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WO2021123394A1 - G protein-coupled receptor modulators and a pharmaceutical composition - Google Patents

G protein-coupled receptor modulators and a pharmaceutical composition Download PDF

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Publication number
WO2021123394A1
WO2021123394A1 PCT/EP2020/087341 EP2020087341W WO2021123394A1 WO 2021123394 A1 WO2021123394 A1 WO 2021123394A1 EP 2020087341 W EP2020087341 W EP 2020087341W WO 2021123394 A1 WO2021123394 A1 WO 2021123394A1
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Prior art keywords
ring
pyridin
methoxy
pyran
nmr
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French (fr)
Inventor
Trond Ulven
Loukas IEREMIAS
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Københavns Universitet
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Københavns Universitet
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • 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
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/69—Two or more oxygen atoms

Definitions

  • the invention concerns a compound of formula I, a phamaceutical compostion comprising the compound of formula I and use of the pharmaceutical compoisition for treating fibrotic, inflammatory, diabetic or cognitive disease.
  • GPR84 is a G protein-coupled receptor (GPCR) that is activated by a relatively high concentration of decanoic acid and some related compounds, however its natural activator is still unknown and the receptor is thus considered to be "orphan" GPCR.
  • GPCR G protein-coupled receptor
  • three classes of ligands are suggested to bind to three distinct sites on orphan GPR84, with the medium chain fatty acids agonist ligands (in particular decanoic acid) binding to one site; a second class of allosteric agonists represented by 3,3'-diindolylmethane (DIM), while a third class of allosteric antagonists represented by G9543 may bind to a third site (Mahmud et al. 2017).
  • DIM 3,3'-diindolylmethane
  • GPCRs are cell-surface receptors that are known to be highly “druggable", with 1/3 of current drugs acting through members of this class.
  • GPR84 is expressed on immune cells, especially neutrophils and eosinophils, and is found in organs such as bone marrow, liver, lung, intestines and brain.
  • the receptor has a pro-inflammatory effect and is induced in monocytes and macrophages by lipopolysaccharide (LPS) and activation of GPR84 induces secretion of pro- inflammatory cytokines such as IL-4, IL-8, IL-128, CXCL1 and TNF-a.
  • LPS lipopolysaccharide
  • GPR84 could represent a useful treatment of inflammatory diseases, including asthma, atopic dermatitis, cancer, diabetes, fibrosis and Inflammatory bowel disease (IBD) (Milligan et al. 2018; Miyamoto et al. 2017; Lynch 8i Wang 2016; Suckow 8i Briscoe 2017; Gagnon et al. 2018).
  • IBD Inflammatory bowel disease
  • Nan et al (WO2017/076264A1) have invented dihydroxypyrimidines and similar compounds as GPR84 agonists for treatment of septicemia. Pillalyar et al. (2017) have reported optimized DIM GPR84 agonists, whereas Pillalyar et al. (2016) and Kose et al. (2019) have reported potent uracil-derived GPR84 agonists.
  • the present invention pertains to a compound of the formula I: (formula I) wherein
  • X is -NH-, -0-, -S- or is absent;
  • A is -(Al) j -(Bl) k -(A2)r(B2) m -H, wherein
  • Al and A2 independently are C 1-7 alkylene, C 2-7 alkenylene, C 2-7 alkynylene, or C 1-7 heteroalkylene, optionally substituted with one or two of independently selected Ul;
  • B1 and B2 are independently an aliphatic ring, an aromatic ring or a fused ring, optionally substituted with one or two of independently selected U2;
  • H is hydrogen;
  • j, k, I, and m are independently 0 or 1;
  • Y is -OCH2-, -N(R')CH 2 -, -CH2CH2-, -CH2-, -N(R')-, or -0-, where R' is hydrogen or C1-C3 alkyl; and R is an aromatic ring, an aromatic ring comprising nitrogen, an aliphatic ring or a fused ring, optionally substituted with one, two or three of independently selected U3;
  • the compound of formula I pertains to: (formula I) wherein
  • X is -NH-, -0-, -S- or is absent; A is
  • A1 and A2 are independently C1-7 alkylene, C1-7 alkenylene, C1-7 alkynylene or C1-7 heteroalkylene;
  • B1 is an aliphatic ring, an aromatic ring or a fused ring;
  • B2 is an aliphatic ring, an aromatic ring or a fused ring, and H is hydrogen;
  • Y is -OCH2-, -N(R')CH 2 -, -CH2CH2-, -CH2-, -NCR')-, or -0-, where R' is hydrogen or Ci-C 3 alkyl;
  • R is an aromatic ring comprising nitrogen, an aliphatic ring or a fused ring, where the ring is optionally substituted with -CF 3 , Ci- 3 alkyl, C2-4 heteroalkyl or the ring is optionally substituted with -CF 3 , Ci- 3 alkyl, C 2- heteroalkyl, o wherein Z is -0-, -CH 2 -, -NH- or N-(CH 2 ) 0 -2-CH 3 ,
  • W is -0- or -CH 2 -; and n is 0, 1 or 2; or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a solvate of the pharmaceutically acceptable salt thereof.
  • the invention concerns a pharmaceutical composition for use as a medicament, said pharmaceutical composition comprising a compound according to formula I and a pharmaceutically acceptable carrier, excipient or diluent.
  • the pharmaceutical composition can be used in the treatment of inflammatory or diabetic disease.
  • alkyl by itself or as part of another substituent, means, unless otherwise stated, a straight or branched chain, or cyclic hydrocarbon radical, or combination thereof, which is fully saturated, having the number of carbon atoms designated (e.g., Ci- 7 means one to seven carbon atoms).
  • alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, cyclohexyl, (cyclohexyl)methyl, cyclopropyl, cyclopropylmethyl, and homologs and isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like.
  • cycloalkyl by itself or as part of another substituent, means, unless otherwise stated, a member of the subset of alkyl comprising cyclic hydrocarbon radicals.
  • alkylene by itself or as part of another substituent means a divalent radical derived from alkyl.
  • the two valences may be on any carbon atom of the chain, including on the same carbon, resulting in an alkyl connected by a double bond.
  • an alkyl (or alkylene) group will have from 1 to 24 carbon atoms, with those groups having 8 or fewer carbon atoms being preferred in the present invention.
  • alkenyl means monovalent unsaturated (olefinic) hydrocarbon chains having a specified number of carbon atoms (i.e.
  • alkenyl has 2 to 7 carbon atoms, and more particularly, from 2 to 3 carbon atoms, which can be straight- chained or branched and having at least 1 and particularly from 1 to 2 sites of olefinic unsaturation.
  • alkenylene by itself or as part of another substituent, means a straight or branched chain hydrocarbon radical, or combination thereof, which may be mono- or polyunsaturated, having the number of carbon atoms designated (i.e. C 2-8 means two to eight carbons) and one or more double bonds.
  • alkynyl by itself or as part of another substituent, means a straight or branched chain hydrocarbon radical, or combination thereof, which may be mono- or polyunsaturated, having the number of carbon atoms designated (i.e. C 2 -C 8 means two to eight carbons) and one or more triple bonds.
  • alkynyl groups include ethynyl, 1- and 2-propynyl, 3-butynyl, and higher homologs and isomers thereof.
  • alkynylene means a divalent alkyne radical groups having the number of carbon atoms and the number of triple bonds specified, in particular 2 to 7 carbon atoms and more particularly 2 to 3 carbon atoms which can be straight-chained or branched. This term is exemplified by groups such as -CoC-, -CH 2 -CoC-, and -C(CH 3 )H-CoC-.
  • heteroalkyl by itself or in combination with another term, means, unless otherwise stated, a stable straight or branched chain, or cyclic hydrocarbon radical, or combinations thereof, consisting of carbon atoms and from one to three heteroatoms selected from the group consisting of 0, N, and S, and wherein the nitrogen and sulfur atoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized.
  • the heteroatom(s) 0, N, and S may be placed at any position of the heteroalkyl group.
  • Up to two heteroatoms may be consecutive, such as, for example, -CH 2 NHS(0) 2 CH 3 .
  • a prefix such as C 2-7 is used to refer to a heteroalkyl group, the number of carbons (2 to 7, in this example) is meant to include the heteroatoms as well.
  • a C 2 -heteroalkyl group is meant to include, for example, -CH 2 OH (one carbon atom and one heteroatom replacing a carbon atom), -SCH 3 and -CH 2 SH, and a C 3 -heteroalkyl group is meant to include -N(CH 3 ) 2 .
  • a heteroalkyl group is an, oxyalkyl group.
  • (C 2 -C 8 )oxyalkyl is meant to include, for example -CH 2 0-CH 3 (a C 3 -oxyalkyl group with two carbon atoms and one oxygen replacing a carbon atom), -CH2CH2CH2CH2OH, and the like.
  • heteroalkylene by itself or as part of another substituent means a divalent radical derived from heteroalkyl, as exemplified by -CH2CH2SCH2CH2- and -CH2SCH2CH2NHCH2-.
  • heteroatoms can also occupy either or both of the chain termini (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, and the like).
  • alkylene and heteroalkylene linking groups no orientation of the linking group is implied.
  • Heteroalkylene groups such as oxymethyl groups (-CH 2 0-) may be substituted or unsubstituted.
  • heteroalkylene groups may be substituted with an alkyl group.
  • the carbon atom of an oxymethylene group may be substituted with a methyl group in a group of formula -CH(CH )0-.
  • Cl heteroalkylene may be a divalent radical derived from a heteroatom, as exemplified by -0-, -N-, -S-.
  • cycloalkyl and “heterocycloalkyl” by themselves or in combination with other terms, represent, unless otherwise stated, cyclic versions of “alkyl” and “heteroalkyl” respectively.
  • the terms “cycloalkyl” and “heterocycloalkyl” are meant to be included in the terms “alkyl” and “heteroalkyl”, respectively.
  • a heteroatom can occupy the position at which the heterocycle is attached to the remainder of the molecule.
  • Examples of cycloalkyl include cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like.
  • heterocycloalkyl examples include l-(l,2,5,6-tetrahydropyridyl), 1- piperidinyl, 2-piperidinyl, 3-piperidinyl, 1-pyrrolidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1- piperazinyl, 2-piperazinyl, 4,5-dihydroisoxazol-3-yl, and the like.
  • heterocycloalkyl includes fully saturated compounds such as piperidine and compounds with partial saturation that are not aromatic. Examples of such groups include, but are not limited to, an imidazoline, oxazoline, or isoxazoline.
  • cycloalkylene and heterocycloalkylene represent, unless otherwise stated, cyclic versions of “alkylene” and “heteroalkylene,” respectively.
  • cycloalkylene and heterocycloalkylene are meant to be included in the terms “alkylene” and “heteroalkylene,” respectively.
  • heterocycloalkylene one or more heteroatoms can occupy positions at which the heterocycle is attached to the remainder of the molecule.
  • a cycloalkylene or heterocycloalkylene will have from 3 to 9 atoms forming the ring, more typically, 3 to 7 atoms forming the ring, and even more typically, 5 or 6 atoms will form the cycloalkylene or heterocycloalkylene ring.
  • aliphatic ring by itself or as part of another substituent means a cycloalkyl, a heterocycloalkyl, a cycloalkylene or a heterocycloalkylene of any valency, but typically mono- or divalent. Examples of such groups include cyclopentyl, 1,4-dioxanyl, or piperidinyl.
  • fused ring means, unless otherwise stated, a cyclic aromatic or non-aromatic ring which shares bonds with one or two other cyclic aromatic or non-aromatic ring.
  • fused ring means, unless otherwise stated, a fused ring where at least one of the rings is an aryl.
  • fused heteroaryl means, unless otherwise stated, a fused ring system where at least one of the rings is a heteroaryl.
  • rings, fused aryl and fused heteroaryl groups include, 1- naphthyl, 1-tetrahydronaphthyl, 1-decahydronaphthyl, 2-naphthyl, dibenzofuryl, 5- benzothiazolyl, 2-benzoxazolyl, 5-benzoxazolyl, benzooxadiazolyl, purinyl, 2-benzimidazolyl, 5- indolyl, lH-indazolyl, indanyl, carbazolyl, carbolinyl, 1-isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl, 2-quinolyl, 3- quinolyl, 4-quinolyl, 5-quinolyl, 6-quinolyl, 7-quinolyl, and 8- quinolyl.
  • aryl refers to a monovalent aromatic hydrocarbon group derived by the removal of one hydrogen atom from a single carbon atom of a parent aromatic ring system.
  • aryl refers to an aromatic ring structure, monocyclic or fused polycyclic, with the number of ring atoms specified.
  • the term includes groups that include from 6 to 10 ring members.
  • Particular aryl groups include phenyl, and naphthyl.
  • hetero when used, it describes a compound or a group present on a compound means that one or more carbon atoms in the compound or group have been replaced by a nitrogen, oxygen, or sulfur heteroatom. Hetero may be applied to any of the hydrocarbyl groups described above such as alkyl, e.g. heteroalkyl, cycloalkyl, e.g. heterocycloalkyl, aryl, e.g. heteroaryl, and the like having from 1 to 4, and particularly from 1 to 3 heteroatoms, more typically 1 or 2 heteroatoms, for example a single heteroatom.
  • heteroaryl means an aromatic ring structure, monocyclic or fused polycyclic, that includes one or more heteroatoms independently selected from 0, N and Sand the number of ring atoms specified.
  • aromatic ring by itself or as part of another substituent means aryl or heteroaryl of any valency, but typically mono- or divalent.
  • the aromatic ring structure may have from 5 to 11 ring members.
  • the heteroaryl group is a five membered or six membered monocyclic ring or a fused bicyclic structure formed from fused five and six membered rings or two fused six membered rings or, by way of a further example, two fused five membered rings.
  • Each ring may contain up to four heteroatoms typically selected from nitrogen, sulphur and oxygen.
  • the heteroaryl ring will contain up to 4 heteroatoms, more typically up to 3 heteroatoms, more usually up to 2, for example a single heteroatom.
  • the heteroaryl ring contains at least one ring nitrogen atom.
  • the nitrogen atoms in the heteroaryl rings can be basic, as in the case of an imidazole or pyridine, or essentially non-basic as in the case of an indole or pyrrole nitrogen.
  • the number of basic nitrogen atoms present in the heteroaryl group, including any amino group (Amino refers to -NH2) substituents of the ring will be less than five.
  • Examples of five membered monocyclic heteroaryl groups include but are not limited to pyrrolyl, furanyl, thiophenyl, imidazolyl, furazanyl, oxazolyl, oxadiazolyl, oxatriazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl and tetrazolyl groups.
  • Examples of six membered monocyclic heteroaryl groups include but are not limited to pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl and triazinyl.
  • bi cyclic heteroaryl groups containing a five membered ring fused to another five-membered ring include but are not limited to imidazothiazolyl and imidazoimidazolyl.
  • bicyclic heteroaryl groups containing a six membered ring fused to a five membered ring include but are not limited to benzofuranyl, benzothiophenyl, benzoimidazolyl, benzoxazolyl, isobenzoxazolyl, benzisoxazolyl, benzothiazolyl, benzoisothiazolyl, isobenzofuranyl, indolyl, isoindolyl, indolizinyl, purinyl (e.g. adenine, guanine), indazolyl, pyrazolopyrimidinyl, triazolopyrimidinyl, and pyrazolopyridinyl groups.
  • heteroaryl groups containing two fused six membered rings include but are not limited to quinolinyl, isoquinolinyl, pyridopyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, naphthyridinyl, and pteridinyl groups.
  • Particular heteroaryl groups are those derived from thiophenyl, pyrrolyl, benzothiophenyl, benzofuranyl, indolyl, pyridinyl, quinolinyl, imidazolyl, oxazolyl and pyrazinyl.
  • 'Hydroxyl' refers to the radical -OH.
  • 'Substituted' refers to a group in which one or more hydrogen atoms are each independently replaced with the same or different substituent(s).
  • term 'substituted with one or more' refers to one to four substituents. In one embodiment it refers to one to three substituents. In further embodiments it refers to one or two substituents. In a yet further embodiment it refers to one substituent.
  • R', R", R'" and R IV each independently refer to hydrogen, unsubstituted (Ci-C 3 )alkyl and (C - C 3 )heteroalkyl, unsubstituted aryl, aryl substituted with one to three halogens, unsubstituted (Ci-C )-alkyl, (Ci- C 4 )-alkoxy or (Ci-C )-thioalkoxy groups, halo(Ci-C )alkyl, or aryl-(Ci-C )alkyl groups.
  • R' and R" When R' and R" are attached to the same nitrogen atom, they can be combined with the nitrogen atom to form a 5-, 6- or 7-membered ring.
  • -NR'R is meant to include 1-pyrrolidinyl and 4- morpholinyl.
  • Sulfo' or 'sulfonic acid' refers to a radical such as -S0 3 H.
  • 'Thiol' refers to the group -SH.
  • Thioalkoxy' refers to the group -S-alkyl where the alkyl group has the number of carbon atoms specified. In particular the term refers to the group -S-Ci- 6 alkyl.
  • Particular thioalkoxy groups are thiomethoxy, thioethoxy, n-thiopropoxy, isothiopropoxy, n-thiobutoxy, tert-thiobutoxy, secthiobutoxy, n-thiopentoxy, n-thiohexoxy, and 1,2-dimethylthiobutoxy.
  • Particular thioalkoxy groups are lower thioalkoxy, i.e. with between 1 and 6 carbon atoms. Further particular alkoxy groups have between 1 and 4 carbon atoms.
  • heterocyclic ring may have one to four heteroatoms so long as the heteroaromatic ring is chemically feasible and stable.
  • 'Pharmaceutically acceptable means approved or approvable by a regulatory agency of the Federal or a state government or the corresponding agency in countries other than the United States, or that is listed in the U.S. Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, and more particularly, in humans.
  • 'Pharmaceutically acceptable salt' refers to a salt of a compound of the invention that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound.
  • such salts are non-toxic may be inorganic or organic acid addition salts and base addition salts.
  • such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-( 4- hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4- chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid,
  • salts further include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; and when the compound contains a basic functionality, salts of non-toxic organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate and the like.
  • 'pharmaceutically acceptable cation' refers to an acceptable cationic counter-ion of an acidic functional group. Such cations are exemplified by sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium cations, and the like.
  • 'Pharmaceutically acceptable vehicle' refers to a diluent, adjuvant, excipient or carrier with which a compound of the invention is administered.
  • Prodrugs' refers to compounds, including derivatives of the compounds of the invention, which have cleavable groups and become by solvolysis or under physiological conditions the compounds of the invention which are pharmaceutically active in viva. Such examples include, but are not limited to, choline ester derivatives and the like, N-alkylmorpholine esters and the like.
  • 'Solvate' refers to forms of the compound that are associated with a solvent, usually by a solvolysis reaction. This physical association includes hydrogen bonding.
  • Conventional solvents include water, EtOH, acetic acid and the like.
  • the compounds of the invention may be prepared e.g. in crystalline form and may be solvated or hydrated.
  • Suitable solvates include pharmaceutically acceptable solvates, such as hydrates, and further include both stoichiometric solvates and non-stoichiometric solvates. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid.
  • 'Solvate' encompasses both solution-phase and isolable solvates.
  • Representative solvates include hydrates, ethanolates and methanolates.
  • 'Subject' includes humans, where the terms 'human', 'patient' and 'subject' are used interchangeably herein.
  • 'Effective amount means the amount of a compound of the invention that, when administered to a subject for treating a disease, is sufficient to effect such treatment for the disease.
  • the "effective amount” can vary depending on the compound, the disease and its severity, and the age, weight, etc., of the subject to be treated.
  • 'Preventing' or 'prevention' refers to a reduction in risk of acquiring or developing a disease or disorder (i.e. causing at least one of the clinical symptoms of the disease not to develop in a subject that may be exposed to a disease-causing agent, or predisposed to the disease in advance of disease onset.
  • 'prophylaxis' is related to 'prevention', and refers to a measure or procedure the purpose of which is to prevent, rather than to treat or cure a disease.
  • 'Treating' or 'treatment' of any disease or disorder refers, in one embodiment, to ameliorating the disease or disorder (i.e. arresting the disease or reducing the manifestation, extent or severity of at least one of the clinical symptoms thereof).
  • 'treating' or 'treatment' refers to ameliorating at least one physical parameter, which may not be discernible by the subject.
  • 'treating' or 'treatment' refers to modulating the disease or disorder, either physically, (e.g. stabilization of a discernible symptom), physiologically, (e.g. stabilization of a physical parameter), or both.
  • "treating" or "treatment” relates to slowing the progression of the disease.
  • fibrotic diseases refers to diseases characterized by excessive scarring due to excessive production, deposition, and contraction of extracellular matrix, and are that are associated with the abnormal accumulation of cells and/or fibronectin and/or collagen and/or increased fibroblast recruitment and include but are not limited to fibrosis of individual organs or tissues such as the heart, kidney, liver, joints, lung, pleural tissue, peritoneal tissue, skin, cornea, retina, musculoskeletal and digestive tract.
  • fibrotic diseases refers to idiopathic pulmonary fibrosis (IPF) ; cystic fibrosis, other diffuse parenchymal lung diseases of different etiologies including iatrogenic drug-induced fibrosis, occupational and/or environmental induced fibrosis, granulomatous diseases (sarcoidosis, hypersensitivity pneumonia), collagen vascular disease, alveolar proteinosis, Langerhans cell granulomatosis, lymphangioleiomyomatosis, inherited diseases (Hermansky-Pudlak Syndrome, tuberous sclerosis, neurofibromatosis, metabolic storage diseases, familial interstitial lung disease); radiation induced fibrosis; chronic obstructive pulmonary disease; scleroderma; bleomycin induced pulmonary fibrosis; chronic asthma; silicosis; asbestos induced pulmonary fibrosis; acute respiratory distress syndrome (ARDS); kidney fibrosis; tubulointerstitium fibrosis; glomerular fibros
  • fibrotic diseases refers to idiopathic pulmonary fibrosis (IPF), Dupuytren disease, nonalcoholic steatohepatitis (NASH), nonalcoholic fatty liver disease (NAFLD), Alcoholic steato hepatitis, (ASH), portal hypertension, systemic sclerosis, renal fibrosis, and cutaneous fibrosis.
  • IPF idiopathic pulmonary fibrosis
  • NASH nonalcoholic steatohepatitis
  • ASH Alcoholic steato hepatitis
  • portal hypertension systemic sclerosis
  • renal fibrosis and cutaneous fibrosis
  • fibrotic diseases refers to IPF.
  • Prodrugs include acid derivatives well known to practitioners of the art, such as, for example, esters prepared by reaction of the parent acid with a suitable alcohol, or amides prepared by reaction of the parent acid compound with a substituted or unsubstituted amine, or acid anhydrides, or mixed anhydrides. Simple aliphatic or aromatic esters, amides and anhydrides derived from acidic groups pendant on the compounds of this invention are particularly useful prodrugs.
  • double ester type prodrugs such as (acyloxy)alkyl esters or ((alkoxycarbonyl)oxy)alkylesters.
  • Particular such prodrugs are the C1-7 alkyl, C2-8 alkenyl, C 6 -io optionally substituted aryl, and (C 6 -io aryl)-(Ci- alkyl) esters of the compounds of the invention.
  • the present disclosure includes all isotopic forms of the compounds of the invention provided herein, whether in a form (i) wherein all atoms of a given atomic number have a mass number (or mixture of mass numbers) which predominates in nature (referred to herein as the "natural isotopic form") or (ii) wherein one or more atoms are replaced by atoms having the same atomic number, but a mass number different from the mass number of atoms which predominates in nature (referred to herein as an "unnatural variant isotopic form"). It is understood that an atom may naturally exists as a mixture of mass numbers.
  • unnatural variant isotopic form also includes embodiments in which the proportion of an atom of given atomic number having a mass number found less commonly in nature (referred to herein as an "uncommon isotope") has been increased relative to that which is naturally occurring e.g. to the level of >20%, >50%, >75%, >90%, >95% or> 99% by number of the atoms of that atomic number (the latter embodiment referred to as an "isotopically enriched variant form").
  • the term “unnatural variant isotopic form” also includes embodiments in which the proportion of an uncommon isotope has been reduced relative to that which is naturally occurring.
  • Isotopic forms may include radioactive forms (i.e. they incorporate radioisotopes) and non-radioactive forms. Radioactive forms will typically be isotopically enriched variant forms.
  • An unnatural variant isotopic form of a compound may thus contain one or more artificial or uncommon isotopes such as deuterium (2H or D), carbon-11 (1 1C), carbon-13 (13C), carbon-14 (14C), nitrogen-13 (13N), nitrogen-15 (15N), oxygen-15 (150), oxygen-17 (170), oxygen-18 (1 80), phosphorus-32 (32P), sulphur-35 (35S), chlorine-36 (36CI), chlorine-37 (37CI), fluorine-18 (1 8F) iodine-123 (1 231), iodine-125 (1 251) in one or more atoms or may contain an increased proportion of said isotopes as compared with the proportion that predominates in nature in one or more atoms.
  • isotopes such as deuterium (2H or D), carbon-11 (1 1C), carbon-13 (13C), carbon-14 (14C), nitrogen-13 (13N), nitrogen-15 (15N), oxygen-15 (150), oxygen-17 (170), oxygen-18 (1 80), phosphorus-32 (32P),
  • Unnatural variant isotopic forms comprising radioisotopes may, for example, be used for drug and/or substrate tissue distribution studies.
  • the radioactive isotopes tritium, i.e. 3H, and carbon- 14, i.e. 14C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.
  • Unnatural variant isotopic forms which incorporate deuterium i.e 2H or D may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in viva halflife or reduced dosage requirements, and hence may be preferred in some circumstances.
  • unnatural variant isotopic forms may be prepared which incorporate positron emitting isotopes, such as 11C, 18F, 150 and 13N, and would be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.
  • PET Positron Emission Topography
  • Stereoisomers that are not mirror images of one another are termed 'diastereomers' and those that are non-superimposable mirror images of each other are termed 'enantiomers'.
  • a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible.
  • An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e. as (+)- or (-)-isomers respectively).
  • a chiral compound can exist as either individual enantiomer or as a mixture thereof.
  • a mixture containing equal proportions of the enantiomers is called a 'racemic mixture'.
