 and A are as defined in formula (V).
  • Compounds of formula (III) in which X represents —CH2— may be prepared by reacting a compound of formula (VIII)
  • Figure US20190010129A1-20190110-C00013
  • in which L3 represents a leaving group (e.g. a halogen atom such as bromine), P1 represents a suitable protecting group (e.g. an alkoxy group such as methoxy) and m, R2 and A are as defined in formula (III), with a compound of formula (IX), R1—B(OH)2, in which R1 is as defined in formula (III), in the presence of a suitable palladium catalyst, e.g. [1,1′-bis(diphenylphosphino)ferrocene]palladium(11) chloride complex with dichloromethane (see, for example, WO 2012/080221 in the name of Katholieke Universiteit Leuven), followed by ester hydrolysis.
  • Compounds of formula (III) in which X represents —CH2CH2— may be prepared by a Heck Reaction by reacting a compound of formula (X)
  • Figure US20190010129A1-20190110-C00014
  • in which P2 is as defined for P1 above and m, R2 and A are as defined in formula (III), with a compound of formula (XI), R1-L4, in which L4 represents a leaving group (e.g. a halogen atom such as iodine) and R1 is as defined in formula (III), in the presence of a suitable palladium catalyst, followed by a hydrogenation reaction and then ester hydrolysis.
  • Compounds of formula (III) in which X represents —OCH2— may be prepared by reacting a compound of formula (VIII) as defined above with a compound of formula (XII), R1—X′H, wherein R1 and X′ are as defined in formula (VI), in the presence of a base such as potassium carbonate and in a solvent such as N,N-dimethylformamide (see, for example, WO 2012/007868 in the name of Pfizer Limited), followed by ester hydrolysis.
  • Compounds of formula (V) in which X represents —CH2NR17 may be prepared by reacting a compound of formula (VII) as defined above with a compound of formula (XIII), R1—CH2NR17H, in which R1 and R17 are as defined in formula (V), in the presence of a suitable copper catalyst such as copper (I) iodide (see, for example, Kwong et al., Organic Letters, 2002, volume 4, pages 581 to 584).
  • Compounds of formula (III) in which X represents —NR17CH2— may be prepared by reacting a compound of formula (VIII) as defined above with a compound of formula (XIV), R1—NR17H, wherein R1 and R17 are as defined in formula (III), in the presence of a base such as calcium carbonate and a solvent such as iosbutyramide (see, for example, WO 2007/120096 in the names of AstraZeneca AB and Astex Therapeutics Limited), followed by ester hydrolysis.
  • Compounds of formula (III) in which X represents —CHF— may be prepared by reacting a compound of formula (XV)
  • Figure US20190010129A1-20190110-C00015
  • in which P3 is as defined for P1 above and m, R2 and A are as defined in formula (III), with a compound of formula (XI) as defined above in the presence of an organolithium such as phenyllithium, followed by a fluorination reaction using, for example, diethylaminosulfur trifluoride and then ester hydrolysis.
  • Compounds of formula (III) in which X represents —CF2— may be prepared by reacting a compound of formula (VIIa)
  • Figure US20190010129A1-20190110-C00016
  • in which P4 is as defined for P1 above and m, R2 and A are as defined in formula (VII), with a compound of formula (IX) as defined above, in the presence of carbon monoxide and a suitable palladium catalyst such as tris-(dibenzylideneacetone)dipalladium (0), followed by a fluorination reaction using, for example, diethylaminosulfur trifluoride and then ester hydrolysis.
  • Compounds of formula (IV) in which Z is CH2 or CH(CH3) may be prepared by reacting a compound of formula (XVI), R3—Y—NH2, in which R3 and Y are as defined in formula in (IV), with a compound of formula (XVII)
  • Figure US20190010129A1-20190110-C00017
  • in which R20 represents hydrogen or methyl, and L1, n, R4 and B are as defined in formula (IV), in the presence of a reducing agent such as sodium triacetoxyborohydride.
  • Compounds of formulae (V) to (XVII) are either commercially available, are well known in the literature or may be prepared using known techniques.
  • It will be appreciated by those skilled in the art that it may be necessary or desirable at any stage in the synthesis of the compounds of the invention to protect one or more sensitive groups, so as to prevent undesirable side reactions. In particular, it may be necessary or desirable to protect certain functional groups such as hydroxyl, carboxyl or amino groups. Thus, the preparation of the compounds of formula (I) may involve, at an appropriate stage, the introduction and/or removal of one or more protecting groups.
  • The protection and deprotection of functional groups is described in ‘Protective Groups in Organic Chemistry’, edited by J. W. F. McOmie, Plenum Press (1973) and ‘Protective Groups in Organic Synthesis’, 3rd edition, T. W. Greene and P. G. M. Wuts, Wiley-Interscience (1999).
  • The compounds of formula (I) above may be converted to a pharmaceutically acceptable salt thereof, preferably an acid addition salt such as a hydrochloride, hydrobromide, benzenesulphonate (besylate), saccharin (e.g. monosaccharin), trifluoroacetate, sulphate, nitrate, phosphate, acetate, fumarate, maleate, tartrate, lactate, citrate, pyruvate, succinate, valerate, propanoate, butanoate, malonate, oxalate, 1-hydroxy-2-napthoate (xinafoate), methanesulphonate or p-toluenesulphonate salt.
  • In one aspect of the invention, compounds of formula (I) may bear one or more radiolabels. Such radiolabels may be introduced by using radiolabel-containing reagents in the synthesis of the compounds of formula (I), or may be introduced by coupling the compounds of formula (I) to chelating moieties capable of binding to a radioactive metal atom. Such radiolabeled versions of the compounds may be used, for example, in diagnostic imaging studies.
  • Unless stated otherwise, any atom specified herein may also be an isotope of said atom. For example, the term “hydrogen” encompasses 1H, 2H and 3H. Similarly carbon atoms are to be understood to include 12C, 13C and 14C, nitrogen atoms are to be understood to include 14N and 15N, and oxygen atoms are to be understood to include 16O, 17O and 18O.
  • In a further aspect of the invention, compounds of formula (I) may be isotopically labelled. As used herein, an “isotopically labelled” compound is one in which the abundance of a particular nuclide at a particular atomic position within the molecule is increased above the level at which it occurs in nature.
  • Compounds of formula (I) and their salts may be in the form of hydrates or solvates which form an aspect of the present, invention. Such solvates may be formed with common organic solvents, including but not limited to, alcoholic solvents e.g. methanol, ethanol or isopropanol.
  • Where compounds of formula (I) are capable of existing in stereoisomeric forms, it will be understood that the invention encompasses the use of all geometric and optical isomers (including atropisomers) of the compounds of formula (I) and mixtures thereof including racemates. The use of tautomers and mixtures thereof also forms an aspect of the present invention. Enantiomerically pure forms are particularly desired.
  • Compounds of formula (I) and their salts may be amorphous or in a polymorphic form or a mixture of any of these, each of which forms an aspect of the present invention.
  • The compounds of formula (I) and their pharmaceutically acceptable salts have activity as pharmaceuticals, in particular as modulators (e.g. antagonists) of LPAR5 and, optionally also, as modulators (e.g. antagonists) of LPAR1, and thus may be used in the treatment of: fibrosis of organs such as liver, kidney, skin, lung, heart and the like; liver diseases (acute hepatitis, chronic hepatitis, liver fibrosis, liver cirrhosis, portal hypertension, regenerative failure, non-alcoholic steato hepatitis (NASH), liver hypofunction, hepatic blood flow disorder, and the like); cardiovascular disorders (restenosis, atherosclerosis, heart failure, cardiomyopathy, myocardial infarction, myocardial remodelling, vascular remodelling, hypertension, peripheral arterial occlusive disease, thrombosis, vascular permeability disorders, and the like); cell proliferative disease (cancer (solid tumour, solid tumour metastasis, vascular fibroma, myeloma, multiple myeloma, Kaposi's sarcoma, leukaemia, chronic lymphocytic leukaemia (CLL) and the like) and invasive metastasis of cancer cell, and the like); inflammatory disease (rheumatoid arthritis, osteoarthritis, psoriasis, nephropathy, pneumonia and the like); transplant rejection; gastrointestinal tract disease (irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), abnormal pancreatic secretion, and the like); renal disease; urinary tract-associated disease (benign prostatic hyperplasia or symptoms associated with neuropathic bladder disease, spinal cord tumour, hernia of intervertebral disk, spinal canal stenosis, symptoms derived from diabetes, lower urinary tract disease (obstruction of lower urinary tract, and the like); inflammatory disease of lower urinary tract (dysuria; overactive bladder, interstitial cystitis, frequent urination and the like); pancreas disease; abnormal angiogenesis associated disease (arterial obstruction and the like); systemic sclerosis including localised scleroderma; brain associated disease (cerebral infarction, cerebral hemorrhage, and the like); pain (neuropathic pain, peripheral neuropathy, lightning pains, phamtom pains, shooting pains, acute pain, inflammatory pain, neuralgia, tissue injury pain and the like); ocular disease (choroidal neovascularisation, age related macular degeneration (AMD), diabetic retinopathy, proliferative vitreoretinopathy (PVR), cicatricial pemphigold, glaucoma filtration surgery scarring and the like); pulmonary disease (chronic obstructive pulmonary disease, asthma, acute respiratory distress syndrome); psychiatric disorders; neurodegenerative diseases; cerebral and peripheral nerve disorders; scarring disorders; and wound healing.
  • Thus, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof as hereinbefore defined for use in therapy, in particular for the treatment of conditions whose development or symptoms are linked to LPAR5 or LPAR1 activity.
  • The present invention also provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof as hereinbefore defined for the preparation of a medicament for the treatment of conditions whose development or symptoms are linked to LPAR5 or LPAR1 activity.
  • In the context of the present specification, the terms “therapy” and “treatment” also include “prophylaxis” unless there are specific indications to the contrary. The terms “therapeutic”, “therapeutically” and “treating” should be construed accordingly.
  • Prophylaxis is expected to be particularly relevant to the treatment of persons who have suffered a previous episode of, or are otherwise considered to be at increased risk of, the disorder or condition in question. Persons at risk of developing a particular disorder or condition generally include those having a family history of the disorder or condition, or those who have been identified by genetic testing or screening to be particularly susceptible to developing the disorder or condition or those in the prodromal phase of a disorder.
  • In particular, the compounds of the invention (including pharmaceutically acceptable salts) may be used in the treatment of pain (such as neuropathic pain), atherosclerosis and fibrosis.
  • “Pain” means the more or less localised sensation of discomfort, distress or agony resulting from the stimulation of specialised nerve endings. There are many types of pain (as illustrated above) and the goal of treatment of pain is to reduce the degree or severity of pain perceived by a treatment subject.
  • The invention also provides a method of treating pain (e.g. neuropathic pain), atherosclerosis or fibrosis which comprises administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof as hereinbefore defined.
  • For the above-mentioned therapeutic uses the dosage administered will, of course, vary as with the compound employed, the mode of administration, the treatment desired and the disorder indicated. For example, the daily dosage of the compound of the invention, if inhaled, may be in the range from 0.05 micrograms per kilogram body weight (μg/kg) to 100 micrograms per kilogram body weight (μg/kg). Alternatively, if the compound is administered orally, then the daily dosage of the compound of the invention may be in the range from 0.01 micrograms per kilogram body weight (μg/kg) to 100 milligrams per kilogram body weight (mg/kg).
  • The compounds of formula (I) and pharmaceutically acceptable salts thereof may be used on their own but will generally be administered in the form of a pharmaceutical composition in which the formula (I) compound/salt (active ingredient) is in association with a pharmaceutically acceptable adjuvant, diluent or carrier.
  • Therefore the present invention further provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof as hereinbefore defined, in association with a pharmaceutically acceptable adjuvant, diluent or carrier.
  • The invention still further provides a process for the preparation of a pharmaceutical composition of the invention which comprises mixing a compound of formula (I) or a pharmaceutically acceptable salt thereof as hereinbefore defined with a pharmaceutically acceptable adjuvant, diluent or carrier.
  • Conventional procedures for the selection and preparation of suitable pharmaceutical formulations are described in, for example, “Pharmaceutics—The Science of Dosage Form Design”, M. E. Aulton, Churchill Livingstone, 1988.
  • Pharmaceutically acceptable adjuvants, diluents or carriers that may be used in the pharmaceutical compositions of the invention are those conventionally employed in the field of pharmaceutical formulation, and include, but are not limited to, sugars, sugar alcohols, starches, ion exchangers, alumina, aluminium stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycerine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulphate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.
  • The pharmaceutical compositions of the present invention may be administered orally, topically, parenterally, by inhalation spray, rectally, nasally, buccally, vaginally or via an implanted reservoir. Oral or topical administration is preferred. The pharmaceutical compositions of the invention may contain any conventional non-toxic pharmaceutically acceptable adjuvants, diluents or carriers. The term parenteral as used herein includes subcutaneous, intracutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques.
  • The pharmaceutical compositions may be in the form of a sterile injectable preparation, for example, as a sterile injectable aqueous or oleaginous suspension. The suspension may be formulated according to techniques known in the art using suitable dispersing or wetting agents (such as, for example, Tween 80) and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable diluents and solvents that may be employed are mannitol, water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono- or diglycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant.
  • The pharmaceutical compositions of this invention may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, powders, granules, and aqueous suspensions and solutions. These dosage forms are prepared according to techniques well-known in the art of pharmaceutical formulation. In the case of tablets for oral use, carriers which are commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried corn starch. When aqueous suspensions are administered orally, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening and/or flavouring and/or colouring agents may be added.
  • The pharmaceutical compositions of the invention may also be administered in the form of suppositories for rectal administration. These compositions can be prepared by mixing the active ingredient with a suitable non-irritating excipient which is solid at room temperature but liquid at the rectal temperature and therefore will melt in the rectum to release the active ingredient. Such materials include, but are not limited to, cocoa butter, beeswax and polyethylene glycols.
  • The pharmaceutical compositions of this invention may be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other solubilising or dispersing agents known in the art.
  • Depending on the mode of administration, the pharmaceutical composition will preferably comprise from 0.05 to 99% w (percent by weight), more preferably from 0.05 to 80% w, still more preferably from 0.10 to 70% w, and even more preferably from 0.10 to 50% w, of active ingredient, all percentages by weight being based on total composition.
  • The compounds of the invention (that is, compounds of formula (I) and pharmaceutically acceptable salts thereof) may also be administered in conjunction with other compounds used for the treatment of the above conditions.
  • The invention therefore further relates to combination therapies wherein a compound of the invention or a pharmaceutical composition or formulation comprising a compound of the invention is administered concurrently, sequentially or as a combined preparation with another therapeutic agent or agents, for the treatment of one or more of the conditions previously indicated. Such therapeutic agents may be selected from the following:
  • (i) opioid agonists, partial agonists or antagonists such as, for example, morphine, buprenorphine, alfentanil, fentanyl, pethidine, oxycodone, tramadol and codeine, and equivalents and pharmaceutically active isomer(s) and/or metabolite(s) thereof;
    (ii) antidepressants such as, for example, amitriptyline, amoxapine, bupropion, citalopram, clomipramine, desipramine, doxepin duloxetine, elzasonan, escitalopram, fluvoxamine, fluoxetine, gepirone, imipramine, ipsapirone, maprotiline, nortriptyline, nefazodone, paroxetine, phenelzine, protriptyline, reboxetine, robaizotan, sertraline, sibutramine, thionisoxetine, tranylcypromaine, trazodone, trimipramine, venlafaxine, ketamine, vortioxetine, and equivalents and pharmaceutically active isomer(s) and/or metabolite(s) thereof;
    (iii) anxiolytics including, for example, alnespirone, azapirones, benzodiazepines, barbiturates, and equivalents and pharmaceutically active isomer(s) and/or metabolite(s) thereof. Example anxiolytics include adinazolam, alprazolam, balezepam, bentazepam, bromazepam, brotizolam, buspirone, clonazepam, clorazepate, chlordiazepoxide, cyprazepam, diazepam, diphenhydramine; estazolam, fenobam, flunitrazepam, flurazepam, fosazepam, lorazepam, lormetazepam, meprobamate, midazolam, nitrazepam, oxazepam; prazepam, quazepam, reclazepam, tracazolate, trepipam, temazepam, triazolam, uldazepam, and zolazepam; and equivalents and pharmaceutically active isomer(s) and/or metabolite(s) thereof;
    (iv) anticonvulsants including, for example, carbamazepine, valproate, lamotrigine, and gabapentin, and equivalents and pharmaceutically active isomer(s) and/or metabolite(s) thereof;
    (v) migraine therapies including, for example, almotriptan, amantadine, bromocriptine, butalbital, cabergoline, dichloralphenazone, eletriptan, frovatriptan, lisuride, naratriptan, pergolide, pramipexole; rizatriptan, ropinirole, sumatriptan, zolmitriptan, and zomitriptan, and equivalents and pharmaceutically active isomer(s) and/or metabolite(s) thereof;
    (vi) stroke therapies including, for example, abciximab, activase, NXY-059, citicoline, crobenetine, desmoteplase; repinotan, traxoprodil, and equivalents and pharmaceutically active isomer(s) and/or metabolite(s) thereof;
    (vii) urinary incontinence therapies including, for example, darafenacin, falvoxate, oxybutynin, propiverine, robalzotan, solifenacin, and tolterodine, and equivalents and pharmaceutically active isomer(s) and/or metabolite(s) thereof;
    (viii) neuropathic pain therapies including, for example, gabapentin, lidoderm, and pregablin, and equivalents and pharmaceutically active isomer(s) and/or metabolite(s) thereof; and
    (ix) nociceptive pain therapies such as, for example, celecoxib, etoricoxib, lumiracoxib, rofecoxib, valdecoxib, diclofenac, loxoprofen, naproxen, and paracetamol, and equivalents and pharmaceutically active isomer(s) and/or metabolite(s) thereof.
  • Such combination products employ the compounds of this invention within the dosage range described herein and the other pharmaceutically active agent within approved dosage ranges.
  • The present invention will now be further explained by reference to the following illustrative examples. In the illustrative examples, the compounds synthesised are both named and illustrated structurally. Whilst every effort has been made to ensure that the chemical names and the chemical structures are consistent, if any inconsistencies occur the illustrated chemical structure should be taken to be correct, unless the illustrated chemical structure is chemically impossible.
  • Nuclear magnetic resonance (NMR) spectra were typically recorded at 400 MHz; the chemical shifts (δ) are reported in parts per million. Spectra were recorded using a Bruker 400 Avance instrument fitted with a 5 mm BBFO probe or DUL probe. Instrument control was by Bruker TopSpin 2.1 software, unless stated otherwise.
  • Purity was assessed using UPLC with UV (photodiode array) detection over a wide range of wavelengths, normally 220-450 nm, using a Waters Acquity UPLC system equipped with Acquit), UPLC BEH or HSS C18 columns (2.1 mm id×50 mm long) operated at 50 or 60° C. Mobile phases typically consisted of MeCN or MeOH mixed with water containing either 0.05% formic acid or 0.025% NH4OH. Mass spectra were recorded with a Waters SQD single quadrupole mass spectrometer using atmospheric pressure ionisation, unless stated otherwise.
  • Compounds were purified using normal phase chromatography on silica or alumina, or by reverse-phase chromatographic methods, using Biotage or Isolute KPNH Cartridge, SCX cartridge and SCX-2 solid phase extraction cartridges.
  • Preparative HPLC was typically performed using an Agilent Technologies 1100 Series system or a Waters autopurification LC/MS system typically using Waters 19 mm id×100 mm long C18 columns such as XBridge or SunFire 5 μm materials at room temperature. Mobile phases typically consisted of MeCN or MeOH mixed with water containing either 0.1% formic acid or 0.1% NH4OH, unless stated otherwise.
  • The compound names were generated using ChemBioDraw Ultra 12.0 (Perkin Elmer Inc.).
    • Generally:
    • (i) Operations were typically carried out at ambient temperature; i.e. in the range 15-25° C., and under an atmosphere of an inert gas such as nitrogen or argon unless otherwise stated.
    • (ii) Inorganic solutions were aqueous unless otherwise stated.
    • (iii) Drying of solutions was carried out with magnesium sulfate or sodium sulfate, or using a phase-separating cartridge.
    • (iv) Concentration was typically carried out by rotary evaporation under vacuum.
    • (v) Column chromatography and high pressure liquid chromatography (HPLC) were performed on silica or reverse-phase C18 silica; unless otherwise stated, preparative HPLC was carried out using MeCN/water (both with 0.1% NH4OH).