  • 'Tautomers' refer to compounds that are interchangeable forms of a particular compound structure, and that vary in the displacement of hydrogen atoms and electrons. Thus, two structures may be in equilibrium through the movement of n electrons and an atom (usually H).
  • enols and ketones are tautomers because they are rapidly interconverted by treatment with either acid or base.
  • Another example of tautomerism is the aci- and nitro- forms of phenylnitromethane that are likewise formed by treatment with acid or base. Tautomeric forms may be relevant to the attainment of the optimal chemical reactivity and biological activity of a compound of interest.
  • the compounds of the invention may possess one or more asymmetric centers; such compounds can therefore be produced as individual (R)- or (S)- stereoisomers or as mixtures thereof. Unless indicated otherwise, the description or naming of a particular compound in the specification and claims is intended to include both individual enantiomers and mixtures, racemic or otherwise, thereof. The methods for the determination of stereochemistry and the separation of stereoisomers are well-known in the art.
  • the inventors have found that the compounds of the present invention are useful for modulating the GPR84 receptor, a G-protein-coupled receptor which may be useful in the treatment of inflammatory or diabetic disease.
  • the compounds can be used in a pharmaceutical composition, which further comprises a pharmaceutically acceptable carrier, excipient or diluent.
  • the pharmaceutical composition of the invention can be used in the treatment of inflammatory or diabetic disease such as for the treatment of fibrosis in the kidney, liver, lung, pancreas and skin.
  • the present invention pertains to a compound of the formula I: (formula I) wherein
  • X is -NH-, -0-, -S- or is absent
  • A is -(Al) j -(Bl) k -(A2)r(B2) m -H, wherein o A1 and A2 independently are C1-7 alkylene, C2-7 alkenylene, C2-7 alkynylene, or C1-7 heteroalkylene, optionally substituted with one or two of independently selected Ul; o B1 and B2 are independently an aliphatic ring, an aromatic ring or a fused ring, optionally substituted with one or two of independently selected U2; H is hydrogen; o j, k, I, and m are independently 0 or 1;
  • Y is -OCH 2 -, -N(R')CH 2 -, -CH 2 CH 2 -, -CH 2 -, -NCR')-, or -0-, where R' is hydrogen or C 1 -C 3 alkyl;
  • R is an aromatic ring, an aromatic ring comprising nitrogen, an aliphatic ring or a fused ring, optionally substituted with one, two or three of independently selected U3;
  • X is -NH-, -0-, -S- or is absent; A is
  • A1 and A2 are independently C 1-7 alkylene, C 1-7 alkenylene, C 1-7 alkynylene or C 1-7 heteroalkylene;
  • B1 is an aliphatic ring, an aromatic ring or a fused ring;
  • B2 is an aliphatic ring, an aromatic ring or a fused ring, and H is hydrogen;
  • Y is -OCH 2 -, -N(R')CH 2 -, -CH 2 CH 2 -, -CH 2 -, -NCR')-, or -0-, where R' is hydrogen or C 1 -C 3 alkyl;
  • an aromatic ring comprising nitrogen, an aliphatic ring or a fused ring, where the ring is optionally substituted with -CF 3 , C 1-3 alkyl, C 2-4 heteroalkyl or the ring is optionally substituted with -CF 3 , C 1-3 alkyl, C 2-4 heteroalkyl, wherein Z is -0-, -CH 2 -, -NH- or N-(CH 2 ) 0 -2-CH 3 , o W is -0- or -CH2-; and o n is 0, 1 or 2; or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a solvate of the pharmaceutically acceptable salt thereof.
  • the invention comprises compounds that can treat diseases by modulating GPR84-mediated signaling, in particular reducing GPR84-mediated signaling by acting as antagonists, partial agonists or inverse agonists at GPR84.
  • the compounds of the invention provide a new class of GPR84 antagonists that modulate the decanoic acid binding site; in contrast to the antagonist ligands previously reported by Mahmud et. al. (2017) that are believed to bind at a site that is distinct from the decanoic acid and DIM agonist binding sites.
  • the compounds of the invention have the advantage that they are small and ionizable which potentially results in a better uptake of the compounds and a better distribution of the compounds in the body.
  • X is -NH-, -S-, -0-, or is absent.
  • X is -NH- or is absent.
  • A is -A1-B1-A2-B2-H, where Al is C 1-7 alkylene, C 1-7 alkenylene, C 1-7 alkynylene or C 1-7 heteroalkylene, A2 is C 1-7 alkylene, C 1-7 alkenylene, C 1-7 alkynylene or C 1-7 heteroalkylene, B1 is an aliphatic ring, an aromatic ring or a fused ring, and B2 is an aliphatic ring, an aromatic ring or a fused ring, and H is hydrogen.
  • A is Al-Bl- A2-B2-H, where Al is C 1-5 alkylene, C 1-5 alkenylene, C 1-5 alkynylene or C 1-5 heteroalkylene, A2 is Ci- 5 alkyl, C 1-5 alkenyl, C 1-5 alkynylene or C 1-5 heteroalkylene, B1 is an aliphatic ring, an aromatic ring or a fused ring, and B2 is an aliphatic ring, an aromatic ring or a fused ring.
  • A is -A1-B1-A2-B2-H, where A1 is C 1-5 alkylene, C 1-5 alkenylene, C 1-5 alkynylene or C 1-5 heteroalkylene, A2 is C 1-5 alkyl, C 1-5 alkenyl, C 1-5 alkynyl or C 1-5 heteroalkylene, B1 is -(C 6 H 4 )- and B2 is -(C 6 H 4 )-.
  • A is -A1-B1-A2-H, where A1 is C 1-7 alkylene, C 1-7 alkenylene, C 1 -7 alkynylene or C 1 -7 heteroalkylene, A2 is C 1 -7 alkylene, C 1 -7 alkenylene, C 1 -7 alkynylene or C 1-7 heteroalkylene, and B1 is an aliphatic ring, an aromatic ring or a fused ring, and H is hydrogen.
  • A is -A1-B1-A2-H, where A1 is C 1-5 alkylene, C 1-5 alkenylene, C 1-5 alkynylene or C 1-5 heteroalkylene, A2 is C 1-5 alkyl, C 1-5 alkenyl, C 1-5 alkynylene or C 1-5 heteroalkylene, and B1 is an aliphatic ring, an aromatic ring or a fused ring.
  • A is -A1-B1-A2, where A1 is C 1-5 alkylene, C 1-5 alkenylene, C 1-5 alkynylene or C 1-5 heteroalkylene, A2 is Ci- 5 alkyl, C 1-5 alkenyl, C 1-5 alkynylene or C 1-5 heteroalkylene and B1 is -(C 6 H 4 )-.
  • A is -A1-B1-A2-H is -(CH 2 ) 2 -(C 6 H 4 )-(CH 2 ) 2 -CH 3 .
  • A is -B1-A2-H, where A2 is C 1-7 alkylene, C 1-7 alkenylene, C 1-7 alkynylene or C 1-7 heteroalkylene, and B1 is an aliphatic ring, an aromatic ring or a fused ring, and H is hydrogen.
  • A is -B1-A2-H, where A2 is C 1-5 alkyl, C 1-5 alkenyl, C 1-5 alkynylene or Ci- 5 heteroalkylene and B1 is an aliphatic ring, an aromatic ring or a fused ring.
  • A is -B1-A2-H, where A2 is C 1-5 alkyl, C 1-5 alkenyl, C 1-5 alkynylene or C 1-5 heteroalkylene and B1 is -(C 6 H 4 )-.
  • A is -A1-B2-H, where A1 is C 1-7 alkylene, C 1-7 alkenylene, C 1-7 alkynylene or C 1-7 heteroalkylene and B2 is an aliphatic ring, an aromatic ring or a fused ring, and H is hydrogen.
  • A is -A1-B2-H, where A1 is C 1-5 alkyl, C 1-5 alkenyl, C 1-5 alkynylene or Ci- 5 heteroalkylene and B2 is an aliphatic ring, an aromatic ring or a fused ring.
  • A is -A1-B2-H, where A1 is C 1-5 alkyl, C 1-5 alkenyl, C 1-5 alkynylene or C 1-5 heteroalkylene and B2 is -(C 6 H 4 )-.
  • A is -A1-A2-H, where A1 is C 1-7 alkylene, C 1-7 alkenylene, C 1-7 alkynylene or C 1 -7 heteroalkylene and A2 is C 1 -7 alkylene, C 1 -7 alkenylene, C 1 -7 alkynylene or C 1 -7 heteroalkylene, and H is hydrogen.
  • A is -A1-A2-H, where A1 is C 1-5 alkylene or C 1-5 alkenylene and A2 is C 1-5 alkylene or C 1-5 alkenylene, or more preferred A1 is C 1-5 alkylene and A2 is C 1-5 alkylene.
  • -A is -(OH2) 8 -OH 3 .
  • X is absent and A is -A1-B1-A2-B2-H, where A1 is C 1-7 alkylene, C 1-7 alkenylene, C 1 -7 alkynylene or C 1 -7 heteroalkylene, A2 is C 1 -7 alkylene, C 1 -7 alkenylene, C 1 -7 alkynylene or C 1-7 heteroalkylene, B1 is an aliphatic ring, an aromatic ring or a fused ring, and B2 is an aliphatic ring, an aromatic ring or a fused ring, and H is hydrogen.
  • X is absent and A is A1-B1-A2-B2-H, where A1 is C 1-5 alkylene, C 1-5 alkenylene, C 1-5 alkynylene or C 1-5 heteroalkylene, A2 is C 1-5 alkyl, C 1-5 alkenyl, C 1-5 alkynylene or C 1-5 heteroalkylene, B1 is an aliphatic ring, an aromatic ring or a fused ring, and B2 is an aliphatic ring, an aromatic ring or a fused ring.
  • X is absent and A is -A1-B1-A2-B2-H, where A1 is C 1-5 alkylene, C 1-5 alkenylene, C 1-5 alkynylene or C 1-5 heteroalkylene, A2 is C 1-5 alkyl, C 1-5 alkenyl, C 1-5 alkynyl or Ci- 5 heteroalkylene, B1 is -(C 6 H 4 )- and B2 is -(C 6 H 4 )-.
  • X is absent and A is -A1-B1-A2-H, where A1 is C 1-7 alkylene, C 1-7 alkenylene, Ci-7 alkynylene or C 1-7 heteroalkylene, A2 is C 1-7 alkylene, C 1-7 alkenylene, C 1-7 alkynylene or C 1-7 heteroalkylene, and B1 is an aliphatic ring, an aromatic ring or a fused ring, and H is hydrogen.
  • X is absent and A is -A1-B1-A2-H, where A1 is C 1-5 alkylene, C 1-5 alkenylene, C 1-5 alkynylene or C 1-5 heteroalkylene, A2 is C 1-5 alkyl, C 1-5 alkenyl, C 1-5 alkynylene or C 1-5 heteroalkylene, and B1 is an aliphatic ring, an aromatic ring or a fused ring.
  • X is absent and A is -A1-B1-A2, where A1 is C 1-5 alkylene, C 1-5 alkenylene, C 1-5 alkynylene or C 1-5 heteroalkylene, A2 is C 1-5 alkyl, C 1-5 alkenyl, C 1-5 alkynylene or C 1-5 heteroalkylene and B1 is - (C 6 H 4 )-.
  • Preferred embodiments of -X-A are -(CH 2 ) 2 -(C 6 H 4 )-(CH 2 )i-CH 3 , -(CH 2 ) 2 -(C 6 H 4 )-(CH 2 ) 2 - CH 3 , -(CH 2 ) 2 -(C 6 H 4 )-(CH 2 ) 3 -CH 3 , -(CH 2 ) I -(C 6 H 4 )-(CH 2 ) 2 -CH 3 , -(CH 2 ) 3 -(C 6 H 4 )-(CH 2 ) 2 -CH 3 , -(CH 2 ) I - (C 6 H 4 )-(CH 2 ) I -CH 3 , -(CH 2 ) I -(C 6 H 4 )-(CH 2 ) I -CH 3 , -(CH 2 ) I -(C 6 H 4 )-(CH 2 ) 3 -CH 3 , -(CH
  • X is absent and A is B1-A2, where A2 is C 1-7 alkylene, C 1-7 alkenylene, Ci- 7 alkynylene or C 1-7 heteroalkylene, and B1 is an aliphatic ring, an aromatic ring or a fused ring, and H is hydrogen.
  • X is absent and A is -B1-A2-H, where A2 is C 1-5 alkyl, C 1-5 alkenyl, C 1-5 alkynylene or C 1-5 heteroalkylene and B1 is an aliphatic ring, an aromatic ring or a fused ring.
  • X is absent and A is -B1-A2-H, where A2 is C 1-5 alkyl, C 1-5 alkenyl, Ci- 5 alkynylene or C 1-5 heteroalkylene and B1 is -(C 6 H 4 )-.
  • X is absent and A is -A1-B2-H, where A1 is C 1-7 alkylene, C 1-7 alkenylene, C 1-7 alkynylene or C 1-7 heteroalkylene and B2 is an aliphatic ring, an aromatic ring or a fused ring, and H is hydrogen.
  • X is absent and A is -A1-B2-H, where A1 is C 1-5 alkyl, Ci- 5 alkenyl, C 1-5 alkynylene or C 1-5 heteroalkylene and B2 is an aliphatic ring, an aromatic ring or a fused ring.
  • X is absent and A is -A1-B2-H, where A1 is C 1-5 alkyl, C 1-5 alkenyl, Ci- 5 alkynylene or C 1-5 heteroalkylene and B2 is -(C 6 H 4 )-.
  • X is absent and A is -A1-A2-H, where A1 is C 1-7 alkylene, C 1-7 alkenylene, C 1-7 alkynylene or C 1-7 heteroalkylene and A2 is C 1-7 alkylene, C 1-7 alkenylene, C 1-7 alkynylene or C 1-7 heteroalkylene, and H is hydrogen.
  • X is absent and A is -A1-A2-H, where A1 is C 1-5 alkylene or C 1-5 alkenylene and A2 is Ci- 5 alkylene or C 1-5 alkenylene, or more preferred X is absent and A1 is C 1-5 alkylene and A2 is Ci- 5 alkylene.
  • Preferred embodiment of -X-A are -(CH 2 ) 5 -CH 3 , -(CH 2 ) 6 -CH 3 , -(CH 2 )7-CH 3 , -(CH 2 ) 8 - CH , -(CH 2 ) 9 -CH 3 and -(CH 2 ) IO -CH .
  • -X-A is - (CH 2 ) 8 -CH 3 .
  • X is -NH- and A is -A1-B1-A2-B2-H, where A1 is C 1-7 alkylene, C 1-7 alkenylene, C 1 -7 alkynylene or C 1 -7 heteroalkylene, A2 is C 1 -7 alkylene, C 1 -7 alkenylene, C 1 -7 alkynylene or C 1-7 heteroalkylene, B1 is an aliphatic ring, an aromatic ring or a fused ring, and B2 is an aliphatic ring, an aromatic ring or a fused ring, and H is hydrogen.
  • X is -NH- and A is A1-B1-A2-B2-H, where A1 is C 1-5 alkylene, C 1-5 alkenylene, C 1-5 alkynylene or C 1-5 heteroalkylene, A2 is C 1-5 alkyl, C 1-5 alkenyl, C 1-5 alkynylene or C 1-5 heteroalkylene, B1 is an aliphatic ring, an aromatic ring or a fused ring, and B2 is an aliphatic ring, an aromatic ring or a fused ring.
  • X is -NH- and A is -A1-B1-A2-B2-H, where A1 is C 1-5 alkylene, C 1-5 alkenylene, C 1-5 alkynylene or C 1-5 heteroalkylene, A2 is C 1-5 alkyl, C 1-5 alkenyl, C 1-5 alkynyl or Ci- 5 heteroalkylene, B1 is -(C 6 H 4 )- and B2 is -(C 6 H 4 )-.
  • X is -NH- and A is -A1-B1-A2-H, where A1 is C 1-7 alkylene, C 1-7 alkenylene, Ci-7 alkynylene or C 1 -7 heteroalkylene, A2 is C 1 -7 alkylene, C 1 -7 alkenylene, C 1 -7 alkynylene or C 1 -7 heteroalkylene, and B1 is an aliphatic ring, an aromatic ring or a fused ring, and H is hydrogen.
  • X is -NH- and A is -A1-B1-A2-H, where A1 is C 1-5 alkylene, C 1-5 alkenylene, C 1-5 alkynylene or C 1-5 heteroalkylene, A2 is C 1-5 alkyl, C 1-5 alkenyl, C 1-5 alkynylene or C 1-5 heteroalkylene, and B1 is an aliphatic ring, an aromatic ring or a fused ring.
  • X is -NH- and A is -A1-B1-A2, where A1 is C 1-5 alkylene, C 1-5 alkenylene, C 1-5 alkynylene or C 1-5 heteroalkylene, A2 is C 1-5 alkyl, C 1-5 alkenyl, C 1-5 alkynylene or C 1-5 heteroalkylene and B1 is - (C 6 H 4 )-.
  • Preferred embodiments of -X-A are -NH-(CH 2 ) 2 -(C 6 H 4 )-(CH 2 )I-CH 3 , -NH-(CH 2 ) 2 -(C 6 H 4 )- (CH 2 ) 2 -CH 3 , -NH-(CH 2 ) 2 -(C 6 H 4 )-(CH 2 ) 3 -CH 3 , -NH-(CH 2 )I-(C 6 H 4 )-(CH 2 ) 2 -CH 3 , -NH-(CH 2 ) 3 -(C 6 H 4 )- (CH 2 ) 2 -CH 3 , -NH-(CH 2 )I-(C 6 H 4 )-(CH 2 )I-CH 3 , -NH-(CH 2 )I-(C 6 H 4 )-(CH 2 )I-CH 3 , -NH-(CH 2 )I-(C 6 H 4 )-(CH 2 ) 3
  • X is -NH- and A is B1-A2, where A2 is C 1-7 alkylene, C 1-7 alkenylene, Ci- 7 alkynylene or C 1-7 heteroalkylene, and B1 is an aliphatic ring, an aromatic ring or a fused ring, and H is hydrogen.
  • X is -NH- and A is -B1-A2-H, where A2 is C 1-5 alkyl, C 1-5 alkenyl, Ci- 5 alkynylene or C 1-5 heteroalkylene and B1 is an aliphatic ring, an aromatic ring or a fused ring.
  • X is -NH- and A is -B1-A2-H, where A2 is C 1-5 alkyl, C 1-5 alkenyl, C 1-5 alkynylene or Ci- 5 heteroalkylene and B1 is -(C 6 H 4 )-.
  • X is -NH- and A is -A1-B2-H, where A1 is C 1-7 alkylene, C 1-7 alkenylene, Ci- 7 alkynylene or C 1-7 heteroalkylene and B2 is an aliphatic ring, an aromatic ring or a fused ring, and H is hydrogen.
  • X is -NH- and A is -A1-B2-H, where A1 is C 1-5 alkyl, C 1-5 alkenyl, Ci- 5 alkynylene or C 1-5 heteroalkylene and B2 is an aliphatic ring, an aromatic ring or a fused ring.
  • X is -NH- and A is -A1-B2-H, where A1 is C 1-5 alkyl, C 1-5 alkenyl, C 1-5 alkynylene or Ci- 5 heteroalkylene and B2 is -(C 6 H 4 )-.
  • X is -NH- and A is -A1-A2-H, where A1 is C 1-7 alkylene, C 1-7 alkenylene, Ci-7 alkynylene or C 1 -7 heteroalkylene and A2 is C 1 -7 alkylene, C 1 -7 alkenylene, C 1 -7 alkynylene or Ci- 7 heteroalkylene, and H is hydrogen.
  • X is -NH- and A is -A1-A2-H, where A1 is C 1-5 alkylene or C 1-5 alkenylene and A2 is C 1-5 alkylene or C 1-5 alkenylene, or more preferred X is -NH- and A1 is C 1-5 alkylene and A2 is C 1-5 alkylene.
  • Preferred embodiment of -X-A are -NH-(CH 2 ) 5 -CH 3 , -NH-(CH 2 ) 6 -CH 3 , -NH-(CH 2 ) 7 -CH 3 , -NH-(CH 2 ) 8 -CH 3 , - NH-(CH 2 )g-CH and -NH-(CH 2 ) I0 -CH .
  • -X-A is - NH-(CH 2 ) 7 -CH 3 .
  • X is -0- and A is -A1-B1-A2-B2-H, where A1 is C 1-7 alkylene, C 1-7 alkenylene, Ci-7 alkynylene or C 1 -7 heteroalkylene, A2 is C 1 -7 alkylene, C 1 -7 alkenylene, C 1 -7 alkynylene or C 1 -7 heteroalkylene, B1 is an aliphatic ring, an aromatic ring or a fused ring, and B2 is an aliphatic ring, an aromatic ring or a fused ring, and H is hydrogen.
  • X is -0- and A is A1-B1-A2- B2-H, where A1 is C 1-5 alkylene, C 1-5 alkenylene, C 1-5 alkynylene or C 1-5 heteroalkylene, A2 is C 1-5 alkyl, C 1-5 alkenyl, C 1-5 alkynylene or C 1-5 heteroalkylene, B1 is an aliphatic ring, an aromatic ring or a fused ring, and B2 is an aliphatic ring, an aromatic ring or a fused ring.
  • X is -0- and A is -A1-B1-A2-B2-H, where A1 is C 1-5 alkylene, C 1-5 alkenylene, C 1-5 alkynylene or C 1-5 heteroalkylene, A2 is C 1-5 alkyl, C 1-5 alkenyl, C 1-5 alkynyl or C 1-5 heteroalkylene, B1 is -(C 6 H 4 )- and B2 is -(C 6 H 4 )-.
  • X is -0- and A is -A1-B1-A2-H, where A1 is C 1-7 alkylene, C 1-7 alkenylene, Ci-7 alkynylene or C 1 -7 heteroalkylene, A2 is C 1 -7 alkylene, C 1 -7 alkenylene, C 1 -7 alkynylene or C 1 -7 heteroalkylene, and B1 is an aliphatic ring, an aromatic ring or a fused ring, and H is hydrogen.
  • X is -0- and A is -A1-B1-A2-H, where A1 is C 1-5 alkylene, C 1-5 alkenylene, C 1-5 alkynylene or C 1-5 heteroalkylene, A2 is C 1-5 alkyl, C 1-5 alkenyl, C 1-5 alkynylene or C 1-5 heteroalkylene, and B1 is an aliphatic ring, an aromatic ring or a fused ring.
  • X is -0- and A is -A1-B1-A2, where A1 is C 1-5 alkylene, C 1-5 alkenylene, C 1-5 alkynylene or C 1-5 heteroalkylene, A2 is C 1-5 alkyl, C 1-5 alkenyl, C 1-5 alkynylene or C 1-5 heteroalkylene and B1 is - (C 6 H 4 )-.
  • Preferred embodiments of -X-A are -0-(CH 2 ) 2 -(C 6 H 4 )-(CH 2 )i-CH 3 , -0-(CH 2 ) 2 -(C 6 H 4 )- (CH 2 ) 2 -CH 3 , -0-(CH 2 ) 2 -(C 6 H 4 )-(CH 2 ) 3 -CH 3 , -0-(CH 2 )I-(C 6 H 4 )-(CH 2 ) 2 -CH 3 , -0-(CH 2 ) 3 -(C 6 H 4 )-
  • X is -0- and A is B1-A2, where A2 is C 1-7 alkylene, C 1-7 alkenylene, C 1-7 alkynylene or C 1-7 heteroalkylene, and B1 is an aliphatic ring, an aromatic ring or a fused ring, and H is hydrogen.
  • X is -0- and A is -B1-A2-H, where A2 is C 1-5 alkyl, C 1-5 alkenyl, C 1-5 alkynylene or C 1-5 heteroalkylene and B1 is an aliphatic ring, an aromatic ring or a fused ring.
  • X is -0- and A is -B1-A2-H, where A2 is C 1-5 alkyl, C 1-5 alkenyl, C 1-5 alkynylene or Ci- 5 heteroalkylene and B1 is -(C 6 H 4 )-.
  • X is -0- and A is -A1-B2-H, where A1 is C 1-7 alkylene, C 1-7 alkenylene, Ci- 7 alkynylene or C 1-7 heteroalkylene and B2 is an aliphatic ring, an aromatic ring or a fused ring, and H is hydrogen.
  • X is -0- and A is -A1-B2-H, where A1 is C 1-5 alkyl, C 1-5 alkenyl, C 1-5 alkynylene or C 1-5 heteroalkylene and B2 is an aliphatic ring, an aromatic ring or a fused ring. More preferably, X is -0- and A is -A1-B2-H, where A1 is C 1-5 alkyl, C 1-5 alkenyl, C 1-5 alkynylene or Ci- 5 heteroalkylene and B2 is -(C 6 H 4 )-.
  • X is -0- and A is -A1-A2-H, where A1 is C 1-7 alkylene, C 1-7 alkenylene, Ci-7 alkynylene or C 1 -7 heteroalkylene and A2 is C 1 -7 alkylene, C 1 -7 alkenylene, C 1 -7 alkynylene or Ci- 7 heteroalkylene, and H is hydrogen.
  • X is -0- and A is -A1-A2-H, where A1 is C 1-5 alkylene or C 1-5 alkenylene and A2 is C 1-5 alkylene or C 1-5 alkenylene, or more preferred X is -0- and A1 is C 1-5 alkylene and A2 is C 1-5 alkylene.
  • Preferred embodiment of -X-A are -0-(CH 2 ) 5 -CH 3 , -0-(CH 2 ) 6 -CH 3 , -0-(CH 2 ) 7 -CH 3 , -0-(CH 2 ) 8 -CH 3 , -0- (CH 2 )g-CH 3 and -O-(CH 2 ) I0 -CH 3 .
  • X is -S- and A is -A1-B1-A2-B2-H, where A1 is C 1-7 alkylene, C 1-7 alkenylene, Ci-7 alkynylene or C 1 -7 heteroalkylene, A2 is C 1 -7 alkylene, C 1 -7 alkenylene, C 1 -7 alkynylene or C 1 -7 heteroalkylene, B1 is an aliphatic ring, an aromatic ring or a fused ring, and B2 is an aliphatic ring, an aromatic ring or a fused ring, and H is hydrogen.
  • X is -S- and A is A1-B1-A2- B2-H, where A1 is C 1-5 alkylene, C 1-5 alkenylene, C 1-5 alkynylene or C 1-5 heteroalkylene, A2 is C 1-5 alkyl, C 1-5 alkenyl, C 1-5 alkynylene or C 1-5 heteroalkylene, B1 is an aliphatic ring, an aromatic ring or a fused ring, and B2 is an aliphatic ring, an aromatic ring or a fused ring.
  • X is -S- and A is -A1-B1-A2-B2-H, where A1 is C 1-5 alkylene, C 1-5 alkenylene, C 1-5 alkynylene or C 1-5 heteroalkylene, A2 is C 1-5 alkyl, C 1-5 alkenyl, C 1-5 alkynyl or C 1-5 heteroalkylene, B1 is -(C 6 H 4 )- and B2 is -(C 6 H 4 )-.
  • X is -S- and A is -A1-B1-A2-H, where A1 is C 1-7 alkylene, C 1-7 alkenylene, Ci-7 alkynylene or C 1 -7 heteroalkylene, A2 is C 1 -7 alkylene, C 1 -7 alkenylene, C 1 -7 alkynylene or C 1 -7 heteroalkylene, and B1 is an aliphatic ring, an aromatic ring or a fused ring, and H is hydrogen.
  • X is -S- and A is -A1-B1-A2-H, where A1 is C 1-5 alkylene, C 1-5 alkenylene, C 1-5 alkynylene or C 1-5 heteroalkylene, A2 is C 1-5 alkyl, C 1-5 alkenyl, C 1-5 alkynylene or C 1-5 heteroalkylene, and B1 is an aliphatic ring, an aromatic ring or a fused ring.
  • X is -S- and A is -A1-B1-A2, where A1 is C 1-5 alkylene, C 1-5 alkenylene, C 1-5 alkynylene or C 1-5 heteroalkylene, A2 is C 1-5 alkyl, C 1-5 alkenyl, C 1-5 alkynylene or C 1-5 heteroalkylene and B1 is - (C 6 H 4 )-.
  • Preferred embodiments of -X-A are -S-(CH 2 ) 2 -(C 6 H 4 )-(CH 2 ) I -CH 3 , -S-(CH 2 ) 2 -(C 6 H 4 )- (CH 2 ) 2 -CH 3 , -S-(CH 2 ) 2 -(C 6 H 4 )-(CH 2 ) 3 -CH 3 , -S-(CH 2 ) 1 -(C 6 H 4 )-(CH 2 ) 2 -CH 3 , -S-(CH 2 ) 3 -(C 6 H 4 )-
  • X is -S- and A is B1-A2, where A2 is C 1-7 alkylene, C 1-7 alkenylene, C 1-7 alkynylene or C 1-7 heteroalkylene, and B1 is an aliphatic ring, an aromatic ring or a fused ring, and H is hydrogen.
  • X is -S- and A is -B1-A2-H, where A2 is C 1-5 alkyl, C 1-5 alkenyl, C 1-5 alkynylene or C 1-5 heteroalkylene and B1 is an aliphatic ring, an aromatic ring or a fused ring. More preferably, X is -S- and A is -B1-A2-H, where A2 is C 1-5 alkyl, C 1-5 alkenyl, C 1-5 alkynylene or Ci- 5 heteroalkylene and B1 is -(C 6 H 4 )-.
  • X is -S- and A is -A1-B2-H, where A1 is C 1-7 alkylene, C 1-7 alkenylene, Ci- 7 alkynylene or C 1-7 heteroalkylene and B2 is an aliphatic ring, an aromatic ring or a fused ring, and H is hydrogen.
  • X is -S- and A is -A1-B2-H, where A1 is C 1-5 alkyl, C 1-5 alkenyl, C 1-5 alkynylene or C 1-5 heteroalkylene and B2 is an aliphatic ring, an aromatic ring or a fused ring.
  • X is -S- and A is -A1-B2-H, where A1 is C 1-5 alkyl, C 1-5 alkenyl, C 1-5 alkynylene or Ci- 5 heteroalkylene and B2 is -(C 6 H 4 )-.
  • X is -S- and A is -A1-A2-H, where A1 is C 1-7 alkylene, C 1-7 alkenylene, Ci- 7 alkynylene or C 1 -7 heteroalkylene and A2 is C 1 -7 alkylene, C 1 -7 alkenylene, C 1 -7 alkynylene or C 1 -7 heteroalkylene, and H is hydrogen.
  • X is -S- and A is -A1-A2-H, where A1 is C 1-5 alkylene or C 1-5 alkenylene and A2 is C 1-5 alkylene or C 1-5 alkenylene, or more preferred X is -S- and A1 is C 1-5 alkylene and A2 is C 1-5 alkylene.
  • a preferred embodiment of -X-A are -S-(CH 2 ) 5 -CH 3 , -S-(CH 2 ) 6 -CH 3 , -S-(CH 2 ) 7 -CH 3 , -S-(CH 2 ) 8 -CH 3 , -S- (CH 2 )g-CH 3 and -S-(CH 2 )I 0 -CH 3 .
  • Y is -OCH 2 -, -N(R')CH 2 -, -CH 2 CH 2 -, -CH 2 -, -N(R')-, or -0-, where R' is hydrogen or Ci-C 3 alkyl.
  • R is
  • R is an aromatic ring comprising nitrogen, an aliphatic ring or a fused ring, where the ring is optionally substituted with -CF 3 , Ci- 3 alkyl or C 2- heteroalkyl or , where the ring is optionally substituted with -CF 3 , Ci- 3 alkyl or C 2- heteroalkyl; o Wherein Z is -0-, -CH 2 -, -NH- or N-(CH 2 ) 0-2 -CH 3 ; o W is -0-, or -CH 2 -; and o n is 0, 1 or 2.
  • R is an aromatic ring comprising nitrogen, preferably the aromatic ring comprises 1, 2 or 3 nitrogen atoms.
  • the aromatic ring is an aromatic heterocyclic ring having 3 to 5 carbon atoms and 1 to 3 nitrogen atoms, such as an aromatic ring having 3 carbon atoms and 3 nitrogen atoms, or an aromatic ring having 4 carbon atoms and 2 nitrogen atoms or an aromatic ring having 5 carbon atoms and 1 nitrogen atom.
  • the aromatic heterocyclic ring is pyridine, pyrimidine.
  • the aromatic ring can be substituted with -CF 3 , C1-3 alkyl or C2-4 heteroalkyl. In one embodiment, the aromatic ring is substituted with -(CH 2 ) I -CH 3 , -(CH 2 ) 2 - CH 3 or -CH 3 .
  • the aromatic ring is an aromatic heterocyclic ring having 3 to 6 carbon atoms and 1 to 3 nitrogen atoms, where the aromatic ring is substituted with -CF 3 .
  • the aromatic ring substituted with -CF 3 can have 3 carbon atoms and 3 nitrogen atoms, 4 carbon atoms and 2 nitrogen atoms or 5 carbon atoms and 1 nitrogen atom.
  • the aromatic ring has 5 carbon atoms and 1 nitrogen atom and is substituted with -CF 3 .
  • the aromatic ring is an aromatic heterocyclic ring having 3 to 6 carbon atoms and 1 to 3 nitrogen atoms, where the aromatic ring is substituted with Ci- 3 alkyl, e.g. - (CH 2 ) O-2 -CH 3 .
  • the aromatic ring can be substituted with Ci- 3 alkyl and can have 3 carbon atoms and 3 nitrogen atoms, 4 carbon atoms and 2 nitrogen atoms or 5 carbon atoms and 1 nitrogen atom.
  • the aromatic ring has 5 carbon atoms and 1 nitrogen atom and is substituted with Ci alkyl.
  • the aromatic ring is an aromatic heterocyclic ring having 3 to 6 carbon atoms and 1 to 3 nitrogen atoms, where the aromatic ring is substituted with -0-CH 3 .
  • the aromatic ring can be substituted with C 2-4 heteroalkyl and can have 3 carbon atoms and 3 nitrogen atoms, 4 carbon atoms and 2 nitrogen atoms or 5 carbon atoms and 1 nitrogen atom.
  • the aromatic ring has 5 carbon atoms and 1 nitrogen atom and is substituted with C 2-4 heteroalkyl.
  • Y is -OCH 2 - and R is an aromatic ring comprising nitrogen, preferably the aromatic ring comprises 1, 2 or 3 nitrogen atoms.
  • Y is -OCH 2 - and the aromatic ring is an aromatic heterocyclic ring having 3 to 6 carbon atoms and 1 to 3 nitrogen atoms, such as an aromatic ring having 3 carbon atoms and 3 nitrogen atoms, or an aromatic ring having 4 carbon atoms and 2 nitrogen atoms or an aromatic ring having 5 carbon atoms and 1 nitrogen atom.
  • the aromatic heterocyclic ring is pyridine, pyrimidine.
  • Y is -OCH 2 -, and the aromatic ring can be substituted with - CF 3 , Ci-3 alkyl or C2-4 heteroalkyl.
  • the aromatic ring is substituted with - (CH 2 )I-CH 3 , -(CH 2 ) 2 -CH 3 or -CH 3 .
  • Y is -OCH 2 - and the aromatic ring is an aromatic heterocyclic ring having 3 to 6 carbon atoms and 1 to 3 nitrogen atoms, where the aromatic ring is substituted with -CF 3 .
  • the aromatic ring substituted with -CF 3 can have 3 carbon atoms and 3 nitrogen atoms, 4 carbon atoms and 2 nitrogen atoms or 5 carbon atoms and 1 nitrogen atom.
  • the aromatic ring has 5 carbon atoms and 1 nitrogen atom and is substituted with - CF 3 .
  • Y is -OCH 2 - and the aromatic ring is an aromatic heterocyclic ring having 3 to 6 carbon atoms and 1 to 3 nitrogen atoms, where the aromatic ring is substituted with Ci- 3 alkyl, e.g. -(CH 2 ) 0-2 -CH 3 .
  • the aromatic ring can be substituted with -(CH 2 ) 0-2 -CH 3 and can have 3 carbon atoms and 3 nitrogen atoms, 4 carbon atoms and 2 nitrogen atoms or 5 carbon atoms and 1 nitrogen atom.
  • the aromatic ring has 5 carbon atoms and 1 nitrogen atom and is substituted with Ci- 3 alkyl.
  • Y is -OCH 2 - and the aromatic ring is an aromatic heterocyclic ring having 3 to 6 carbon atoms and 1 to 3 nitrogen atoms, where the aromatic ring is substituted with C 2- heteroalkyl.
  • the aromatic ring can be substituted with C 2-4 heteroalkyl and can have 3 carbon atoms and 3 nitrogen atoms, 4 carbon atoms and 2 nitrogen atoms or 5 carbon atoms and 1 nitrogen atom.
  • the aromatic ring has 5 carbon atoms and 1 nitrogen atom and is substituted with C 2- heteroalkyl.
  • Y is -NHCH 2 - and R is an aromatic ring comprising nitrogen, preferably the aromatic ring comprises 1, 2 or 3 nitrogen atoms.
  • Y is -NHCH 2 - and the aromatic ring is an aromatic heterocyclic ring having 3 to 6 carbon atoms and 1 to 3 nitrogen atoms, such as an aromatic ring having 3 carbon atoms and 3 nitrogen atoms, or an aromatic ring having 4 carbon atoms and 2 nitrogen atoms or an aromatic ring having 5 carbon atoms and 1 nitrogen atom.
  • the aromatic heterocyclic ring is pyridine, pyrimidine.
  • Y is -NHCH 2 - and the aromatic ring can be substituted with -CF 3 , CI-3 alkyl or C 2-4 heteroalkyl.
  • the aromatic ring is substituted with - (CH 2 )I-CH 3 , -(CH 2 ) 2 -CH 3 or -CH 3 .
  • Y is -NHCH 2 - and the aromatic ring is an aromatic heterocyclic ring having 3 to 6 carbon atoms and 1 to 3 nitrogen atoms, where the aromatic ring is substituted with -CF 3 .
  • the aromatic ring substituted with -CF 3 can have 3 carbon atoms and 3 nitrogen atoms, 4 carbon atoms and 2 nitrogen atoms or 5 carbon atoms and 1 nitrogen atom.
  • the aromatic ring has 5 carbon atoms and 1 nitrogen atom and is substituted with - CF 3 .
  • Y is -NHCH 2 - and the aromatic ring is an aromatic heterocyclic ring having 3 to 6 carbon atoms and 1 to 3 nitrogen atoms, where the aromatic ring is substituted with -(CH 2 )o- 2-CH3.
  • the aromatic ring can be substituted with -(CH 2 )o- 2 -CH 3 and can have 3 carbon atoms and 3 nitrogen atoms, 4 carbon atoms and 2 nitrogen atoms or 5 carbon atoms and 1 nitrogen atom.
  • the aromatic ring has 5 carbon atoms and 1 nitrogen atom and is substituted with Ci- 3 alkyl.
  • Y is -NHCH 2 - and the aromatic ring is an aromatic heterocyclic ring having 3 to 6 carbon atoms and 1 to 3 nitrogen atoms, where the aromatic ring is substituted with -0- CH 3 .
  • the aromatic ring can be substituted with -0-CH 3 and can have 3 carbon atoms and 3 nitrogen atoms, 4 carbon atoms and 2 nitrogen atoms or 5 carbon atoms and 1 nitrogen atom.
  • the aromatic ring has 5 carbon atoms and 1 nitrogen atom and is substituted with C2-4 heteroalkyl.
  • R is an aliphatic ring, which may be homocyclic or heterocyclic.
  • the aliphatic ring can be a 5-7 membered ring, such as aliphatic rings having 5, 6 or 7 carbon atoms or a heterocyclic aliphatic ring having 4, 5 or 6 carbon and which may further comprise one or more oxygen atoms.
  • the aliphatic ring has 4 or 5 carbon atoms and 1 or 2 oxygen, such as 4 carbon atoms and 2 oxygen atoms or 5 carbon atoms and 1 oxygen atom.
  • the aliphatic ring can be substituted with -CF 3 , Ci- 3 alkyl or C2- 4 heteroalkyl. In one embodiment, the aliphatic ring is substituted with -(CH 2 ) I -CH 3 , -(CH 2 ) 2 - CH 3 or -CH 3 .
  • the aliphatic ring may be a 5-7 membered ring, which is substituted with -CF 3 .
  • the aliphatic ring has 5 carbon, 6 carbon, or 7 carbon and is substituted with -CF 3 .
  • the ring may be a heterocyclic aliphatic ring having 4, 5 or 6 carbon atoms, and may further comprise one or more oxygen atoms, which ring is substituted with -CF 3 .
  • the aliphatic ring is substituted with -CF 3 and the ring has 4 or 5 carbon atoms and 1 or 2 oxygen, such as 4 carbon atoms and 2 oxygen atoms or 5 carbon atoms and 1 oxygen atom.
  • the aliphatic ring may be a 5-7 membered ring, which is substituted with Ci- 3 alkyl.
  • the aliphatic ring has 5 carbon, 6 carbon, or 7 carbon and is substituted with Ci- 3 alkyl, e.g. -(CH 2 )o- 2 -CH 3 .
  • the ring may be a heterocyclic aliphatic ring having 4, 5 or 6 carbon atoms, and may further comprise one or more oxygen atoms, which ring is substituted with Ci- 3 alkyl.
  • the aliphatic ring is substituted with C 1-3 alkyl and the ring has 4 or 5 carbon atoms and 1 or 2 oxygen, such as 4 carbon atoms and 2 oxygen atoms or 5 carbon atoms and 1 oxygen atom.
  • the aliphatic ring may be a 5-7 membered ring, which is substituted with C2-4 heteroalkyl.
  • the aliphatic ring has 5 carbon, 6 carbon, or 7 carbon and is substituted with C2-4 heteroalkyl.
  • the ring may be a heterocyclic aliphatic ring having 4, 5 or 6 carbon atoms, and may further comprise one or more oxygen atoms, which ring is substituted with C2-4 heteroalkyl.
  • the aliphatic ring is substituted with C2-4 heteroalkyl and the ring has 4 or 5 carbon atoms and 1 or 2 oxygen, such as 4 carbon atoms and 2 oxygen atoms or 5 carbon atoms and 1 oxygen atom.
  • Y is -OCH 2 - and R is an aliphatic ring, which may be homocyclic or heterocyclic.
  • Y is -OCH 2 - and the aliphatic ring can be a 5-7 membered ring, such as aliphatic rings having 5, 6 or 7 carbon atoms or a heterocyclic aliphatic ring having 4, 5 or 6 carbon and which may further comprise one or more oxygen atoms.
  • the aliphatic ring has 4 or 5 carbon atoms and 1 or 2 oxygen, such as 4 carbon atoms and 2 oxygen atoms or 5 carbon atoms and 1 oxygen atom.
  • Y is -OCH 2 - and the aliphatic ring can be substituted with -- CF 3 , Ci-3 alkyl or C2-4 heteroalkyl. In one embodiment, the aliphatic ring is substituted with - (CH 2 )I-CH 3 , -(CH 2 ) 2 -CH 3 or -CH 3 .
  • Y is -OCH 2 - and the aliphatic ring may be a 5-7 membered ring, which is substituted with -CF 3 .
  • the aliphatic ring has 5 carbon, 6 carbon, or 7 carbon and is substituted with -CF 3 .
  • the ring may be a heterocyclic aliphatic ring having 4, 5 or 6 carbon atoms, and may further comprise one or more oxygen atoms, which ring is substituted with -CF 3 .
  • the aliphatic ring is substituted with -CF 3 and the ring has 4 or 5 carbon atoms and 1 or 2 oxygen, such as 4 carbon atoms and 2 oxygen atoms or
  • Y is -OCH 2 - and the aliphatic ring may be a 5-7 membered ring, which is substituted with C 1-3 alkyl, e.g. -(CH 2 )o- 2 -CH 3 .
  • the aliphatic ring has 5 carbon
  • the ring may be a heterocyclic aliphatic ring having 4, 5 or 6 carbon atoms, and may further comprise one or more oxygen atoms, which ring is substituted with C1-3 alkyl.
  • the aliphatic ring is substituted with C1-3 alkyl and the ring has 4 or 5 carbon atoms and 1 or 2 oxygen, such as 4 carbon atoms and 2 oxygen atoms or 5 carbon atoms and 1 oxygen atom.
  • Y is -OCH 2 - and the aliphatic ring may be a 5-7 membered ring, which is substituted with C2-4 heteroalkyl.
  • the aliphatic ring has 5 carbon, 6 carbon, or 7 carbon and is substituted with C2-4 heteroalkyl.
  • the ring may be a heterocyclic aliphatic ring having 4, 5 or 6 carbon atoms, and may further comprise one or more oxygen atoms, which ring is substituted with C2-4 heteroalkyl.
  • the aliphatic ring is substituted with C2-4 heteroalkyl and the ring has 4 or 5 carbon atoms and 1 or 2 oxygen, such as 4 carbon atoms and 2 oxygen atoms or 5 carbon atoms and 1 oxygen atom.
  • Y is -NHCH 2 - and R is an aliphatic ring, which may be homocyclic or heterocyclic.
  • Y is -NHCH 2 - and the aliphatic ring can be a 5-7 membered ring, such as aliphatic rings having 5, 6 or 7 carbon atoms or a heterocyclic aliphatic ring having 4, 5 or 6 carbon and which may further comprise one or more oxygen atoms.
  • the aliphatic ring has 4 or 5 carbon atoms and 1 or 2 oxygen, such as 4 carbon atoms and 2 oxygen atoms or 5 carbon atoms and 1 oxygen atom.
  • Y is -NHCH 2 - and the aliphatic ring can be substituted with - CF 3 , Ci-3 alkyl or C2-4 heteroalkyl. In one embodiment, the aliphatic ring is substituted with - (CH 2 )I-CH 3 , -(CH 2 ) 2 -CH 3 or -CH 3 .
  • Y is -NHCH 2 - and the aliphatic ring may be a 5-7 membered ring, which is substituted with -CF 3 .
  • the aliphatic ring has 5 carbon, 6 carbon, or 7 carbon and is substituted with -CF 3 .
  • the ring may be a heterocyclic aliphatic ring having 4, 5 or 6 carbon atoms, and may further comprise one or more oxygen atoms, which ring is substituted with -CF 3 .
  • the aliphatic ring is substituted with -CF 3 and the ring has 4 or 5 carbon atoms and 1 or 2 oxygen, such as 4 carbon atoms and 2 oxygen atoms or 5 carbon atoms and 1 oxygen atom.
  • Y is -NHCH 2 - and the aliphatic ring may be a 5-7 membered ring, which is substituted with -(CH 2 )o-2-CH 3 .
  • the aliphatic ring has 5 carbon, 6 carbon, or 7 carbon and is substituted with Ci- 3 alkyl, e.g. -(CH 2 )o-2-CH 3 .
  • the ring may be a heterocyclic aliphatic ring having 4, 5 or 6 carbon atoms, and may further comprise one or more oxygen atoms, which ring is substituted with Ci- 3 alkyl.
  • the aliphatic ring is substituted with Ci- 3 alkyl and the ring has 4 or 5 carbon atoms and 1 or 2 oxygen, such as 4 carbon atoms and 2 oxygen atoms or 5 carbon atoms and 1 oxygen atom.
  • Y is -NHCH 2 - and the aliphatic ring may be a 5-7 membered ring, which is substituted with C2-4 heteroalkyl.
  • the aliphatic ring has 5 carbon, 6 carbon, or 7 carbon and is substituted with C2-4 heteroalkyl.
  • the ring may be a heterocyclic aliphatic ring having 4, 5 or 6 carbon atoms, and may further comprise one or more oxygen atoms, which ring is substituted with C2-4 heteroalkyl.
  • the aliphatic ring is substituted with C2-4 heteroalkyl and the ring has 4 or 5 carbon atoms and 1 or 2 oxygen, such as 4 carbon atoms and 2 oxygen atoms or 5 carbon atoms and 1 oxygen atom.
  • R is a fused ring, where the ring is optionally substituted with -CF 3 , Ci-3 alkyl or C2-4 heteroalkyl.
  • R is
  • ring is optionally substituted with -CF 3 , Ci- 3 alkyl or C 2-4 heteroalkyl o wherein Z is -0-, -CH 2 -, -NH- or N-(CH 2 ) 0 -2-CH 3 ; o W is -0-, or -CH2-; and o n is 0, 1 or 2.
  • Y is -OCH 2 - and R is the ring is optionally substituted with -CF 3 , Ci- 3 alkyl or C2-4 heteroalkyl wherein Z is -0-, -CH 2 -, -NH- or N-(CH 2 ) 0 -2-CH 3 ;
  • W is -0-, or -CH2-; and n is 0, 1 or 2.
  • Y is -NHCH 2 - and R is , where the ring is optionally substituted with -CF 3 , Ci- 3 alkyl or C 2-4 heteroalkyl wherein Z is -0-, -CH 2 -, -NH- or N-(CH 2 ) 0 -2-CH 3 ; o W is -0-, or -CH 2 -; and o n is 0, 1 or 2.
  • the ring is optionally substituted with -CF 3 , Ci- 3 alkyl or C 2- heteroalkyl.
  • i iss --00--
  • W is -0-, or -CH 2 -
  • n is 1, where the ring is optionally substituted with -CF 3 , Ci- 3 alkyl or C 2-4 heteroalkyl.
  • the ring is optionally substituted with -CF 3 , Ci- 3 alkyl or C 2- heteroalkyl.
  • the ring is optionally substituted with -CF 3 , Ci- 3 alkyl or C 2- heteroalkyl.
  • i iss - -00--
  • W is -CH 2 -
  • n is 1, where the ring is optionally substituted with -CF heteroalkyl.
  • W is -CH 2 -
  • n is 2, where the ring is optionally substituted with -CF heteroalkyl. In one embodiment, or 2, where the ring is optionally substituted with -CF 3 , Ci- 3 alkyl or C 2- heteroalkyl.
  • i iss - -00--
  • W w i iss - -00--, or -CH 2 -
  • n is 1, where the ring is optionally substituted with -CF 3 , Ci- 3 alkyl or C 2-4 heteroalkyl. In one embodiment, where the ring is optionally substituted with -CF 3 , Ci- 3 alkyl or C 2- heteroalkyl.
  • ring is optionally substituted with -CF 3 , Ci- 3 alkyl or C 2- heteroalkyl.
  • Y is -OCH is -0-
  • W is -CH 2 -
  • n is 2, where the ring is optionally substituted w heteroalkyl.
  • Y is -NHCH 2 - and R is , , z Z i iss - -00--,, W w i iss - -O0--, or -CH 2 -, and n is 2, where the ring is optionally substituted with -CF 3 , Ci- 3 alkyl or C 2-4 heteroalkyl. In one embodiment, where the ring is optionally substituted with -CF 3 , Ci- 3 alkyl or C 2- heteroalkyl.
  • Y is -NHCH 2 i iss - -00--,
  • W is -CH 2 -, and
  • n is 1, where the ring is optionally substituted 2- heteroalkyl.
  • the ring is optionally substituted with -CF 3 , Ci- 3 alkyl or C 2- heteroalkyl.
  • i iss -NH-
  • W is -0-, or -CH 2 -
  • n is 1, where the ring is optionally substituted with -CF 3 , Ci- 3 alkyl or C 2- heteroalkyl. In one embodiment the ring is optionally substituted with -CF 3 , Ci- 3 alkyl or C 2- heteroalkyl.
  • the ring is optionally substituted with -CF 3 , Ci- 3 alkyl or C 2- heteroalkyl.
  • the ring is optionally substituted with -CF 3 , Ci- 3 alkyl or C 2- heteroalkyl.
  • the ring is optionally substituted with -CF 3 , Ci- 3 alkyl or C 2- heteroalkyl.
  • i iss -NH-
  • W is -0-, or -CH 2 -
  • n is 1, where the ring is optionally substituted with -CF 3 , Ci- 3 alkyl or C 2- heteroalkyl.
  • the ring is optionally substituted with -CF 3 , Ci- 3 alkyl or C 2- heteroalkyl. In one embodiment, where the ring is optionally substituted with -CF 3 , Ci- 3 alkyl or C 2- heteroalkyl.
  • ring is optionally substituted with -CF 3 , Ci- 3 alkyl or C 2- heteroalkyl.