    • (vi) Yields, where present, are not necessarily the maximum attainable.
    • (vii) In general, the structures of the end-products of the Formula I were confirmed by nuclear magnetic resonance (NMR) and/or mass spectral (MS) techniques; electrospray ionization (in positive or negative mode, ES+ or ES−) mass spectral data were obtained using a Waters Amity SQD spectrometer and, where appropriate, either positive ion data or negative ion data were collected; NMR chemical shift values were measured on the delta scale; the following abbreviations have been used: s, singlet; m, multiplet; br, broad; br s, broad singlet.
    • (viii) Intermediates were not necessarily fully purified but their structures and purity were assessed by thin layer chromatography (TLC), HPLC, infra-red (IR) and/or NMR analysis.
  • The following abbreviations are used:
    • bp boiling point
    • DBU 1,8-diazabicyclo[5.4.0]undec-7-ene
    • DCM dichloromethane
    • DIPEA diisopropylethylamine
    • DMF N,N-dimethylformamide
    • DMSO dimethyl sulfoxide
    • DMSO-d6 deuterated dimethyl sulfoxide
    • eq equivalent(s)
    • Et ethyl
    • Et2O diethyl ether
    • EtOAc ethyl acetate
    • EtOH ethanol
    • h hour(s)
    • HATU O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate
    • HBTU O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate
    • HCl hydrochloric acid
    • IMS industrial methylated spirit
    • iPr isopropyl
    • M molar
    • Me methyl
    • MeCN acetonitrile
    • MeOH methanol
    • mmHg millimetres of mercury
    • mmol millimoles
    • NaOH sodium hydroxide
    • petrol petroleum ether, typically bp 40-60° C.
    • RT room temperature, typically 15-25° C.
    • THF tetrahydrofuran
    A. Preparation of Acid Intermediates
  • Figure US20190010129A1-20190110-C00018
    • Intermediate A1: 4-(2-Fluorophenoxy)benzoic Acid
  • Figure US20190010129A1-20190110-C00019
  • Step (i) Potassium carbonate (31.1 g, 225 mmol) was added to a solution of 4-fluorobenzaldehyde (7.96 mL, 75 mmol) and 2-fluorophenol (9 mL, 98 mmol) in DMF (100 mL). The mixture was heated at 100° C. under nitrogen for 24 h. After cooling to RT, the mixture was partitioned between EtOAc (200 mL) and water (150 mL). The aqueous phase was extracted with EtOAc (200 mL). The combined organic phases were washed with brine (3×50 mL), dried and concentrated. The residue was purified by silica chromatography (0-20% EtOAc/petrol) to give 4-(2-fluorophenoxy)benzaldehyde (crude, 17.7 g) which was used in the next step (ii) without further purification or characterisation.
  • Step (ii) 4-(2-Fluorophenoxy)benzaldehyde (crude, 17.7 g) was dissolved in THF (100 mL), tert-butanol (100 mL) and water (50 mL), and the mixture cooled in an ice-water bath. 2-Methyl-2-butene (43.3 mL, 409 mmol), potassium dihydrogen phosphate (27.8 g, 205 mmol) and sodium chlorite (23.12 g, 205 mmol) were added sequentially and the mixture was stirred at KT for 18 h. The mixture was partitioned between water (100 mL) and Et2O (200 mL), and the aqueous phase extracted with Et2O (200 mL). The combined organic phases were washed sequentially with saturated sodium thiosulfate solution (100 mL) and brine (100 mL), dried and concentrated. Addition of EtOAc and petrol resulted in a precipitate which was isolated by filtration and air-dried to give the title compound (11.95 g, 63%) as a pale yellow solid.
  • MS ES−: 231
    • Intermediate A2: 4-(2,6-Dimethylphenoxy)benzoic Acid
  • Figure US20190010129A1-20190110-C00020
  • Step (i) Tripotassium phosphate (9.27 g, 43.7 mmol) and palladium(II) acetate (0.490 g, 2.18 mmol) were added to a solution of ethyl 4-bromobenzoate (5 g, 21.8 mmol) and 2,6-dimethylphenol (3.73 g, 30.6 mmol) in toluene (40 mL). The mixture was degassed for about 5 minutes and purged with nitrogen. A solution of di-tert-butyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (1.390 g, 3.27 mmol) in toluene (5 mL) was added. The mixture was degassed for a further 2 minutes, purged with nitrogen, and heated under reflux for 1.5 h. The mixture was partitioned between water and EtOAc (50 mL each), and the organic phase dried and concentrated. The residue was purified by silica chromatography (0-20% EtOAc/petrol) to give ethyl 4-(2,6-dimethylphenoxy)benzoate (crude, 2 g) which was used in the next step (ii) without further purification or characterisation.
  • Step (ii) Ethyl 4-(2,6-dimethylphenoxy)benzoate (crude, 2 g) was dissolved in MeOH (7 mL). NaOH (2 M, 7 mL) was added, and the mixture heated under microwave irradiation at 120° C. for 20 minutes. The mixture was acidified to pH 1 (2 M HCl), diluted with water (50 mL) and extracted with EtOAc (50 mL). The organic phase was dried and concentrated. The residue was dissolved/suspended in EtOAc (50 mL) and the mother liquor concentrated. This process was repeated with Et2O:EtOAc (4:1, 20 mL) and then Et2O (20 mL) to give the title compound (crude, 800 mg) which was used in the next step without further purification or characterisation.
    • Intermediate A3: 4-(2,6-Difluorophenoxy)benzoic Acid
  • Figure US20190010129A1-20190110-C00021
  • Step (i) 4-(2,6-Difluorophenoxy)benzaldehyde was prepared as described for 4-(2-fluorophenoxy)benzaldehyde (Intermediate A1, step (i)) from 4-fluorobenzaldehyde and 2,6-difluorophenol, except with 2 eq potassium carbonate and 1.2 eq of the phenol.
  • 1H NMR (400 MHz, DMSO-d6) δ ppm 7.12-7.21 (m, 2H) 7.32-7.50 (m, 3H) 7.90-7.99 (m, 2H) 9.94 (s, 1H)
  • Step (ii) 4-(2,6-Difluorophenoxy)benzaldehyde (0.500 g, 2.14 mmol) was dissolved in tert-butanol (6 mL) and water (3 mL). 2-Methyl-2-butene (2 M in THF, 5.34 mL, 10.67 mmol), potassium dihydrogen phosphate (0.73 g, 5.34 mmol) and sodium chlorite (0.72 g, 2.14 mmol) were added sequentially and the mixture was stirred at RT for 4 h. The mixture was partitioned between water (30 mL) and Et2O (30 mL). The aqueous phase was acidified with HCl (2 M, 10 mL) and extracted with Et2O (30 mL). The combined organic phases were washed sequentially with saturated sodium thiosulfate solution (15 mL) and brine (15 mL), dried and concentrated. The residue was loaded onto an anion exchange cartridge.
  • After washing with MeCN, the product was eluted with 2 M HCl/MeCN then concentrated to give the title compound (0.367 g, 69%) as a white solid.
  • MS ES+: 249
    • Intermediate A4: 4-(2-Fluoro-6-methylphenoxy)benzoic Acid
  • Figure US20190010129A1-20190110-C00022
  • Step (i) 4-(2-Fluoro-6-methylphenoxy)benzaldehyde was prepared as described for 4-(2-fluorophenoxy)benzaldehyde (Intermediate A1, step (i)) from 4-fluorobenzaldehyde and 2-fluoro-6-methylphenol, and used in the next step (ii) without further purification or characterisation.
  • Step (ii) The title compound was prepared as described for 4-(2-fluorophenoxy)benzoic acid (Intermediate A1, step (ii)) from 4-(2-fluoro-6-methylphenoxy)benzaldehyde (step (i) above), with recrystallisation of the product from EtOAc/petrol, and used in the next step without further purification or characterisation.
    • Intermediate A5: 4-(2-Chloro-6-fluorophenoxy)benzoic Acid
  • Figure US20190010129A1-20190110-C00023
  • Step (i) 4-(2-Chloro-6-fluorophenoxy)benzaldehyde was prepared as described for 4-(2-fluorophenoxy)benzaldehyde (Intermediate A1, step (i)) from 4-fluorobenzaldehyde and 2-chloro-6-fluorophenol.
  • 1H NMR (400 MHz, DMSO-d6) δ ppm 7.07-7.17 (m, 2H) 7.40-7.60 (m, 3H) 7.89-7.99 (m, 2H) 9.93 (s, 1H)
  • Step (ii) The title compound was prepared as described for 4-(2-fluorophenoxy)benzoic acid (Intermediate A1, step (ii)) from 4-(2-chloro-6-fluorophenoxy)benzaldehyde (step (i) above).
  • MS ES−: 265
    • Intermediate A6: 2-Fluoro-4-(2-fluorophenoxy)benzoic Acid
  • Figure US20190010129A1-20190110-C00024
  • Step (i) 2-Fluoro-4-(2-fluorophenoxy)benzaldehyde was prepared as described for 4-(2-fluorophenoxy)benzaldehyde (Intermediate A1, step (i)) from 2,4-difluorobenzaldehyde and 2-fluorophenol, except with 1 eq of the phenol and heating at 80° C.
  • MS ES+: 235
  • Step (ii) The title compound was prepared as described for 4-(2-fluorophenoxy)benzoic acid (Intermediate A1, step (ii)) from 2-fluoro-4-(2-fluorophenoxy)benzaldehyde (step (i) above).
  • MS ES+: 251
    • Intermediate A7: 4-((2-Fluorobenzyl)oxy)benzoic Acid
  • Figure US20190010129A1-20190110-C00025
  • Step (i) Sodium hydride (60% dispersion in mineral oil, 0.177 g, 4.43 mmol) was added to a mixture of 4-fluorobenzaldehyde (0.437 mL, 4.03 mmol) and (2-fluorophenyl)methanol (0.508 g, 4.03 mmol) in DMF (20 mL). The reaction was stirred under nitrogen at room temperature for 18 h. The mixture was diluted with EtOAc and washed with sodium bicarbonate and then brine. The organic phase was dried and concentrated to give 4-((2-fluorobenzyl)oxy)benzaldehyde as a residue which was used in the next step (ii) without further purification or characterisation.
  • Step (ii) The title compound was prepared as described for 4-(2,6-difluorophenoxy)benzoic acid (Intermediate A3, step (ii)) from 4-((2-fluorobenzyl)oxy)benzaldehyde (step (i) above) and used in the next step without further purification or characterisation.
    • Intermediate A8: 2-Fluoro-4-(2-methoxyphenoxy)benzoic Acid
  • Figure US20190010129A1-20190110-C00026
  • Prepared by a two step process analogous to that described for Intermediate A1 in which, in the first step, 2,4-difluorobenzaldehyde was reacted with 2-methoxyphenol to yield 2-fluoro-4-(2-methoxyphenoxy)benzaldehyde which, without further purification or characterisation, was used in the second oxidation step to yield the titled compound.
  • The intermediates 4-(2-methylphenoxy)benzoic acid and 4-(2-chlorophenoxy)benzoic acid used in the preparation of several of the final compounds is known in the art and is commercially available from chemical suppliers such as Apollo Scientific.
    • B. Preparation of 4-(Aminomethyl)Benzoates and Analogues
  • Figure US20190010129A1-20190110-C00027
  • Intermediates of formula (B) shown in Table I below were prepared according to one of the following methods R1 to R6:
    • Method R1
  • A solution of the amine (50 mmol) and methyl 4-formylbenzoate (50 mmol) in IMS or EtOH (100 mL) was heated under reflux for 2 h. After cooling, the mixture was concentrated and the residue was dissolved in MeOH (400 mL). The resulting solution was cooled in an ice-water bath and sodium borohydride (40 mmol) was added, typically in several portions over 10 minutes. The mixture was stirred and allowed to warm to RT. After 2 h, the mixture was concentrated. The residue was stirred in water (20 mL). The mixture was acidified HCl (2 M) and extracted with DCM (3×20 mL). The aqueous phase was basified with solid NaOH and extracted with DCM (3×50 mL). The latter extracts were dried and concentrated to give the intermediate of formula (B).
    • Method R2
  • As for Method R1, except that after concentrating the sodium borohydride reaction, the residue was dissolved/suspended in HCl (2 M) or HCl (4 M in 1,4-dioxane). The resulting precipitate was filtered, washed with water, and dried to give the hydrochloride salt of the intermediate of formula (B).
    • Method R3
  • A solution of the amine (5 mmol) and methyl 4-formylbenzoate (5 mmol) was stirred in DCM (20 mL) for 2 h at RT. Sodium triacetoxyborohydride (10 mmol) was added, followed by acetic acid (6 mmol). After stirring for 2 h, the mixture was diluted with DCM (20 mL) and washed with NaOH (2 M, 20 mL) or saturated sodium bicarbonate solution (20 mL). The aqueous phase was extracted with DCM (20 mL), and the combined organic phases dried and concentrated to give the intermediate of formula (B).
    • Method R4
  • As for Method R1, except that after concentrating the sodium borohydride reaction and adding water and HCl, the mixture was basified with sodium hydrogencarbonate and extracted with EtOAc. The organic phase was dried and concentrated, and the residue was dissolved/suspended in an organic solvent, typically EtOAc or Et2O. HCl (4 M in MeOH) was added, and the mixture stirred at RT. The resulting precipitate was filtered, and the filter cake air-dried to give the hydrochloride salt of the intermediate of formula (B).
    • Method R5
  • As for Method R1, except that (a) in the imine formation, triethylamine (typically 1 eq) was added, and (b) after concentrating the sodium borohydride reaction, the residue was partitioned between (i) sodium hydrogencarbonate or sodium hydroxide and (ii) EtOAc or DCM. The organic phase was dried and concentrated to give the intermediate of formula (B). In some cases, the residue was dissolved/suspended in an organic solvent, typically EtOAc or Et2O. HCl (4 M in MeOH) was added, and the mixture stirred at RT. The resulting precipitate was filtered, and the filter cake air-dried to give the hydrochloride salt of the intermediate of formula (B). In some cases, the residue was dissolved/suspended in aqueous HCl (2 M). The resulting precipitate was filtered, washed with water, and dried to give the hydrochloride salt of the intermediate of formula (B).
    • Method R6
  • As for Method R1, except that after stirring the sodium borohydride reaction for 1 h, the mixture was quenched with HCl (2 M). The resulting precipitate was isolated by filtration and dried under vacuum to give the hydrochloride salt of the intermediate of formula (B).
  • Figure US20190010129A1-20190110-C00028
  • TABLE 1
    Inter-
    mediate R Product Method Data
    B1 CH2CH3 methyl 4- R1, using MS
    ((ethylamino)methyl)benzoate 2M ES+:
    EtNH2 in 194
    THF (1.8
    eq)
    B2 CH2CHF2 methyl 4-(((2,2- R1 MS
    difluoroethyl)amino)methyl) ES+:
    benzoate 231
    B3 CH2CF2 methyl 4-(((2,2,2- R2, using MS
    (HCl trifluoroethyl)amino)methyl) 5 eq ES+:
    salt) benzoate hydrochloride NaBH4 248
    B4 CH2 iPr methyl 4- R4 n/a
    (HCl ((isobutylamino)methyl)
    salt) benzoate hydrochloride
    B5 (HCl salt)
    Figure US20190010129A1-20190110-C00029
         		methyl 4- (((cyclopropylmethyl)amino) methyl)benzoate hydrochloride R4 MS ES+: 220
    B6 (HCl salt)
    Figure US20190010129A1-20190110-C00030
         		methyl 4- (((cyclobutylmethyl)amino) methyl)benzoate hydrochloride R5, from Amine 1* MS ES+: 234
    B7 (HCl salt)
    Figure US20190010129A1-20190110-C00031
         		methyl 4- ((isopentylamino)methyl) benzoate hydrochloride R4 MS ES+: 236
    B8 (HCl salt)
    Figure US20190010129A1-20190110-C00032
         		methyl 4-(((2- cyclopropylethyl)amino) methyl)benzoate hydrochloride R4, from Amine 2** MS ES+: 234
    B9 (HCl salt)
    Figure US20190010129A1-20190110-C00033
         		methyl 4-(((2- cyclobutylethyl)amino)methyl) benzoate hydrochloride R4, from Amine 3*** MS ES+: 248
    B10 (HCl salt)
    Figure US20190010129A1-20190110-C00034
         		methyl 4- ((benzylamino)methyl) benzoate hydrochloride R4 MS ES+: 256
    B11 (HCl salt)
    Figure US20190010129A1-20190110-C00035
         		methyl 4-(((2- fluorobenzyl)amino)methyl) benzoate hydrochloride R2 MS ES+: 274
    B12 (HCl salt)
    Figure US20190010129A1-20190110-C00036
         		methyl 4-(((3- methoxybenzyl)amino)methyl) benzoate hydrochloride R2 MS ES+: 286
    B13 (HCl salt)
    Figure US20190010129A1-20190110-C00037
         		methyl 4-(((4- methoxybenzyl)amino)methyl) benzoate hydrochloride R2 MS ES+: 286
    B14
    Figure US20190010129A1-20190110-C00038
         		methyl 4- ((phenethylamino)methyl) benzoate R3 MS ES+: 270
    B15 (HCl salt)
    Figure US20190010129A1-20190110-C00039
         		methyl 4-(((3- phenylpropyl)amino)methyl) benzoate hydrochloride R6 MS ES+: 284
    B16
    Figure US20190010129A1-20190110-C00040
         		methyl 4-((((trans-2- phenylcyclopropyl)methyl) amino)methyl)benzoate R3 MS ES+: 296
    B17 (HCl salt)
    Figure US20190010129A1-20190110-C00041
         		methyl 4-(((3-(2- fluorophenyl)propyl)amino) methyl)benzoate hydrochloride R5 MS ES+: 302
    B18 (HCl salt)
    Figure US20190010129A1-20190110-C00042
         		methyl 4-(((3-(3- fluorophenyl)propyl)amino) methyl)benzoate hydrochloride R5 MS ES+: 302
    B19 (HCl salt)
    Figure US20190010129A1-20190110-C00043
         		methyl 4-(((4- phenylbutyl)amino)methyl) benzoate hydrochloride R4 n/a
    B19a CH2CH2CH3 methyl 4- R2 n/a
    (HCl ((propylamino)methyl)
    salt) benzoate hydrochloride
    B19b (HCl salt)
    Figure US20190010129A1-20190110-C00044
         		methyl 4-(((2,2- difluoropropyl)amino)methyl) benzoate R5 MS ES+: 244
    B19c
    Figure US20190010129A1-20190110-C00045
         		methyl 4-(((3,3,3- trifluoropropyl)amino)methyl) R3 MS ES+:
    benzoate 262
    B19d (HCl
    Figure US20190010129A1-20190110-C00046
         		methyl 4- ((butylamino)methyl)benzoate R2 n/a
    salt) hydrochloride
    • Amine 1: Cyclobutylmethanamine Hydrochloride
  • A solution of borane in THF (1 M, 296 mL, 296 mmol) was added to a solution of cyclobutanecarbonitrile (20 g, 247 mmol) in THF (60 mL) under argon, and the mixture heated under reflux overnight. The mixture was cooled in an ice-water bath and MeOH (120 mL) added dropwise while keeping the temperature of the mixture below 20° C. HCl in MeOH (4 M, 300 mL) was added, again keeping the temperature below 20° C. The resulting solution was heated under reflux for 2.5 h. After cooling, the mixture was concentrated. The residue was diluted with MeOH (100 mL) and concentrated, and this process was repeated. Ether was added to the residue, and the mixture stirred for 30 minutes before filtering to give the title compound (25.9 g, 86%) as a white solid.
  • 1H NMR (300 MHz, DMSO-d6) δ ppm 1.70-1.86 (m, 4H) 1.97-2.04 (m, 2H) 2.46-2.61 (m, 1H) 2.75-2.84 (m, 2H) 8.02 (br s, 3H)
    • Amine 2: 2-Cyclopropylethanamine
  • Sulfuric acid (17.25 mL, 324 mmol) was added dropwise to a suspension of lithium aluminium hydride (24.56 g, 647 mmol) in Et2O (900 mL) in an ice-water bath under argon. The mixture was stirred at RT for 1 h. A solution of 2-cyclopropylacetonitrile (17.5 g, 216 mmol) in Et2O (100 mL) was added and the mixture heated under reflux for 18 h. The mixture was cooled in an ice-water bath and sodium sulfate decahydrate was added until effervescence ceased. The mixture was filtered and concentrated to give the title compound (crude, 18.6 g) which was used without further purification or characterisation.
    • Amine 3: 2-Cyclobutylethanamine
  • Prepared as described for Amine 2 from 2-cyclobutylacetonitrile and used in the next step without further purification or characterisation.
    • Intermediate B20: (S)-methyl 4-(((2-hydroxy-3-phenylpropyl)amino)methyl)benzoate
  • Figure US20190010129A1-20190110-C00047
  • Step (i) (S,S)-(+)-N′,N′-Bis(3,5-di-tert-butylsalicylidene)-1,2-cyclohexanediaminocobalt(II) (0.048 g, 0.080 mmol), THF (0.25 mL) and acetic acid (0.018 mL, 0.318 mmol) were added to 2-benzyloxirane (4.27 g, 31.8 mmol). The mixture was cooled in an ice-water bath and water (0.129 mL, 7.16 mmol) was added in one portion. After stirring at RT overnight, the mixture was distilled under vacuum (2 mmHg, bp 60-80° C.) to give (S)-2-benzyloxirane (crude, 2.74 g) which was used in the next step without further purification or characterisation.
  • Step (ii) (S)-2-Benzyloxirane (step (i) above) (2.74 g, 20.42 mmol) was added to a solution of methyl 4-(aminomethyl)benzoate hydrochloride (7.41 g, 36.8 mmol) and DIPEA (8.92 mL, 51.1 mmol) in MeOH (300 mL). After stirring for 3 days, the reaction mixture was concentrated. The residue was partitioned between saturated sodium hydrogencarbonate solution (200 mL) and DCM (2×200 mL). The aqueous phase was extracted with DCM (200 mL). The combined organic phases were concentrated and purified by silica chromatography (0-10% MeOH/DCM) and then reverse-phase chromatography on C18 silica (eluted with 0-95% MeOH/H2O with 0.1% NH4OH) to give the title compound (3.27 g, 53%) as a pale brown gum.
  • MS ES+: 300
    • Intermediate B21: (R)-methyl 4-(((2-hydroxy-3-phenylpropyl)amino)methyl)benzoate
  • Figure US20190010129A1-20190110-C00048
  • Step (i) Prepared as described for (S)-2-benzyloxirane (Intermediate B48, step (i)), except using (R,R)-(−)-N, N′-bis(3,5-di-tert-butylsalicylidene)-1,2-cyclohexanediaminocobalt(II) to give (R)-2-benzyloxirane which was used in the next step without further purification or characterisation.
  • Step (ii) Prepared as described for (S)-methyl 4-(((2-hydroxy-3-phenylpropyl)amino)methyl)benzoate (Intermediate B20, step (ii)) from (R)-2-benzyloxirane (step (i) above) and methyl 4-(aminomethyl)benzoate hydrochloride to give the title compound as a pale brown gum.
  • MS ES+: 300
    • C. Preparation of Intermediate Esters
  • Intermediates of formula (C) shown in Tables 2 to 4 below were prepared according to one of the following methods E1 to E5:
  • Figure US20190010129A1-20190110-C00049
    • Method E1
  • Triethylamine (6 mmol), 1-hydroxy-7-azabenzotriazole (2.4 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) (2.4 mmol) were added to a solution/suspension of the relevant amine or amine hydrochloride (2 mmol) and 4-phenoxybenzoic acid (2 mmol) in THF (10 mL). The reaction was stirred at RT for 18 h. (In cases where the amine hydrochloride was used, an extra 2 mmol triethylamine was added.) The mixture was partitioned between (i) water or saturated sodium hydrogencarbonate solution (10 mL) and (ii) DCM or EtOAc (10 mL). The aqueous phase was extracted with further DCM or EtOAc, and the combined organic phases dried and concentrated. The residue was purified by silica chromatography (typically 0-100% EtOAc/petrol).
    • Method E2
  • DIPEA (2.2 mmol) and HBTU (1.1 mmol) were added to a solution of the relevant acid in DMF (5 mL) and the mixture stirred for 5 minutes at RT. The relevant amine or amine hydrochloride (0.95 mmol) and DBU (1.5 mmol) were added. The mixture was stirred for 1 h at RT. (In cases where the amine hydrochloride was used, an extra 1 mmol DIPEA was added.) The mixture was partitioned between EtOAc (30 mL) and either water or saturated sodium hydrogencarbonate solution (30 mL). In some cases the aqueous phase was further extracted with EtOAc. The combined organic phases were dried and concentrated. The residue was purified by silica chromatography (typically 0-100% EtOAc/petrol).
    • Method E3
  • Thionyl chloride or oxalyl chloride (3-12 mmol) was added to a solution of the acid (3 mmol) in DCM (10 mL) in an ice-water bath. In some cases, several drops of DMF were added. The reaction mixture was stirred at RT for 4 h and then concentrated to yield the crude acid chloride, which was dissolved in THF (3 mL) and added to a solution/suspension of the amine hydrochloride (2 mmol) and potassium carbonate (10 mmol) in THF (10 mL). The reaction was heated under reflux for 18 h. After cooling, the mixture was partitioned between water and EtOAc. The organic phase was dried and concentrated and the residue purified by silica chromatography (0-50% EtOAc/petrol).
    • Method E4
  • HATU (1.1 mmol) was added to a solution of the acid (1 mmol) and DIPEA (2.2 mmol) in DMF or THF (2 mL). The mixture was stirred at RT and allowed to stand. After 5 minutes, the relevant amine or amine hydrochloride (1.1 mmol) was added. (In some cases, 0.9 mmol of amine or amine hydrochloride was used.) When the amine hydrochloride was used, DBU (1.5 mmol) was added at this stage. After 10 minutes, the mixture was diluted with EtOAc or DCM (30 mL) and washed with either HCl (1 M, 20 mL) or saturated sodium bicarbonate solution (20 mL) or water (20 mL). In some cases, the aqueous phase was further extracted with EtOAc or DCM. The combined organic phases were washed with water (2×20 mL), dried and concentrated. In somes cases further purification was carried out, by silica chromatography (typically 0-100% EtOAc/petrol), reverse-phase chromatography on C18 silica (typically eluting with 5-95% MeCN/water) or preparative HPLC.
  • Figure US20190010129A1-20190110-C00050
    • Method E5
  • Step (i) Triethylamine (1.351 mL, 9.69 mmol) was added slowly to a mixture of 4-bromobenzoyl chloride (0.851 g, 3.88 mmol) and methyl 4-((phenethylamino)methyl)-benzoate (Intermediate B14) (0.870 g, 3.23 mmol) in DCM (20 mL) at RT under nitrogen and the mixture stirred for 18 h. The mixture was diluted with DCM (30 mL), water (10 mL) and HCl (2 M, 10 mL), and the phases separated. The aqueous phase was extracted with DCM (30 mL) and the combined organic phases washed with water (10 mL), dried and concentrated. The residue was purified by silica chromatography (0-50% EtOAc/petrol) to give methyl 4-((4-bromo-N-phenethylbenzamido)methyl)benzoate (1.21 g, 83%) as a pale orange oil.
  • MS ES+: 452, 454
  • Step (ii) Tripotassium phosphate (2 mmol), palladium(II) acetate (0.1 mmol) and di-tert-butyl(2′,4′,6′ triisopiopylbiphenyl-2-yl)phosphine (0.15 mmol) were added to a solution of methyl 4-((4-bromo-N-phenethylbenzamido)methyl)benzoate (step (i) above) (1 mmol) and the relevant phenol (1.2 mmol) in toluene (5 mL). The mixture was degassed for about 5 minutes, purged with nitrogen and heated either thermally or under microwave irradiation at 120° C. for 20 h. The mixture was filtered through diatomaceous earth, washing through with EtOAc. The filtrate was concentrated and purified either by silica chromatography (typically 0-100% EtOAc/petrol) or preparative HPLC.
  • Figure US20190010129A1-20190110-C00051
  • TABLE 2
    Inter-
    mediate R Product Method Data
    C6 CH2CH3 methyl 4-((N-ethyl-4-(2- E2 MS ES+:
    fluorophenoxy)benzamido) 408
    methyl)benzoate
    C7 CH2CHF2 methyl 4-((N-(2,2- E2 MS ES+:
    difluoroethyl)-4-(2- 444
    fluorophenoxy)benzamido)
    methyl)benzoate
    C8 CH2CF3 methyl 4-((4-(2- E3 MS ES+:
    fluorophenoxy)-N-(2,2,2- 462
    trifluoroethyl)benzamido)
    methyl)benzoate
    C9 CH2iPr methyl 4-((4-(2- E1 MS ES+:
    fluorophenoxy)-N- 436
    isobutylbenzamido)methyl)
    benzoate
    C10
    Figure US20190010129A1-20190110-C00052
         		methyl 4-((N- (cyclopropylmethyl)-4-(2- fluorophenoxy)benzamido) methyl)benzoate E1 MS ES+: 434
    C11
    Figure US20190010129A1-20190110-C00053
         		methyl 4-((N- (cyclobutylmethyl)-4-(2- fluorophenoxy)benzamido) methyl)benzoate E4 MS ES+: 448
    C12
    Figure US20190010129A1-20190110-C00054
         		methyl 4-((4-(2- fluorophenoxy)-N- isopentylbenzamido)methyl) benzoate E1 MS ES+: 450
    C13
    Figure US20190010129A1-20190110-C00055
         		methyl 4-((N-(2- cyclopropylethyl)-4-(2- fluorophenoxy)benzamido) methyl)benzoate E1 MS ES+: 448
    C14
    Figure US20190010129A1-20190110-C00056
         		methyl 4-((N-(2- cyclobutylethyl)-4-(2- fluorophenoxy)benzamido) methyl)benzoate E1 MS ES+: 462
    C15
    Figure US20190010129A1-20190110-C00057
         		methyl 4-((N-benzyl-4-(2- fluorophenoxy)benzamido) methyl)benzoate E1 MS ES+: 470
    C16
    Figure US20190010129A1-20190110-C00058
         		methyl 4-((N-(2- fluorobenzyl)-4-(2- fluorophenoxy)benzamido) methyl)benzoate E4 MS ES+: 488
    C17
    Figure US20190010129A1-20190110-C00059
         		methyl 4-((4-(2- fluorophenoxy)-N-(3- methoxybenzyl)benzamido) methyl)benzoate E4 n/a
    C18
    Figure US20190010129A1-20190110-C00060
         		methyl 4-((4-(2- fluorophenoxy)-N-(4- methoxybenzyl)benzamido) methyl)benzoate E4 n/a
    C19
    Figure US20190010129A1-20190110-C00061
         		methyl 4-((4-(2- fluorophenoxy)-N- phenethylbenzamido)methyl) benzoate E4 MS ES+: 484
    C20
    Figure US20190010129A1-20190110-C00062
         		methyl 4-((4-(2- fluorophenoxy)-N-(3-(2- fluorophenyl)propyl) benzamido)methyl)benzoate E4 MS ES+: 516
    C21
    Figure US20190010129A1-20190110-C00063
         		methyl 4-((4-(2- fluorophenoxy)-N-(3-(3- fluorophenyl)propyl) benzamido)methyl)benzoate E4 MS ES+: 516
    C22
    Figure US20190010129A1-20190110-C00064
         		methyl 4-((4-(2- fluorophenoxy)-N-((trans-2- phenylcyclopropyl)methyl) benzamido)methyl)benzoate E4 MS ES+: 510
    C23
    Figure US20190010129A1-20190110-C00065
         		(S)-methyl 4-((4-(2- fluorophenoxy)-N-(2- hydroxy-3- phenylpropyl)benzamido) methyl)benzoate E4 MS ES+: 514
    C24
    Figure US20190010129A1-20190110-C00066
         		(R)-methyl 4-((4-(2- fluorophenoxy)-N-(2- hydroxy-3- phenylpropyl)benzamido) methyl)benzoate E4 MS ES+: 514
    C25
    Figure US20190010129A1-20190110-C00067
         		methyl 4-((4-(2- fluorophenoxy)-N-(4- phenylbutyl)benzamido) methyl)benzoate E2 MS ES+: 512
    C25a CH2CH2CH3 methyl 4-((4-(2- E4 MS ES+:
    fluorophenoxy)-N- 422
    propylbenzamido)-
    methyl)benzoate
    C25b CH2CH2CF3 methyl 4-((4-(2- E4 MS ES+:
    fluorophenoxy)-N-(3,3,3- n/a
    trifluoropropyl)benzamido)
    methyl)benzoate
    C25c CH2CF2CH3 methyl 4-((N-(2,2- E3 MS ES+:
    difluoropropyl)-4-(2- n/a
    fluorophenoxy)benzamido)
    methyl)benzoate
    C25d
    Figure US20190010129A1-20190110-C00068
         		methyl 4-((N-butyl-(2- fluorophenoxy)benzamido) E4 MS ES+: 436
    methyl)benzoate
  • Figure US20190010129A1-20190110-C00069
  • TABLE 3
    Inter-
    mediate X R Product Method Data
    C26 Me
    Figure US20190010129A1-20190110-C00070
         		methyl 4-((N- (cyclopropylmethyl)-4-(o- tolyloxy)benzamido)methyl) benzoate E4 MS ES+: 430
    C27 Me
    Figure US20190010129A1-20190110-C00071
         		methyl 4-((N- (cyclobutylmethyl)-4-(o- tolyloxy)benzamido)methyl) benzoate E4 MS ES+: 444
    C28 Me
    Figure US20190010129A1-20190110-C00072
         		methyl 4-((N-benzyl-4-(o- tolyloxy)benzamido)methyl) benzoate E4 MS ES+: 466
    C29 Me
    Figure US20190010129A1-20190110-C00073
         		methyl 4-((N-phenethyl-4-(o- tolyloxy)benzamido)methyl) benzoate E5 MS ES+: 480
    C30 CF3
    Figure US20190010129A1-20190110-C00074
         		methyl 4-((N-phenethyl-4-(2- (trifluoromethyl)phenoxy) benzamido)-methyl)benzoate E5 MS ES+: 534
    C31 CN
    Figure US20190010129A1-20190110-C00075
         		methyl 4-((N-benzyl-4-(2- cyanophenoxy)benzamido) methyl)-benzoate E4 MS ES+: 477
    C32 OMe CH2CH3 methyl 4-((N-ethyl-4-(2- E2 MS ES+:
    methoxyphenoxy)benzamido) 420
    methyl)-benzoate
    C33 OMe CH2CHF2 methyl 4-((N-(2,2- E2 MS ES+:
    difluoroethyl)-4-(2- 456
    methoxyphenoxy)benzamido)
    methyl)-benzoate
    C34 OMe CH2iPr methyl 4-((N-isobutyl-4-(2- E4 MS ES+:
    methoxyphenoxy)benzamido) 448
    methyl)-benzoate
    C35 OMe
    Figure US20190010129A1-20190110-C00076
         		methyl 4-((N- (cyclopropylmethyl)-4-(2- methoxyphenoxy)benzamido) methyl)-benzoate E4 MS ES+: 446
    C36 OMe
    Figure US20190010129A1-20190110-C00077
         		methyl 4-((4-(2- methoxyphenoxy)-N-(3- phenylpropyl)benzamido)- methyl)benzoate E1 MS ES+: 510
    C37 OMe
    Figure US20190010129A1-20190110-C00078
         		methyl 4-((N-(3-(3- fluorophenyl)propyl)-4-(2- methoxyphenoxy)benzamido) methyl)-benzoate E1 MS ES+: 528
    C38 OEt
    Figure US20190010129A1-20190110-C00079
         		methyl 4-((N- (cyclopropylmethyl)-4-(2- ethoxyphenoxy)benzamido) methyl)-benzoate E5 MS ES+: 460
    C39 Cl
    Figure US20190010129A1-20190110-C00080
         		methyl 4-((4-(2- chlorophenoxy)-N- (cyclopropylmethyl) benzamido)methyl)benzoate E4 MS ES+: 450
    C40 Cl
    Figure US20190010129A1-20190110-C00081
         		methyl 4-((4-(2- chlorophenoxy)-N- phenethylbenzamido)methyl) benzoate E5 MS ES+: 500
    C40a OMe CH2CF3 methyl 4-((4-(2- E3 MS ES+:
    methoxyphenoxy)-N-(2,2,2- n/a
    trifluoroethyl)benzamido)-
    methyl)benzoate
    C40b OMe CH2CH2CH3 methyl 4-((4-(2- E4 MS ES+:
    methoxyphenoxy)-N- n/a
    propylbenzamido)methyl)
    benzoate
    C40c OMe CH2CF2CH3 methyl 4-((N-(2,2- E3 MS ES+:
    difluoropropyl)-4-(2- n/a
    methoxyphenoxy)benzamido)
    methyl)-benzoate
    C40d OMe CH2CH2CF3 methyl 4-((N-(3,3,3- E4 MS ES+:
    trifluoropropyl)-4-(2- 488
    methoxyphenoxy)benzamido)-
    methyl)benzoate
    C40e OMe
    Figure US20190010129A1-20190110-C00082
         		methyl 4-((N-butyl-4-(2- methoxyphenoxy)benzamido) E4 MS ES+: n/a
    methyl)-benzoate
    C40f Me CH2CF3 methyl 4-((4-(•-tolyloxy)-N- E3 MS ES+:
    (2,2,2- n/a
    trifluoroethyl)benzamido)
    methyl)-benzoate
    C40g Cl CH2CF3 methyl 4-((4-(2- E3 MS ES+:
    chlorophenoxy)-N-(2,2,2- n/a
    trifluoroethyl)benzamido)-
    methyl)benzoate
    C40h Me CH2CH3 methyl 4-((N-ethyl-4-(o- E4 MS ES+:
    tolyloxy)benzamido)methyl) n/a
    benzoate
    C40i Cl CH2CH3 methyl 4-((4-(2- E4 MS ES+:
    chlorophenoxy)-N- n/a
    ethylbenzamido)methyl)
    benzoate
    C40j Cl CH2CHF2 methyl 4-((4-(2- E3 MS ES+:
    chlorophenoxy)-N-(2,2- n/a
    difluoroethyl)benzamido)
    methyl)-benzoate
  • Figure US20190010129A1-20190110-C00083
  • TABLE 4
    Inter-
    mediate R1 R Product Method Data
    C41
    Figure US20190010129A1-20190110-C00084
    Figure US20190010129A1-20190110-C00085
         		methyl 4-((N- (cyclopropylmethyl)- 4-(2,6- difluorophenoxy)- benzamido)methyl) benzoate E1 MS ES+: 452
    C42
    Figure US20190010129A1-20190110-C00086
    Figure US20190010129A1-20190110-C00087
         		methyl 4-((N-(2- cyclopropylethyl)-4- (2,6- difluorophenoxy)- benzamido)methyl) benzoate E1 MS ES+: 466
    C43
    Figure US20190010129A1-20190110-C00088
    Figure US20190010129A1-20190110-C00089
         		methyl 4-((N-benzyl- 4-(2,6- difluorophenoxy) benzamido)- methyl)benzoate E1 MS ES+: 488
    C44
    Figure US20190010129A1-20190110-C00090
    Figure US20190010129A1-20190110-C00091
         		methyl 4-((N- (cyclopropylmethyl)- 4-(2-fluoro-6- methylphenoxy) benzamido)- methyl)benzoate E4 MS ES+: 448
    C45
    Figure US20190010129A1-20190110-C00092
    Figure US20190010129A1-20190110-C00093
         		methyl 4-((N- (cyclobutylmethyl)- 4-(2-fluoro-6- methylphenoxy)- benzamido)methyl) benzoate E4 MS ES+: 462
    C46
    Figure US20190010129A1-20190110-C00094
    Figure US20190010129A1-20190110-C00095
         		methyl 4-((4-(2- chloro-6- fluorophenoxy)-N- (cyclopropylmethyl) benzamido)- methyl)benzoate E1 MS ES+: 468
    C47
    Figure US20190010129A1-20190110-C00096
    Figure US20190010129A1-20190110-C00097
         		methyl 4-((4-(2- chloro-6- fluorophenoxy)-N- (2-cyclopropylethyl) benzamido)- methyl)benzoate E1 MS ES+: 482
    C48
    Figure US20190010129A1-20190110-C00098
    Figure US20190010129A1-20190110-C00099
         		methyl 4-((N-benzyl- 4-(2-chloro-6- fluorophenoxy) benzamido)methyl)- benzoate E1 MS ES+: 504
    C49
    Figure US20190010129A1-20190110-C00100
    Figure US20190010129A1-20190110-C00101
         		methyl 4-((4-(2,6- dimethylphenoxy)- N- isopentylbenzamido) methyl)-benzoate E4 MS ES+: 460
    C50
    Figure US20190010129A1-20190110-C00102
    Figure US20190010129A1-20190110-C00103
         		methyl 4-((N-benzyl- 4-(2,6- dimethylphenoxy) benzamido)- methyl)benzoate E4 MS ES+: 480
    C51
    Figure US20190010129A1-20190110-C00104
    Figure US20190010129A1-20190110-C00105
         		methyl 4-((4-(2,6- dimethylphenoxy)- N-phenethyl benzamido)methyl)- benzoate E4 MS ES+: 494
    C52
    Figure US20190010129A1-20190110-C00106
    Figure US20190010129A1-20190110-C00107
         		methyl 4-((4-(3- methoxyphenoxy)- N-phenethyl benzamido)methyl)- benzoate E5 MS ES+: 496
    C53
    Figure US20190010129A1-20190110-C00108
    Figure US20190010129A1-20190110-C00109
         		methyl 4-((4-(4- methoxyphenoxy)- N-phenethyl benzamido)- methyl)benzoate E5 MS ES+: 496
    C54
    Figure US20190010129A1-20190110-C00110
    Figure US20190010129A1-20190110-C00111
         		methyl 4-((4-(3- chlorophenoxy)-N- phenethyl benzamido)methyl)- benzoate E5 MS ES+: 500
    C55
    Figure US20190010129A1-20190110-C00112
    Figure US20190010129A1-20190110-C00113
         		methyl 4-((N- (cyclopropylmethyl)- 4-((2- fluorobenzyl)oxy) benzamido)- methyl)benzoate E4 MS ES+: 448
    C56
    Figure US20190010129A1-20190110-C00114
    Figure US20190010129A1-20190110-C00115
         		methyl 4-((N- (cyclobutylmethyl)- 4-((2- fluorobenzyl)oxy) benzamido)- methyl)benzoate E4 MS ES+: 462
    C57
    Figure US20190010129A1-20190110-C00116
    Figure US20190010129A1-20190110-C00117
         		methyl 4-((N-benzyl- 4-((2- fluorobenzyl)oxy) benzamido)- methyl)benzoate E4 MS ES+: 484
    • Intermediate C58: Methyl 4-((4-(2-fluorophenoxy)-N-((3-methoxycyclobutyl)methyl)benzamido)methyl)benzoate (Mixture of Cis and Trans Ring Isomers)
  • Figure US20190010129A1-20190110-C00118
  • Step (i) Prepared using the HATU coupling procedure described in Method E4 above from 3-methoxycyclobutanecarboxylic acid (500 mg, 3.84 mmol) and (4-bromophenyl)methanamine hydrochloride (940 mg, 4.23 mmol) to give N-(4-bromobenzyl)-3-methoxycyclobutanecarboxamide (mixture of cis and trans ring isomers) (880 mg, 77%).