  • ring is optionally substituted with -CF 3 , Ci- 3 alkyl or C 2- heteroalkyl.
  • ring is optionally substituted with -CF 3 , Ci- 3 alkyl or C 2- heteroalkyl.
  • the invention pertains to a compound of formula I: (formula I) wherein X is -NH- or is absent;
  • A1 and A2 are independently C 1-7 alkylene, C 1-7 alkenylene, C 1-7 alkynylene or C 1-7 heteroalkylene; B1 is an aromatic ring, and H is hydrogen;
  • Y is -OCH 2 - or -NHCH 2 -
  • R is an aromatic ring comprising nitrogen or an aliphatic, where the ring is optionally substituted with -CF 3 , Ci- 3 alkyl or C 2- heteroalkyl, or , where the ring is optionally substituted with -CF 3 , Ci- 3 alkyl or C 2- heteroalkyl, o wherein Z is -0- or -NH-, o W is -0- or -CH 2 -; and o n is 1 or 2; or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a solvate of the pharmaceutically acceptable salt thereof.
  • the invention pertains to a compound of formula I: (formula I) wherein X is -NH-;
  • A1 is C 1-5 alkylene or C 1-5 alkenylene and A2 is C 1-5 alkylene or C 1-5 alkenylene and
  • H is hydrogen, or more preferred A1 is C 1-5 alkylene and A2 is C 1-5 alkylene, such as -Al- A2-H is -(CH 2 ) 5 -CH 3 , -(CH 2 ) 6 -CH 3 , -(CH 2 ) 7 -CH 3 , -(CH 2 ) 8 -CH 3 , -(CH 2 ) 9 -CH 3 or -(CH 2 )I 0 -CH 3 ;
  • Y is -OCH 2 -
  • R is , where the ring is optionally substituted with -CF 3 , Ci- 3 alkyl or C 2- heteroalkyl, o
  • Z is -0- or -NH-, o W is -0- or -CH 2 -; and n is 1 or 2; o preferably Z is -0-, W is -CH 2 -, and n is 1; or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a solvate of the pharmaceutically acceptable salt thereof.
  • the compound is 2-(octylamino)-6-((tetrahydro-2/-/-
  • the invention pertains to a compound of formula I: (formula I) wherein
  • X is absent
  • A is ⁇ -A1-B1-A2-H;
  • A1 is C1-5 alkylene or C1-5 alkenylene and A2 is C1-5 alkylene or C1-5 alkenylene
  • B1 is an aromatic ring
  • H is hydrogen
  • A1 is C1-5 alkylene and A2 is C1-5 alkylene
  • B1 is -(C 6 H 4 )-
  • Y is -OCH 2 - or -NHCH 2 -
  • An aromatic ring comprising nitrogen or an aliphatic, where the ring is optionally substituted with -CF 3 , Ci- 3 alkyl or C 2-4 heteroalkyl, or , where the ring is optionally substituted with -CF 3 , Ci- 3 alkyl or C 2- heteroalkyl, o
  • Z is -0- or -NH-
  • o W is -0- or -CH 2 -
  • o n is 1 or 2; or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a solvate of the pharmaceutically acceptable salt thereof.
  • -X-A is -(CH2) 5 -CH , -(CH2) 6 -CH , -(CH2) 7 -CH , - (CH2) S -CH 3 , -(CH2)g-CH 3 or -(CH2) I0 -CH 3 , or most preferred -(CH2) 8 -CH 3
  • Y is -OCH 2 - or -
  • the compound is 2-((l,4-dioxan-2-yl)methoxy)-6-nonylpyridin-4-ol:
  • the compound is 2-nonyl-6-((tetrahydro-2H-pyran-2- yl)methoxy)pyridin-4-ol : In a preferred embodiment, the compound is 2-nonyl-6-(((tetrahydro-2H-pyran-2- yl)methyl)amino)pyridin-4-ol :
  • the compound is 2-nonyl-6-(oxepan-2-ylmethoxy)pyridin-4-ol :
  • -X-A is -(CH2) 5 -CH , -(CH2) 6 -CH , -(CH2) 7 -CH , - (CH2) 8 -CH 3 , -(CH2)g-CH 3 or -(CH2)I 0 -CH 3 , or most preferred -(CH2) 8 -CH 3
  • Y is -OCH 2 - and R is an aromatic ring comprising nitrogen.
  • the compound is 2-nonyl-6-(pyridin-2-ylmethoxy)pyridin-4-ol :
  • the compound is 2-nonyl-6-(pyridin-3-ylmethoxy)pyridin-4-ol :
  • -X-A is -(CH ) -(C 6 H )-(CH 2 )i-CH , -(CH 2 ) 2 - (C 6 H4)-(CH 2 )2-CH3, -(CH 2 )2-(C 6 H4)-(CH2)3-CH3, -(CH 2 )I-(C 6 H4)-(CH2)2-CH3, -(CH2)3-(C 6 H4)-(CH 2 )2- CH 3 , -(CH 2 )I-(C 6 H 4 )-(CH 2 )I-CH3, -(CH 2 )I-(C 6 H 4 )-(CH 2 ) 3 -CH 3 , -(CH 2 ) 3 -(C 6 H 4 )-(CH 2 ) 1 -CH 3 and - (CH 2 )3-(C 6 H4)-(CH 2 ) 2 -CH3, or most preferred -X-A is -(CH 2 ) 2 -(CH 2 ) 2
  • the compound is 2-(4-propylphenethyl)-6-((tetrahydro-2AY-pyran-2- yl)methoxy)pyridin-4-ol :
  • X is -NH-, -0-, -S- or is absent
  • A is ⁇ -A1-B1-A2-B2-H;
  • A1 and A2 are independently C 1-7 alkylene, C 1-7 alkenylene, C 1-7 alkynylene or C 1-7 heteroalkylene; B1 and B2 are independently an aliphatic ring, an aromatic ring or a fused ring, and H is hydrogen; Y is -OCH 2 -, -N(R')CH 2 -, -CH 2 CH 2 -, -CH 2 -, -NCR')-, or -0-, where R' is hydrogen or C 1 -C 3 alkyl; and
  • an aromatic ring comprising nitrogen, an aliphatic ring or a fused ring, where the ring is optionally substituted with -CF 3 , C 1-3 alkyl or C 2-4 heteroalkyl, or , where the ring is optionally substituted with -CF 3 , C 1-3 alkyl or C 2-4 heteroalkyl, o wherein Z is -0-, -CH 2 -, -NH- or N-(CH 2 ) 0 -2-CH 3 , o W is -0- or -CH2-; and o n is 0, 1 or 2; or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a solvate of the pharmaceutically acceptable salt thereof.
  • A is A1-A2-H, where A1 and A2 are C1-5 alkylene or C1-5 alkenylene.
  • A1 and A2 are C5 alkylene, Y is -OCH 2 - or -NHCH 2 - and R is Z is -0- and W is -0- or -(CH 2 )-.
  • A1-A2-H where A1 is Cs alkylene and A2 is C 4 alkylene,
  • a pharmaceutical composition for use as a medicament comprising a compound according to any of paragraphs 1-30 and a pharmaceutically acceptable carrier, excipient or diluent.
  • composition according to paragraph 33 wherein the composition is for use in treatment of fibrosis of an one of the kidney, liver, lung, pancreas
  • composition as used herein is intended to encompass a product comprising the specified ingredients (and in the specified amounts, if indicated), as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
  • pharmaceutically acceptable it is meant that the carrier, excipient, or diluent is compatible with the other ingredients of the formulation and is not deleterious to the recipient thereof.
  • Composition formulations may improve one or more pharmacokinetic properties (eg oral bioavailability, membrane permeability) of a compound of the invention (herein referred to as the active ingredient).
  • pharmacokinetic properties eg oral bioavailability, membrane permeability
  • compositions for the administration of the compounds of this invention may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art. All methods include the step of bringing the active ingredient into association with the carrier which constitutes one or more accessory ingredients.
  • the pharmaceutical compositions are prepared by uniformly and intimately bringing the active ingredient into association with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired formulation.
  • the active object compound is included in an amount sufficient to produce the desired effect upon the process or condition of diseases.
  • compositions containing the active ingredient may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs.
  • Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions. Such compositions may contain one or more agents selected from sweetening agents, flavouring agents, colouring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets may contain the active ingredient in admixture with other non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets.
  • excipients may be, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid, or talc.
  • the tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. They may also be coated by the techniques described in US Patent No. 4,256,108, 4,160,452, and 4,265,874 to form osmotic therapeutic tablets for control release.
  • Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate, or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
  • an inert solid diluent for example, calcium carbonate, calcium phosphate, or kaolin
  • water or an oil medium for example peanut oil, liquid paraffin, or olive oil.
  • Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions.
  • excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxy-propylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxy-ethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monoo
  • the aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl, p-hydroxybenzoate, one or more colouring agents, one or more flavouring agents, and one or more sweetening agents, such as sucrose or saccharin.
  • preservatives for example ethyl, or n-propyl, p-hydroxybenzoate, one or more colouring agents, one or more flavouring agents, and one or more sweetening agents, such as sucrose or saccharin.
  • Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil, or coconut oil, or in a mineral oil such as liquid paraffin.
  • the oily suspensions may contain a thickening agent, for example beeswax, hard paraffin, or cetyl alcohol.
  • Sweetening agents such as those set forth above, and flavouring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti oxidant such as ascorbic acid.
  • Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavouring and colouring agents, may also be present.
  • the pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions.
  • the oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these.
  • Suitable emulsifying agents may be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate.
  • the emulsions may also contain sweetening and flavouring agents.
  • Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, and flavouring and colouring agents.
  • the pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above.
  • 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-butane diol.
  • the acceptable vehicles and solvents that may be employed are 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 find use in the preparation of injectables.
  • the pharmaceutical compositions may also be administered in the form of suppositories for rectal administration of the drug.
  • These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • suitable non-irritating excipient include, for example, cocoa butter and polyethylene glycols.
  • topical application For topical use, creams, ointments, jellies, solutions, or suspensions etc containing the compounds of the invention are employed. As used herein, topical application is also meant to include the use of mouthwashes and gargles.
  • MS Mass spectrometry
  • Method A Gradient 0-15min, 50-100% Mobile phase B.
  • Method B Gradient 0-15min, 30-100% Mobile phase B.
  • Method A is the default method, except if it is stated otherwise in the experimental procedures.
  • Mass analysis by matrix-assisted laser desorption/ionization high-resolution mass spectrometry was performed on a QExactive Orbitrap mass spectrometer (Thermo Scientific, Bremen, Germany) equipped with a SMALDI5 ion source (TransMIT GmbH, Giessen, Germany). The sample was analyzed in the positive ion mode using a peak from the DHB matrix for internal mass calibration whereby a mass accuracy of 2 ppm or better was achieved.
  • Figure 1 i) Benzyl alcohol (for 2) or (4-Methoxyphenyl)methanol (for 9), NaH, DMF, 0 °C to rt, 23 h; ii) (tetrahydro-2H-pyran-2-yl)methanamine, Cul, H 2 0, 185 °C, MW, 4 h; iii) (tetrahydro-2H- pyran-2-yl)methanol (6a) or (l,4-dioxan-2-yl)methanol (6b) or oxepan-2-ylmethanol (6c) or (Tetrahydrofuran-2-yl)methanol (6d) or pyridin-2-ylmethanol (10), NaH, THF, 0 °C to 100 °C, 3h; iv) PdCI 2 (MeCN) 2, XPhos, Cs 2 C0 3, 1-nonyne (for 4, 7a-e) or l-ethyn
  • Figure 3 Reagents and conditions: i) Benzyl alcohol (for 2) or (4-methoxyphenyl)methanol (for 9), NaH, DMF, 0 °C to rt, 23 h; ii) corresponding alcohol, NaH, THF, 0 °C to 100 °C, 3h; iii) propane-1, 3-diol, p-TsOH, DCM, rt, 7 h; iv) PdCI 2 (MeCN) 2 XPhos, Cs 2 C0 3 corresponding alkyne, MeCN, 90 °C, 18 h ; v) (4-pentylphenyl)boronic acid (for 7s) or (4-phenoxyphenyl)boronic acid (for 7t), SPhos, PdCI 2 (MeCN) 2 , K 3 P0 4 , toluene, 100 °C, 2 d ; vi) 10% Pd-C, H 2, 1 atm, MeOH:
  • Figure 6 Reagents and conditions: i) Benzyl bromide, Cs 2 C0 3 , acetone, reflux, 5 h; ii) (tetrahydro-2H-pyran-2-yi)methanoi, NaH, THF, 0-100 °C, 24 h ; Hi) a) trimethylsilylacetylene, PdCI 2 (PPh 3 )2, TEA, Cul, THF, rt, 17 h; b) K 2 C0 3 , MeOH, 0 °C to rt, 1 h; iv) 2-ethoxy -5- iodopyridine, Pd(PPh 3 ) 4 , TEA, Cul, THF, rt, 17 h; v) H 2 , Pd/C, MeOH:EtOAc (1:2), rt, 6 h.
  • a vial was charged with PdCh(MeCN) 2 (1.8 mg, 0.007 mmol), XPhos (9.8 mg, 0.021 mmol) and anhydrous CS 2 CO 3 (290.1 mg, 0.890 mmol).
  • the vial was evacuated and backfilled with Ar (x3) and the contents were suspended in anhydrous MeCN (0.2 ml).
  • 1-nonyne (0.08 mL, 0.488 mmol) was added and the reaction was allowed to stir for 15 min after which a solution of 6a (114.3 mg, 0.342 mmol) in anhydrous MeCN (0.8 mL) was added to the yellow solution.
  • the vial was capped and heated to 90 °C for 18 h.
  • reaction mixture was filtered over a Celite pad, washed with DEE, the solvents were concentrated in vacuo and the residue was purified by silica gel column chromatography (0-20% DEE in heptane) to give 7a as an orange oil (64mg, 44%).
  • R f 0.10 (Et 2 0:PE, 1 :9).
  • Example 3 2-nonyl-6-(((tetrahydro-2H-pyran-2-yl)methyl)amino)pyridin-4-ol (5).
  • the target compound was synthesized as described for 8a using compound 4 (14.3 mg, 0.034 mmol) instead of 7a and purified by silica gel column chromatography (8-9% MeOH in DCM) to yield 9.7 mg (85%) colorless oil.
  • R f 0.29 (DCM:MeOH, 9: 1), HPLC: 5.99 min, Purity: 99.9%.
  • Example 1 2-((l,4-dioxan-2-yl)methoxy)-6-nonylpyridin-4-ol (8b).
  • the target compound was synthesized as described for 8a using compound 7b (190.0 mg, 0.449 mmol) instead of 7a and purified by silica gel column chromatography (10% MeOH in DCM) to yield 139 mg (92%) slightly yellow oil.
  • R f 0.36 (DCM:MeOH, 9: 1), HPLC: 4.32 min, Purity: 98.3%.
  • IR (neat) A max 2923(m), 2853(m), 1611(s), 1588(m), 1489(m), 1448(m), 1222(m), 1129(s) cm 1 .
  • Example 5 2-nonyl-6-(oxepan-2-ylmethoxy)pyridin-4-ol (8c).
  • the target compound was synthesized as described for 8a using compound 7c (70 mg, 0.161 mmol) instead of 7a and purified by silica gel column chromatography (4% MeOH in DCM) to yield 51 mg (91%) slightly yellow oil.
  • R f 0.45 (DCM:MeOH, 9: 1), HPLC: 4.88 min, Purity: 99.57%.
  • Example 4 2-(4-propylphenethyl)-6-((tetrahydro-2H-pyran-2-yl)methoxy)pyridin-4-ol (8d).
  • the target compound was synthesized as described for 8a using compound 7d (49 mg, 0.11 mmol) instead of 7a and purified by silica gel column chromatography (5-10% MeOH in DCM) to yield 39 mg (99%) slightly yellow oil.
  • R f 0.49 (DCM:MeOH, 9.5:0.5), HPLC: 4.04 min, Purity: 99%.
  • Example 9 2-nonyl-6-((tetrahydrofuran-2-yl)methoxy)pyridin-4-ol (8e).
  • the target compound was synthesized as described for 8a using compound 7e (57.4 mg, 0.141 mmol) instead of 7a and purified by silica gel column chromatography (5% MeOH in DCM) to yield 37.2 mg (82%) slightly yellow oil.
  • R f 0.43 (DCM:MeOH, 9: 1), HPLC: 4.85 min, Purity: 99.9%.
  • the target compound was synthesized as described for 8a using compound 7f (37 mg, 0.09 mmol) instead of 7a and purified by silica gel column chromatography (3-5% MeOH in DCM) to yield 28 mg (96%) green oil that solidifies upon standing.
  • R f 0.33 (DCM:MeOH, 9.5:0.5), HPLC: 4.15 min, Purity: 93%.
  • IR (neat) A max 3263(w), 3095(w), 2925(m), 2854(m), 1649(m), 1610(s), 1466(m), 1200(m), 1179(m) cm 1 .
  • the target compound was synthesized as described for 6a using 2,2-dimethoxyethan-l-ol (38.0 pL, 0.376 mmol) and purified by silica gel column chromatography (8% EtOAc in heptane) to yield 63 mg (55%) colorless oil.
  • R f 0.35 (PE:EtOAc, 8:2).
  • the target compound was synthesized as described for 7a using 1- ethyl-4-ethynylbenzene (50 pL, 0.36 mmol) instead of 1-nonyne and purified by silica gel column chromatography (8% EtOAc in heptane) to yield 85 mg (89%) brown oil.
  • R f 0.39 (EtOAc: heptane, 1:4).
  • Example 10 2-(4-butylphenethyl)-6-((tetrahydro-2H-pyran-2-yl)methoxy)pyridin-4-ol (8g).
  • the target compound was synthesized as described for 8a using compound 7g (36 mg, 0.08 mmol) instead of 7a and purified by silica gel column chromatography (3% MeOH in DCM) to yield 25 mg (86%) slightly yellow oil.
  • R f 0.28 (MeOH:DCM, 5:95).
  • Example 11 2-(4-isobutylphenethyl)-6-((tetrahydro-2H-pyran-2-yl)methoxy)pyridin- 4-ol (8h).
  • the target compound was synthesized as described for 8a using compound 7h (30 mg, 0.07 mmol) instead of 7a and purified by silica gel column chromatography (3% MeOH in DCM) to yield 23 mg (95%) slightly yellow oil.
  • R f 0.28 (MeOH:DCM, 5:95).
  • Example 12 2-(4-ethoxyphenethyl)-6-((tetrahydro-2H-pyran-2-yl)methoxy)pyridin-4- ol (8i).
  • the target compound was synthesized as described for 8a using compound 7i (39 mg, 0.088 mmol) instead of 7a and purified by silica gel column chromatography (3-10% MeOH in DCM) to yield 29.7 mg (95%) slightly yellow oil.
  • R f 0.22 (MeOH:DCM, 5:95).
  • IR (neat) A max 2935(w), 2853(w), 1610(s), 1586(w), 1510(s), 1478(m), 1440(m), 1227(s), 1160(m) cm 1 .
  • Example 13 2-((tetrahydro-2H-pyran-2-yl)methoxy)-6-(4-(trifluoromethyl)- phenethyl)pyridin-4-ol (8j).
  • the target compound was synthesized as described for 8a using compound 7j (61 mg, 0.13 mmol) instead of 7a and purified by silica gel column chromatography (3-6% MeOH in DCM) to yield 32.8 mg (66%) slightly yellow oil.
  • R f 0.16 (MeOH:DCM, 5:95).
  • Example 14 2-((tetrahydro-2H-pyran-2-yl)methoxy)-6-(3-(trifluoromethyl)- phenethyl)pyridin-4-ol (8k).
  • the target compound was synthesized as described for 8a using compound 7k (61 mg, 0.13 mmol) instead of 7a and purified by silica gel column chromatography (6% MeOH in DCM) to yield 28.1 mg (56%) slightly yellow oil.
  • R f 0.17 (MeOH:DCM, 5:95).
  • Example 15 2-(4-ethylphenethyl)-6-((tetrahydro-2H-pyran-2-yl)methoxy)pyridin-4-ol (81).
  • the target compound was synthesized as described for 8a using compound 71 (78 mg, 0.18 mmol) instead of 7a and purified by silica gel column chromatography (6% MeOH in DCM) to yield 42 mg (67%) slightly yellow oil.
  • R f 0.15 (MeOH:DCM, 5:95).
  • the target compound was synthesized as described for 8a using compound 7m (90 mg, 0.203 mmol) instead of 7a and purified by silica gel column chromatography (5% MeOH in DCM) to yield 64 mg (88%) slightly yellow oil.
  • R f 0.46 (DCM:MeOH, 9: 1).
  • the target compound was synthesized as described for 8a using compound 7n (34.5 mg, 0.077 mmol) instead of 7a and purified by silica gel column chromatography (1-6% MeOH in DCM) to yield 20.2 mg (73%) colorless oil.
  • R f 0.60 (EtOAcDCM, 1 :9).
  • IR (neat) A max 2915(w), 2856(m), 1610(s), 1587(m), 1510(s), 1479(m), 1444(m), 1241(s), 1162(m) cm 1 .
  • Example 18 2-((l,3-dioxan-2-yl)methoxy)-6-(4-propylphenethyl)pyridin-4-ol (80).
  • the target compound was synthesized as described for 8a using compound 7o (48 mg, 0.111 mmol) instead of 7a and purified by silica gel column chromatography (5% MeOH in DCM) to yield 31 mg (79%) slightly yellow oil.
  • R f 0.55 (DCM :MeOH, 9: 1).
  • IR (neat) A max 2927(w), 2859(w), 1612(m), 1590(m), 1513(m), 1488(m), 1440(s), 1227(m), 1160(s) cm 1 .
  • Example 19 2-(benzo[d][l,3]dioxol-2-ylmethoxy)-6-(4-propylphenethyl)pyridin-4-ol (8p).
  • the target compound was synthesized as described for 8a using compound 7p (69.2 mg, 0.14 mmol) instead of 7a and purified by silica gel column chromatography (6% MeOH in DCM) to yield 52.4 mg (92%) yellow oil.
  • R f 0.3 (MeOH:DCM, 5:95).
  • Example 20 2-((2,3-dihydrobenzofuran-2-yl)methoxy)-6-(4-propylphenethyl)pyridin- 4-ol (8q).
  • the target compound was synthesized as described for 8a using compound 7q (97 mg, 0.20 mmol) instead of 7a and purified by silica gel column chromatography (6% MeOH in DCM) to yield 77.2 mg (97%) yellow oil.
  • R f 0.31 (MeOH:DCM, 5:95).
  • Example 21 2-((2,3-dihydrobenzo[b][l,4]dioxin-2-yl)methoxy)-6-(4-propyl- phenethyl)pyridin-4-ol (8r).
  • the target compound was synthesized as described for 8a using compound 7r (12 mg, 0.024 mmol) instead of 7a and purified by silica gel column chromatography (6% MeOH in DCM) to yield 8.3 mg (84%) slightly yellow oil.
  • R f 0.31 (MeOH:DCM, 5:95).
  • Example 22 2-(4-pentylphenyl)-6-((tetrahydro-2H-pyran-2-yl)methoxy)pyridin-4-ol (8s).
  • the target compound was synthesized as described for 8a using compound 7s (63 mg, 0.14 mmol) instead of 7a and purified by silica gel column chromatography (6% MeOH in DCM) to yield 18.9 mg (38%) white powder.
  • R f 0.32 (MeOH:DCM, 5:95).
  • IR (neat) A max 2929(m), 2856(m), 1606(s), 1588(s), 1512(m), 1488(m), 1438(s), 1162(s) cm 1 .
  • Example 23 2-(4-phenoxyphenyl)-6-((tetrahydro-2H-pyran-2-yl)methoxy)pyridin-4-ol (8t).
  • the target compound was synthesized as described for 8a using compound 7t (65 mg, 0.14 mmol) instead of 7a and purified by silica gel column chromatography (5% MeOH in DCM) to yield 15.7 mg (30%) white powder.
  • R f 0.18 (MeOH:DCM, 5:95).
  • Example 25 2-((4-propylbenzyl)amino)-6-((tetrahydro-2H-pyran-2-yl)methoxy)- pyridin-4-ol (12c).
  • the target compound was synthesized as described for 12b using compound 11c (70 mg, 0.161 mmol) instead of lib and purified by silica gel column chromatography (5% MeOH in DCM) and further purified by prep HPLC (40-60% solvent B in 15 min) to yield 4.2 mg (45%) slightly yellow oil.
  • R f 0.25 (MeOH:DCM, 5:95).
  • Example 26 2-(methyl(4-propylbenzyl)amino)-6-((tetrahydro-2H-pyran-2-yl)- methoxy)pyridin-4-ol (12d).
  • the target compound was synthesized as described for 12b using compound lid (23.2 mg, 47.3 pmol) instead of lib and purified by silica gel column chromatography (5% MeOH in DCM) and further purified by prep HPLC (45% solvent B) to yield 9.1 mg (52%) colorless oil.
  • R f 0.4 (MeOH:DCM, 5:95).
  • IR (neat) A max 2935(w), 2860(w), 1672(m), 1621(s), 1180(s), 1135(m) cm 1 .
  • Example 27 2-((5-methyl-l,3-dioxan-2-yl)methoxy)-6-(4-propylphenethyl)pyridin-4- ol (18a).
  • the target compound was synthesized as described for 8a using compound 17a (40.9 mg, 89.4 pmol) instead of 7a, stirred for 2.5 h and purified by silica gel column chromatography (6% MeOH in DCM) to yield 26.4 mg (80%) colorless oil.
  • R f 0.26 (MeOH:DCM, 7:93).
  • Example 28 2-((4-methyl-l,3-dioxan-2-yl)methoxy)-6-(4-propylphenethyl)pyridin-4- ol (18b).
  • the target compound was synthesized as described for 8a using compound 17b (43.9 mg, 95.9 pmol) instead of 7a, stirred for 3 h and purified by silica gel column chromatography (6-7% MeOH in DCM) to yield 26.6 mg (75%) colorless oil.
  • R f 0.46 (MeOH:DCM, 7:93).
  • Example 29 2-(4-propylphenethyl)-6-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)pyridin- 4-ol (24).