  • MS ES+: 298, 300
  • Step (ii) Lithium aluminium hydride (1 M solution in THF, 2.62 mL, 2.62 mmol) was added to a solution of N-(4-bromobenzyl)-3-methoxycyclobutanecarboxamide from step (i) above (780 mg, 2.62 mmol) in THF (20 mL) at RT. After stirring for 18 h, the mixture was quenched with saturated sodium sulfate dodecahydrate solution (5 mL), filtered and concentrated. The residue was dissolved in DCM (50 mL) and washed with NaOH (2 M, 50 mL). The organic phase was concentrated and the residue purified by silica chromatography (0-30% EtOAc/petrol) to give N-(4-bromobenzyl)-1-(3-methoxycyclobutyl)methanamine (mixture of cis and trans ring isomers) which was used in the next step without further purification or characterisation.
  • Step (iii) Prepared using the HATU coupling procedure described in Method E4 above from 4-(2-fluorophenoxy)benzoic acid (Intermediate A1) (310 mg, 1.337 mmol) and N-(4-bromobenzyl)-1-(3-methoxycyclobutyl)methanamine from step (ii) above (380 mg, 1.337 mmol) to give the desired compound, N-(4-bromobenzyl)-4-(2-fluorophenoxy)-N-((3-methoxycyclobutyl)methyl)benzamide (mixture of cis and trans ring isomers), along with the corresponding des-bromo analogue N-benzyl-4-(2-fluorophenoxy)-N-((3-methoxycyclobutyl)methyl)benzamide (also a mixture of cis and trans ring isomers). This material (approximately 1:1 mixture of bromo:des-bromo compound, 684 mg in total) was used in the next step without further purification. MS ES+: 498, 500
  • Step (iv) A solution of palladium(II) acetate (27.0 mg, 0.120 mmol), 1,3-bis(diphenylphosphino)propane (49.7 mg, 0.120 mmol), and N-(4-bromobenzyl)-4-(2-fluorophenoxy)-N-((3-methoxycyclobutyl)methyl)benzamide from step (iii) above (300 mg, 0.602 mmol) in MeOH (5 mL) and DMF (3 mL) was degassed and purged with nitrogen. Triethylamine (0.168 mL, 1.204 mmol) was added, the reaction mixture was evacuated and carbon monoxide passed through the solution. After stirring under carbon monoxide at 70° C. for 18 h, the mixture was MeOH-evaporated and the residue dissolved in DCM (20 mL). The organic phase was washed with water (20 mL) and concentrated. The resulting residue was purified by silica chromatography (0-30% EtOAc/petrol) to give the title compound (115 mg, 80% based on starting material being 50% pure).
  • MS ES+: 478
    • Intermediate C59: Methyl 4-((N-(cyclopropylmethyl)-2-fluoro-1-(2-fluorophenoxy)benzamido)methyl)benzoate
  • Figure US20190010129A1-20190110-C00119
  • Prepared using the EDC coupling procedure described in Method E1 above from 2-fluoro-4-(2-fluorophenoxy)benzoic acid (Intermediate A6) and methyl 4-((cyclopropylmethylamino)methyl)benzoate hydrochloride (Intermediate B5).
  • MS ES+: 452
    • Intermediate C60: Methyl 4-((N-benzyl-4-(2-fluorophenoxy)-cyclohexanecarboxamido)methyl)benzoate (Ca. 1:1 Mixture of Cis and Trans Ring Isomers)
  • Figure US20190010129A1-20190110-C00120
  • Step (i) 4-Toluenesulfonyl chloride (18.29 g, 96 mmol) was added in several portions to a solution of ethyl 4-hydroxycyclohexanecarboxylate (ca. 1:1 mixture of cis and trans ring isomers) (29.5 g, 90 mmol) in pyridine (100 mL) in an ice-water bath, and the mixture stirred, allowing to warm to RT. After the solid had dissolved, the mixture was allowed to stand. After 24 h, the mixture was concentrated and the residue partitioned between water and EtOAc (100 mL each). The organic phase was dried and concentrated to give ethyl 4-(tosyloxy)cyclohexanecarboxylate (ca. 1:1 mixture of cis and trans ring isomers) (crude, 29.5 g) as a colourless oil which was used in the next step without further purification.
  • 1H NMR (400 MHz, CDCl3) δ ppm 1.20-1.30 (m, 3H) 1.44-2.08 (m, 8H) 2.21-2.43 (m, 1H) 2.48 (s, 3H) 4.08-4.20 (m, 2H) 4.40-4.50 and 4.70-4.78 (both m, total 1H) 7.28-7.40 (m, 2H) 7.78-7.86 (m, 2H)
  • Step (ii) 2-Fluorophenol (2.145 mL, 23.25 mmol) was added to a solution/suspension of ethyl 4-(tosyloxy)cyclohexanecarboxylate from step (i) above and cesium carbonate (7.58 g, 23.25 mmol) in DMF (100 mL) and the mixture stirred for 18 h at 80° C. After cooling, the mixture was diluted with EtOAc (200 mL) and washed with saturated sodium hydrogencarbonate solution (100 mL) and brine (100 mL). The organic phase was dried and concentrated, and the residue purified by silica chromatography (0-100% EtOAc/petrol) to give ethyl 4-(2-fluorophenoxy)cyclohexanecarboxylate (ca. 1:1 mixture of cis and trans ring isomers) (crude, 3.41 g) which was used without further purification or characterisation.
  • Step (iii) Lithium hydroxide (0.307 g, 12.80 mmol) was added to a solution of ethyl 4-(2-fluorophenoxy)cyclohexanecarboxylate from step (ii) above (crude, 3.41 g) in 1,4-dioxane (30 mL) and water (30 mL), and the mixture heated under microwave irradiation at 100° C. for 15 minutes. The mixture was concentrated. The residue was loaded onto an anion exchange cartridge. After washing with MeCN, the product was eluted with 2 M HCl/MeCN and concentrated to give 4-(2-fluorophenoxy)cyclohexanecarboxylic acid (ca. 1:1 mixture of cis and trans ring isomers) (crude, 1.0 g) as a pale yellow solid which was used in the next step without further purification.
  • MS ES+: 237
  • Step (iv) The title compound was prepared using the HATU coupling procedure described in Method E4 above, from 4-(2-fluorophenoxy)cyclohexanecarboxylic acid from step (iii) above and methyl 4-((benzylamino)methyl)benzoate hydrochloride (Intermediate B10).
  • MS ES+: 476
    • Intermediate C61: Methyl 4-((trans-N-benzyl-4-(2-methoxyphenoxy)cyclohexanecarboxamido)methyl)benzoate
  • Figure US20190010129A1-20190110-C00121
  • Step (i) A solution of ethyl 4-hydroxycyclohexanecarboxylate (ca. 1:1 mixture of cis and trans ring isomers) (5 g, 29 mmol), 2-methoxyphenol (3.96 g, 31.9 mmol), triphenylphosphine (8.38 g, 31.9 mmol) and trans-diisopropyl diazene-1,2-dicarboxylate (DIAD) (6.21 mL, 31.9 mmol) in THF (150 mL) was stirred at RT. The mixture was diluted with EtOAc (100 mL) and washed with saturated sodium hydrogencarbonate solution (50 mL) and brine (50 mL). The organic phase was dried and concentrated, and the residue purified by silica chromatography (0-100% EtOAc/petrol) to give ethyl 4-(2-methoxyphenoxy)cyclohexanecarboxylate (ca. 1:1 mixture of cis and trans ring isomers) (crude, 4.0 g) which was used without further purification or characterisation.
  • Step (ii) 4-(2-Methoxyphenoxy)cyclohexanecarboxylic acid was prepared as described for 4-(2-fluorophenoxy)cyclohexanecarboxylic acid (Intermediate C60, step (iii)) using ethyl 4-(2-methoxyphenoxy)cyclohexanecarboxylate from step (i) above.
  • MS ES+: 249
  • Step (iii) The title compound was prepared using the HATU coupling procedure described in Method E4 above from 4-(2-methoxyphenoxy)cyclohexanecarboxylic acid (step (ii) above) and methyl 4-((benzylamino)methyl)benzoate hydrochloride (Intermediate B10).
  • MS ES+: 488
    • Intermediate C62: Methyl-1-((cis-N-(3-(3-fluorophenyl)propyl)-4-(2-methoxyphenoxy)cyclohexanecarboxamido)methyl)benzoate
  • and
    • Intermediate C63: Methyl 4-((trans-N-(3-(3-fluorophenyl)propyl)-4-(2-methoxyphenoxy)cyclohexanecarboxamido)methyl)benzoate
  • Figure US20190010129A1-20190110-C00122
  • The title compounds were prepared using the HATU coupling procedure described in Method E4 above, from 4-(2-methoxyphenoxy)cyclohexanecarboxylic acid (ca. 1:1 mixture of cis and trans ring isomers) (Intermediate C61, step (ii)) and methyl 4-(((3-(3-fluorophenyl)propyl)methyl)benzoate hydrochloride (Intermediate B18), and separated by preparative HPLC.
  • MS ES+: 534 in both cases
    • Intermediate C64: Methyl 2-fluoro-4-((4-(2-fluorophenoxy)-N-(3-methoxybenzyl)benzamido)methyl)benzoate
  • Figure US20190010129A1-20190110-C00123
  • Step (i) Potassium carbonate (3.70 g, 26.7 mmol) was added to a solution of 4-cyano-2-fluorobenzoic acid (4 g, 24.3 mmol) in DMF (350 mL). After stirring at RT for 15 minutes, iodomethane (1.66 mL, 26.7 mmol) was added. The flask was stoppered, and the mixture stirred at 40° C. for 2 h. The mixture was concentrated under reduced pressure and the residue partitioned between DCM (50 mL) and brine (50 mL). The organic phase was passed through silica and concentrated to give methyl 4-cyano-2-fluorobenzoate (4.1 g, 94%).
  • 1H NMR (300 MHz, CDCl3) δ ppm 3.96 (s, 3H) 7.44-7.48 (m, 1H) 7.49-7.53 (m, 1H) 8.01-8.05 (m, 1H)
  • Step (ii) Raney nickel (2.0 g) was added to a solution of methyl 4-cyano-2-fluorobenzoate (obtained as described in step (i) above) (10.1 g, 61.6 mmol) in acetic acid (200 mL) and water (100 mL). The mixture was stirred at RT under argon at 20 bar. After 18 h the mixture was filtered through diatomaceous earth, washing through with water (1000 mL). The filtrate was extracted with EtOAc (3×300 mL). The combined organic phases were dried and concentrated, adding toluene to assist removal of acetic acid, to give methyl 2-fluoro-4-(hydroxymethyl)benzoate (crude, 6.06 g) which was used in the next step without further purification or characterisation.
  • Step (iii) Methyl 2-fluoro-4-(hydroxymethyl)benzoate (step (ii) above) (1 g, 5.4 mmol) was dissolved in chloroform (40 mL) and THF (5 mL). Manganese(IV) oxide (2.36 g, 27 mmol) was added and the mixture stirred at RT for 2 h and then at 60° C. for 1 h. Further manganese(IV) oxide (2.36 g, 27 mmol) was added and heating was continued at 60° C. After 18 h the mixture was filtered through diatomaceous earth to give methyl 2-fluoro-4-formylbenzoate which was used without further purification.
  • 1H NMR (300 MHz, CDCl3) δ ppm 3.95 (s, 3H) 7.58-7.62 (m, 1H) 7.63-7.67 (m, 1H) 8.08-8.12 (m, 1H) 10.04 (s, 1H)
  • Step (iv) Methyl 2-fluoro-4-(((3-methoxybenzyl)amino)methyl)benzoate was prepared using the reductive amination procedure described in Method R3 above from (3-methoxyphenyl)methanamine and methyl 2-fluoro-4-formylbenzoate (step (iii) above).
  • MS ES+: 304
  • Step (v) Oxalyl chloride (0.30 mL, 3.51 mmol) was added to a solution of 4-(2-fluorophenoxy)benzoic acid (Intermediate A1) (746 mg, 2.34 mmol) in DCM (10 mL) at RT. DMF (1 drop) was added, and the mixture stirred, allowing to warm to RT. After 2 h, the mixture was concentrated. The residue was dissolved in DCM (5 mL) and added to a solution of methyl 2-fluoro-4-(((3-methoxybenzyl)amino)methyl)benzoate (step (iv) above) (708 mg, 23.4 mmol) and triethylamine (0.49 mL, 3.51 mmol). After 2 h the mixture was partitioned between water (30 mL) and DCM (30 mL). The organic phase was washed sequentially with saturated sodium carbonate solution, citric acid (20% in water) and water, and then dried and concentrated. The residue was purified by silica chromatography (10-30% EtOAc/heptane) to give the title compound which was used in the next step without further purification or characterisation.
    • Intermediate C65: Methyl 4-((N-(cyclopropylmethyl)-2-fluoro-4-(2-methoxyphenoxy)benzamido)methyl)benzoate
  • Figure US20190010129A1-20190110-C00124
  • Prepared using the HATU coupling procedure described in Method E4 above, from 2-fluoro-4-(2-methoxyphenoxy)benzoic acid (Intermediate A8) and methyl 4-(((cyclopropylmethyl)amino)methyl)benzoate hydrochloride (Intermediate B5). In this case, the acid, amine hydrochloride and DIPEA were combined in DMF first, and HATU added last.
  • MS ES+: 464
    • Intermediate C65a: Methyl 4-((4-bromo-N-(cyclopropylmethyl)benzamido)methyl)benzoate
  • Figure US20190010129A1-20190110-C00125
  • Prepared using a coupling procedure analogous to that described in Method E5 above, from 4-bromobenzoyl chloride and methyl 4-(((cyclopropylmethyl)amino)methyl)benzoate hydrochloride (Intermediate B5).
  • MS ES+: 402, 404
    • Intermediate C65b: Methyl 4-((4-bromo-N-propylbenzamido)methyl)benzoate
  • Figure US20190010129A1-20190110-C00126
  • Prepared using a coupling procedure analogous to that described in Method E5 above, from 4-bromobenzoyl chloride and methyl 4-((propylamino)methyl)benzoate hydrochloride (Intermediate B19a).
  • MS ES+: 390, 392
    • Intermediate C66: Methyl 4-((N-(cyclopropylmethyl)-4-(2-fluoro-6-methoxyphenoxy)benzamido)methyl)benzoate
  • Figure US20190010129A1-20190110-C00127
  • A mixture of methyl 4-((4-bromo-N-(cyclopropylmethyl)benzamido)methyl)benzoate (Intermediate C65a) (300 mg (0.75 mmol), 2-fluoro-6-methoxyphenol (212 mg, 1.49 mmol) and copper(I) oxide (107 mg, 0.75 mmol) in 2,4,6-trimethylpyridine (3 mL) was heated under microwave irradiation at 220° C. for 2 h. Further 2-fluoro-6-methoxyphenol (212 mg, 1.49 mmol) was added, and the mixture heated under microwave irradiation at 220° C. for another 1 h. The mixture was diluted with water and EtOAc (20 mL each) and filtered through diatomaceous earth. The phases were separated. The aqueous phase was acidified to pH ˜3 by addition of HCl (2 M) and extracted with EtOAc (3×50 mL). The combined organic phases were dried and concentrated. The residue was purified by silica chromatography (0-60% EtOAc/heptane) to give methyl 4-((N-(cyclopropylmethyl)-4-(2-fluoro-6-methoxyphenoxy)benzamido)methyl)benzoate (90 mg, 26%) as a colourless gum.
  • 1H NMR (400 MHz, CDCl3) δ ppm −0.12-0.31 (m, 2H) 0.38-0.61 (m, 2H) 0.77-1.15 (m, 1H) 2.99-3.50 (m, 2H) 3.90 (s, 3H), 3.79 (s, 3H) 4.59-5.09 (m, 2H) 6.68-7.58 (m, 9H) 7.93-8.10 (m, 2H)
    • Intermediate C67: Methyl 4-((N-(cyclopropylmethyl)-4-(4-fluoro-2-methoxyphenoxy)benzamido)methyl)benzoate
  • Figure US20190010129A1-20190110-C00128
  • Prepared as described above for Intermediate C66 from methyl 4-((4-bromo-N-(cyclopropylmethyl)benzamido)methyl)benzoate (Intermediate C65a) and 4-fluoro-2-methoxyphenol, except that the mixture was heated under microwave irradiation at 220° C. for 1 h, no additional phenol was required, and slight modifications were made to the workup and purification. In this case the crude reaction mixture was poured into HCl (2 M, 30 mL) and the resulting mixture extracted with EtOAc (3×50 mL). The combined organic phases were washed with a mixture of NaOH (1 M) and brine (ca. 1:1, total 30 mL), dried and concentrated, and the residue was purified by silica chromatography (20-40% EtOAc/heptane).
  • 1H NMR (400 MHz, CDCl3) δ ppm 0.15-0.30 (m, 2H) 0.40-0.59 (m, 2H) 0.78-1.01 (m, 1H) 2.98-3.45 (m, 2H) 3.78 (s, 3H) 3.91 (s, 3H) 4.64-5.05 (m, 2H) 6.58-7.50 (On, 9H) 7.96-8.10 (m, 2H)
    • Intermediate C67a: Methyl 4-((4-(4-fluoro-2-methoxyphenoxy)-N-propylbenzamido)methyl)benzoate
  • Figure US20190010129A1-20190110-C00129
  • Prepared as described above for Intermediate C66, from methyl 4-((4-bromo-N-propylbenzamido)methyl)benzoate (Intermediate C65b) and 4-fluoro-2-methoxyphenol, except that the mixture was heated thermally at reflux in air for 18 h, the combined organic phases were washed with HCl (1 M), saturated sodium hydrogencarbonate solution and brine (100 mL each), and the residue was purified by silica chromatography (10-20% EtOAc/heptane).
  • MS ES+: 452
    • Intermediate C67b: Methyl 4-((N-(cyclopropylmethyl)-4-(5-fluoro-2-methoxyphenoxy)benzamido)methyl)benzoate
  • Figure US20190010129A1-20190110-C00130
  • Prepared as described above for Intermediate C66, from methyl 4-((4-bromo-N-(cyclopropylmethyl)benzamido)methyl)benzoate (Intermediate C65a) and 5-fluoro-2-methoxyphenol, except that the combined organic phases were washed with HCl (1 M), NaOH (2 M) and brine (25 mL each).
  • 1H NMR (400 MHz, CDCl3) δ ppm −0.10-0.30 (m, 2H) 0.34-0.62 (m, 2H) 0.75-1.20 (m, 1H) 3.00-3.60 (m, 2H) 3.78 (s, 3H) 3.91 (s, 3H) 4.70-5.00 (m, 2H) 6.70-7.01 (m, 5H) 7.20-7.50 (m, 4H) 7.96-8.06 (m, 2H)
    • Intermediate C67e: Methyl 4-((4-(5-fluoro-2-methoxyphenoxy)-N-propylbenzamido)methyl)benzoate
  • Figure US20190010129A1-20190110-C00131
  • Prepared as described above for Intermediate C66, from methyl 4-((4-bromo-N-propyl benzamido)methyl)benzoate (Intermediate C65b) and 5-fluoro-2-methoxyphenol, except that the mixture was heated under microwave irradiation at 210° C. for 4 h, the combined organic phases were washed with HCl (1 M), saturated sodium hydrogencarbonate solution and brine (50 mL each), the residue was purified by silica chromatography (20-50% EtOAc/heptane), and the material obtained was used in the next step without further purification or characterisation.
    • Intermediate C67d: Methyl 4-((N-(cyclopropylmethyl)-4-(3-fluoro-2-methoxyphenoxy)benzamido)methyl)benzoate
  • Figure US20190010129A1-20190110-C00132
  • Prepared as described above for Intermediate C66, from methyl 4-((4-bromo-N-(cyclopropylmethyl)benzamido)methyl)benzoate (Intermediate C65a) and 3-fluoro-2-methoxyphenol (prepared as described in Synthetic Communications, 1985, 15(1), 61-69), except that the mixture was heated under microwave irradiation at 210° C. for 5 h, the combined organic phases were washed with HCl (1 M), saturated sodium hydrogencarbonate solution and brine (100 mL each), and the residue was purified by preparative HPLC.
  • MS ES+: 464
    • Intermediate C67e: Methyl 4-((5-bromo-N-(cyclopropylmethyl)picolinamido)methyl)benzoate
  • Figure US20190010129A1-20190110-C00133
  • Prepared using the coupling procedure described in Method E4 above, from 5-bromopicolinic acid and methyl 4-(((cyclopropylmethyl)amino)methyl)benzoate hydrochloride (Intermediate B5), using 1.3 eq HATU and 6 eq DIPEA.
  • MS ES+: 403, 405
    • Intermediate C68: Methyl 4-((N-(cyclopropylmethyl)-5-(2-methoxyphenoxy)picolinamido)methyl)benzoate
  • Figure US20190010129A1-20190110-C00134
  • Prepared as described above for Intermediate C66, from methyl 4-((5-bromo-N-(cyclopropylmethyl)picolinamido)methyl)benzoate (Intermediate C67e) and 2-methoxyphenol, except that 5 eq phenol and 2.5 eq copper(I) oxide were used, the mixture was heated thermally at reflux in air for 40 h, the aqueous phase was adjusted to pH ˜7, and the residue was purified by silica chromatography (20-40% EtOAc/heptane).
  • 1H NMR (400 MHz, CDCl3) δ ppm −0.10-0.27 (m, 2H) 0.32-0.57 (m, 2H) 0.85-1.35 (m, 1H) 3.27-3.41 (m, 2H) 3.69-3.85 (m, 3H) 3.89 (s, 3H) 4.89-5.05 (m, 2H) 6.87-7.47 (m, 8H) 7.62-7.71 (m, 1H) 7.90-8.06 (m, 2H)
    • Intermediate C69: Methyl 4-((N-(cyclopropylmethyl)-5-(2-fluorophenoxy)picolinamido)methyl)benzoate
  • Figure US20190010129A1-20190110-C00135
  • Prepared as described above for Intermediate C68, from methyl 4-((5-bromo-N-(cyclopropylmethyl)picolinamido)methyl)benzoate (Intermediate C67e) and 2-fluorophenol, except that 4 eq phenol was used, the mixture was not filtered through diatomaceous earth, and the residue was purified by silica chromatography (40% EtOAc/heptane).
  • 1H NMR (400 MHz, CDCl3) δ ppm −0.50-0.22 (m, 2H) 0.37-0.52 (m, 2H) 0.95-1.10 (m, 1H) 3.28-3.37 (m, 2H) 3.89 (s, 3H) 4.96 (s, 2H) 7.05-7.40 (m, 7H) 7.64-7.74 (m, 1H) 7.91-8.03 (m, 2H), 8.19-8.34 (m, 1H)
    • Intermediate C70: 5-(2-Fluorophenoxy)pyrimidine-2-carboxylic Acid
  • Figure US20190010129A1-20190110-C00136
  • Step (i) Sodium hydride (60% dispersion in mineral oil, 0.258 g, 6.42 mmol) was added to a solution of 2-fluorophenol (0.492 mL, 5.34 mmol) in pyridine (15 mL) in an ice-water bath. Copper(I) bromide was added, and the mixture heated at 100° C. for 5 h. The mixture was concentrated and the residue triturated with EtOAc and purified by silica chromatography (20% EtOAc/heptane) to give 5-(2-fluorophenoxy)pyrimidine-2-carbonitrile (555 mg, 47%).
  • 1H NMR (400 MHz, CDCl3) δ ppm 7.20-7.40 (m, 4H) 8.46 (s, 2H)
  • Step (ii) 5-(2-Fluorophenoxy)pyrimidine-2-carbonitrile, NaOH (2 M, 10 mL) and IMS (2 mL) were combined and heated at 70° C. for 18 h. After concentration to remove IMS, HCl (2 M) was added until the pH was 3, and the mixture was extracted with DCM (50 mL). The organic phase was dried and concentrated to give 5-(2-fluorophenoxy)pyrimidine-2-carboxylic acid (250 mg, 48%) as a white solid, which was used in the next step without further purification or characterisation.
    • Intermediate C71: 5-(2-Methoxyphenoxy)pyrimidine-2-carboxylic Acid
  • Figure US20190010129A1-20190110-C00137
  • Step (i) Prepared as for step (i) of Intermediate C70 to give 5-(2-methoxyphenoxy)pyrimidine-2-carbonitrile (555 mg, 47%).
  • MS ES+: 228
  • Step (ii) Prepared as for step (ii) of Intermediate C70, from 5-(2-methoxyphenoxy)pyrimidine-2-carbonitrile, to give 5-(2-methoxyphenoxy)pyrimidine-2-carboxylic acid.
  • 1H NMR (400 MHz, CDCl3) δ ppm 3.77 (s, 3H) 7.03-7.07 (m, 2H) 7.15-7.19 (m, 1H) 7.28-7.34 (m, 1H) 8.44 (s, 2H)
    • Intermediate C72: Methyl 4-((N-(cyclopropylmethyl)-5-(2-fluorophenoxy)pyrimidine-2-carboxamido)methyl)benzoate
  • Figure US20190010129A1-20190110-C00138
  • Prepared using the coupling procedure described in Method E4 above, from 5-(2-fluorophenoxy)pyrimidine-2-carboxylic acid (Intermediate C70) and methyl 4-(((cyclopropylmethyl)amino)methyl)benzoate hydrochloride (Intermediate B5).
  • MS ES+: 436
    • Intermediate C73: Methyl 4-((N-(cyclopropylmethyl)-5-(2-methoxyphenoxy)pyrimidine-2-carboxamido)methyl)benzoate
  • Figure US20190010129A1-20190110-C00139
  • Prepared using the coupling procedure described in Method E4 above, from 5-(2-methoxyphenoxy)pyrimidine-2-carboxylic acid (Intermediate C71) and methyl 4-(((cyclopropylmethyl)amino)methyl)benzoate hydrochloride (Intermediate B5).
  • MS ES+: 448
    • Intermediate C74: Methyl 4-((5-(2-methoxyphenoxy)-N-propylpyrimidine-2-carboxamido)methyl)benzoate
  • Figure US20190010129A1-20190110-C00140
  • Prepared using the coupling procedure described in Method E4 above, from 5-(2-methoxyphenoxy)pyrimidine-2-carboxylic acid (Intermediate C71) and methyl 4-((propylamino)methyl)benzoate hydrochloride (Intermediate B19a).
  • MS ES+: 436
    • PREPARATION OF EXAMPLES
  • Compounds derived from the Intermediates C6 to C74 above were prepared according to Method H1 or H2:
    • Method H1
  • Lithium hydroxide or lithium hydroxide monohydrate (5 mmol) was added to a solution of the relevant ester (1 mmol) in water (2 mL) and either THF or 1,4-dioxane (4 mL). In some cases, MeOH was added in addition to THF. The mixture was stirred, typically at RT for 18 h, 50° C. for 4 h or 100° C. for 20 minutes. In some cases the reaction was diluted with NaOH (2 M) and extracted with EtOAc or DCM, and the resulting aqueous phase acidified with HCl (2 M) and extracted with EtOAc. In other cases the crude mixture was partitioned between HCl (2 M) and EtOAc. The combined organic phases from the extraction of the acidic aqueous phase were dried and concentrated. In some cases the residue was loaded onto an anion exchange cartridge. After washing with MeCN, the product was eluted with 1 M HCl/MeCN then concentrated. In some cases the material obtained was purified by reverse-phase chromatography on C18 silica (typically eluted with 5-95% MeOH/H2O with 0.1% NH4OH). In some cases the crude product was heated under reflux in HCl (4 M), allowed to cool and filtered. In some cases the final product was recrystallised, typically using one or more of the following: water, EtOH, EtOAc, methyl acetate, methyl tert-butyl ether, pentane, heptane.
    • Method H2
  • Sodium hydroxide (2 M, 6 mmol) was added to a solution of the relevant ester (2 mmol) in THF (3 mL). In some cases, MeOH was added instead of or in addition to THF. The mixture was stirred at RT for 18 h or heated under microwave irradiation at 100° C. for 5 minutes. The mixture was partitioned between HCl (1 M) and EtOAc (30 mL each). The organic phases were dried and concentrated. The residue was loaded onto an anion exchange cartridge. After washing with MeCN, the product was eluted with 4 M HCl/1,4-dioxane then concentrated.
    • Example 1: 4-((N-Ethyl-4-(2-fluorophenoxy)benzamido)methyl)benzoic Acid
  • Figure US20190010129A1-20190110-C00141
  • Prepared from the parent methyl ester (Intermediate C6) using Method H1.
  • 1H NMR (300 MHz, DMSO-d6) δ ppm 0.84-1.36 (m, 3H) 3.05-3.64 (m, 2H) 4.67 (br s, 2H) 6.73-7.09 (m, 2H) 7.09-7.61 (m, 8H) 7.74-8.05 (m, 2H) 12.90 (br s, 1H)
  • MS ES+: 394
    • Example 2: 4-((N-(2,2-Difluoroethyl)-4-(2-fluorophenoxy)benzamido)-methyl)benzoic Acid
  • Figure US20190010129A1-20190110-C00142
  • Prepared from the parent methyl ester (Intermediate C7) using Method H1.
  • 1H NMR (300 MHz, DMSO-do) δ ppm 3.57-3.91 (m, 2H) 4.71 (br s, 2H) 5.95-6.52 (m, 1H) 6.82-7.08 (m, 2H) 7.10-7.57 (m, 8H) 7.79-7.98 (m, 2H) 12.93 (br s, 1H)
  • MS ES+: 430
    • Example 3: 4-((4-(2-Fluorophenoxy)-N-(2,2,2-trifluoroethyl)benzamido)-methyl)benzoic Acid
  • Figure US20190010129A1-20190110-C00143
  • Prepared from the parent methyl ester (Intermediate C8) using H1.
  • 1H NMR (400 MHz, DMSO-d6) δ ppm 4.14-4.36 (m, 2H) 4.76 (s, 2H) 6.92-7.10 (m, 2H) 7.16-7.37 (m, 5H) 7.39-7.55 (m, 3H) 7.84-7.99 (m, 2H) 12.94 (br s, 1H)
  • MS ES+: 448
    • Example 4: 4-((4-(2-Fluorophenoxy)-N-isobutylbenzamido)methyl)benzoic Acid
  • Figure US20190010129A1-20190110-C00144
  • Prepared from the parent methyl ester (Intermediate C9) using Method H1.
  • 1H NMR (400 MHz, DMSO-d6) δ ppm 0.50-1.08 (m, 6H) 1.77-2.17 (m, 1H) 3.00-3.25 (m, 2H) 4.49-4.86 (m, 2H) 6.88-7.13 (m, 2H) 7.13-7.57 (m, 8H) 7.83-8.04 (m, 2H) 12.69-13.02 (m, 1H)
  • MS ES+: 422
    • Example 5: 4-((N-(Cyclopropylmethyl)-4-(2-fluorophenoxy)benzamido)-methyl)benzoic Acid
  • Figure US20190010129A1-20190110-C00145
  • Prepared from the parent methyl ester (Intermediate C10) using Method H1.
  • 1H NMR (400 MHz, DMSO-d6) δ ppm −0.13-0.26 (m, 2H) 0.30-0.50 (m, 2H) 0.75-1.06 (m, 1H) 2.97-3.22 (m, 2H) 4.79 (br s, 2H) 6.88-7.12 (m, 2H) 7.12-7.55 (m, 8H) 7.86-7.97 (m, 2H) 12.87 (br s, 1H)
  • MS ES+: 420
    • Example 6: 4-((N-(Cyclobutylmethyl)-4-(2-fluorophenoxy)benzamido)-methyl)benzoic Acid
  • Figure US20190010129A1-20190110-C00146
  • Prepared from the parent methyl ester (Intermediate C11) using Method H1.
  • 1H NMR (400 MHz, CD3OD) δ ppm 1.37-2.15 (m, 6H) 2.49-2.82 (m, 1H) 3.34-3.58 (m, 2H) 4.60-4.78 (m, 2H) 6.90-7.04 (m, 2H) 7.14-7.29 (m, 5H) 7.33-7.49 (m, 3H) 7.82-8.03 (m, 2H)
  • MS ES+: 434
    • Example 7: 4-((4-(2-Fluorophenoxy)-N-((3-methoxycyclobutyl)methyl)-benzamido)methyl)benzoic Acid (Mixture of Cis and Trans Ring Isomers)
  • Figure US20190010129A1-20190110-C00147
  • Prepared from the parent methyl ester (Intermediate C58) using Method H1.
  • 1H NMR (400 MHz, DMSO-d6) δ ppm 1.64-2.30 (m, 4H) 3.04 (br s, 3H) 3.16-3.70 (m, 4H) 4.65 (br s, 2H) 6.85-7.14 (m, 2H) 7.14-7.59 (m, 8H) 7.82-8.00 (m, 2H)
  • MS ES+:464
    • Example 8: 4-((4-(2-Fluorophenoxy)-N-isopentylbenzamido)methyl)benzoic Acid
  • Figure US20190010129A1-20190110-C00148
  • Prepared from the parent methyl ester (Intermediate C12) using Method H1.
  • 1H NMR (400 MHz, DMSO-d6) δ ppm 0.48-1.00 (m, 6H) 1.39 (br s, 3H) 3.21 (br s, 2H) 4.49-4.84 (m, 2H) 7.01 (br s, 2H) 7.17-7.57 (m, 8H) 7.88-7.97 (m, 2H) 12.90 (br s, 1H)
  • MS ES+: 436
    • Example 9: 4-((N-(2-Cyclopropylethyl)-4-(2-fluorophenoxy)benzamido)-methyl)benzoic Acid
  • Figure US20190010129A1-20190110-C00149
  • Prepared from the parent methyl ester (Intermediate C13) using Method H1.
  • 1H NMR (400 MHz, CD3OD) δ ppm −0.22-0.17 (m, 2H) 0.26-0.51 (m, 2H) 0.52-0.79 (m, 1H) 1.35-1.64 (m, 2H) 3.35-3.63 (m, 2H) 4.58-4.79 (m, 2H) 6.90-7.08 (m, 2H) 7.13-7.34 (m, 5H) 7.37-7.54 (m, 3H) 8.06-8.22 (m, 2H)
  • MS ES+: 434
    • Example 10: 4-((N-(2-Cyclobutylethyl)-4-(2-fluorophenoxy)benzamido)-methyl)benzoic Acid
  • Figure US20190010129A1-20190110-C00150
  • Prepared from the parent methyl ester (Intermediate C14) using Method H1.
  • 1H NMR (400 MHz, DMSO-d6) δ ppm 1.24-2.30 (m, 9H) 2.88-3.40 (m, 2H) 4.48-4.82 (m, 2H) 7.01 (br s, 2H) 7.19-7.54 (m, 8H) 7.88-7.96 (m, 2H) 12.90 (br s, 1H)
  • MS ES+: 448
    • Example 11: 4-((N-Benzyl-4-(2-fluorophenoxy)benzamido)methyl)benzoic Acid
  • Figure US20190010129A1-20190110-C00151
  • Prepared from the parent methyl ester (Intermediate C15) using Method H1.
  • 1H NMR (400 MHz, DMSO-d6) δ ppm 4.37-4.80 (m, 4H) 6.92-7.06 (m, 2H) 7.11-7.60 (m, 13H) 7.85-7.99 (m, 2H)
  • MS ES+: 456
    • Example 12: 4-((N-(2-Fluorobenzyl)-4-(2-fluorophenoxy)benzamido)-methyl)benzoic Acid
  • Figure US20190010129A1-20190110-C00152
  • Prepared from the parent methyl ester (Intermediate C16) using Method H1.
  • 1H NMR (400 MHz, DMSO-d6) δ ppm 4.45-4.66 (m, 4H) 6.96-7.03 (m, 2H) 7.03-7.45 (m, 10H) 7.45-7.54 (m, 2H) 7.78-7.89 (m, 2H)
  • MS ES+: 474
    • Example 13: 4-((4-(2-Fluorophenoxy)-N-(3-methoxybenzyl)benzamido)-methyl)benzoic Acid
  • Figure US20190010129A1-20190110-C00153
  • Prepared from the parent methyl ester (Intermediate C17) using Method H1.
  • 1H NMR (400 MHz, DMSO-d6) δ ppm 3.72 (s, 3H) 4.42-4.71 (m, 4H) 6.55-7.10 (m, 5H) 7.16-7.62 (m, 9H) 7.76-7.99 (m, 2H) 12.92 (br s, 1H)
  • MS ES+: 486
    • Example 14: 4-((4-(2-Fluorophenoxy)-N-(4-methoxybenzyl)benzamido)-methyl)benzoic Acid
  • Figure US20190010129A1-20190110-C00154
  • Prepared from the parent methyl ester (Intermediate C18) using Method H1.
  • 1H NMR (400 MHz, DMSO-d6) δ ppm 3.74 (s, 3H) 4.24-4.80 (m, 4H) 6.83-7.65 (m, 14H) 7.84-8.05 (m, 2H) 12.90 (br s, 1H)
  • MS ES+: 486
    • Example 15: 4-((4-(2-Fluorophenoxy)-N-phenethylbenzamido)methyl)benzoic Acid
  • Figure US20190010129A1-20190110-C00155
  • Prepared from the parent methyl ester (Intermediate C19) using Method H1.
  • 1H NMR (400 MHz, CDCl3) δ ppm 2.40-3.07 (m, 2H) 3.07-4.11 (m, 2H) 4.11-4.95 (m, 2H) 6.55-7.49 (m, 15H) 7.86-8.05 (m, 2H)
  • MS ES+: 470
    • Example 16: 4-((4-(2-Fluorophenoxy)-N-(3-(2-fluorophenyl)propyl)benzamido)methyl)benzoic Acid
  • Figure US20190010129A1-20190110-C00156
  • Prepared from the parent methyl ester (Intermediate C20) using Method H1.
  • 1H NMR (400 MHz, DMSO-do) δ ppm 1.66-1.98 (m, 2H) 2.17-2.80 (m, 2H) 3.05-3.52 (m, 2H) 4.44-4.90 (m, 2H) 6.83-7.55 (m, 14H) 7.85-8.01 (m, 2H) 12.90 (br s, 1H)
  • MS ES+: 502
    • Example 17: 4-((4-(2-Fluorophenoxy)-N-(3-(3-fluorophenyl)propyl)benzamido)methyl)benzoic Acid
  • Figure US20190010129A1-20190110-C00157
  • Prepared from the parent methyl ester (Intermediate C21) using Method H1.