  • the target compound was synthesized as described for 8a using compound 23 (55.8 mg, 0.118 mmol) instead of 7a and purified by silica gel column chromatography (5-7% MeOH in DCM) to yield 28.4 mg (68%) colorless oil.
  • R f 0.48 (DCM :MeOH, 9: 1).
  • IR (neat) A max 2929(m), 2869(w), 1623(s), 1510(s), 1200(w), 1123(m) cm 1 .
  • Example 30 2-(((4-propylbenzyl)oxy)methyl)-6-((tetrahydro-2H-pyran-2-yl)- methoxy)pyridin-4-ol (28).
  • TFA 70 pL, 10% final solution
  • phosphate buffer pH 7.0, 0.1 M, 10 mL
  • Example 31 2-((4-propylphenoxy)methyl)-6-((tetrahydro-2H-pyran-2-yl)methoxy)- pyridin-4-ol (30).
  • the target compound was synthesized as described for 28 using compound 29 (28.4 mg, 59.5 pmol) instead of 27 and purified initially by silica gel column chromatography (0-10% MeOH in DCM) and subsequently by preparative HPLC (30-70% solvent B in 15 min) to yield 17.7 mg (83%) colorless oil.
  • R f 0.70 (DCM:MeOH, 9: 1).
  • Example 32 2-(2-(6-ethoxypyridin-3-yl)ethyl)-6-((tetrahydro-2H-pyran-2-yl)- methoxy)pyridin-4-ol (36).
  • the target compound was synthesized as described for 8a using compound 35 (39.8 mg, 0.090 mmol) instead of 7a, stirred for 6 h and purified by silica gel column chromatography (5-7% MeOH in DCM) to yield 23.9 mg (75%) colorless oil.
  • R f 0.51 (DCM:MeOH, 9: 1).
  • HTLA cells a HEK293 cell line stably expressing a tTA-dependent luciferase reporter and a 3-arrestin2-TEV fusion gene
  • DMEM Dulbecco's Modified Eagle's Medium
  • dFBS Fetal Bovine Serum
  • cells were plated at 9 x 10 6 to 10 x 10 6 cells per 15-cm cell-culture dish (day 1). The following day (day 2), cells were transfected by adding 5pg DNA and 15pg polyethylenimine (PEI) diluted in lmL Opti-MEM (Reduced Serum Medium supplied by ThermoFisher). On day 3, transfected cells were transferred at 25000 cells per well in 40 pi of medium into poly-l-lysine-coated and rinsed 384-well white, clear-bottomed cell-culture plates (Greiner Bio-One). On day 4, dilutions of the ligands to be tested were prepared in 1% dFBS DMEM and 10pL were added to each well.
  • PEI polyethylenimine
  • the GPR84 antagonistic activity of compounds 1-34 was determined using the PRESTO-Tango b- arrestin2 recruitment assay (Assay I, see assays above), from which the concentration of each compound required for 50% inhibition (IC 5 o) of the response from the agonist ZQ-16 (100 nM) was determined.
  • the antagonistic activity for each compound is given in Table 3 as the pIC 5 o, which is the negative log of the IC 50 value when converted to molar.
  • the GPR84 antagonistic activity of compounds 1-34 was determined using the PRESTO-Tango ⁇ - arrestin2 recruitment assay (Assay I, see assays above), from which the concentration of each compound required for 50% of maximal activation (EC50) was determined. Maximal activation is indicated as Emax in % relative to the maximal activation of ZQ16. Thus, Emax values between 0% and 100%, preferably below 50% indicate partial agonism, and negative Emax values indicate inverse agonism, i.e. a more efficient receptor inhibition than classical antagonists.
  • the potency of the agonistic activity for each compound in the Table is stated as pEC50, denoting the negative loglO of the molar EC50 value.
  • the cAMP assay kit from CisBio (cat. No. : 62AM4PEC) was used for performing the assay.
  • a Flp-In 293 T-REx cell line with a stably integrated gene for GPR84-Gai fusion receptor was grown in 10cm dishes and induced with doxycycline (1 pL / 10 mL growth medium*) when confluency reached -60%.
  • the next day, dilutions of the compounds (x 2.5) to be tested and agonist EC80 solution (x 4) were prepared in the stimulation buffer provided with the kit.
  • 4 pL of the dilution solutions were transferred to the final 384 well plate (PerkinElmer, cat. No. 6008289) in triplicate.
  • the growth medium of the cells was discarded, and the dishes were washed with 10 mL 1% PBS.
  • the cells were detached by adding 1 mL Versene to the dishes and they were transferred to a 50 mL falcon tube with the addition of 3 mL stimulation buffer per dish.
  • the cells were counted, and the tube was centrifuged at 1500 rpm for 5min.
  • the supernatant liquid was decanted, and a precise amount of stimulation buffer was added to result in a concentration of 2*10 6 cells / mL.
  • a certain amount of cell suspension that it will be added to the final plate was transferred to a vial and a DMSO solution of IBMX was added to a final concentration 0.5 mM.
  • DMEM Dulbecco's Modified Eagle Medium lx
  • the compounds' dilutions (x 10) and agonist EC80 concentration (x 10) were prepared in Buffer A (20 mM HEPES, 5 mM MgC , 160 mM NaCI, 0.05% BSA). In deep 96-well plates were added sequentially 40 pL Buffer A, 20 pL from the compounds' dilutions, 20 pL agonist solution, 20 pL membrane preparation (3 pg) originating from cells expressing GPR84-Gai fusion protein and 100 pL Buffer B (Buffer A, 0.2nM GTP-y- 35 S, 2pM GDP). The plates were incubated for 1 h at 37°C, then filtered through Unifilter plates (Perkin Elmer, cat no.
  • Sprague Dawley rats are orally administered with 0.25 pL/g carbon tetrachloride (CCU) in olive oil solution, starting from day 0, 3 times per week for 6 weeks. Animals are sacrificed 48 hours after the last CCI4 administration. The test compound is given by oral gavage after 3 weeks of CCI4 administration and continued throughout the remainder of the study at 3 mg/kg, 10 mg/kg or 30 mg/kg once a day. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels are assessed in the plasma. One lobe of the liver tissue are fixed in 10% formalin, stained for Sirius red and the percentage coverage area is measured.
  • CCU carbon tetrachloride
  • Non-alcoholic steatohepatitis is established in male C57/BL6 mice by a single subcutaneous injection of 200 pg streptozotocin after birth and with a high fat diet ad libitum from 4 until 14 weeks of age. Mice are orally administered with the test compound (3, 10 or 30 mg/kg once daily) from 8 to 14 weeks of age. Plasma ALT levels are determined. One lobe of the liver tissue was fixed in 10% formalin, stained for Sirius red and the percentage coverage area is measured. Hematoxylin and eosin (HE) staining is performed to estimate non-alcoholic fatty liver disease (NAFLD) activity score according to the criteria of Kleiner et al (2005).
  • NASH non-alcoholic fatty liver disease
  • the bleomycin-induced model of pulmonary fibrosis is performed essentially as described by Gagnon et al (2016). Briefly, 10-week old C57BL/6 mice are intratracheally instilled with bleomycin (0.025 U per mouse). Mice are grouped according to their body weight loss and treated with test compound (3, 10 or 30 mg/kg per day) or vehicle from day 7 to day 20 via gastric gavage. On day 21, lungs are prepared for histologic assessment of lesions with Masson's trichrome staining.
  • mice are fed either standard chow with or without supplement of 0.25% adenine ad libitum for 4 weeks. After 1 week of adenine administration, mice were given either vehicle or test compound (3, 10 or 30 mg/kg per day) by gastric gavage for 3 weeks. Kidney sections were stained with Masson' s trichrome for histologic evaluation of tubulointerstitial fibrosis and cystic lesions scores.
  • doxorubicin nephropathy mouse model was performed as described by Gagnon et al. (2018). Briefly, nephrotoxicity was induced in 6-10 weeks old mice by i.v. injection of doxorubicin (10 mg/kg) on day 0. Test compound (3, 10 or 30 mg/kg per day) or vehicle was administered from day -3 to -1 and day 1 to day 10, and mice were sacrificed on the following day. Kidneys were prepared for histologic assessment of glomerular and tubular lesions with hematoxylin and eosin staining.

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Abstract

The invention concerns a compound of formula I, a pharmaceutical formulation comprising the compound of formula I and use of the pharmaceutical composition for treating inflammatory or diabetic disease.

Description

Title: G protein-coupled receptor modulators and a pharmaceutical composition Field of the invention
The invention concerns a compound of formula I, a phamaceutical compostion comprising the compound of formula I and use of the pharmaceutical compoisition for treating fibrotic, inflammatory, diabetic or cognitive disease.
Background of the invention
GPR84 is a G protein-coupled receptor (GPCR) that is activated by a relatively high concentration of decanoic acid and some related compounds, however its natural activator is still unknown and the receptor is thus considered to be "orphan" GPCR. To date, three classes of ligands are suggested to bind to three distinct sites on orphan GPR84, with the medium chain fatty acids agonist ligands (in particular decanoic acid) binding to one site; a second class of allosteric agonists represented by 3,3'-diindolylmethane (DIM), while a third class of allosteric antagonists represented by G9543 may bind to a third site (Mahmud et al. 2017).
GPCRs are cell-surface receptors that are known to be highly "druggable", with 1/3 of current drugs acting through members of this class. GPR84 is expressed on immune cells, especially neutrophils and eosinophils, and is found in organs such as bone marrow, liver, lung, intestines and brain. The receptor has a pro-inflammatory effect and is induced in monocytes and macrophages by lipopolysaccharide (LPS) and activation of GPR84 induces secretion of pro- inflammatory cytokines such as IL-4, IL-8, IL-128, CXCL1 and TNF-a. Several scientific groups have suggested that inhibition of GPR84 could represent a useful treatment of inflammatory diseases, including asthma, atopic dermatitis, cancer, diabetes, fibrosis and Inflammatory bowel disease (IBD) (Milligan et al. 2018; Miyamoto et al. 2017; Lynch 8i Wang 2016; Suckow 8i Briscoe 2017; Gagnon et al. 2018).
Recently, a low-potency dual GPR84 antagonist/GPR40 agonist was demonstrated to have efficacy against fibrosis in both mice and humans (Gagnon et al. 2018). This strongly suggests that GPR84 antagonism has potential for treatment of fibrosis. Besides this low-potency compound, only one series of GPR84 antagonists, discovered by Galapagos Pharmaceuticals, is known (WO2013/092791A1, WO2014/095798A1, WO2016/169911A1).
Liu et al. (ACS Med. Chem. Lett. 2016, 7:579-583) describes a series of alkylpyrimidine-4,6-diol derivatives which were designed and synthesized as novel GRP84 agonists based on a high- throughput screening (HTS) hit. 6-Nonylpyridine-2,4-diol was identified as the most potent agonist of GPR84 reported so far, with an EC50 of 0.189 nM. Yang Liu et al. concludes that these novel GPR84 agonists will provide valuable tools for the study of the physiological functions of GPR84.
Nan et al (WO2017/076264A1) have invented dihydroxypyrimidines and similar compounds as GPR84 agonists for treatment of septicemia. Pillalyar et al. (2017) have reported optimized DIM GPR84 agonists, whereas Pillalyar et al. (2018) and Kose et al. (2019) have reported potent uracil-derived GPR84 agonists.
International patent application published under number WO2019/096944 (Galapagos N.V.) discloses compounds useful in the prophylaxis and/or treatment of one or more fibrotic diseases. In particular, the compounds antagonize GPR84, a G-protein-coupled receptor. The document also discloses pharmaceutical compositions comprising the compounds for use and methods for the prophylaxis and/or treatment of one or more fibrotic diseases by administering said compound.
SUMMARY OF THE INVENTION The present invention pertains to a compound of the formula I:
Figure imgf000003_0001
(formula I) wherein
X is -NH-, -0-, -S- or is absent; A is -(Al)j-(Bl)k-(A2)r(B2)m-H, wherein
Al and A2 independently are C1-7 alkylene, C2-7 alkenylene, C2-7 alkynylene, or C1-7 heteroalkylene, optionally substituted with one or two of independently selected Ul;
B1 and B2 are independently an aliphatic ring, an aromatic ring or a fused ring, optionally substituted with one or two of independently selected U2; H is hydrogen; j, k, I, and m are independently 0 or 1;
Y is -OCH2-, -N(R')CH2-, -CH2CH2-, -CH2-, -N(R')-, or -0-, where R' is hydrogen or C1-C3 alkyl; and R is an aromatic ring, an aromatic ring comprising nitrogen, an aliphatic ring or a fused ring, optionally substituted with one, two or three of independently selected U3;
Ul, U2 and U3 are independently hydrogen, -CF3, Ci-3 alkyl, Ci-3 haloalkyl, C -4 heteroalkyl, halogen, =0, =NR' =N-OR' -NR'R", -SR', -CN, C2-5 alkynyl, C2-5 alkenyl, C3-5 cycloalkyl, C3-5 heterocycloalkyl and -NO2, where R', R", R'" and R"" independently refer to hydrogen, unsubstituted Ci-3 alkyl and C2-3 heteroalkyl that can be connected by bonds to form rings, cycloalkyl or heterocycloalkyl; or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a solvate of the pharmaceutically acceptable salt thereof. In a second aspect, the compound of formula I pertains to:
Figure imgf000004_0001
(formula I) wherein
X is -NH-, -0-, -S- or is absent; A is
• -A1-B1-A2-B2-H;
• -A1-B1-A2-H;
• -B1-A2-H;
• -A1-B2-H; or · -A1-A2-H;
• where A1 and A2 are independently C1-7 alkylene, C1-7 alkenylene, C1-7 alkynylene or C1-7 heteroalkylene; B1 is an aliphatic ring, an aromatic ring or a fused ring; B2 is an aliphatic ring, an aromatic ring or a fused ring, and H is hydrogen;
Y is -OCH2-, -N(R')CH2-, -CH2CH2-, -CH2-, -NCR')-, or -0-, where R' is hydrogen or Ci-C3 alkyl; and
R is an aromatic ring comprising nitrogen, an aliphatic ring or a fused ring, where the ring is optionally substituted with -CF3, Ci-3 alkyl, C2-4 heteroalkyl or
Figure imgf000005_0001
the ring is optionally substituted with -CF3, Ci-3 alkyl, C2- heteroalkyl, o wherein Z is -0-, -CH2-, -NH- or N-(CH2)0-2-CH3,
W is -0- or -CH2-; and n is 0, 1 or 2; or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a solvate of the pharmaceutically acceptable salt thereof.
In a further aspect, the invention concerns a pharmaceutical composition for use as a medicament, said pharmaceutical composition comprising a compound according to formula I and a pharmaceutically acceptable carrier, excipient or diluent.
In one aspect, the pharmaceutical composition can be used in the treatment of inflammatory or diabetic disease.
DEFINITIONS The term "alkyl", by itself or as part of another substituent, means, unless otherwise stated, a straight or branched chain, or cyclic hydrocarbon radical, or combination thereof, which is fully saturated, having the number of carbon atoms designated (e.g., Ci-7 means one to seven carbon atoms). Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, cyclohexyl, (cyclohexyl)methyl, cyclopropyl, cyclopropylmethyl, and homologs and isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like.
The term "cycloalkyl" by itself or as part of another substituent, means, unless otherwise stated, a member of the subset of alkyl comprising cyclic hydrocarbon radicals.
The term "alkylene" by itself or as part of another substituent means a divalent radical derived from alkyl. The two valences may be on any carbon atom of the chain, including on the same carbon, resulting in an alkyl connected by a double bond. Typically, an alkyl (or alkylene) group will have from 1 to 24 carbon atoms, with those groups having 8 or fewer carbon atoms being preferred in the present invention. Typical examples of alkylene include -CH2CH2CH2CH2-, -CH(CH3)- and =CHCH2CH3. The term "alkenyl" means monovalent unsaturated (olefinic) hydrocarbon chains having a specified number of carbon atoms (i.e. C2-8 means two to eight carbons). Preferably, alkenyl has 2 to 7 carbon atoms, and more particularly, from 2 to 3 carbon atoms, which can be straight- chained or branched and having at least 1 and particularly from 1 to 2 sites of olefinic unsaturation. Preferred alkenyl groups include ethenyl (-CH=CH2), n-propenyl (-CH2CH=CH2), isopropenyl (-C(CH3)=CH2) and the like.
The term "alkenylene", by itself or as part of another substituent, means a straight or branched chain hydrocarbon radical, or combination thereof, which may be mono- or polyunsaturated, having the number of carbon atoms designated (i.e. C2-8 means two to eight carbons) and one or more double bonds. Examples of alkenylene groups include ethenylene (-CH=CH-), -CH2CH=CH-, -CH2C(CH3)=CH-, and higher homologs and isomers thereof.
The term "alkynyl", by itself or as part of another substituent, means a straight or branched chain hydrocarbon radical, or combination thereof, which may be mono- or polyunsaturated, having the number of carbon atoms designated (i.e. C2-C8 means two to eight carbons) and one or more triple bonds. Examples of alkynyl groups include ethynyl, 1- and 2-propynyl, 3-butynyl, and higher homologs and isomers thereof.
The term "alkynylene' means a divalent alkyne radical groups having the number of carbon atoms and the number of triple bonds specified, in particular 2 to 7 carbon atoms and more particularly 2 to 3 carbon atoms which can be straight-chained or branched. This term is exemplified by groups such as -CºC-, -CH2-CºC-, and -C(CH3)H-CºC-.
The term "heteroalkyl", by itself or in combination with another term, means, unless otherwise stated, a stable straight or branched chain, or cyclic hydrocarbon radical, or combinations thereof, consisting of carbon atoms and from one to three heteroatoms selected from the group consisting of 0, N, and S, and wherein the nitrogen and sulfur atoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized. The heteroatom(s) 0, N, and S may be placed at any position of the heteroalkyl group. Examples include -CH2CH2OCH3, -CH2CH2NHCH3, -CH2CH2N(CH3)CH3, -CH2SCH2CH3, -CH2CH2S(0)CH3, -CH2CH2S(0)2CH3, -OCH3 and -CH2CH=N-OCH3. Up to two heteroatoms may be consecutive, such as, for example, -CH2NHS(0)2CH3. When a prefix such as C2-7 is used to refer to a heteroalkyl group, the number of carbons (2 to 7, in this example) is meant to include the heteroatoms as well. For example, a C2-heteroalkyl group is meant to include, for example, -CH2OH (one carbon atom and one heteroatom replacing a carbon atom), -SCH3 and -CH2SH, and a C3-heteroalkyl group is meant to include -N(CH3)2.
To further illustrate the definition of a heteroalkyl group, where the heteroatom is oxygen, a heteroalkyl group is an, oxyalkyl group. For instance, (C2-C8)oxyalkyl is meant to include, for example -CH20-CH3 (a C3-oxyalkyl group with two carbon atoms and one oxygen replacing a carbon atom), -CH2CH2CH2CH2OH, and the like.
The term "heteroalkylene" by itself or as part of another substituent means a divalent radical derived from heteroalkyl, as exemplified by -CH2CH2SCH2CH2- and -CH2SCH2CH2NHCH2-. For heteroalkylene groups, heteroatoms can also occupy either or both of the chain termini (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, and the like). Still further, for alkylene and heteroalkylene linking groups, no orientation of the linking group is implied. Heteroalkylene groups such as oxymethyl groups (-CH20-) may be substituted or unsubstituted. In some embodiments, heteroalkylene groups may be substituted with an alkyl group. For example, the carbon atom of an oxymethylene group may be substituted with a methyl group in a group of formula -CH(CH )0-. Still further, Cl heteroalkylene may be a divalent radical derived from a heteroatom, as exemplified by -0-, -N-, -S-.
The terms "cycloalkyl" and "heterocycloalkyl" by themselves or in combination with other terms, represent, unless otherwise stated, cyclic versions of "alkyl" and "heteroalkyl" respectively. Thus, the terms "cycloalkyl" and "heterocycloalkyl" are meant to be included in the terms "alkyl" and "heteroalkyl", respectively. Additionally, for heterocycloalkyl, a heteroatom can occupy the position at which the heterocycle is attached to the remainder of the molecule. Examples of cycloalkyl include cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like. Examples of heterocycloalkyl include l-(l,2,5,6-tetrahydropyridyl), 1- piperidinyl, 2-piperidinyl, 3-piperidinyl, 1-pyrrolidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1- piperazinyl, 2-piperazinyl, 4,5-dihydroisoxazol-3-yl, and the like. The term "heterocycloalkyl" includes fully saturated compounds such as piperidine and compounds with partial saturation that are not aromatic. Examples of such groups include, but are not limited to, an imidazoline, oxazoline, or isoxazoline.
The term "cycloalkylene" and "heterocycloalkylene," by themselves or in combination with other terms, represent, unless otherwise stated, cyclic versions of "alkylene" and "heteroalkylene," respectively. Thus, the terms "cycloalkylene" and "heterocycloalkylene" are meant to be included in the terms "alkylene" and "heteroalkylene," respectively. Additionally, for heterocycloalkylene, one or more heteroatoms can occupy positions at which the heterocycle is attached to the remainder of the molecule. Typically, a cycloalkylene or heterocycloalkylene will have from 3 to 9 atoms forming the ring, more typically, 3 to 7 atoms forming the ring, and even more typically, 5 or 6 atoms will form the cycloalkylene or heterocycloalkylene ring.
The term "aliphatic ring" by itself or as part of another substituent means a cycloalkyl, a heterocycloalkyl, a cycloalkylene or a heterocycloalkylene of any valency, but typically mono- or divalent. Examples of such groups include cyclopentyl, 1,4-dioxanyl, or piperidinyl. The term "fused ring" means, unless otherwise stated, a cyclic aromatic or non-aromatic ring which shares bonds with one or two other cyclic aromatic or non-aromatic ring. The term "fused aryl" means, unless otherwise stated, a fused ring where at least one of the rings is an aryl. The term "fused heteroaryl" means, unless otherwise stated, a fused ring system where at least one of the rings is a heteroaryl. Examples of rings, fused aryl and fused heteroaryl groups include, 1- naphthyl, 1-tetrahydronaphthyl, 1-decahydronaphthyl, 2-naphthyl, dibenzofuryl, 5- benzothiazolyl, 2-benzoxazolyl, 5-benzoxazolyl, benzooxadiazolyl, purinyl, 2-benzimidazolyl, 5- indolyl, lH-indazolyl, indanyl, carbazolyl, carbolinyl, 1-isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl, 2-quinolyl, 3- quinolyl, 4-quinolyl, 5-quinolyl, 6-quinolyl, 7-quinolyl, and 8- quinolyl.
The term "aryl" refers to a monovalent aromatic hydrocarbon group derived by the removal of one hydrogen atom from a single carbon atom of a parent aromatic ring system. In particular aryl refers to an aromatic ring structure, monocyclic or fused polycyclic, with the number of ring atoms specified. Specifically, the term includes groups that include from 6 to 10 ring members. Particular aryl groups include phenyl, and naphthyl.
When the term "hetero" is used, it describes a compound or a group present on a compound means that one or more carbon atoms in the compound or group have been replaced by a nitrogen, oxygen, or sulfur heteroatom. Hetero may be applied to any of the hydrocarbyl groups described above such as alkyl, e.g. heteroalkyl, cycloalkyl, e.g. heterocycloalkyl, aryl, e.g. heteroaryl, and the like having from 1 to 4, and particularly from 1 to 3 heteroatoms, more typically 1 or 2 heteroatoms, for example a single heteroatom.
The term "heteroaryl" means an aromatic ring structure, monocyclic or fused polycyclic, that includes one or more heteroatoms independently selected from 0, N and Sand the number of ring atoms specified.
The term "aromatic ring" by itself or as part of another substituent means aryl or heteroaryl of any valency, but typically mono- or divalent.
In particular, the aromatic ring structure may have from 5 to 11 ring members. Preferably, the heteroaryl group is a five membered or six membered monocyclic ring or a fused bicyclic structure formed from fused five and six membered rings or two fused six membered rings or, by way of a further example, two fused five membered rings. Each ring may contain up to four heteroatoms typically selected from nitrogen, sulphur and oxygen. Typically, the heteroaryl ring will contain up to 4 heteroatoms, more typically up to 3 heteroatoms, more usually up to 2, for example a single heteroatom.
In one embodiment, the heteroaryl ring contains at least one ring nitrogen atom. The nitrogen atoms in the heteroaryl rings can be basic, as in the case of an imidazole or pyridine, or essentially non-basic as in the case of an indole or pyrrole nitrogen. In general, the number of basic nitrogen atoms present in the heteroaryl group, including any amino group (Amino refers to -NH2) substituents of the ring, will be less than five.
Examples of five membered monocyclic heteroaryl groups include but are not limited to pyrrolyl, furanyl, thiophenyl, imidazolyl, furazanyl, oxazolyl, oxadiazolyl, oxatriazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl and tetrazolyl groups.
Examples of six membered monocyclic heteroaryl groups include but are not limited to pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl and triazinyl.
Particular examples of bi cyclic heteroaryl groups containing a five membered ring fused to another five-membered ring include but are not limited to imidazothiazolyl and imidazoimidazolyl.
Particular examples of bicyclic heteroaryl groups containing a six membered ring fused to a five membered ring include but are not limited to benzofuranyl, benzothiophenyl, benzoimidazolyl, benzoxazolyl, isobenzoxazolyl, benzisoxazolyl, benzothiazolyl, benzoisothiazolyl, isobenzofuranyl, indolyl, isoindolyl, indolizinyl, purinyl (e.g. adenine, guanine), indazolyl, pyrazolopyrimidinyl, triazolopyrimidinyl, and pyrazolopyridinyl groups.
Particular examples ofbicyclic heteroaryl groups containing two fused six membered rings include but are not limited to quinolinyl, isoquinolinyl, pyridopyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, naphthyridinyl, and pteridinyl groups. Particular heteroaryl groups are those derived from thiophenyl, pyrrolyl, benzothiophenyl, benzofuranyl, indolyl, pyridinyl, quinolinyl, imidazolyl, oxazolyl and pyrazinyl.
'Hydroxyl' refers to the radical -OH.
Όco' refers to the radical =0.