  • 1H NMR (400 MHz, DMSO-d6) ppm 1.70-1.95 (m, 2H) 2.30-2.40 (m, 2H) 3.30-3.40 (m, 2H) 4.74 (br s, 2H) 6.80-7.56 (m, 14H) 7.87-7.99 (m, 2H) 12.88 (br s, 1H)
  • MS ES+: 502
    • Example 18: 4-((4-(2-Fluorophenoxy)-N-((trans-2-phenylcyclopropyl)methyl)-benzamido)methyl)benzoic Acid
  • Figure US20190010129A1-20190110-C00158
  • Prepared from the parent methyl ester (Intermediate C22) using Method H1.
  • 1H NMR (400 MHz, CD2Cl2) δ ppm 0.92 (br s, 2H) 1.20-1.35 (m, 1H) 1.52-1.78 (m, 1H) 3.42 (s, 2H) 4.75-4.99 (m, 2H) 6.86-7.10 (m, 4H) 7.10-7.29 (m, 6H) 7.29-7.50 (m, 5H) 8.00-8.12 (m, 2H)
  • MS ES+: 496
    • Example 19: (S)-4-((4-(2-Fluorophenoxy)-N-(2-hydroxy-3-phenylpropyl)benzamido)methyl)benzoic Acid
  • Figure US20190010129A1-20190110-C00159
  • Prepared from the parent methyl ester (Intermediate C23) using Method H1.
  • 1H NMR (400 MHz, DMSO-d6) δ ppm 2.60-2.76 (m, 1H) 2.95-3.30 (m, 2H) 3.88-4.17 (m, 1H) 4.65 (br s, 2H) 4.85-4.97 (m, 1H) 5.00-5.29 (m, 1H) 6.85-7.33 (m, 12H) 7.33-7.50 (m, 3H) 7.79-7.90 (m, 2H)
  • MS ES+: 500
    • Example 20: (R)-1-((4-(2-Fluorophenoxy)-N-(2-hydroxy-3-phenylpropyl)-benzamido)methyl)benzoic Acid
  • Figure US20190010129A1-20190110-C00160
  • Prepared from the parent methyl ester (Intermediate C24) using Method H1.
  • 1H NMR (400 MHz, DMSO-d6) δ ppm 2.55-2.79 (m, 1H) 2.92-3.40 (m, 2H) 3.83-4.17 (m, 1H) 4.72 (br s, 2H) 4.85-5.05 (m, 1H) 5.06-5.23 (m, 1H) 6.83-7.53 (m, 15H) 7.84-7.97 (m, 2H)
  • MS ES+: 500
    • Example 21: 4-((4-(2-Fluorophenoxy)-N-(4-phenylbutyl)-benzamido)methyl)benzoic Acid
  • Figure US20190010129A1-20190110-C00161
  • Prepared from the parent methyl ester (Intermediate C25) using Method H1.
  • 1H NMR (400 MHz, DMSO-d6) δ ppm 1.29-1.70 (m, 2H) 2.32-2.84 (m, 2H) 3.10-3.55 (m, 2H) 4.62 (br s, 2H) 6.86-7.46 (m, 15H) 7.77-7.95 (m, 2H) 12.57 (br s, 1H)
  • MS ES+: 498
    • Example 22: 4-((N-(Cyclopropylmethyl)-4-(o-tolyloxy)benzamido)methyl)benzoic Acid
  • Figure US20190010129A1-20190110-C00162
  • Prepared from the parent methyl ester (Intermediate C26) using Method 111.
  • 1H NMR (400 MHz, DMSO-d6) ppm −0.25-0.25 (m, 2H) 0.25-0.50 (m, 2H) 0.74-1.11 (m, 1H) 2.13 (s, 3H) 2.87-3.47 (m, 2H) 4.78 (br s, 2H) 6.75-7.62 (m, 10H) 7.83-7.98 (m, 2H) 12.87 (br s, 1H)
  • MS ES+: 416
    • Example 23: 4-((N-(Cyclobutylmethyl)-4-(o-tolyloxy)benzamido)methyl)benzoic Acid
  • Figure US20190010129A1-20190110-C00163
  • Prepared from the parent methyl ester (Intermediate C27) using Method H1.
  • 1H NMR (400 MHz, DMSO-d6) ppm 1.23-1.99 (m, 7H) 2.15 (s, 3H) 2.40-2.74 (m, 2H) 4.65 (br s, 2H) 6.76-7.64 (m, 10H) 7.87-8.02 (m, 2H) 12.90 (br s, 1H)
  • MS ES+: 430
    • Example 24: 4-((N-Benzyl-4-(o-tolyloxy)benzamido)methyl)benzoic Acid
  • Figure US20190010129A1-20190110-C00164
  • Prepared from the parent methyl ester (Intermediate C28) using Method H1.
  • 1H NMR (400 MHz, DMSO-d6) δ ppm 2.14 (s, 3H) 4.58 (br s, 4H) 6.62-7.04 (m, 3H) 7.07-7.60 (m, 12H) 7.84-8.00 (m, 2H) 12.90 (br s, 1H)
  • MS ES+: 452
    • Example 25: 4-((N-Phenethyl-4-(o-tolyloxy)benzamido)methyl)benzoic Acid
  • Figure US20190010129A1-20190110-C00165
  • Prepared from the parent methyl ester (Intermediate C29) using Method H1.
  • 1H NMR (400 MHz, DMSO-d6) δ ppm 2.15 (br s, 3H) 2.72-2.98 (m, 2H) 3.34-3.59 (m, 2H) 4.43-4.88 (m, 2H) 6.82-7.02 (m, 4H) 7.28 (br s, 11H) 7.88-7.96 (m, 2H)
  • MS ES+: 466
    • Example 26: 4-((N-Phenethyl-4-(2-(trifluoromethyl)phenoxy)benzamido)-methyl)benzoic Acid
  • Figure US20190010129A1-20190110-C00166
  • Prepared from the parent methyl ester (Intermediate C30) using Method H1.
  • 1H NMR (400 MHz, DMSO-d6) δ ppm 2.71-2.99 (m, 2H) 3.34-3.59 (m, 2H) 4.43-4.87 (m, 2H) 6.89-7.42 (m, 12H) 7.43-7.54 (m, 1H) 7.64-7.73 (m, 1H) 7.77-7.85 (m, 1H) 7.88-7.98 (m, 2H)
  • MS ES+: 520
    • Example 27: 4-((iv-Benzyl-4-(2-cyanophenoxy)benzamido)methyl)benzoic Acid
  • Figure US20190010129A1-20190110-C00167
  • Prepared from the parent methyl ester (Intermediate C31) using Method H1.
  • 1H NMR (400 MHz, DMSO-d6) ppm 4.40-4.76 (m, 4H) 7.00-7.77 (m, 15H) 7.85-8.00 (m, 2H) 12.97 (br s, 1H)
  • MS ES+: 463
    • Example 28: 4-((N-Ethyl-4-(2-methoxyphenoxy)benzamido)methyl)benzoic Acid
  • Figure US20190010129A1-20190110-C00168
  • Prepared from the parent methyl ester (Intermediate C32) using Method H1.
  • 1H NMR (400 MHz, DMSO-do) δ ppm 1.01-1.11 (m, 3H) 3.22-3.33 (m, 2H) 3.73 (s, 3H) 4.68 (br s, 2H) 6.79-6.88 (m, 2H) 6.96-7.03 (m, 1H) 7.07-7.13 (m, 1H) 7.16-7.28 (m, 2H) 7.40 (br s, 4H) 7.89-7.96 (m, 2H) 12.88 (br s, 1H)
  • MS ES+: 406
    • Example 29: 4-((N-(2,2-Difluoroethyl)-4-(2-methoxyphenoxy)benzamido)-methyl benzoic Acid
  • Figure US20190010129A1-20190110-C00169
  • Prepared from the parent methyl ester (Intermediate C33) using Method H1.
  • 1H NMR (400 MHz, DMSO-d6) δ ppm 3.64-3.86 (m, 5H) 4.74 (br s, 2H) 6.07-6.44 (m, 1H) 6.78-6.92 (m, 2H) 6.96-7.03 (m, 1H) 7.07-7.13 (m, 1H) 7.15-7.46 (m, 6H) 7.87-7.97 (m, 2H) 12.93 (br s, 111)
  • MS ES+: 442
    • Example 30: 4-((N-Isobutyl-4-(2-methoxyphenoxy)benzamido)methyl)benzoic Acid
  • Figure US20190010129A1-20190110-C00170
  • Prepared from the parent methyl ester (Intermediate C34) using Method H1.
  • 1H NMR (400 MHz, DMSO-d6) δ ppm 0.58-0.97 (m, 6H) 1.80-2.13 (m, 1H) 3.06-3.19 (m, 2H) 3.72 (s, 3H) 4.68 (s, 2H) 6.77-6.90 (m, 2H) 6.94-7.05 (m, 1H) 7.05-7.13 (m, 1H) 7.16-7.53 (m, 6H) 7.87-7.97 (m, 2H) 12.91 (br s, 1H)
  • MS ES+: 434
    • Example 31: 4-((N-(Cyclopropylmethyl)-4-(2-methoxyphenoxy)benzamido)-methyl)benzoic Acid
  • Figure US20190010129A1-20190110-C00171
  • Prepared from the parent methyl ester (Intermediate C35) using Method H1.
  • 1H NMR (400 MHz, DMSO-d6) δ −0.14-0.20 (m, 2H) 0.30-0.44 (m, 2H) 0.81-1.03 (m, 1H) 3.15 (br s, 2H) 3.70 (s, 3H) 4.79 (br s, 2H) 6.78-6.91 (m, 2H) 6.96-7.03 (m, 1H) 7.08-7.14 (m, 1H) 7.16-7.28 (m, 2H) 7.30-7.50 (m, 4H) 7.87-7.96 (m, 2H) 12.88 (s, 1H)
  • MS ES+: 432
    • Example 32: 4-((4-(2-Methoxyphenoxy)-N-(3-phenylpropyl)benzamido)-methyl)benzoic Acid
  • Figure US20190010129A1-20190110-C00172
  • Prepared from the parent methyl ester (Intermediate C36) using Method H1.
  • 1H NMR (400 MHz, DMSO-do) δ ppm 1.83 (br s, 2H) 2.40 (br s, 2H) 3.22 (br s, 2H) 3.73 (s, 3H) 4.70 (br s, 2H) 6.77-6.82 (m, 2H) 6.95-7.44 (m, 13H) 7.88-7.93 (m, 2H) 12.89 (s, 1H)
  • MS ES+: 496
    • Example 33: 4-((N-(3-(3-Fluorophenyl)propyl)-4-(2-methoxyphenoxy)-benzamido)methyl)benzoic Acid
  • Figure US20190010129A1-20190110-C00173
  • I.
  • Prepared from the parent methyl ester (Intermediate C37) using Method H1.
  • 1H NMR (400 MHz, DMSO-d6) δ ppm 1.84 (br s, 2H) 2.42 (br s, 2H) 3.21 (br s, 2H) 3.73 (s, 3H) 4.70 (br s, 2H) 6.76-6.82 (m, 2H) 6.83-7.47 (m, 12H) 7.86-7.94 (m, 2H) 12.88 (br s, 1H)
  • MS ES+: 514
    • Example 34: 4-((N-(Cyclopropylmethyl)-4-(2-ethoxyphenoxy)-benzamido)methyl)benzoic Acid
  • Figure US20190010129A1-20190110-C00174
  • Prepared from the parent methyl ester (Intermediate C38) using Method H1.
  • 1H NMR (300 MHz, DMSO-do) δ ppm −0.24-0.60 (m, 4H) 0.69-1.41 (m, 4H) 2.87-3.31 (m, 2H) 3.80-4.15 (m, 2H) 4.76 (br s, 2H) 6.60-7.57 (m, 10H) 7.75-8.00 (m, 2H) 12.86 (br s, 11-1)
  • MS ES+: 446
    • Example 35: 4-((4-(2-Chlorophenoxy)-N-(cyclopropylmethyl)benzamido)-methyl)benzoic Acid
  • Figure US20190010129A1-20190110-C00175
  • Prepared from the parent methyl ester (Intermediate C39) using Method H1.
  • 1H NMR (400 MHz, DMSO-do) ppm ppm −0.30-0.23 (m, 2H) 0.23-0.50 (m, 2H) 0.74-1.12 (m, 1H) 2.81-3.41 (m, 2H) 4.79 (br s, 2H) 6.86-7.04 (m, 2H) 7.12-7.66 (m, 8H) 7.84-7.97 (m, 2H) 12.87 (br s, 1H)
  • MS ES+: 436
    • Example 36: 4-((4-(2-Chlorophenoxy)-N-phenethylbenzamido)methyl)benzoic Acid
  • Figure US20190010129A1-20190110-C00176
  • Prepared from the parent methyl ester (Intermediate C40) using Method H1.
  • 1H NMR (400 MHz, DMSO-d6) δ ppm 2.72-2.95 (m, 2H) 3.35-3.60 (m, 2H) 4.41-4.88 (m, 2H) 6.88-7.01 (m, 3H) 7.14-7.54 (m, 11H) 7.58-7.66 (m, 1H) 7.87-7.98 (m, 2H) 12.89 (br s, 1H)
  • MS ES+: 486
    • Example 37: 4-((N-(Cyclopropylmethyl)-4-(2,6-difluorophenoxy)benzamido)-methyl)benzoic Acid
  • Figure US20190010129A1-20190110-C00177
  • Prepared from the parent methyl ester (Intermediate C41) using Method H1.
  • 1H NMR (400 MHz, DMSO-d6) δ ppm 0.00 (br s, 2H) 0.38 (br s, 2H) 0.92 (br s, 1H) 3.12 (br s, 2H) 4.80 (br s, 2H) 7.01 (br s, 2H) 7.24-7.56 (m, 7H) 7.84-7.99 (m, 2H) 12.88 (br s, 1H)
  • MS ES+: 438
    • Example 38: 4-((N-(2-Cyclopropylethyl)-4-(2,6-difluorophenoxy)benzamido)-methyl)benzoic Acid
  • Figure US20190010129A1-20190110-C00178
  • Prepared from the parent methyl ester (Intermediate C42) using Method H1.
  • 1H NMR (400 MHz. DMSO-d6) δ ppm −0.27-0.10 (m, 2H) 0.18-0.75 (m, 3H) 1.25-1.57 (m, 2H) 3.14-3.47 (m, 2H) 4.52-4.81 (m, 2H) 6.87-7.11 (m, 2H) 7.22-7.56 (m, 7H) 7.84-8.00 (m, 2H) 12.88 (br s, 111)
  • MS ES+: 452
    • Example 39: 4-((N-Benzyl-4-(2,6-difluorophenoxy)benzamido)methyl)benzoic Acid
  • Figure US20190010129A1-20190110-C00179
  • Prepared from the parent methyl ester (Intermediate C43) using Method H1.
  • 1H NMR (400 MHz, DMSO-d6) δ ppm 4.40-4.68 (m, 4H) 6.95-7.04 (m, 2H) 7.11-7.44 (m, 10H) 7.45-7.55 (m, 2H) 7.86-7.94 (m, 2H)
  • MS ES+: 474
    • Example 40: 4-((N-(Cyclopropylmethyl)-4-(2-fluoro-6-methylphenoxy)-benzamido)methyl)benzoic Acid
  • Figure US20190010129A1-20190110-C00180
  • Prepared from the parent methyl ester (Intermediate C44) using Method H1.
  • 1H NMR (400 MHz, DMSO-d6) δ ppm −0.16-0.24 (m, 2H) 0.26-0.48 (m, 2H) 0.77-1.08 (m, 1H) 2.15 (s, 3H) 2.94-3.32 (m, 2H) 4.78 (br s, 2H) 6.88 (br s, 2H) 7.09-7.28 (m, 3H) 7.42 (br s, 4H) 7.85-7.96 (m, 2H) 12.87 (br s, 1H)
  • MS ES+: 434
    • Example 41: 4-((N-(Cyclobutylmethyl)-4-(2-fluoro-6-methylphenoxy)benzamido)methyl)benzoic Acid
  • Figure US20190010129A1-20190110-C00181
  • Prepared from the parent methyl ester (Intermediate C45) using Method H1.
  • 1H NMR (400 MHz, DMSO-d6) δ ppm 1.36-2.01 (m, 6H) 2.16 (s, 3H) 3.22-3.42 (m, 3H) 4.64 (br s, 2H) 6.80-6.95 (m, 2H) 7.17-7.29 (m, 3H) 7.32-7.56 (m, 4H) 7.81-8.02 (m, 2H) 12.88 (br s, 1H)
  • MS ES+: 448
    • Example 42: 4-((4-(2-Chloro-6-fluorophenoxy)-N-(cyclopropylmethyl)-benzamido)methyl)benzoic Acid
  • Figure US20190010129A1-20190110-C00182
  • Prepared from the parent methyl ester (Intermediate C46) using Method H1.
  • 1H NMR (400 MHz, DMSO-d6) δ ppm 0.00 (br s, 2H) 0.38 (br s, 2H) 0.93 (br s, 1H) 3.13 (br s, 2H) 4.80 (br s, 2H) 6.95 (br s, 2H) 7.24-7.60 (m, 7H) 7.86-7.99 (m, 2H) 12.88 (br s, 1H)
  • MS ES+: 454
    • Example 43: 4-((4-(2-Chloro-6-fluorophenoxy)-N-(2-cyclopropylethyl)-benzamido)methyl)benzoic Acid
  • Figure US20190010129A1-20190110-C00183
  • Prepared from the parent methyl ester (Intermediate C47) using Method H1.
  • 1H NMR (400 MHz, DMSO-d6) δ ppm −0.29-0.77 (m, 511) 1.23-1.57 (m, 2H) 3.15-3.52 (m, 2H) 4.49-4.84 (m, 2H) 6.95 (m, 2H) 7.21-7.57 (m, 711) 7.89-7.96 (m, 2H) 12.89 (br s, 1H)
  • MS ES+: 468
    • Example 44: 4-((N-Benzyl-4-(2-chloro-6-fluorophenoxy)benzamido)-methyl)benzoic acid
  • Figure US20190010129A1-20190110-C00184
  • Prepared from the parent methyl ester (Intermediate C48) using Method H1.
  • 1H NMR (400 MHz, DMSO-do) δ ppm 4.39-4.70 (m, 4H) 6.87-6.99 (m, 2H) 7.08-7.59 (m, 12H) 7.86-7.95 (m, 2H) 12.97 (br s, 1H)
  • MS ES+: 490
    • Example 45: 4-((4-(2,6-Dimethylphenoxy)-N-isopentylbenzamido)methyl)benzoic Acid
  • Figure US20190010129A1-20190110-C00185
  • Prepared from the parent methyl ester (Intermediate C49) using Method H2.
  • 1H NMR (400 MHz, DMSO-do) δ ppm 0.39-1.61 (m, 9H) 2.06 (s, 6H) 2.75-3.48 (m, 2H) 4.47-4.86 (m, 2H) 6.62-6.89 (m, 2H) 7.05-7.25 (m, 3H) 7.25-7.58 (m, 4H) 7.85-8.02 (m, 2H) 12.89 (br s, 1H)
  • MS ES+: 446
    • Example 46: 4-((N-Benzyl-4-(2,6-dimethylphenoxy)benzamido)methyl)benzoic Acid
  • Figure US20190010129A1-20190110-C00186
  • Prepared from the parent methyl ester (Intermediate C50) using Method H2.
  • 1H NMR (400 MHz, DMSO-d6) δ ppm 2.04 (s, 6H) 4.35-4.79 (m, 4H) 6.68-6.87 (m, 2H) 7.02-7.58 (m, 12H) 7.82-8.02 (m, 2H) 12.89 (br s, 1H)
  • MS ES+: 466
    • Example 47: 4-((4-(2,6-Dimethylphenoxy)-N-phenethylbenzamido)methyl)benzoic Acid
  • Figure US20190010129A1-20190110-C00187
  • Prepared from the parent methyl ester (Intermediate C51) using Method 1-12.
  • 1H NMR (400 MHz, DMSO-d6) δ ppm 2.07 (s, 6H) 2.62-3.04 (m, 2H) 3.10-3.70 (m, 2H) 4.35-4.98 (m, 2H) 6.65-7.63 (m, 14H) 7.85-8.03 (m, 2H)
  • MS ES+: 480
    • Example 48: 4-((4-(3-Methoxyphenoxy)-N-phenethylbenzamido)methyl)benzoic Acid
  • Figure US20190010129A1-20190110-C00188
  • Prepared from the parent methyl ester (Intermediate C52) using Method H1.