'Substituted' refers to a group in which one or more hydrogen atoms are each independently replaced with the same or different substituent(s). As used herein, term 'substituted with one or more' refers to one to four substituents. In one embodiment it refers to one to three substituents. In further embodiments it refers to one or two substituents. In a yet further embodiment it refers to one substituent.
The term 'substituent', which may be present on alkyl or heteroalkyi radicals, as well as those groups referred to as alkylene, alkenyl, heteroalkylene, heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl and heterocycloalkenyl, or on other groups indicated as "optionally substituted", can be a variety of groups selected from: -C1-5 alkyl, -OR', =0, =NR'
= N-OR' -NR'R", -SR', halogen, -0C(0)R' -C(0)R', -C02R', -CONR'R", - 0C(0)NR'R", -NR"C(0)R', -NR'C(0)NR"R"', -NR'S02NR"R"', -NR"C02R', -NR'C(NR"R"') = NRiv, -SiR'R"R'", -S(0)R', -S02R', -S02NR R", -NR"S02R', -CN, -(C2-Cs)alkynyl, -(C2-Cs)alkenyl, and -N02, in a number ranging from zero to three, with those groups having zero, one or two substituents being particularly preferred. Other suitable substituents include aryl and heteroaryl groups. R', R", R'" and RIV each independently refer to hydrogen, unsubstituted (Ci-C3)alkyl and (C - C3)heteroalkyl, unsubstituted aryl, aryl substituted with one to three halogens, unsubstituted (Ci-C )-alkyl, (Ci- C4)-alkoxy or (Ci-C )-thioalkoxy groups, halo(Ci-C )alkyl, or aryl-(Ci-C )alkyl groups. When R' and R" are attached to the same nitrogen atom, they can be combined with the nitrogen atom to form a 5-, 6- or 7-membered ring. For example, -NR'R" is meant to include 1-pyrrolidinyl and 4- morpholinyl.
Sulfo' or 'sulfonic acid' refers to a radical such as -S03H.
'Thiol' refers to the group -SH.
Thioalkoxy' refers to the group -S-alkyl where the alkyl group has the number of carbon atoms specified. In particular the term refers to the group -S-Ci-6 alkyl. Particular thioalkoxy groups are thiomethoxy, thioethoxy, n-thiopropoxy, isothiopropoxy, n-thiobutoxy, tert-thiobutoxy, secthiobutoxy, n-thiopentoxy, n-thiohexoxy, and 1,2-dimethylthiobutoxy. Particular thioalkoxy groups are lower thioalkoxy, i.e. with between 1 and 6 carbon atoms. Further particular alkoxy groups have between 1 and 4 carbon atoms.
One having ordinary skill in the art of organic synthesis will recognize that the maximum number of heteroatoms in a stable chemically feasible heterocyclic ring, whether it is aromatic or non aromatic, is determined by the size of the ring, the degree of unsaturation and the valence of the heteroatoms. In general, a heterocyclic ring may have one to four heteroatoms so long as the heteroaromatic ring is chemically feasible and stable.
'Pharmaceutically acceptable' means approved or approvable by a regulatory agency of the Federal or a state government or the corresponding agency in countries other than the United States, or that is listed in the U.S. Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, and more particularly, in humans.
'Pharmaceutically acceptable salt' refers to a salt of a compound of the invention that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound. In particular, such salts are non-toxic may be inorganic or organic acid addition salts and base addition salts. Specifically, such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-( 4- hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4- chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]-oct-2-ene-l-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like; or (2) salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g. an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine and the like. Salts further include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; and when the compound contains a basic functionality, salts of non-toxic organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate and the like.
The term 'pharmaceutically acceptable cation' refers to an acceptable cationic counter-ion of an acidic functional group. Such cations are exemplified by sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium cations, and the like.
'Pharmaceutically acceptable vehicle' refers to a diluent, adjuvant, excipient or carrier with which a compound of the invention is administered.
'Prodrugs' refers to compounds, including derivatives of the compounds of the invention, which have cleavable groups and become by solvolysis or under physiological conditions the compounds of the invention which are pharmaceutically active in viva. Such examples include, but are not limited to, choline ester derivatives and the like, N-alkylmorpholine esters and the like.
'Solvate' refers to forms of the compound that are associated with a solvent, usually by a solvolysis reaction. This physical association includes hydrogen bonding. Conventional solvents include water, EtOH, acetic acid and the like. The compounds of the invention may be prepared e.g. in crystalline form and may be solvated or hydrated. Suitable solvates include pharmaceutically acceptable solvates, such as hydrates, and further include both stoichiometric solvates and non-stoichiometric solvates. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. 'Solvate' encompasses both solution-phase and isolable solvates. Representative solvates include hydrates, ethanolates and methanolates.
'Subject' includes humans, where the terms 'human', 'patient' and 'subject' are used interchangeably herein.
'Effective amount' means the amount of a compound of the invention that, when administered to a subject for treating a disease, is sufficient to effect such treatment for the disease. The "effective amount" can vary depending on the compound, the disease and its severity, and the age, weight, etc., of the subject to be treated. 'Preventing' or 'prevention' refers to a reduction in risk of acquiring or developing a disease or disorder (i.e. causing at least one of the clinical symptoms of the disease not to develop in a subject that may be exposed to a disease-causing agent, or predisposed to the disease in advance of disease onset.
The term 'prophylaxis' is related to 'prevention', and refers to a measure or procedure the purpose of which is to prevent, rather than to treat or cure a disease.
'Treating' or 'treatment' of any disease or disorder refers, in one embodiment, to ameliorating the disease or disorder (i.e. arresting the disease or reducing the manifestation, extent or severity of at least one of the clinical symptoms thereof). In another embodiment 'treating' or 'treatment' refers to ameliorating at least one physical parameter, which may not be discernible by the subject. In yet another embodiment, 'treating' or 'treatment' refers to modulating the disease or disorder, either physically, (e.g. stabilization of a discernible symptom), physiologically, (e.g. stabilization of a physical parameter), or both. In a further embodiment, "treating" or "treatment" relates to slowing the progression of the disease.
As used herein the term 'fibrotic diseases' refers to diseases characterized by excessive scarring due to excessive production, deposition, and contraction of extracellular matrix, and are that are associated with the abnormal accumulation of cells and/or fibronectin and/or collagen and/or increased fibroblast recruitment and include but are not limited to fibrosis of individual organs or tissues such as the heart, kidney, liver, joints, lung, pleural tissue, peritoneal tissue, skin, cornea, retina, musculoskeletal and digestive tract. In particular, the term fibrotic diseases refers to idiopathic pulmonary fibrosis (IPF) ; cystic fibrosis, other diffuse parenchymal lung diseases of different etiologies including iatrogenic drug-induced fibrosis, occupational and/or environmental induced fibrosis, granulomatous diseases (sarcoidosis, hypersensitivity pneumonia), collagen vascular disease, alveolar proteinosis, Langerhans cell granulomatosis, lymphangioleiomyomatosis, inherited diseases (Hermansky-Pudlak Syndrome, tuberous sclerosis, neurofibromatosis, metabolic storage diseases, familial interstitial lung disease); radiation induced fibrosis; chronic obstructive pulmonary disease; scleroderma; bleomycin induced pulmonary fibrosis; chronic asthma; silicosis; asbestos induced pulmonary fibrosis; acute respiratory distress syndrome (ARDS); kidney fibrosis; tubulointerstitium fibrosis; glomerular nephritis; diabetic nephropathy, focal segmental glomerular sclerosis; IgA nephropathy; hypertension; Alport; gut fibrosis; liver fibrosis; cirrhosis; alcohol induced liver fibrosis; toxic/drug induced liver fibrosis; hemochromatosis; alcoholic steato hepatitis (ASH), nonalcoholic steatohepatitis (NASH), nonalcoholic fatty liver disease (NAFLD); cholestasis, biliary duct injury; primary sclerosing cholangitis (PSC), primary biliary cirrhosis (PBC); infection induced liver fibrosis; viral induced liver fibrosis; and autoimmune hepatitis; corneal scarring; hypertrophic scarring; Dupuytren disease, keloids, cutaneous fibrosis; cutaneous scleroderma; systemic sclerosis, spinal cord injury/fibrosis; myelofibrosis; Duchenne muscular dystrophy (DMD) associated musculoskeletal fibrosis, vascular restenosis; atherosclerosis; arteriosclerosis; W egener's granulomatosis; Peyronie's disease, or chronic lymphocytic. More particularly, the term "fibrotic diseases" refers to idiopathic pulmonary fibrosis (IPF), Dupuytren disease, nonalcoholic steatohepatitis (NASH), nonalcoholic fatty liver disease (NAFLD), Alcoholic steato hepatitis, (ASH), portal hypertension, systemic sclerosis, renal fibrosis, and cutaneous fibrosis. Most particularly, the term "fibrotic diseases" refers to nonalcoholic steatohepatitis (NASH), and/or nonalcoholic fatty liver disease (NAFLD). Alternatively, most particularly, the term "fibrotic diseases" refers to IPF.
'Compound(s) of the invention', and equivalent expressions, are meant to embrace compounds of the Formula(e) as herein described, which expression includes the pharmaceutically acceptable salts, and the solvates, e.g. hydrates, and the solvates of the pharmaceutically acceptable salts where the context so permits. Similarly, reference to intermediates, whether or not they themselves are claimed, is meant to embrace their salts, and solvates, where the context so permits.
When ranges are referred to herein, for example but without limitation, C1-7 alkyl, the citation of a range should be considered a representation of each member of said range.
Other derivatives of the compounds of this invention have activity in both their acid and acid derivative forms, but the acid sensitive form often offers advantages of solubility, tissue compatibility, or delayed release in the mammalian organism (Bundgard, H, 1985). Prodrugs include acid derivatives well known to practitioners of the art, such as, for example, esters prepared by reaction of the parent acid with a suitable alcohol, or amides prepared by reaction of the parent acid compound with a substituted or unsubstituted amine, or acid anhydrides, or mixed anhydrides. Simple aliphatic or aromatic esters, amides and anhydrides derived from acidic groups pendant on the compounds of this invention are particularly useful prodrugs. In some cases it is desirable to prepare double ester type prodrugs such as (acyloxy)alkyl esters or ((alkoxycarbonyl)oxy)alkylesters. Particular such prodrugs are the C1-7 alkyl, C2-8 alkenyl, C6-io optionally substituted aryl, and (C6-io aryl)-(Ci- alkyl) esters of the compounds of the invention.
The present disclosure includes all isotopic forms of the compounds of the invention provided herein, whether in a form (i) wherein all atoms of a given atomic number have a mass number (or mixture of mass numbers) which predominates in nature (referred to herein as the "natural isotopic form") or (ii) wherein one or more atoms are replaced by atoms having the same atomic number, but a mass number different from the mass number of atoms which predominates in nature (referred to herein as an "unnatural variant isotopic form"). It is understood that an atom may naturally exists as a mixture of mass numbers. The term "unnatural variant isotopic form" also includes embodiments in which the proportion of an atom of given atomic number having a mass number found less commonly in nature (referred to herein as an "uncommon isotope") has been increased relative to that which is naturally occurring e.g. to the level of >20%, >50%, >75%, >90%, >95% or> 99% by number of the atoms of that atomic number (the latter embodiment referred to as an "isotopically enriched variant form"). The term "unnatural variant isotopic form" also includes embodiments in which the proportion of an uncommon isotope has been reduced relative to that which is naturally occurring. Isotopic forms may include radioactive forms (i.e. they incorporate radioisotopes) and non-radioactive forms. Radioactive forms will typically be isotopically enriched variant forms.
An unnatural variant isotopic form of a compound may thus contain one or more artificial or uncommon isotopes such as deuterium (2H or D), carbon-11 (1 1C), carbon-13 (13C), carbon-14 (14C), nitrogen-13 (13N), nitrogen-15 (15N), oxygen-15 (150), oxygen-17 (170), oxygen-18 (1 80), phosphorus-32 (32P), sulphur-35 (35S), chlorine-36 (36CI), chlorine-37 (37CI), fluorine-18 (1 8F) iodine-123 (1 231), iodine-125 (1 251) in one or more atoms or may contain an increased proportion of said isotopes as compared with the proportion that predominates in nature in one or more atoms.
Unnatural variant isotopic forms comprising radioisotopes may, for example, be used for drug and/or substrate tissue distribution studies. The radioactive isotopes tritium, i.e. 3H, and carbon- 14, i.e. 14C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection. Unnatural variant isotopic forms which incorporate deuterium i.e 2H or D may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in viva halflife or reduced dosage requirements, and hence may be preferred in some circumstances. Further, unnatural variant isotopic forms may be prepared which incorporate positron emitting isotopes, such as 11C, 18F, 150 and 13N, and would be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.
It is also to be understood that compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed 'isomers'. Isomers that differ in the arrangement of their atoms in space are termed 'stereoisomers'.
Stereoisomers that are not mirror images of one another are termed 'diastereomers' and those that are non-superimposable mirror images of each other are termed 'enantiomers'. When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible. An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e. as (+)- or (-)-isomers respectively). A chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a 'racemic mixture'. 'Tautomers' refer to compounds that are interchangeable forms of a particular compound structure, and that vary in the displacement of hydrogen atoms and electrons. Thus, two structures may be in equilibrium through the movement of n electrons and an atom (usually H). For example, enols and ketones are tautomers because they are rapidly interconverted by treatment with either acid or base. Another example of tautomerism is the aci- and nitro- forms of phenylnitromethane that are likewise formed by treatment with acid or base. Tautomeric forms may be relevant to the attainment of the optimal chemical reactivity and biological activity of a compound of interest.
The compounds of the invention may possess one or more asymmetric centers; such compounds can therefore be produced as individual (R)- or (S)- stereoisomers or as mixtures thereof. Unless indicated otherwise, the description or naming of a particular compound in the specification and claims is intended to include both individual enantiomers and mixtures, racemic or otherwise, thereof. The methods for the determination of stereochemistry and the separation of stereoisomers are well-known in the art.
It will be appreciated that compounds of the invention may be metabolized to yield biologically active metabolites.
DETAILED DESCRIPTION
The inventors have found that the compounds of the present invention are useful for modulating the GPR84 receptor, a G-protein-coupled receptor which may be useful in the treatment of inflammatory or diabetic disease. The compounds can be used in a pharmaceutical composition, which further comprises a pharmaceutically acceptable carrier, excipient or diluent. The pharmaceutical composition of the invention can be used in the treatment of inflammatory or diabetic disease such as for the treatment of fibrosis in the kidney, liver, lung, pancreas and skin.
The present invention pertains to a compound of the formula I:
Figure imgf000015_0001
(formula I) wherein
• X is -NH-, -0-, -S- or is absent;
. A is -(Al)j-(Bl)k-(A2)r(B2)m-H, wherein o A1 and A2 independently are C1-7 alkylene, C2-7 alkenylene, C2-7 alkynylene, or C1-7 heteroalkylene, optionally substituted with one or two of independently selected Ul; o B1 and B2 are independently an aliphatic ring, an aromatic ring or a fused ring, optionally substituted with one or two of independently selected U2; H is hydrogen; o j, k, I, and m are independently 0 or 1;
. Y is -OCH2-, -N(R')CH2-, -CH2CH2-, -CH2-, -NCR')-, or -0-, where R' is hydrogen or C1-C3 alkyl; and
• R is an aromatic ring, an aromatic ring comprising nitrogen, an aliphatic ring or a fused ring, optionally substituted with one, two or three of independently selected U3;
• Ul, U2 and U3 are independently hydrogen, -CF3, C1-3 alkyl, C1-3 haloalkyl, C2-4 heteroalkyl, halogen, =0, =NR' =N-OR' -NR'R", -SR', -CN, C2-5 alkynyl, C2-5 alkenyl, C3-5 cycloalkyl, C3-5 heterocycloalkyl and -NO2, where R', R", R'" and R"" independently refer to hydrogen, unsubstituted C1-3 alkyl and C2-3 heteroalkyl that can be connected by bonds to form rings, cycloalkyl or heterocycloalkyl; or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a solvate of the pharmaceutically acceptable salt thereof. In a second aspect, the compound of formula I pertains to:
Figure imgf000016_0001
(formula I) wherein
X is -NH-, -0-, -S- or is absent; A is
-A1-B1-A2-B2-H;
-A1-B1-A2-H;
-B1-A2-H;
-A1-B2-H; or
-A1-A2-H; where A1 and A2 are independently C1-7 alkylene, C1-7 alkenylene, C1-7 alkynylene or C1-7 heteroalkylene; B1 is an aliphatic ring, an aromatic ring or a fused ring; B2 is an aliphatic ring, an aromatic ring or a fused ring, and H is hydrogen; Y is -OCH2-, -N(R')CH2-, -CH2CH2-, -CH2-, -NCR')-, or -0-, where R' is hydrogen or C1-C3 alkyl; and
R is
• an aromatic ring comprising nitrogen, an aliphatic ring or a fused ring, where the ring is optionally substituted with -CF3, C1-3 alkyl, C2-4 heteroalkyl or
Figure imgf000017_0001
the ring is optionally substituted with -CF3, C1-3 alkyl, C2-4 heteroalkyl, wherein Z is -0-, -CH2-, -NH- or N-(CH2)0-2-CH3, o W is -0- or -CH2-; and o n is 0, 1 or 2; or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a solvate of the pharmaceutically acceptable salt thereof.
The invention comprises compounds that can treat diseases by modulating GPR84-mediated signaling, in particular reducing GPR84-mediated signaling by acting as antagonists, partial agonists or inverse agonists at GPR84.
According to one embodiment, the compounds of the invention provide a new class of GPR84 antagonists that modulate the decanoic acid binding site; in contrast to the antagonist ligands previously reported by Mahmud et. al. (2017) that are believed to bind at a site that is distinct from the decanoic acid and DIM agonist binding sites. The compounds of the invention have the advantage that they are small and ionizable which potentially results in a better uptake of the compounds and a better distribution of the compounds in the body.
In one embodiment of the invention, X is -NH-, -S-, -0-, or is absent.
In a preferred embodiment of the invention, X is -NH- or is absent. In one embodiment of the invention, A is -A1-B1-A2-B2-H, where Al is C1-7 alkylene, C1-7 alkenylene, C1-7 alkynylene or C1-7 heteroalkylene, A2 is C1-7 alkylene, C1-7 alkenylene, C1-7 alkynylene or C1-7 heteroalkylene, B1 is an aliphatic ring, an aromatic ring or a fused ring, and B2 is an aliphatic ring, an aromatic ring or a fused ring, and H is hydrogen. Preferably, A is Al-Bl- A2-B2-H, where Al is C1-5 alkylene, C1-5 alkenylene, C1-5 alkynylene or C1-5 heteroalkylene, A2 is Ci-5 alkyl, C1-5 alkenyl, C1-5 alkynylene or C1-5 heteroalkylene, B1 is an aliphatic ring, an aromatic ring or a fused ring, and B2 is an aliphatic ring, an aromatic ring or a fused ring. More preferably, A is -A1-B1-A2-B2-H, where A1 is C1-5 alkylene, C1-5 alkenylene, C1-5 alkynylene or C1-5 heteroalkylene, A2 is C1-5 alkyl, C1-5 alkenyl, C1-5 alkynyl or C1-5 heteroalkylene, B1 is -(C6H4)- and B2 is -(C6H4)-.
In another embodiment of the invention, A is -A1-B1-A2-H, where A1 is C1-7 alkylene, C1-7 alkenylene, C1-7 alkynylene or C1-7 heteroalkylene, A2 is C1-7 alkylene, C1-7 alkenylene, C1-7 alkynylene or C1-7 heteroalkylene, and B1 is an aliphatic ring, an aromatic ring or a fused ring, and H is hydrogen. Preferably, A is -A1-B1-A2-H, where A1 is C1-5 alkylene, C1-5 alkenylene, C1-5 alkynylene or C1-5 heteroalkylene, A2 is C1-5 alkyl, C1-5 alkenyl, C1-5 alkynylene or C1-5 heteroalkylene, and B1 is an aliphatic ring, an aromatic ring or a fused ring. More preferably, A is -A1-B1-A2, where A1 is C1-5 alkylene, C1-5 alkenylene, C1-5 alkynylene or C1-5 heteroalkylene, A2 is Ci-5 alkyl, C1-5 alkenyl, C1-5 alkynylene or C1-5 heteroalkylene and B1 is -(C6H4)-. In a most preferred embodiment, A is -A1-B1-A2-H is -(CH2)2-(C6H4)-(CH2)2-CH3.
In another embodiment, A is -B1-A2-H, where A2 is C1-7 alkylene, C1-7 alkenylene, C1-7 alkynylene or C1-7 heteroalkylene, and B1 is an aliphatic ring, an aromatic ring or a fused ring, and H is hydrogen. Preferably, A is -B1-A2-H, where A2 is C1-5 alkyl, C1-5 alkenyl, C1-5 alkynylene or Ci-5 heteroalkylene and B1 is an aliphatic ring, an aromatic ring or a fused ring. More preferably, A is -B1-A2-H, where A2 is C1-5 alkyl, C1-5 alkenyl, C1-5 alkynylene or C1-5 heteroalkylene and B1 is -(C6H4)-.
In another embodiment, A is -A1-B2-H, where A1 is C1-7 alkylene, C1-7 alkenylene, C1-7 alkynylene or C1-7 heteroalkylene and B2 is an aliphatic ring, an aromatic ring or a fused ring, and H is hydrogen. Preferably, A is -A1-B2-H, where A1 is C1-5 alkyl, C1-5 alkenyl, C1-5 alkynylene or Ci-5 heteroalkylene and B2 is an aliphatic ring, an aromatic ring or a fused ring. More preferably, A is -A1-B2-H, where A1 is C1-5 alkyl, C1-5 alkenyl, C1-5 alkynylene or C1-5 heteroalkylene and B2 is -(C6H4)-.
In another embodiment, A is -A1-A2-H, where A1 is C1-7 alkylene, C1-7 alkenylene, C1-7 alkynylene or C1-7 heteroalkylene and A2 is C1-7 alkylene, C1-7 alkenylene, C1-7 alkynylene or C1-7 heteroalkylene, and H is hydrogen. In a preferred embodiment of the invention, A is -A1-A2-H, where A1 is C1-5 alkylene or C1-5 alkenylene and A2 is C1-5 alkylene or C1-5 alkenylene, or more preferred A1 is C1-5 alkylene and A2 is C1-5 alkylene. In a most preferred embodiment of the invention, -A is -(OH2)8-OH3.
In one embodiment, X is absent and A is -A1-B1-A2-B2-H, where A1 is C1-7 alkylene, C1-7 alkenylene, C1-7 alkynylene or C1-7 heteroalkylene, A2 is C1-7 alkylene, C1-7 alkenylene, C1-7 alkynylene or C1-7 heteroalkylene, B1 is an aliphatic ring, an aromatic ring or a fused ring, and B2 is an aliphatic ring, an aromatic ring or a fused ring, and H is hydrogen. Preferably, X is absent and A is A1-B1-A2-B2-H, where A1 is C1-5 alkylene, C1-5 alkenylene, C1-5 alkynylene or C1-5 heteroalkylene, A2 is C1-5 alkyl, C1-5 alkenyl, C1-5 alkynylene or C1-5 heteroalkylene, B1 is an aliphatic ring, an aromatic ring or a fused ring, and B2 is an aliphatic ring, an aromatic ring or a fused ring. More preferably, X is absent and A is -A1-B1-A2-B2-H, where A1 is C1-5 alkylene, C1-5 alkenylene, C1-5 alkynylene or C1-5 heteroalkylene, A2 is C1-5 alkyl, C1-5 alkenyl, C1-5 alkynyl or Ci- 5 heteroalkylene, B1 is -(C6H4)- and B2 is -(C6H4)-.
In one embodiment, X is absent and A is -A1-B1-A2-H, where A1 is C1-7 alkylene, C1-7 alkenylene, Ci-7 alkynylene or C1-7 heteroalkylene, A2 is C1-7 alkylene, C1-7 alkenylene, C1-7 alkynylene or C1-7 heteroalkylene, and B1 is an aliphatic ring, an aromatic ring or a fused ring, and H is hydrogen. Preferably, X is absent and A is -A1-B1-A2-H, where A1 is C1-5 alkylene, C1-5 alkenylene, C1-5 alkynylene or C1-5 heteroalkylene, A2 is C1-5 alkyl, C1-5 alkenyl, C1-5 alkynylene or C1-5 heteroalkylene, and B1 is an aliphatic ring, an aromatic ring or a fused ring. More preferably, X is absent and A is -A1-B1-A2, where A1 is C1-5 alkylene, C1-5 alkenylene, C1-5 alkynylene or C1-5 heteroalkylene, A2 is C1-5 alkyl, C1-5 alkenyl, C1-5 alkynylene or C1-5 heteroalkylene and B1 is - (C6H4)-. Preferred embodiments of -X-A are -(CH2)2-(C6H4)-(CH2)i-CH3, -(CH2)2-(C6H4)-(CH2)2- CH3, -(CH2)2-(C6H4)-(CH2)3-CH3, -(CH2)I-(C6H4)-(CH2)2-CH3, -(CH2)3-(C6H4)-(CH2)2-CH3, -(CH2)I- (C6H4)-(CH2)I-CH3, -(CH2)I-(C6H4)-(CH2)3-CH3, -(CH2)3-(C6H4)-(CH2)I-CH3 and -(CH2)3-(C6H4)- (CH2)2-CH3. In a most preferred embodiment of the invention, -X-A is -(CH2)2-(C6H4)-(CH2)2-CH3.
In another embodiment, X is absent and A is B1-A2, where A2 is C1-7 alkylene, C1-7 alkenylene, Ci-7 alkynylene or C1-7 heteroalkylene, and B1 is an aliphatic ring, an aromatic ring or a fused ring, and H is hydrogen. Preferably, X is absent and A is -B1-A2-H, where A2 is C1-5 alkyl, C1-5 alkenyl, C1-5 alkynylene or C1-5 heteroalkylene and B1 is an aliphatic ring, an aromatic ring or a fused ring. More preferably, X is absent and A is -B1-A2-H, where A2 is C1-5 alkyl, C1-5 alkenyl, Ci- 5 alkynylene or C1-5 heteroalkylene and B1 is -(C6H4)-.