  • 1H NMR (400 MHz, DMSO-do) δ ppm 2.72-2.95 (m, 2H) 3.35-3.61 (m, 2H) 3.74 (s, 3H) 4.40-4.88 (m, 2H) 6.54-6.66 (m, 2H) 6.72-6.80 (m, 1H) 6.90-7.11 (m, 3H) 7.13-7.57 (m, 9H) 7.86-8.01 (m, 2H) 12.87 (br s, 1H)
  • MS ES+: 482
    • Example 49: 4-((4-(4-Methoxyphenoxy)-N-phenethylbenzamido)methyl)benzoic Acid
  • Figure US20190010129A1-20190110-C00189
  • Prepared from the parent methyl ester (Intermediate C53) using Method H1.
  • 1H NMR (400 MHz, DMSO-d6) δ ppm 2.70-2.96 (m, 2H) 3.35-3.57 (m, 2H) 3.76 (s, 3H) 4.40-4.87 (m, 2H) 6.85-7.56 (m, 15H) 7.85-8.00 (m, 2H) 12.90 (br s, 1H)
  • MS ES+: 482
    • Example 50: 4-((4-(3-Chlorophenoxy)-N-phenethylbenzamido)methyl)benzoic Acid
  • Figure US20190010129A1-20190110-C00190
  • Prepared from the parent methyl ester (Intermediate C54) using Method H1.
  • 1H NMR (400 MHz, DMSO-d6) δ ppm 2.73-2.98 (m, 2H) 3.36-3.62 (m, 2H) 4.42-4.90 (m, 2H) 6.87-7.57 (m, 15H) 7.93 (br s, 2H) 12.90 (br s, 1H)
  • MS ES+: 486
    • Example 51: 4-((N-(Cyclopropylmethyl)-4-((2-fluorobenzyl)oxy)benzamido)-methyl)benzoic Acid
  • Figure US20190010129A1-20190110-C00191
  • Prepared from the parent methyl ester (Intermediate C55) using Method H1.
  • 1H NMR (400 MHz, DMSO-d6) ppm ppm −0.22-0.25 (m, 2H) 0.26-0.47 (m, 2H) 0.77-1.08 (m, 1H) 2.73-3.45 (m, 2H) 4.77 (br s, 2H) 5.15 (s, 2H) 6.98-7.63 (m, 10H) 7.85-7.97 (m, 2H) 12.84 (br s, 1H)
  • MS ES+: 434
    • Example 52: 4-((N-(Cyclobutylmethyl)-1-((2-fluorobenzyl)oxy)benzamido)-methyl)benzoic Acid
  • Figure US20190010129A1-20190110-C00192
  • Prepared from the parent methyl ester (Intermediate C56) using Method H1.
  • 1H NMR (400 MHz, DMSO-d6) ppm 1.20-2.20 (m, 7H) 2.26-2.74 (m, 2H) 4.64 (s, 2H) 5.18 (s, 2H) 6.97-7.66 (m, 10H) 7.83-8.07 (m, 2H) 12.81 (br s, 1H)
  • MS ES+: 448
    • Example 53: 4-((N-Benzyl-4-((2-fluorobenzyl)oxy)benzamido)methyl)benzoic Acid
  • Figure US20190010129A1-20190110-C00193
  • Prepared from the parent methyl ester (Intermediate C57) using Method H1.
  • 1H NMR (400 MHz, DMSO-d6) ppm 4.56 (br s, 4H) 5.16 (s, 2H) 7.00-7.61 (m, 15H) 7.87-7.99 (m, 2H) 12.92 (br s, 1H)
  • MS ES+: 470
    • Example 54: 4-((N-(Cyclopropylmethyl)-2-fluoro-4-(2-fluorophenoxy)-Acid
  • Figure US20190010129A1-20190110-C00194
  • Prepared from the parent methyl ester (Intermediate C59) using Method H1.
  • 1H NMR (400 MHz, DMSO-d6) δ ppm −40.06-0.28 (m, 2H) 0.31-0.52 (m, 2H) 0.73-1.15 (m, 1H) 2.99-3.41 (m, 2H) 4.55-4.97 (m, 2H) 6.73-7.07 (m, 2H) 7.25-7.56 (m, 7H) 7.86-8.02 (m, 2H) 12.91 (br s, 1H)
  • MS ES+: 438
    • Example 55: 4-((N-Benzyl-4-(2-fluorophenoxy)cyclohexanecarboxamido)-methyl)benzoic Acid (Ca. 1:1 Mixture of Cis and Trans Ring Isomers)
  • Figure US20190010129A1-20190110-C00195
  • Prepared from the parent methyl ester (Intermediate C60) using Method H1.
  • 1H NMR (400 MHz, DMSO-d6) ppm 1.27-2.13 (m, 8H) 2.61-2.86 (m, 1H) 4.00-4.40 (m, 1H) 4.45-4.73 (m, 4H) 6.88-7.00 (m, 1H) 7.05-7.44 (m, 10H) 7.85-8.00 (m, 2H) 12.90 (br s, 1H)
  • MS ES+: 462
    • Example 56; trans ((N Benzyl 4-(2-methoxyphenoxy)cyclohexanecarboxamido)methyl)benzoic Acid
  • Figure US20190010129A1-20190110-C00196
  • Prepared from the parent methyl ester (Intermediate C61) using Method H1.
  • 1H NMR (400 MHz, DMSO-d6) ppm 1.10-2.11 (m, 8H) 2.57-2.78 (m, 1H) 3.73 (s, 3H) 4.11-4.25 (m, 1H) 4.46-4.74 (m, 4H) 6.81-7.04 (m, 4H) 7.15-7.44 (m, 7H) 7.86-8.00 (m, 2H) 12.90 (br s, 1H)
  • MS ES+: 474
    • Example 57: cis-4-((N-(3-(3-Fluorophenyl)propyl)-4-(2-methoxyphenoxy)cyclohexanecarboxamido)methyl)benzoic Acid
  • Figure US20190010129A1-20190110-C00197
  • Prepared from the parent methyl ester (Intermediate C62) using Method H1.
  • 1H NMR (400 MHz, DMSO-do) ppm 1.34-1.98 (m, 10H) 2.39-2.66 (m, 3H) 3.15-3.40 (m, 2H) 3.71-3.87 (m, 3H) 4.37-4.51 (m, 1H) 4.52-4.78 (m, 2H) 6.79-7.12 (m, 7H) 7.19-7.39 (m, 3H) 7.82-8.01 (m, 2H) 12.80 (br s, 1H)
  • MS ES+: 520
    • Example 58: trans-40V-(3-(3-Fluorophenyl)propyl)-4-(2-methoxyphenoxy)cyclohexanecarboxamido)methyl)benzoic Acid
  • Figure US20190010129A1-20190110-C00198
  • Prepared from the parent methyl ester (Intermediate C63) using Method H1.
  • 1H NMR (400 MHz, DMSO-d6) ppm 1.19-2.13 (m, 10H) 2.36-2.65 (m, 3H) 3.15-3.49 (m, 2H) 3.67-3.81 (m, 3H) 4.09-4.24 (m, 1H) 4.51-4.78 (m, 2H) 6.79-7.10 (m, 7H) 7.18-7.40 (m, 3H) 7.81-8.00 (m, 2H) 12.86 (br s, 1H)
  • MS ES+: 520
    • Example 59: 2-Fluoro-4-((4-(2-fluorophenoxy)-N-(3-methoxybenzyl)benzamido)methyl)benzoic Acid
  • Figure US20190010129A1-20190110-C00199
  • Prepared from the parent methyl ester (Intermediate C64) using Method H1.
  • 1H NMR (300 MHz, CDCl3) δ ppm 3.79 (s, 3H) 4.34-4.91 (m, 4H) 6.57-7.34 (m, 12H) 7.34-7.61 (m, 2H) 7.90-8.07 (m, 1H)
  • MS ES+: 504
    • Example 60: 4-((4-(2-Fluorophenoxy)-N-propylbenzamido)methyl)benzoic Acid
  • Figure US20190010129A1-20190110-C00200
  • Prepared from the parent methyl ester (Intermediate C25a) using Method H1.
  • 1H NMR (400 MHz, CDCl3) δ ppm 0.65-1.06 (m, 3H) 1.48-1.79 (m, 2H) 3.11-3.52 (m, 2H), 4.56-4.85 (m, 2H) 6.87-7.52 (m, 10H) 8.06-8.12 (m, 2H)
  • MS ES+: 408
    • Example 61: 4-((4-(2-Methoxyphenoxy)-N-(2,2,2-trifluoroethyl)benzamido)methyl)benzoic Acid
  • Figure US20190010129A1-20190110-C00201
  • Prepared from the parent methyl ester (Intermediate C40a) using Method H1.
  • 1H NMR (400 MHz, CDCl3) δ ppm 3.79 (s, 3H) 3.84-4.12 (m, 2H) 4.77-4.95 (m, 2H) 6.85-7.47 (m, 10H) 8.03-8.12 (m, 2H)
  • MS ES+: 460
    • Example 62: 4-((4-(2-Methoxyphenoxy)-N-propylbenzamido)methyl)benzoic Acid
  • Figure US20190010129A1-20190110-C00202
  • Prepared from the parent methyl ester (Intermediate C40b) using Method H1.
  • 1H NMR (400 MHz, CDCl3) δ ppm 0.65-1.05 (m, 3H) 1.41-1.78 (m, 2H) 3.12-3.52 (m, 2H), 3.80 (s, 3H) 4.55-4.87 (m, 2H) 6.81-7.51 (m, 10H) 8.04-8.12 (m, 2H)
  • MS ES+: 420
    • Example 63: 4-((N-(2,2-Difluoropropyl)-4-(2-methoxyphenoxy)-benzamido)methyl)benzoic Acid
  • Figure US20190010129A1-20190110-C00203
  • Prepared from the parent methyl ester (Intermediate C40c) using Method H1.
  • 1H NMR (400 MHz, CDCl3) δ ppm 1.32-1.84 (m, 3H) 3.45-4.02 (m, 5H) 4.65-5.06 (m, 2H) 6.79-7.50 (m, 10H) 7.99-8.15 (m, 2H)
  • MS ES+: 456
    • Example 64: 4-((4-(2-Methoxyphenoxy)-N-(3,3,3-trifluoropropyl)-benzamido)methyl)benzoic Acid
  • Figure US20190010129A1-20190110-C00204
  • Prepared from the parent methyl ester (Intermediate C40d) using Method H1.
  • 1H NMR (400 MHz, CDCl3) δ ppm 2.35-2.67 (m, 2H) 3.50-3.69 (m, 5H) 4.58-4.81 (m, 2H) 6.80-7.48 (m, 10H) 8.06-8.14 (m, 2H)
  • MS ES+: 474
    • Example 65: 4-((N-Butyl-4-(2-methoxyphenoxy)benzamido)methyl)benzoic Acid
  • Figure US20190010129A1-20190110-C00205
  • Prepared from the parent methyl ester (Intermediate C40e) using Method H1.
  • 1H NMR (400 MHz, CDCl3) δ ppm 0.67-1.01 (m, 3H) 1.01-1.74 (m, 4H) 3.11-3.56 (m, 2H) 4.56-4.90 (m, 2H) 6.80-7.58 (m, 10H) 8.03-8.14 (m, 2H)
  • MS ES+: 434
    • Example 66: 4-((N-(Cyclopropylmethyl)-2-fluoro-4-(2-methoxyphenoxy)benzamido)methyl)benzoic Acid
  • Figure US20190010129A1-20190110-C00206
  • Prepared from the parent methyl ester (Intermediate C65) using Method H1.
  • 1H NMR (400 MHz, DMSO-do) δ ppm −0.06-0.29 (m, 2H) 0.30-0.53 (m, 2H) 0.78-1.16 (m, 1H) 2.98-3.45 (m, 2H) 3.77 (s, 3H) 4.57-4.98 (m, 2H) 6.59-6.87 (m, 2H) 6.98-7.51 (m, 7H) 7.84-8.00 (m, 2H) 12.90 (br s, 1H)
  • MS ES+: 450
    • Example 67: 4-((N-(Cyclopropylmethyl)-4-(2-fluoro-6-methoxyphenoxy)benzamido)methyl)benzoic Acid
  • Figure US20190010129A1-20190110-C00207
  • Prepared from the parent methyl ester (Intermediate C66) using Method H1.
  • 1H NMR (400 MHz, CDCl3) δ ppm −0.10-0.28 (m, 2H) 0.37-0.58 (m, 2H) 0.78-1.15 (m, 1H) 2.98-3.50 (m, 2H) 3.79 (s, 3H) 4.68-5.05 (m, 2H) 6.69-7.50 (m, 9H) 8.02-8.11 (m, 2H)
  • MS ES+: 450
    • Example 68: 4-((N-(Cyclopropylmethyl)-4-(4-fluoro-2-methoxyphenoxy)benzamidomethyl)benzoic Acid
  • Figure US20190010129A1-20190110-C00208
  • Prepared from the parent methyl ester (Intermediate C67) using Method H1.
  • 1H NMR (400 MHz, CDCl3) δ ppm −0.09-0.29 (m, 2H) 0.44-0.58 (m, 2H) 0.78-1.17 (m, 1H) 3.01-3.55 (m, 2H) 3.78 (s, 3H) 4.70-5.05 (m, 2H) 6.70-7.52 (m, 9H) 8.03-8.12 (m, 2H)
  • MS ES+: 450
    • Example 69: 4-((N-(Cyclopropylmethyl)-5-(2-methoxyphenoxy)-picolinamido)methyl)benzoic Acid
  • Figure US20190010129A1-20190110-C00209
  • Prepared from the parent methyl ester (Intermediate C68) using Method H1.
  • 1H NMR (400 MHz, CDCl3) δ ppm −0.08-0.68 (m, 4H) 0.85-1.33 (m, 1H) 3.16-3.56 (m, 2H) 3.61-4.04 (m, 3H) 4.78-5.19 (m, 2H) 6.80-8.55 (m, 11H)
  • MS ES+: 433
    • Example 70: 4-((4-(o-Tolyloxy)-N-(2,2,2-trifluoroethyl)benzamido)methyl)benzoic Acid
  • Figure US20190010129A1-20190110-C00210
  • Prepared from the parent methyl ester (Intermediate C40f) using Method H1.
  • 1H NMR (400 MHz, CDCl3) δ ppm 2.18 (s, 3H) 4.02 (br s, 2H) 4.85 (br s, 2H) 6.81-7.58 (m, 10H) 8.00-8.20 (m, 2H)
  • MS ES+: 444
    • Example 71: 4-((4-(2-Fluorophenoxy)-N-(3,3,3-trifluoropropyl)benzamido)methyl)benzoic Acid
  • Figure US20190010129A1-20190110-C00211
  • Prepared from the parent methyl ester (Intermediate C25b) using Method H1.
  • 1H NMR (400 MHz, CDCl3) δ ppm 2.35-2.65 (m, 2H) 3.53-3.68 (m, 2H) 4.60-4.78 (m, 2H) 6.88-7.45 (m, 10H) 8.06-8.13 (m, 2H)
  • MS ES+: 462
    • Example 72: 4-((4-(2-Chlorophenoxy)-N-(2,2,2-trifluoroethyl)benzamido)methyl)benzoic Acid
  • Figure US20190010129A1-20190110-C00212
  • Prepared from the parent methyl ester (Intermediate C40g) using Method H1.
  • 1H NMR (400 MHz, CDCl3) δ ppm 3.81-4.18 (m, 2H) 4.84 (br s, 2H) 6.88-7.57 (m, 10H) 8.01-8.16 (m, 2H)
  • MS ES+: 464
    • Example 73: 4-((N-Ethyl-4-(o-tolyloxy)benzamido)methyl)benzoic Acid
  • Figure US20190010129A1-20190110-C00213
  • Prepared from the parent methyl ester (Intermediate C4011) using Method H1.
  • 1H NMR (400 MHz, DMSO-d6) δ ppm 0.92-1.12 (m, 3H) 2.11 (s, 3H) 3.08-3.40 (m, 2H) 4.46-4.78 (m, 2H) 6.74-7.50 (m, 10H) 7.82-7.93 (m, 2H)
  • MS ES+: 390
    • Example 74: 4-((N-(2,2-Difluoropropyl)-4-(2-fluorophenoxy)benzamido)methyl)benzoic Acid
  • Figure US20190010129A1-20190110-C00214
  • Prepared from the parent methyl ester (Intermediate C25c) using Method H1.
  • 1H NMR (400 MHz, CDCl3) δ ppm 1.24-1.92 (m, 3H) 3.36-4.08 (m, 2H) 4.57-5.13 (m, 2H) 6.79-7.58 (m, 10H) 7.90-8.20 (m, 2H)
  • MS ES+: 444
    • Example 75: 4-((N-Butyl-4-(2-fluorophenoxy)benzamido)methyl)benzoic Acid
  • Figure US20190010129A1-20190110-C00215
  • Prepared from the parent methyl ester (Intermediate C25d) using Method H1.
  • 1H NMR (400 MHz, CDCl3) δ ppm 0.66-1.77 (m, 7H) 3.08-3.57 (m, 2H) 4.49-4.93 (m, 2H) 6.81-7.57 (m, 10H) 8.04-8.18 (m, 2H)
  • MS ES+: 422
    • Example 76: 4-((4-(2-Chlorophenoxy)-N-ethylbenzamido)methyl)benzoic Acid
  • Figure US20190010129A1-20190110-C00216
  • Prepared from the parent methyl ester (Intermediate C40i) using Method H1.
  • 1H NMR (400 MHz, DMSO-d6) δ ppm 0.78-1.23 (m, 3H) 2.98-3.65 (m, 2H) 4.40-4.82 (m, 2H) 6.70-7.70 (m, 10H) 7.77-8.01 (m, 2H)
  • MS ES+: 410
    • Example 77: 4-((N-(Cyclopropylmethyl)-5-(2-fluorophenoxy)picolinamido)methyl)benzoic Acid
  • Figure US20190010129A1-20190110-C00217
  • Prepared from the parent methyl ester (Intermediate C69) using Method H1.
  • 1H NMR (400 MHz, CDCl3) δ ppm −0.06-0.25 (m, 2H) 0.38-0.56 (m, 2H) 0.77-1.33 (m, 1H) 3.27-3.40 (m, 2H) 4.99 (s, 2H) 7.07-8.44 (m, 11H)
  • MS ES+: 421
    • Example 78: 4-((4-(2-Chlorophenoxy)-N-(2,2-difluoroethyl)benzamido)methyl)benzoic Acid
  • Figure US20190010129A1-20190110-C00218
  • Prepared from the parent methyl ester (Intermediate C40j) using Method H1.
  • 1H NMR (400 MHz, CDCl3) δ ppm 3.59-3.81 (m, 2H) 4.80 (br s, 2H) 5.05-6.40 (m, 1H) 6.81-7.53 (m, 10H) 8.04-8.17 (m, 2H)
  • MS ES+: 446
    • Example 79: 4-((N-(Cyclopropylmethyl)-4-(5-fluoro-2-methoxyphenoxy)benzamido)methyl)benzoic Acid
  • Figure US20190010129A1-20190110-C00219
  • Prepared from the parent methyl ester (Intermediate C67b) using Method H1.
  • 1H NMR (400 MHz, CDCl3) δ −0.12-0.32 (m, 2H) 0.41-0.58 (m, 2H) 0.78-1.15 (m, 1H) 3.02-3.52 (m, 2H) 3.78 (s, 3H) 4.68-5.08 (m, 2H) 6.69-7.08 (m, 5H) 7.19-7.58 (m, 4H) 8.04-8.12 (m, 2H)
  • MS ES+: 450
    • Example 80: 4-((4-(4-Fluoro-2-methoxyphenoxy)-N-propylbenzamido)methyl)benzoic Acid
  • Figure US20190010129A1-20190110-C00220
  • Prepared from the parent methyl ester (Intermediate C67a) using Method H1.
  • 1H NMR (300 MHz, CDCl3) δ ppm 0.65-1.08 (m, 3H) 1.47-1.74 (m, 2H) 3.10-3.50 (m, 2H), 3.77 (s, 3H) 4.55-4.98 (m, 2H) 6.58-7.58 (m, 9H) 7.90-8.23 (m, 2H)
  • MS ES+: 438
    • Example 81: 4-((4-(5-Fluoro-2-methoxyphenoxy)-N-propylbenzamido)methyl)benzoic Acid
  • Figure US20190010129A1-20190110-C00221
  • Prepared from the parent methyl ester (Intermediate C67c) using Method H1.