In another embodiment, X is absent and A is -A1-B2-H, where A1 is C1-7 alkylene, C1-7 alkenylene, C1-7 alkynylene or C1-7 heteroalkylene and B2 is an aliphatic ring, an aromatic ring or a fused ring, and H is hydrogen. Preferably, X is absent and A is -A1-B2-H, where A1 is C1-5 alkyl, Ci-5 alkenyl, C1-5 alkynylene or C1-5 heteroalkylene and B2 is an aliphatic ring, an aromatic ring or a fused ring. More preferably, X is absent and A is -A1-B2-H, where A1 is C1-5 alkyl, C1-5 alkenyl, Ci-5 alkynylene or C1-5 heteroalkylene and B2 is -(C6H4)-.
In another embodiment, X is absent and A is -A1-A2-H, where A1 is C1-7 alkylene, C1-7 alkenylene, C1-7 alkynylene or C1-7 heteroalkylene and A2 is C1-7 alkylene, C1-7 alkenylene, C1-7 alkynylene or C1-7 heteroalkylene, and H is hydrogen. In a preferred embodiment of the invention, X is absent and A is -A1-A2-H, where A1 is C1-5 alkylene or C1-5 alkenylene and A2 is Ci-5 alkylene or C1-5 alkenylene, or more preferred X is absent and A1 is C1-5 alkylene and A2 is Ci-5 alkylene. Preferred embodiment of -X-A are -(CH2)5-CH3, -(CH2)6-CH3, -(CH2)7-CH3, -(CH2)8- CH , -(CH2)9-CH3 and -(CH2)IO-CH . In a most preferred embodiment of the invention, -X-A is - (CH2)8-CH3.
In one embodiment, X is -NH- and A is -A1-B1-A2-B2-H, where A1 is C1-7 alkylene, C1-7 alkenylene, C1-7 alkynylene or C1-7 heteroalkylene, A2 is C1-7 alkylene, C1-7 alkenylene, C1-7 alkynylene or C1-7 heteroalkylene, B1 is an aliphatic ring, an aromatic ring or a fused ring, and B2 is an aliphatic ring, an aromatic ring or a fused ring, and H is hydrogen. Preferably, X is -NH- and A is A1-B1-A2-B2-H, where A1 is C1-5 alkylene, C1-5 alkenylene, C1-5 alkynylene or C1-5 heteroalkylene, A2 is C1-5 alkyl, C1-5 alkenyl, C1-5 alkynylene or C1-5 heteroalkylene, B1 is an aliphatic ring, an aromatic ring or a fused ring, and B2 is an aliphatic ring, an aromatic ring or a fused ring. More preferably, X is -NH- and A is -A1-B1-A2-B2-H, where A1 is C1-5 alkylene, C1-5 alkenylene, C1-5 alkynylene or C1-5 heteroalkylene, A2 is C1-5 alkyl, C1-5 alkenyl, C1-5 alkynyl or Ci- 5 heteroalkylene, B1 is -(C6H4)- and B2 is -(C6H4)-.
In one embodiment, X is -NH- and A is -A1-B1-A2-H, where A1 is C1-7 alkylene, C1-7 alkenylene, Ci-7 alkynylene or C1-7 heteroalkylene, A2 is C1-7 alkylene, C1-7 alkenylene, C1-7 alkynylene or C1-7 heteroalkylene, and B1 is an aliphatic ring, an aromatic ring or a fused ring, and H is hydrogen. Preferably, X is -NH- and A is -A1-B1-A2-H, where A1 is C1-5 alkylene, C1-5 alkenylene, C1-5 alkynylene or C1-5 heteroalkylene, A2 is C1-5 alkyl, C1-5 alkenyl, C1-5 alkynylene or C1-5 heteroalkylene, and B1 is an aliphatic ring, an aromatic ring or a fused ring. More preferably, X is -NH- and A is -A1-B1-A2, where A1 is C1-5 alkylene, C1-5 alkenylene, C1-5 alkynylene or C1-5 heteroalkylene, A2 is C1-5 alkyl, C1-5 alkenyl, C1-5 alkynylene or C1-5 heteroalkylene and B1 is - (C6H4)-. Preferred embodiments of -X-A are -NH-(CH2)2-(C6H4)-(CH2)I-CH3, -NH-(CH2)2-(C6H4)- (CH2)2-CH3, -NH-(CH2)2-(C6H4)-(CH2)3-CH3, -NH-(CH2)I-(C6H4)-(CH2)2-CH3, -NH-(CH2)3-(C6H4)- (CH2)2-CH3, -NH-(CH2)I-(C6H4)-(CH2)I-CH3, -NH-(CH2)I-(C6H4)-(CH2)3-CH3, -NH-(CH2)3-(C6H4)- (CH2)I-CH3 and -NH-(CH2)3-(C6H4)-(CH2)2-CH3.
In another embodiment, X is -NH- and A is B1-A2, where A2 is C1-7 alkylene, C1-7 alkenylene, Ci- 7 alkynylene or C1-7 heteroalkylene, and B1 is an aliphatic ring, an aromatic ring or a fused ring, and H is hydrogen. Preferably, X is -NH- and A is -B1-A2-H, where A2 is C1-5 alkyl, C1-5 alkenyl, Ci-5 alkynylene or C1-5 heteroalkylene and B1 is an aliphatic ring, an aromatic ring or a fused ring. More preferably, X is -NH- and A is -B1-A2-H, where A2 is C1-5 alkyl, C1-5 alkenyl, C1-5 alkynylene or Ci-5 heteroalkylene and B1 is -(C6H4)-.
In another embodiment, X is -NH- and A is -A1-B2-H, where A1 is C1-7 alkylene, C1-7 alkenylene, Ci-7 alkynylene or C1-7 heteroalkylene and B2 is an aliphatic ring, an aromatic ring or a fused ring, and H is hydrogen. Preferably, X is -NH- and A is -A1-B2-H, where A1 is C1-5 alkyl, C1-5 alkenyl, Ci-5 alkynylene or C1-5 heteroalkylene and B2 is an aliphatic ring, an aromatic ring or a fused ring. More preferably, X is -NH- and A is -A1-B2-H, where A1 is C1-5 alkyl, C1-5 alkenyl, C1-5 alkynylene or Ci-5 heteroalkylene and B2 is -(C6H4)-. In another embodiment, X is -NH- and A is -A1-A2-H, where A1 is C1-7 alkylene, C1-7 alkenylene, Ci-7 alkynylene or C1-7 heteroalkylene and A2 is C1-7 alkylene, C1-7 alkenylene, C1-7 alkynylene or Ci-7 heteroalkylene, and H is hydrogen. In a preferred embodiment of the invention, X is -NH- and A is -A1-A2-H, where A1 is C1-5 alkylene or C1-5 alkenylene and A2 is C1-5 alkylene or C1-5 alkenylene, or more preferred X is -NH- and A1 is C1-5 alkylene and A2 is C1-5 alkylene. Preferred embodiment of -X-A are -NH-(CH2)5-CH3, -NH-(CH2)6-CH3, -NH-(CH2)7-CH3, -NH-(CH2)8-CH3, - NH-(CH2)g-CH and -NH-(CH2)I0-CH . In a most preferred embodiment of the invention, -X-A is - NH-(CH2)7-CH3.
In one embodiment, X is -0- and A is -A1-B1-A2-B2-H, where A1 is C1-7 alkylene, C1-7 alkenylene, Ci-7 alkynylene or C1-7 heteroalkylene, A2 is C1-7 alkylene, C1-7 alkenylene, C1-7 alkynylene or C1-7 heteroalkylene, B1 is an aliphatic ring, an aromatic ring or a fused ring, and B2 is an aliphatic ring, an aromatic ring or a fused ring, and H is hydrogen. Preferably, X is -0- and A is A1-B1-A2- B2-H, where A1 is C1-5 alkylene, C1-5 alkenylene, C1-5 alkynylene or C1-5 heteroalkylene, A2 is C1-5 alkyl, C1-5 alkenyl, C1-5 alkynylene or C1-5 heteroalkylene, B1 is an aliphatic ring, an aromatic ring or a fused ring, and B2 is an aliphatic ring, an aromatic ring or a fused ring. More preferably, X is -0- and A is -A1-B1-A2-B2-H, where A1 is C1-5 alkylene, C1-5 alkenylene, C1-5 alkynylene or C1-5 heteroalkylene, A2 is C1-5 alkyl, C1-5 alkenyl, C1-5 alkynyl or C1-5 heteroalkylene, B1 is -(C6H4)- and B2 is -(C6H4)-.
In one embodiment, X is -0- and A is -A1-B1-A2-H, where A1 is C1-7 alkylene, C1-7 alkenylene, Ci-7 alkynylene or C1-7 heteroalkylene, A2 is C1-7 alkylene, C1-7 alkenylene, C1-7 alkynylene or C1-7 heteroalkylene, and B1 is an aliphatic ring, an aromatic ring or a fused ring, and H is hydrogen. Preferably, X is -0- and A is -A1-B1-A2-H, where A1 is C1-5 alkylene, C1-5 alkenylene, C1-5 alkynylene or C1-5 heteroalkylene, A2 is C1-5 alkyl, C1-5 alkenyl, C1-5 alkynylene or C1-5 heteroalkylene, and B1 is an aliphatic ring, an aromatic ring or a fused ring. More preferably, X is -0- and A is -A1-B1-A2, where A1 is C1-5 alkylene, C1-5 alkenylene, C1-5 alkynylene or C1-5 heteroalkylene, A2 is C1-5 alkyl, C1-5 alkenyl, C1-5 alkynylene or C1-5 heteroalkylene and B1 is - (C6H4)-. Preferred embodiments of -X-A are -0-(CH2)2-(C6H4)-(CH2)i-CH3, -0-(CH2)2-(C6H4)- (CH2)2-CH3, -0-(CH2)2-(C6H4)-(CH2)3-CH3, -0-(CH2)I-(C6H4)-(CH2)2-CH3, -0-(CH2)3-(C6H4)-
(CH2)2-CH3, -0-(CH2)I-(C6H4)-(CH2)I-CH3, -0-(CH2)I-(C6H4)-(CH2)3-CH3, -0-(CH2)3-(C6H4)-
(CH2)I-CH3 and -0-(CH2)3-(C6H4)-(CH2)2-CH3.
In another embodiment, X is -0- and A is B1-A2, where A2 is C1-7 alkylene, C1-7 alkenylene, C1-7 alkynylene or C1-7 heteroalkylene, and B1 is an aliphatic ring, an aromatic ring or a fused ring, and H is hydrogen. Preferably, X is -0- and A is -B1-A2-H, where A2 is C1-5 alkyl, C1-5 alkenyl, C1-5 alkynylene or C1-5 heteroalkylene and B1 is an aliphatic ring, an aromatic ring or a fused ring. More preferably, X is -0- and A is -B1-A2-H, where A2 is C1-5 alkyl, C1-5 alkenyl, C1-5 alkynylene or Ci-5 heteroalkylene and B1 is -(C6H4)-. In another embodiment, X is -0- and A is -A1-B2-H, where A1 is C1-7 alkylene, C1-7 alkenylene, Ci-7 alkynylene or C1-7 heteroalkylene and B2 is an aliphatic ring, an aromatic ring or a fused ring, and H is hydrogen. Preferably, X is -0- and A is -A1-B2-H, where A1 is C1-5 alkyl, C1-5 alkenyl, C1-5 alkynylene or C1-5 heteroalkylene and B2 is an aliphatic ring, an aromatic ring or a fused ring. More preferably, X is -0- and A is -A1-B2-H, where A1 is C1-5 alkyl, C1-5 alkenyl, C1-5 alkynylene or Ci-5 heteroalkylene and B2 is -(C6H4)-.
In another embodiment, X is -0- and A is -A1-A2-H, where A1 is C1-7 alkylene, C1-7 alkenylene, Ci-7 alkynylene or C1-7 heteroalkylene and A2 is C1-7 alkylene, C1-7 alkenylene, C1-7 alkynylene or Ci-7 heteroalkylene, and H is hydrogen. In a preferred embodiment of the invention, X is -0- and A is -A1-A2-H, where A1 is C1-5 alkylene or C1-5 alkenylene and A2 is C1-5 alkylene or C1-5 alkenylene, or more preferred X is -0- and A1 is C1-5 alkylene and A2 is C1-5 alkylene. Preferred embodiment of -X-A are -0-(CH2)5-CH3, -0-(CH2)6-CH3, -0-(CH2)7-CH3, -0-(CH2)8-CH3, -0- (CH2)g-CH3 and -O-(CH2)I0-CH3.
In one embodiment, X is -S- and A is -A1-B1-A2-B2-H, where A1 is C1-7 alkylene, C1-7 alkenylene, Ci-7 alkynylene or C1-7 heteroalkylene, A2 is C1-7 alkylene, C1-7 alkenylene, C1-7 alkynylene or C1-7 heteroalkylene, B1 is an aliphatic ring, an aromatic ring or a fused ring, and B2 is an aliphatic ring, an aromatic ring or a fused ring, and H is hydrogen. Preferably, X is -S- and A is A1-B1-A2- B2-H, where A1 is C1-5 alkylene, C1-5 alkenylene, C1-5 alkynylene or C1-5 heteroalkylene, A2 is C1-5 alkyl, C1-5 alkenyl, C1-5 alkynylene or C1-5 heteroalkylene, B1 is an aliphatic ring, an aromatic ring or a fused ring, and B2 is an aliphatic ring, an aromatic ring or a fused ring. More preferably, X is -S- and A is -A1-B1-A2-B2-H, where A1 is C1-5 alkylene, C1-5 alkenylene, C1-5 alkynylene or C1-5 heteroalkylene, A2 is C1-5 alkyl, C1-5 alkenyl, C1-5 alkynyl or C1-5 heteroalkylene, B1 is -(C6H4)- and B2 is -(C6H4)-.
In one embodiment, X is -S- and A is -A1-B1-A2-H, where A1 is C1-7 alkylene, C1-7 alkenylene, Ci-7 alkynylene or C1-7 heteroalkylene, A2 is C1-7 alkylene, C1-7 alkenylene, C1-7 alkynylene or C1-7 heteroalkylene, and B1 is an aliphatic ring, an aromatic ring or a fused ring, and H is hydrogen. Preferably, X is -S- and A is -A1-B1-A2-H, where A1 is C1-5 alkylene, C1-5 alkenylene, C1-5 alkynylene or C1-5 heteroalkylene, A2 is C1-5 alkyl, C1-5 alkenyl, C1-5 alkynylene or C1-5 heteroalkylene, and B1 is an aliphatic ring, an aromatic ring or a fused ring. More preferably, X is -S- and A is -A1-B1-A2, where A1 is C1-5 alkylene, C1-5 alkenylene, C1-5 alkynylene or C1-5 heteroalkylene, A2 is C1-5 alkyl, C1-5 alkenyl, C1-5 alkynylene or C1-5 heteroalkylene and B1 is - (C6H4)-. Preferred embodiments of -X-A are -S-(CH2)2-(C6H4)-(CH2)I-CH3, -S-(CH2)2-(C6H4)- (CH2)2-CH3, -S-(CH2)2-(C6H4)-(CH2)3-CH3, -S-(CH2)1-(C6H4)-(CH2)2-CH3, -S-(CH2)3-(C6H4)-
(CH2)2-CH3, -S-(CH2)I-(C6H4)-(CH2)I-CH3, -S-(CH2)1-(C6H4)-(CH2)3-CH3, -S-(CH2)3-(C6H4)-
(CH2)I-CH3 and -S-(CH2)3-(C6H4)-(CH2)2-CH3. In another embodiment, X is -S- and A is B1-A2, where A2 is C1-7 alkylene, C1-7 alkenylene, C1-7 alkynylene or C1-7 heteroalkylene, and B1 is an aliphatic ring, an aromatic ring or a fused ring, and H is hydrogen. Preferably, X is -S- and A is -B1-A2-H, where A2 is C1-5 alkyl, C1-5 alkenyl, C1-5 alkynylene or C1-5 heteroalkylene and B1 is an aliphatic ring, an aromatic ring or a fused ring. More preferably, X is -S- and A is -B1-A2-H, where A2 is C1-5 alkyl, C1-5 alkenyl, C1-5 alkynylene or Ci-5 heteroalkylene and B1 is -(C6H4)-.
In another embodiment, X is -S- and A is -A1-B2-H, where A1 is C1-7 alkylene, C1-7 alkenylene, Ci-7 alkynylene or C1-7 heteroalkylene and B2 is an aliphatic ring, an aromatic ring or a fused ring, and H is hydrogen. Preferably, X is -S- and A is -A1-B2-H, where A1 is C1-5 alkyl, C1-5 alkenyl, C1-5 alkynylene or C1-5 heteroalkylene and B2 is an aliphatic ring, an aromatic ring or a fused ring. More preferably, X is -S- and A is -A1-B2-H, where A1 is C1-5 alkyl, C1-5 alkenyl, C1-5 alkynylene or Ci-5 heteroalkylene and B2 is -(C6H4)-.
In another embodiment, X is -S- and A is -A1-A2-H, where A1 is C1-7 alkylene, C1-7 alkenylene, Ci- 7 alkynylene or C1-7 heteroalkylene and A2 is C1-7 alkylene, C1-7 alkenylene, C1-7 alkynylene or C1-7 heteroalkylene, and H is hydrogen. In a preferred embodiment of the invention, X is -S- and A is -A1-A2-H, where A1 is C1-5 alkylene or C1-5 alkenylene and A2 is C1-5 alkylene or C1-5 alkenylene, or more preferred X is -S- and A1 is C1-5 alkylene and A2 is C1-5 alkylene. A preferred embodiment of -X-A are -S-(CH2)5-CH3, -S-(CH2)6-CH3, -S-(CH2)7-CH3, -S-(CH2)8-CH3, -S- (CH2)g-CH3 and -S-(CH2)I0-CH3.
In one embodiment of the invention, Y is -OCH2-, -N(R')CH2-, -CH2CH2-, -CH2-, -N(R')-, or -0-, where R' is hydrogen or Ci-C3 alkyl.
In one embodiment of the invention, R is
• an aromatic ring comprising nitrogen, an aliphatic ring or a fused ring, where the ring is optionally substituted with -CF3, Ci-3 alkyl or C2- heteroalkyl or
Figure imgf000023_0001
, where the ring is optionally substituted with -CF3, Ci-3 alkyl or C2- heteroalkyl; o Wherein Z is -0-, -CH2-, -NH- or N-(CH2)0-2-CH3; o W is -0-, or -CH2-; and o n is 0, 1 or 2. In one embodiment of the invention, R is an aromatic ring comprising nitrogen, preferably the aromatic ring comprises 1, 2 or 3 nitrogen atoms.
In a preferred embodiment the aromatic ring is an aromatic heterocyclic ring having 3 to 5 carbon atoms and 1 to 3 nitrogen atoms, such as an aromatic ring having 3 carbon atoms and 3 nitrogen atoms, or an aromatic ring having 4 carbon atoms and 2 nitrogen atoms or an aromatic ring having 5 carbon atoms and 1 nitrogen atom. In a preferred embodiment the aromatic heterocyclic ring is pyridine, pyrimidine.
In one embodiment of the invention, the aromatic ring can be substituted with -CF3, C1-3 alkyl or C2-4 heteroalkyl. In one embodiment, the aromatic ring is substituted with -(CH2)I-CH3, -(CH2)2- CH3 or -CH3.
In one embodiment, the aromatic ring is an aromatic heterocyclic ring having 3 to 6 carbon atoms and 1 to 3 nitrogen atoms, where the aromatic ring is substituted with -CF3. According to the invention, the aromatic ring substituted with -CF3 can have 3 carbon atoms and 3 nitrogen atoms, 4 carbon atoms and 2 nitrogen atoms or 5 carbon atoms and 1 nitrogen atom. Preferably, the aromatic ring has 5 carbon atoms and 1 nitrogen atom and is substituted with -CF3.
In one embodiment, the aromatic ring is an aromatic heterocyclic ring having 3 to 6 carbon atoms and 1 to 3 nitrogen atoms, where the aromatic ring is substituted with Ci-3 alkyl, e.g. - (CH2)O-2-CH3. The aromatic ring can be substituted with Ci-3 alkyl and can have 3 carbon atoms and 3 nitrogen atoms, 4 carbon atoms and 2 nitrogen atoms or 5 carbon atoms and 1 nitrogen atom. Preferably, the aromatic ring has 5 carbon atoms and 1 nitrogen atom and is substituted with Ci alkyl.
In one embodiment, the aromatic ring is an aromatic heterocyclic ring having 3 to 6 carbon atoms and 1 to 3 nitrogen atoms, where the aromatic ring is substituted with -0-CH3. The aromatic ring can be substituted with C2-4 heteroalkyl and can have 3 carbon atoms and 3 nitrogen atoms, 4 carbon atoms and 2 nitrogen atoms or 5 carbon atoms and 1 nitrogen atom. Preferably, the aromatic ring has 5 carbon atoms and 1 nitrogen atom and is substituted with C2-4 heteroalkyl.
In one embodiment of the invention, Y is -OCH2- and R is an aromatic ring comprising nitrogen, preferably the aromatic ring comprises 1, 2 or 3 nitrogen atoms.
In a preferred embodiment, Y is -OCH2- and the aromatic ring is an aromatic heterocyclic ring having 3 to 6 carbon atoms and 1 to 3 nitrogen atoms, such as an aromatic ring having 3 carbon atoms and 3 nitrogen atoms, or an aromatic ring having 4 carbon atoms and 2 nitrogen atoms or an aromatic ring having 5 carbon atoms and 1 nitrogen atom. In a preferred embodiment the aromatic heterocyclic ring is pyridine, pyrimidine. In one embodiment of the invention, Y is -OCH2-, and the aromatic ring can be substituted with - CF3, Ci-3 alkyl or C2-4 heteroalkyl. In one embodiment, the aromatic ring is substituted with - (CH2)I-CH3, -(CH2)2-CH3 or -CH3.
In one embodiment, Y is -OCH2- and the aromatic ring is an aromatic heterocyclic ring having 3 to 6 carbon atoms and 1 to 3 nitrogen atoms, where the aromatic ring is substituted with -CF3. According to the invention, the aromatic ring substituted with -CF3 can have 3 carbon atoms and 3 nitrogen atoms, 4 carbon atoms and 2 nitrogen atoms or 5 carbon atoms and 1 nitrogen atom. Preferably, the aromatic ring has 5 carbon atoms and 1 nitrogen atom and is substituted with - CF3.
In one embodiment, Y is -OCH2- and the aromatic ring is an aromatic heterocyclic ring having 3 to 6 carbon atoms and 1 to 3 nitrogen atoms, where the aromatic ring is substituted with Ci-3 alkyl, e.g. -(CH2)0-2-CH3. The aromatic ring can be substituted with -(CH2)0-2-CH3 and can have 3 carbon atoms and 3 nitrogen atoms, 4 carbon atoms and 2 nitrogen atoms or 5 carbon atoms and 1 nitrogen atom. Preferably, the aromatic ring has 5 carbon atoms and 1 nitrogen atom and is substituted with Ci-3 alkyl.
In one embodiment, Y is -OCH2- and the aromatic ring is an aromatic heterocyclic ring having 3 to 6 carbon atoms and 1 to 3 nitrogen atoms, where the aromatic ring is substituted with C2- heteroalkyl. The aromatic ring can be substituted with C2-4 heteroalkyl and can have 3 carbon atoms and 3 nitrogen atoms, 4 carbon atoms and 2 nitrogen atoms or 5 carbon atoms and 1 nitrogen atom. Preferably, the aromatic ring has 5 carbon atoms and 1 nitrogen atom and is substituted with C2- heteroalkyl.
In one embodiment of the invention, Y is -NHCH2- and R is an aromatic ring comprising nitrogen, preferably the aromatic ring comprises 1, 2 or 3 nitrogen atoms.
In a preferred embodiment, Y is -NHCH2- and the aromatic ring is an aromatic heterocyclic ring having 3 to 6 carbon atoms and 1 to 3 nitrogen atoms, such as an aromatic ring having 3 carbon atoms and 3 nitrogen atoms, or an aromatic ring having 4 carbon atoms and 2 nitrogen atoms or an aromatic ring having 5 carbon atoms and 1 nitrogen atom. In a preferred embodiment the aromatic heterocyclic ring is pyridine, pyrimidine.
In one embodiment of the invention, Y is -NHCH2- and the aromatic ring can be substituted with -CF3, CI-3 alkyl or C2-4 heteroalkyl. In one embodiment, the aromatic ring is substituted with - (CH2)I-CH3, -(CH2)2-CH3 or -CH3.
In one embodiment, Y is -NHCH2- and the aromatic ring is an aromatic heterocyclic ring having 3 to 6 carbon atoms and 1 to 3 nitrogen atoms, where the aromatic ring is substituted with -CF3. According to the invention, the aromatic ring substituted with -CF3 can have 3 carbon atoms and 3 nitrogen atoms, 4 carbon atoms and 2 nitrogen atoms or 5 carbon atoms and 1 nitrogen atom. Preferably, the aromatic ring has 5 carbon atoms and 1 nitrogen atom and is substituted with - CF3.
In one embodiment, Y is -NHCH2- and the aromatic ring is an aromatic heterocyclic ring having 3 to 6 carbon atoms and 1 to 3 nitrogen atoms, where the aromatic ring is substituted with -(CH2)o- 2-CH3. The aromatic ring can be substituted with -(CH2)o-2-CH3 and can have 3 carbon atoms and 3 nitrogen atoms, 4 carbon atoms and 2 nitrogen atoms or 5 carbon atoms and 1 nitrogen atom. Preferably, the aromatic ring has 5 carbon atoms and 1 nitrogen atom and is substituted with Ci-3 alkyl.
In one embodiment, Y is -NHCH2- and the aromatic ring is an aromatic heterocyclic ring having 3 to 6 carbon atoms and 1 to 3 nitrogen atoms, where the aromatic ring is substituted with -0- CH3. The aromatic ring can be substituted with -0-CH3 and can have 3 carbon atoms and 3 nitrogen atoms, 4 carbon atoms and 2 nitrogen atoms or 5 carbon atoms and 1 nitrogen atom. Preferably, the aromatic ring has 5 carbon atoms and 1 nitrogen atom and is substituted with C2-4 heteroalkyl.
In one embodiment of the invention, R is an aliphatic ring, which may be homocyclic or heterocyclic.