  • 1H NMR (400 MHz, CDCl3) δ ppm 0.65-1.12 (m, 3H) 1.40-1.84 (m, 2H) 3.03-3.58 (m, 2H), 3.78 (s, 3H) 4.48-5.01 (m, 2H) 6.67-7.12 (m, 5H) 7.20-7.67 (m, 4H) 8.00-8.22 (m, 2H)
  • MS ES+: 438
    • Example 82: 4-((N-(Cyclopropylmethyl)-4-(3-fluoro-2-methoxyphenoxy)benzamido)methyl)benzoic Acid
  • Figure US20190010129A1-20190110-C00222
  • Prepared from the parent methyl ester (Intermediate C67d) using Method H1.
  • 1H NMR (400 MHz, CDCl3) δ −0.09-0.27 (m, 2H) 0.42-0.58 (m, 2H) 0.78-1.15 (m, 1H) 3.03-3.55 (m, 2H) 3.86 (s, 3H) 4.70-5.08 (m, 2H) 6.72-6.87 (m, 1H) 6.87-7.08 (m, 4H) 7.22-7.58 (m, 4H) 8.03-8.12 (m, 2H)
  • MS ES+: 450
    • Example 83: 4-((N-(Cyclopropylmethyl)-5-(2-fluorophenoxy)pyrimidine-2-carboxamido)methyl)benzoic Acid
  • Figure US20190010129A1-20190110-C00223
  • Prepared from the parent methyl ester (Intermediate C72) using Method H1.
  • 1H NMR (400 MHz, CDCl3) δ −0.06-0.20 (m, 2H) 0.38-0.57 (m, 2H) 0.91-1.14 (m, 1H) 3.01-3.43 (m, 2H) 4.64-5.06 (m, 2H), 7.12-7.33 (m, 4H) 7.40-7.53 (m, 2H) 8.01-8.10 (m, 2H) 8.38-8.57 (m, 2H)
  • MS ES+: 422
    • Example 84: 4-((N-(Cyclopropylmethyl)-5-(2-methoxyphenoxy)pyrimidine-2-carboxamido)methyl)benzoic Acid
  • Figure US20190010129A1-20190110-C00224
  • Prepared from the parent methyl ester (Intermediate C73) using Method H1.
  • 1H NMR (300 MHz, DMSO-d6) δ −0.12-0.20 (m, 2H) 0.26-0.42 (m, 2H) 0.76-1.12 (m, 1H) 2.82-3.30 (m, 2H) 3.68-3.76 (m, 3H) 4.35-4.79 (m, 2H), 6.95-7.34 (m, 6H) 7.69-7.82 (m, 2H) 8.39-8.49 (m, 2H)
  • MS ES+: 434
    • Example 85: 4-((5-(2-Methoxyphenoxy)-N-propylpyrimidine-2-carboxamido)methyl)benzoic Acid
  • Figure US20190010129A1-20190110-C00225
  • Prepared from the parent methyl ester (Intermediate C74) using Method H1.
  • 1H NMR (400 MHz, CDCl3) δ ppm 0.63-0.99 (m, 3H) 1.48-1.77 (m, 2H) 3.03-3.50 (m, 2H), 3.71-3.86 (m, 3H) 4.49-4.93 (m, 2H) 6.93-7.53 (m, 6H) 7.96-8.14 (m, 2H) 8.28-8.52
  • MS ES+: 422
    • 3. Biological Efficacy of Compounds of the Invention In Vitro LPA5 Receptor Assay
  • Engagement of the LPA5 receptor by its ligand, oleoyl-L-α-lysophosphatidic acid (LPA), leads to the release of intracellular stores of calcium into the cytoplasm mediated through a Gq-driven increase in inositol triphosphate (IP3) levels. Gq is a heterotrimeric G protein subunit that activates phospholipase C.
  • The ability of test compounds to prevent LPA-driven intracellular release of stored calcium from RH7777 cells expressing human LPA5 receptors was assayed by stimulating the cells with LPA in the presence of various test compounds to measure the test compounds' antagonism, i.e. activity in vitro.
  • Approximately 10,000 cells in normal culture medium (Minimal Essential Media, 10% Foetal Calf Serum) were dispensed per assay well in a black clear bottom poly-D-lysine coated 384 well plate (Corning). Cells were allowed to settle for thirty minutes at room temperature before being incubated overnight at 37° C., 5% CO2. Sixteen to twenty hours after dispensing, the cells were loaded with a calcium-sensitive fluorescent dye by replacing the culture medium with assay buffer (1× Hanks buffered saline, 25 mM HEPES, 0.1% w/v fatty acid free BSA (bovine serum albumin), pH7.4) containing 1.25 mM probenecid and 1× Calcium 5 Reagent (Molecular Devices). Cells were incubated at 37° C. for one hour to allow for dye uptake.
  • To test for antagonist activity, test compounds at a final concentration range between 0.32 nM-10 μM (diluted in assay buffer) were added to the assay wells and allowed to incubate for fifteen minutes. After incubation with test compounds the assay plate was placed in a FLIPR Tetra system (Molecular Devices) and LPA (diluted in assay buffer) was added to give a final concentration equivalent to its determined EC90 against LPA5 receptor. Ligand-dependent changes in intracellular calcium levels were determined by measuring changes in fluorescence of the dye over 515-575 nM following excitation over 470-495 nM. Readings from control wells that did not contain test compounds enabled percentage inhibition curves to be plotted using a 4-parameter curve fit algorithm and IC50 values to be calculated for each compound.
    • Results
  • Example No. Mean IC50 (nM) Example No. Mean IC50 (nM)
    1 840
    2 690 3 43
    4 63 5 16
    6 24 7 31
    8 32 9 15
    10 48 11 6
    12 9 13 3
    14 2 15 120
    16 1 17 1
    18 2 19 9
    20 40 21 11
    22 24 23 44
    24 7 25 29
    26 260 27 200
    28 45 29 43
    30 12 31 5
    32 0.4 33 0.4
    34 460 35 7
    36 24 37 28
    38 140 39 11
    40 31 41 89
    42 17 43 58
    44 11 45 99
    46 17 47 11
    48 3300 49 4600
    50 3600 51 53
    52 370 53 58
    54 26 55 690
    56 180 57 410
    58 32 59 6
    60 60 61 8
    62 9 63 10
    64 7 65 4
    66 5 67 5
    68 10 69 8
    70 140 71 83
    72 42 73 890
    74 98 75 22
    76 140 77 74
    78 170 79 68
    80 45 83 350
    84 91 85 120
    • In Vivo Farnesyl Pyrophosphate-Induced Inflammatory Model
  • Farnesyl pyrophosphate (FPP) is an endogenous ligand for the LPA5 receptor, with a reported in-vitro EC50 of 49 nM and 3-fold selectivity over other LPA receptors (Williams et al. (2009), ‘Unique Ligand Selectivity of the GPR92/LPA5 Lysophosphatidate Receptor Indicates Role in Human Platelet Activation’, J Biol. Chem., 284(25):17304-17319). The FPP-induced hyperalgesia model is a pharmacodynamic rat model which involves inducing pain by injecting FPP, an agonist of LPA5 receptor, into the plantar surface of the hindpaw. Pre-treatment with a LPA5 receptor antagonist prevents the hyperalgesia induced by FPP.
  • In adult male rats baseline measurements were taken by assessing the withdrawal threshold to a painful pressure stimulus applied to the hindpaw according to the Randall-Selitto method (Randall and Selitto (1957), ‘A method for measurement of analgesic activity on inflamed tissue’, Arch Int Pharmacodyn Ther., 111 (4):409-19). The animals were then administered an intraperitoneal (ip) or oral (po) dose of test compound or vehicle 30 to 120 minutes prior to an intra-plantar injection of FPP (1004 at 32 nM) or saline vehicle. Withdrawal responses were reassessed at 30 and 90 minutes after injection of FPP in the ipsilateral paw.
    • Results
  • In vivo efficacy
    Compound of (minimum effective dose
    Example No. Route (MED) mg/kg)
    3 po ≤10
    4 po ≤10
    4 ip 1
    5 po ≤10
    5 ip 0.3
    8 po 100
    11 po ≤10
    24 po 30
    29 po 3
    31 po 1
    40 po 60
    • In Vitro LPA1 Receptor Assay
  • Engagement of the LPA1 receptor by its ligand, oleoyl-L-α-lysophosphatidic acid (LPA), leads to the release of intracellular stores of calcium into the cytoplasm mediated through a Gq-driven increase in inositol triphosphate (IP3) levels. Gq is a heterotrimeric G protein subunit that activates phospholipase C.
  • The ability of test compounds to prevent LPA-driven intracellular release of stored calcium from RH7777 cells expressing human LPA1 receptors was assayed by stimulating the cells with LPA in the presence of various test compounds to measure the test compounds' antagonism, i.e. activity in vitro.
  • Approximately 10,000 cells in normal culture medium (Dulbecco's Modified Eagle Media, 10% Foetal Calf Serum) were dispensed per assay well in a black clear bottom collagen coated 384 well plate (Beckton Dickinson). Cells were allowed to settle for thirty minutes at room temperature before being incubated overnight at 37° C., 5% CO2. Sixteen to twenty hours after dispensing, the cells were loaded with a calcium-sensitive fluorescent dye by replacing the culture medium with assay buffer (1× Hanks buffered saline, 25 mM HEPES, 0.1% w/v fatty acid free BSA (bovine serum albumin), pH7.4) containing 1.25 mM probenecid and 1× Calcium 5 Reagent (Molecular Devices). Cells were incubated at 37° C. for one hour to allow for dye uptake.
  • To test for antagonist activity, test compounds at a final concentration range between 0.32 nM-10 μM (diluted in assay buffer) were added to the assay wells and allowed to incubate for twenty five minutes. After incubation with test compounds the assay plate was placed in a FLIPR Tetra system (Molecular Devices) and LPA (diluted in assay buffer) was added to give a final concentration equivalent to its determined EC80 against LPA1 receptor. Ligand-dependent changes in intracellular calcium levels were determined by measuring changes in fluorescence of the dye over 515-575 nM following excitation over 470-495 nM. Readings from control wells that did not contain test compounds enabled percentage inhibition curves to be plotted using a 4-parameter curve fit algorithm and IC50 values to be calculated for each compound.
  • Example No. Mean IC50 (nM) Example No. Mean IC50 (nM)
    3 35 4 49
    5 46 8 46
    11 6 13 4
    14 2 17 0.4
    18 1 19 7
    20 12 22 30
    24 11 25 14
    28 46 29 34
    30 12 31 4
    32 2 33 0.3
    36 24 37 25
    38 36 40 160
    45 75 46 19
    47 22 54 27
    58 17
    60 33 61 4
    62 5 63 7
    64 9 65 5
    66 7 67 7
    68 13 69 12
    70 47 71 59
    72 29 73 120
    74 40 75 31
    76 130 77 86
    78 390 79 94
    80 110 83 540
    84 170 85 180
    • In Vivo Bleomycin Induced Scleroderma Model Experimental Outline
  • Adult male C57BL/6 mice, aged 8-10 weeks, were assigned to groups and allowed to acclimatise for a week. On Day −1, the back skin of the animals was shaved. From Day 0, animals were administered with 100 μl of a 1 mg/ml solution of bleomycin sulphate in phosphate buffered saline (PBS) by intradermal injection in the shaved skin. Injections were repeated in a one square centimeter area every other day for four weeks. A group of ten animals (Control group) was injected with an identical volume of PBS. Treatments were given according to the administration schedule shown in the table below. Animals were weighed at the beginning of the experiment on Day 0 and then twice weekly throughout the study. At the end of the experiment, on Day 28, animals were culled and samples of back skin were taken for further analysis. All groups were n=10; the vehicle was distilled water and the administration volume was 10 ml/kg for oral gavage (p.o.); administration volume was 25 μl for topical application.
  • Administration
    Group Substance Dose Route Frequency Skin sensitisation
    1 Vehicle n/a p.o. BID, Day 0-Day PBS, i.d.,
    28 QAD,
    Day 0-Day
    28
    2 Vehicle n/a p.o. BID, Day 0-Day Bleomycin,
    28 i.d., QAD,
    3 Imatinib 150 mg/kg  p.o. BID, Day 0-Day Day 0-Day
    mesylate 28 28
    4 Compound of 30 mg/kg p.o. BID, Day 0-Day
    Example 5 28
    5 Compound of 30 mg/kg p.o. BID, Day 14-Day
    Example 5 28
    6 “Protopic” 0.1% topical BID, Day 0-Day
    (trade mark) 28
    7 Betamethasone 0.1% topical BID, Day 0-Day 9
    SID, Day 10-Day
    28
    • Results
  • Bodyweights were graphed along with the standard error of the mean (SEM); Skin samples (two punch biopsies per animal, 4 mm in diameter each) samples were hydrolyzed and hydroxyproline content of the samples was determined from analysis in a semi-automated process using a continuous flow analyzer. Autoanalyser readings were calibrated against hydroxyproline standards and collagen content calculated. The bodyweight loss observed in the Example 5 compound-treated groups did not differ from the bodyweight loss observed in the vehicle-treated group. Some weight loss <10% was observed with bleomycin treatment. Bleomycin administration induced a highly significant increase in skin collagen content when compared to the control, saline-injected, group (p<0.01). Imatinib and Betamethasone 0.1% induced a non-significant reduction in skin collagen content when compared to the vehicle-treated group. The Example 5 compound administered from Day 0 and from Day 14 induced a significant reduction in skin collagen content when compared to the vehicle-treated group (p<0.05). Protopic 0.1% induced a highly significant reduction in skin collagen content when compared to the vehicle-treated group (p<0.001). Thus, the compound of Example 5 demonstrated an anti-fibrotic effect in an in vivo bleomycin-induced scleroderma model as measured by collagen skin content.

Claims (30)

1.-18. (canceled)
19. A method of treating a condition whose development or symptoms are linked to LPAR5 activity comprising administering to a patient in need thereof a pharmaceutically effective amount of a compound selected from 4-((N-(cyclopropylmethyl)-2-fluoro-4-(2-fluorophenoxy)benzamido)methyl)benzoic acid, 4-((N-(cyclopropylmethyl)-4-(2-fluorophenoxy)benzamido)methyl)benzoic acid, 4-((N-(cyclopropylmethyl)-4-(2-methoxyphenoxy)benzamido)methyl)benzoic acid, and a pharmaceutically acceptable salt of any of the foregoing.
20. The method according to claim 19, wherein the condition is chosen from fibrosis, liver diseases, atherosclerosis, inflammatory diseases, gastrointestinal tract diseases, and pain disorders.
21. The method according to claim 19, wherein the compound is 4-((N-(cyclopropylmethyl)-2-fluoro-4-(2-fluorophenoxy)benzamido)methyl)benzoic acid.
22. The method according to claim 19, wherein the compound is 4-((N-(cyclopropylmethyl)-2-fluoro-4-(2-fluorophenoxy)benzamido)methyl)benzoic acid or a pharmaceutically acceptable salt thereof.
23. The method according to claim 19, wherein the compound is 4-((N-(cyclopropylmethyl)-4-(2-fluorophenoxy)benzamido)methyl)benzoic acid.
24. The method according to claim 19, wherein the compound is 4-((N-(cyclopropylmethyl)-4-(2-fluorophenoxy)benzamido)methyl)benzoic acid or a pharmaceutically acceptable salt thereof.
25. The method according to claim 19, wherein the compound is 4-((N-(cyclopropylmethyl)-4-(2-methoxyphenoxy)benzamido)methyl)benzoic acid.
26. The method according to claim 19, wherein the compound is 4-((N-(cyclopropylmethyl)-4-(2-methoxyphenoxy)benzamido)methyl)benzoic acid or a pharmaceutically acceptable salt thereof.
27. The method according to claim 19, further comprising administering at least one additional therapeutic agent.
28. The method according to claim 27, wherein the at least one additional therapeutic agent is selected from opioid agonists, partial agonists or antagonists; antidepressants; anxiolytics; anticonvulsants; migraine therapies; stroke therapies; urinary incontinence therapies; neuropathic pain therapies; and nociceptive pain therapies.
29. A method of treating a condition whose development or symptoms are linked to LPAR1 activity comprising administering to a patient in need thereof a pharmaceutically effective amount of a compound selected from 4-((N-(cyclopropylmethyl)-2-fluoro-4-(2-fluorophenoxy)benzamido)methyl)benzoic acid, 4-((N-(cyclopropylmethyl)-4-(2-fluorophenoxy)benzamido)methyl)benzoic acid, 4-((N-(cyclopropylmethyl)-4-(2-methoxyphenoxy)benzamido)methyl)benzoic acid, and a pharmaceutically acceptable salt of any of the foregoing.
30. The method according to claim 29, wherein the condition is chosen from fibrosis, liver diseases, atherosclerosis, inflammatory diseases, gastrointestinal tract diseases, and pain disorders.
31. The method according to claim 29, wherein the compound is 4-((N-(cyclopropylmethyl)-2-fluoro-4-(2-fluorophenoxy)benzamido)methyl)benzoic acid.
32. The method according to claim 29, wherein the compound is 4-((N-(cyclopropylmethyl)-2-fluoro-4-(2-fluorophenoxy)benzamido)methyl)benzoic acid or a pharmaceutically acceptable salt thereof.
33. The method according to claim 29, wherein the compound is 4-((N-(cyclopropylmethyl)-4-(2-fluorophenoxy)benzamido)methyl)benzoic acid.
34. The method according to claim 29, wherein the compound is 4-((N-(cyclopropylmethyl)-4-(2-fluorophenoxy)benzamido)methyl)benzoic acid or a pharmaceutically acceptable salt thereof.
35. The method according to claim 29, wherein the compound is 4-((N-(cyclopropylmethyl)-4-(2-methoxyphenoxy)benzamido)methyl)benzoic acid.
36. The method according to claim 29, wherein the compound is 4-((N-(cyclopropylmethyl)-4-(2-methoxyphenoxy)benzamido)methyl)benzoic acid or a pharmaceutically acceptable salt thereof.
37. The method according to claim 29, further comprising administering at least one additional therapeutic agent.
38. The method according to claim 37, wherein the at least one additional therapeutic agent is selected from opioid agonists, partial agonists or antagonists; antidepressants; anxiolytics; anticonvulsants; migraine therapies; stroke therapies; urinary incontinence therapies; neuropathic pain therapies; and nociceptive pain therapies.
39. A method of treating a condition chosen from pain disorders and gastrointestinal tract diseases comprising administering to a patient in need thereof a therapeutically effective amount of a compound selected from 4-((N-(cyclopropylmethyl)-2-fluoro-4-(2-fluorophenoxy)benzamido)methyl)benzoic acid, 4-((N-(cyclopropylmethyl)-4-(2-fluorophenoxy)benzamido)methyl)benzoic acid, 4-((N-(cyclopropylmethyl)-4-(2-methoxyphenoxy)benzamido)methyl)benzoic acid, and a pharmaceutically acceptable salt of any of the foregoing.
40. The method according to claim 39, wherein the compound is 4-((N-(cyclopropylmethyl)-2-fluoro-4-(2-fluorophenoxy)benzamido)methyl)benzoic acid.
41. The method according to claim 39, wherein the compound is 4-((N-(cyclopropylmethyl)-2-fluoro-4-(2-fluorophenoxy)benzamido)methyl)benzoic acid or a pharmaceutically acceptable salt thereof.
42. The method according to claim 39, wherein the compound is 4-((N-(cyclopropylmethyl)-4-(2-fluorophenoxy)benzamido)methyl)benzoic acid.
43. The method according to claim 39, wherein the compound is 4-((N-(cyclopropylmethyl)-4-(2-fluorophenoxy)benzamido)methyl)benzoic acid or a pharmaceutically acceptable salt thereof.
44. The method according to claim 39, wherein the compound is 4-((N-(cyclopropylmethyl)-4-(2-methoxyphenoxy)benzamido)methyl)benzoic acid.
45. The method according to claim 39, wherein the compound is 4-((N-(cyclopropylmethyl)-4-(2-methoxyphenoxy)benzamido)methyl)benzoic acid or a pharmaceutically acceptable salt thereof.
46. The method according to claim 39, further comprising administering at least one additional therapeutic agent.
47. The method according to claim 46, wherein the at least one additional therapeutic agent is selected from opioid agonists, partial agonists or antagonists; antidepressants; anxiolytics; anticonvulsants; migraine therapies; stroke therapies; urinary incontinence therapies; neuropathic pain therapies; and nociceptive pain therapies.
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