The aliphatic ring can be a 5-7 membered ring, such as aliphatic rings having 5, 6 or 7 carbon atoms or a heterocyclic aliphatic ring having 4, 5 or 6 carbon and which may further comprise one or more oxygen atoms. In a preferred embodiment of the invention, the aliphatic ring has 4 or 5 carbon atoms and 1 or 2 oxygen, such as 4 carbon atoms and 2 oxygen atoms or 5 carbon atoms and 1 oxygen atom.
In one embodiment of the invention, the aliphatic ring can be substituted with -CF3, Ci-3 alkyl or C2-4 heteroalkyl. In one embodiment, the aliphatic ring is substituted with -(CH2)I-CH3, -(CH2)2- CH3 or -CH3.
The aliphatic ring may be a 5-7 membered ring, which is substituted with -CF3. In an embodiment, the aliphatic ring has 5 carbon, 6 carbon, or 7 carbon and is substituted with -CF3. The ring may be a heterocyclic aliphatic ring having 4, 5 or 6 carbon atoms, and may further comprise one or more oxygen atoms, which ring is substituted with -CF3. In a preferred embodiment of the invention, the aliphatic ring is substituted with -CF3 and the ring has 4 or 5 carbon atoms and 1 or 2 oxygen, such as 4 carbon atoms and 2 oxygen atoms or 5 carbon atoms and 1 oxygen atom.
The aliphatic ring may be a 5-7 membered ring, which is substituted with Ci-3 alkyl. In an embodiment, the aliphatic ring has 5 carbon, 6 carbon, or 7 carbon and is substituted with Ci-3 alkyl, e.g. -(CH2)o-2-CH3. The ring may be a heterocyclic aliphatic ring having 4, 5 or 6 carbon atoms, and may further comprise one or more oxygen atoms, which ring is substituted with Ci-3 alkyl. In a preferred embodiment of the invention, the aliphatic ring is substituted with C1-3 alkyl and the ring has 4 or 5 carbon atoms and 1 or 2 oxygen, such as 4 carbon atoms and 2 oxygen atoms or 5 carbon atoms and 1 oxygen atom.
The aliphatic ring may be a 5-7 membered ring, which is substituted with C2-4 heteroalkyl. In an embodiment, the aliphatic ring has 5 carbon, 6 carbon, or 7 carbon and is substituted with C2-4 heteroalkyl. The ring may be a heterocyclic aliphatic ring having 4, 5 or 6 carbon atoms, and may further comprise one or more oxygen atoms, which ring is substituted with C2-4 heteroalkyl. In a preferred embodiment of the invention, the aliphatic ring is substituted with C2-4 heteroalkyl and the ring has 4 or 5 carbon atoms and 1 or 2 oxygen, such as 4 carbon atoms and 2 oxygen atoms or 5 carbon atoms and 1 oxygen atom.
In one embodiment of the invention, Y is -OCH2- and R is an aliphatic ring, which may be homocyclic or heterocyclic.
In one embodiment Y is -OCH2- and the aliphatic ring can be a 5-7 membered ring, such as aliphatic rings having 5, 6 or 7 carbon atoms or a heterocyclic aliphatic ring having 4, 5 or 6 carbon and which may further comprise one or more oxygen atoms. In a preferred embodiment of the invention, the aliphatic ring has 4 or 5 carbon atoms and 1 or 2 oxygen, such as 4 carbon atoms and 2 oxygen atoms or 5 carbon atoms and 1 oxygen atom.
In one embodiment of the invention, Y is -OCH2- and the aliphatic ring can be substituted with -- CF3, Ci-3 alkyl or C2-4 heteroalkyl. In one embodiment, the aliphatic ring is substituted with - (CH2)I-CH3, -(CH2)2-CH3 or -CH3.
In one embodiment Y is -OCH2- and the aliphatic ring may be a 5-7 membered ring, which is substituted with -CF3. In an embodiment, the aliphatic ring has 5 carbon, 6 carbon, or 7 carbon and is substituted with -CF3. The ring may be a heterocyclic aliphatic ring having 4, 5 or 6 carbon atoms, and may further comprise one or more oxygen atoms, which ring is substituted with -CF3. In a preferred embodiment of the invention, the aliphatic ring is substituted with -CF3 and the ring has 4 or 5 carbon atoms and 1 or 2 oxygen, such as 4 carbon atoms and 2 oxygen atoms or
5 carbon atoms and 1 oxygen atom.
In one embodiment, Y is -OCH2- and the aliphatic ring may be a 5-7 membered ring, which is substituted with C1-3 alkyl, e.g. -(CH2)o-2-CH3. In an embodiment, the aliphatic ring has 5 carbon,
6 carbon, or 7 carbon and is substituted with C1-3 alkyl. The ring may be a heterocyclic aliphatic ring having 4, 5 or 6 carbon atoms, and may further comprise one or more oxygen atoms, which ring is substituted with C1-3 alkyl. In a preferred embodiment of the invention, the aliphatic ring is substituted with C1-3 alkyl and the ring has 4 or 5 carbon atoms and 1 or 2 oxygen, such as 4 carbon atoms and 2 oxygen atoms or 5 carbon atoms and 1 oxygen atom. In one embodiment, Y is -OCH2- and the aliphatic ring may be a 5-7 membered ring, which is substituted with C2-4 heteroalkyl. In an embodiment, the aliphatic ring has 5 carbon, 6 carbon, or 7 carbon and is substituted with C2-4 heteroalkyl. The ring may be a heterocyclic aliphatic ring having 4, 5 or 6 carbon atoms, and may further comprise one or more oxygen atoms, which ring is substituted with C2-4 heteroalkyl. In a preferred embodiment of the invention, the aliphatic ring is substituted with C2-4 heteroalkyl and the ring has 4 or 5 carbon atoms and 1 or 2 oxygen, such as 4 carbon atoms and 2 oxygen atoms or 5 carbon atoms and 1 oxygen atom.
In one embodiment of the invention, Y is -NHCH2- and R is an aliphatic ring, which may be homocyclic or heterocyclic.
In one embodiment Y is -NHCH2- and the aliphatic ring can be a 5-7 membered ring, such as aliphatic rings having 5, 6 or 7 carbon atoms or a heterocyclic aliphatic ring having 4, 5 or 6 carbon and which may further comprise one or more oxygen atoms. In a preferred embodiment of the invention, the aliphatic ring has 4 or 5 carbon atoms and 1 or 2 oxygen, such as 4 carbon atoms and 2 oxygen atoms or 5 carbon atoms and 1 oxygen atom.
In one embodiment of the invention, Y is -NHCH2- and the aliphatic ring can be substituted with - CF3, Ci-3 alkyl or C2-4 heteroalkyl. In one embodiment, the aliphatic ring is substituted with - (CH2)I-CH3, -(CH2)2-CH3 or -CH3.
In one embodiment Y is -NHCH2- and the aliphatic ring may be a 5-7 membered ring, which is substituted with -CF3. In an embodiment, the aliphatic ring has 5 carbon, 6 carbon, or 7 carbon and is substituted with -CF3. The ring may be a heterocyclic aliphatic ring having 4, 5 or 6 carbon atoms, and may further comprise one or more oxygen atoms, which ring is substituted with -CF3. In a preferred embodiment of the invention, the aliphatic ring is substituted with -CF3 and the ring has 4 or 5 carbon atoms and 1 or 2 oxygen, such as 4 carbon atoms and 2 oxygen atoms or 5 carbon atoms and 1 oxygen atom.
In one embodiment, Y is -NHCH2- and the aliphatic ring may be a 5-7 membered ring, which is substituted with -(CH2)o-2-CH3. In an embodiment, the aliphatic ring has 5 carbon, 6 carbon, or 7 carbon and is substituted with Ci-3 alkyl, e.g. -(CH2)o-2-CH3. The ring may be a heterocyclic aliphatic ring having 4, 5 or 6 carbon atoms, and may further comprise one or more oxygen atoms, which ring is substituted with Ci-3 alkyl. In a preferred embodiment of the invention, the aliphatic ring is substituted with Ci-3 alkyl and the ring has 4 or 5 carbon atoms and 1 or 2 oxygen, such as 4 carbon atoms and 2 oxygen atoms or 5 carbon atoms and 1 oxygen atom.
In one embodiment, Y is -NHCH2- and the aliphatic ring may be a 5-7 membered ring, which is substituted with C2-4 heteroalkyl. In an embodiment, the aliphatic ring has 5 carbon, 6 carbon, or 7 carbon and is substituted with C2-4 heteroalkyl. The ring may be a heterocyclic aliphatic ring having 4, 5 or 6 carbon atoms, and may further comprise one or more oxygen atoms, which ring is substituted with C2-4 heteroalkyl. In a preferred embodiment of the invention, the aliphatic ring is substituted with C2-4 heteroalkyl and the ring has 4 or 5 carbon atoms and 1 or 2 oxygen, such as 4 carbon atoms and 2 oxygen atoms or 5 carbon atoms and 1 oxygen atom.
In one embodiment of the invention, R is a fused ring, where the ring is optionally substituted with -CF3, Ci-3 alkyl or C2-4 heteroalkyl.
In one embodiment of the invention, R is
•
Figure imgf000029_0001
, where the ring is optionally substituted with -CF3, Ci-3 alkyl or C2-4 heteroalkyl o wherein Z is -0-, -CH2-, -NH- or N-(CH2)0-2-CH3; o W is -0-, or -CH2-; and o n is 0, 1 or 2.
In one embodiment of the invention, Y is -OCH2- and R is
Figure imgf000029_0002
the ring is optionally substituted with -CF3, Ci-3 alkyl or C2-4 heteroalkyl wherein Z is -0-, -CH2-, -NH- or N-(CH2)0-2-CH3;
W is -0-, or -CH2-; and n is 0, 1 or 2.
In one embodiment of the invention, Y is -NHCH2- and R is
Figure imgf000029_0003
, where the ring is optionally substituted with -CF3, Ci-3 alkyl or C2-4 heteroalkyl wherein Z is -0-, -CH2-, -NH- or N-(CH2)0-2-CH3; o W is -0-, or -CH2-; and o n is 0, 1 or 2.
In one embodiment
Figure imgf000030_0001
the ring is optionally substituted with -CF3, Ci-3 alkyl or C2- heteroalkyl.
In one embodiment
Figure imgf000030_0002
i iss --00--, W is -0-, or -CH2-, and n is 1, where the ring is optionally substituted with -CF3, Ci-3 alkyl or C2-4 heteroalkyl.
In one embodiment
Figure imgf000030_0003
the ring is optionally substituted with -CF3, Ci-3 alkyl or C2- heteroalkyl.
In one embodiment
Figure imgf000030_0004
the ring is optionally substituted with -CF3, Ci-3 alkyl or C2- heteroalkyl.
In one embodiment i iss - -00--, W is -CH2-, and n is 1, where the ring is optionally substituted with -CF
Figure imgf000030_0005
heteroalkyl.
In one embodiment is -0-, W is -CH2-, and n is 2, where the ring is optionally substituted with -CF
Figure imgf000030_0006
heteroalkyl. In one embodiment,
Figure imgf000031_0001
or 2, where the ring is optionally substituted with -CF3, Ci-3 alkyl or C2- heteroalkyl.
In one embodiment,
Figure imgf000031_0002
i iss - -00--,, W w i iss - -00--, or -CH2-, and n is 1, where the ring is optionally substituted with -CF3, Ci-3 alkyl or C2-4 heteroalkyl. In one embodiment,
Figure imgf000031_0003
where the ring is optionally substituted with -CF3, Ci-3 alkyl or C2- heteroalkyl.
In one embodiment,
Figure imgf000031_0004
where the ring is optionally substituted with -CF3, Ci-3 alkyl or C2- heteroalkyl.
Figure imgf000031_0007
In one embodiment, Y is -OCH is -0-, W is -CH2-, and n is 2, where the ring is optionally substituted w
Figure imgf000031_0005
heteroalkyl.
In one embodiment,
Figure imgf000031_0006
or 2, where the ring is optionally substituted with -CF3, Ci-3 alkyl or C2- heteroalkyl. in one embodiment,
Figure imgf000032_0001
where the ring is optionally substituted with -CF3, Ci-3 alkyl or C2- heteroalkyl.
In one embodiment, Y is -NHCH2- and R is
Figure imgf000032_0002
, , z Z i iss - -00--,, W w i iss - -O0--, or -CH2-, and n is 2, where the ring is optionally substituted with -CF3, Ci-3 alkyl or C2-4 heteroalkyl. In one embodiment,
Figure imgf000032_0003
where the ring is optionally substituted with -CF3, Ci-3 alkyl or C2- heteroalkyl.
In one embodiment, Y is -NHCH2 i iss - -00--,, W is -CH2-, and n is 1, where the ring is optionally substituted
Figure imgf000032_0004
2- heteroalkyl.
Figure imgf000032_0007
In one embodiment
Figure imgf000032_0005
the ring is optionally substituted with -CF3, Ci-3 alkyl or C2- heteroalkyl.
In one embodiment
Figure imgf000032_0006
i iss -NH-, W is -0-, or -CH2-, and n is 1, where the ring is optionally substituted with -CF3, Ci-3 alkyl or C2- heteroalkyl. In one embodiment the ring is optionally substituted with -CF3, Ci-3 alkyl or C2- heteroalkyl.
In one embodiment
Figure imgf000033_0001
the ring is optionally substituted with -CF3, Ci-3 alkyl or C2- heteroalkyl.
In one embodiment
Figure imgf000033_0002
the ring is optionally substituted with -CF3, Ci-3 alkyl or C2- heteroalkyl.
In one embodiment
Figure imgf000033_0003
the ring is optionally substituted with -CF3, Ci-3 alkyl or C2- heteroalkyl.
In one embodiment,
Figure imgf000033_0004
or 2, where the ring is optionally substituted with -CF3, Ci-3 alkyl or C2-4 heteroalkyl.
In one embodiment,
Figure imgf000033_0005
i iss -NH-, W is -0-, or -CH2-, and n is 1, where the ring is optionally substituted with -CF3, Ci-3 alkyl or C2- heteroalkyl.
In one embodiment,
Figure imgf000033_0006
where the ring is optionally substituted with -CF3, Ci-3 alkyl or C2- heteroalkyl. In one embodiment,
Figure imgf000034_0001
where the ring is optionally substituted with -CF3, Ci-3 alkyl or C2- heteroalkyl.
Figure imgf000034_0006
Figure imgf000034_0007
In one embodiment,
Figure imgf000034_0002
1 or 2, where the ring is optionally substituted with -CF3, Ci-3 alkyl or C2- heteroalkyl.
In one embodiment,
Figure imgf000034_0003
where the ring is optionally substituted with -CF3, Ci-3 alkyl or C2- heteroalkyl.
In one embodiment,
Figure imgf000034_0004
where the ring is optionally substituted with -CF3, Ci-3 alkyl or C2- heteroalkyl.
In one embodiment,
Figure imgf000034_0005
where the ring is optionally substituted with -CF3, Ci-3 alkyl or C2- heteroalkyl.
Figure imgf000035_0003
Figure imgf000035_0004
In a preferred embodiment of the invention, the invention pertains to a compound of formula I:
Figure imgf000035_0001
(formula I) wherein X is -NH- or is absent;
A is
• -A1-B1-A2-H; or
• -A1-A2-H;
• where A1 and A2 are independently C1-7 alkylene, C1-7 alkenylene, C1-7 alkynylene or C1-7 heteroalkylene; B1 is an aromatic ring, and H is hydrogen;
Y is -OCH2- or -NHCH2-, and
R is an aromatic ring comprising nitrogen or an aliphatic, where the ring is optionally substituted with -CF3, Ci-3 alkyl or C2- heteroalkyl, or
Figure imgf000035_0002
, where the ring is optionally substituted with -CF3, Ci-3 alkyl or C2- heteroalkyl, o wherein Z is -0- or -NH-, o W is -0- or -CH2-; and o n is 1 or 2; or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a solvate of the pharmaceutically acceptable salt thereof.
In another preferred embodiment of the invention, the invention pertains to a compound of formula I:
Figure imgf000036_0001
(formula I) wherein X is -NH-;
A is
• -A1-A2-H; · where A1 is C1-5 alkylene or C1-5 alkenylene and A2 is C1-5 alkylene or C1-5 alkenylene and
H is hydrogen, or more preferred A1 is C1-5 alkylene and A2 is C1-5 alkylene, such as -Al- A2-H is -(CH2)5-CH3, -(CH2)6-CH3, -(CH2)7-CH3, -(CH2)8-CH3, -(CH2)9-CH3 or -(CH2)I0-CH3;
Y is -OCH2-, and
R is
Figure imgf000036_0002
, where the ring is optionally substituted with -CF3, Ci-3 alkyl or C2- heteroalkyl, o Wherein Z is -0- or -NH-, o W is -0- or -CH2-; and n is 1 or 2; o preferably Z is -0-, W is -CH2-, and n is 1; or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a solvate of the pharmaceutically acceptable salt thereof.
In a preferred embodiment of the invention, the compound is 2-(octylamino)-6-((tetrahydro-2/-/-
Figure imgf000037_0001
In another preferred embodiment of the invention, the invention pertains to a compound of formula I:
Figure imgf000037_0002
(formula I) wherein
X is absent;
A is · -A1-B1-A2-H; or
• -A1-A2-H;
• Where A1 is C1-5 alkylene or C1-5 alkenylene and A2 is C1-5 alkylene or C1-5 alkenylene, B1 is an aromatic ring, and H is hydrogen, or more preferred A1 is C1-5 alkylene and A2 is C1-5 alkylene, and B1 is -(C6H4)-; Y is -OCH2- or -NHCH2-, and
R is
An aromatic ring comprising nitrogen or an aliphatic, where the ring is optionally substituted with -CF3, Ci-3 alkyl or C2-4 heteroalkyl, or
Figure imgf000038_0001
, where the ring is optionally substituted with -CF3, Ci-3 alkyl or C2- heteroalkyl, o Wherein Z is -0- or -NH-, o W is -0- or -CH2-; and o n is 1 or 2; or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a solvate of the pharmaceutically acceptable salt thereof.
In a preferred embodiment of the invention, -X-A is -(CH2)5-CH , -(CH2)6-CH , -(CH2)7-CH , - (CH2)S-CH3, -(CH2)g-CH3 or -(CH2)I0-CH3, or most preferred -(CH2)8-CH3, and Y is -OCH2- or -
Figure imgf000038_0002
In a preferred embodiment, the compound is 2-((l,4-dioxan-2-yl)methoxy)-6-nonylpyridin-4-ol:
Figure imgf000038_0003
In a preferred embodiment, the compound is 2-nonyl-6-((tetrahydro-2H-pyran-2- yl)methoxy)pyridin-4-ol :
Figure imgf000038_0004
In a preferred embodiment, the compound is 2-nonyl-6-(((tetrahydro-2H-pyran-2- yl)methyl)amino)pyridin-4-ol :
Figure imgf000039_0001
In a preferred embodiment, the compound is 2-nonyl-6-(oxepan-2-ylmethoxy)pyridin-4-ol :
Figure imgf000039_0002
In a preferred embodiment of the invention, -X-A is -(CH2)5-CH , -(CH2)6-CH , -(CH2)7-CH , - (CH2)8-CH3, -(CH2)g-CH3 or -(CH2)I0-CH3, or most preferred -(CH2)8-CH3, and Y is -OCH2- and R is an aromatic ring comprising nitrogen.
In a preferred embodiment, the compound is 2-nonyl-6-(pyridin-2-ylmethoxy)pyridin-4-ol :
Figure imgf000039_0003
In a preferred embodiment, the compound is 2-nonyl-6-(pyridin-3-ylmethoxy)pyridin-4-ol :
Figure imgf000039_0004
In further preferred embodiments of the invention -X-A is -(CH ) -(C6H )-(CH2)i-CH , -(CH2)2- (C6H4)-(CH2)2-CH3, -(CH2)2-(C6H4)-(CH2)3-CH3, -(CH2)I-(C6H4)-(CH2)2-CH3, -(CH2)3-(C6H4)-(CH2)2- CH3, -(CH2)I-(C6H4)-(CH2)I-CH3, -(CH2)I-(C6H4)-(CH2)3-CH3, -(CH2)3-(C6H4)-(CH2)1-CH3 and - (CH2)3-(C6H4)-(CH2)2-CH3, or most preferred -X-A is -(CH2)2-(C6H4)-(CH2)2-CH3, and Y is -OCH2-
Figure imgf000040_0001
In a preferred embodiment, the compound is 2-(4-propylphenethyl)-6-((tetrahydro-2AY-pyran-2- yl)methoxy)pyridin-4-ol :
Figure imgf000040_0002
The invention is further summarized in the following paragraphs:
1. A compound of the formula I:
Figure imgf000040_0003
(formula I) wherein
X is -NH-, -0-, -S- or is absent;
A is · -A1-B1-A2-B2-H;
• -A1-B1-A2-H;
• -B1-A2-H;
• -A1-B2-H; or
• -A1-A2-H; · where A1 and A2 are independently C1-7 alkylene, C1-7 alkenylene, C1-7 alkynylene or C1-7 heteroalkylene; B1 and B2 are independently an aliphatic ring, an aromatic ring or a fused ring, and H is hydrogen; Y is -OCH2-, -N(R')CH2-, -CH2CH2-, -CH2-, -NCR')-, or -0-, where R' is hydrogen or C1-C3 alkyl; and
R is
• an aromatic ring comprising nitrogen, an aliphatic ring or a fused ring, where the ring is optionally substituted with -CF3, C1-3 alkyl or C2-4 heteroalkyl, or
Figure imgf000041_0001
, where the ring is optionally substituted with -CF3, C1-3 alkyl or C2-4 heteroalkyl, o wherein Z is -0-, -CH2-, -NH- or N-(CH2)0-2-CH3, o W is -0- or -CH2-; and o n is 0, 1 or 2; or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a solvate of the pharmaceutically acceptable salt thereof.
2. The compound according to paragraphs 1, wherein X is -NH- or is absent.
3. The compound according to any of the preceding paragraphs, wherein A is A1-A2-H, where A1 and A2 are C1-5 alkylene or C1-5 alkenylene.
4. The compound according to any of the preceding paragraphs, wherein X is absent and A is A1-A2-H, where A1 and A2 are C1-5 alkylene.
5. The compound according to paragraph 4, wherein -X-A is -(CH2)8-CH3.
6. The compound according to paragraphs 1-2, wherein X is absent and A is A1-B1-A2-H, where A1 and A2 are C1-5 alkylene, and B1 is -(C6H4)-.
7. The compound according to paragraph 6, wherein -X-A-H is -(CH2)2-(C6H4)-(CH2)2-CH3.
8. The compound according to paragraphs 1-2, wherein X is -NH- and A is A1-A2-H, where A1 and A2 are C1-5 alkylene.
9. The compound according to any of paragraphs 1-2 and 8, wherein -X-A-H is -NH-(CH2)7- CH3.
10. The compound according to any of the preceding paragraphs, wherein Y is -NHCH2- or -OCH2- 11. The compound according to any of paragraphs 1-10, wherein Y is -NHCH2-.
12. The compound according to any of paragraphs 1-10, wherein Y is -OCH2-.
13. The compound according to any of the preceding paragraphs, wherein R is
Figure imgf000042_0001
14. The compound according to paragraph 13, wherein n is 1. 15. The compound according to paragraph 13, wherein n is 2.
16. The compound according to any of the preceding paragraphs, wherein Z is -0-.
17. The compound according to any of paragraphs 1-14 and 16, wherein n is 1 and Z is -0-.
18. The compound according to any of the preceding paragraphs, wherein W is -0-.
19. The compound according to any of paragraphs 1-14 and 16-18, wherein n is 1, Z is -0- and W is -0-.
20. The compound according to any of paragraphs 1-14 and 16-17, wherein n is 1, Z is -0- and W is -(CH2)-.
21. The compound according to any of paragraphs 1-13 and 15-16, wherein n is 2, Z is -0- and W is -(CH2)-. 22. The compound according to paragraph 1, wherein X is -NH- or absent, A is A1-A2-H, where
A1 and A2 are C5 alkylene, Y is -OCH2- or -NHCH2- and R is
Figure imgf000042_0002
Z is -0- and W is -0- or -(CH2)-.
23. The compound according to paragraph 1, wherein X is -NH- or absent, A is A1-B1-A2-H, where A1 and A2 are C1-5 alkylene; and B1 is -(C6H4)-, Y is -OCH2- or -NH- and R is
Figure imgf000042_0003
, where n is 1 or 2, Z is -0- and W is -0- or -(CH2)-.
24. The compound according to any of paragraphs 1-12, wherein R is an aromatic ring comprising nitrogen, where the ring is optionally substituted with -CF3, -(CH2)0-2-CH3 or -0-CH3. The compound according to paragraph 24, wherein R is -(C5H4N), -(C5H3N)-CF3, -(C5H3N)- (CH2)O-2-CH3, or -(C5H3N)-CH2-(CH3)2. The compound according to any of paragraphs 1-12 and 24-25, wherein
Figure imgf000043_0001
The compound according to any of paragraphs 1-7, 10, 12 and 26, wherein X is absent, A is
A1-A2-H, where A1 is Cs alkylene and A2 is C4 alkylene,
Figure imgf000043_0002
The compound according paragraph 1, wherein the compound is selected from the group consisting of
2-((l,4-dioxan-2-yl)methoxy)-6-nonylpyridin-4-ol,
2-nonyl-6-((tetrahydro-2H-pyran-2-yl)methoxy)pyridin-4-ol,
2-nonyl-6-(((tetrahydro-2H-pyran-2-yl)methyl)amino)pyridin-4-ol,
2-(4-propylphenethyl)-6-((tetrahydro-2fy-pyran-2-yl)methoxy)pyridin-4-ol,
2-(4-butylphenethyl)-6-((tetrahydro-2H-pyran-2-yl)methoxy)pyridin-4-ol,
2-(4-isobutylphenethyl)-6-((tetrahydro-2H-pyran-2-yl)methoxy)pyridin-4-ol,
2-(4-ethoxyphenethyl)-6-((tetrahydro-2H-pyran-2-yl)methoxy)pyridin-4-ol,
2-((tetrahydro-2H-pyran-2-yl)methoxy)-6-(4-(trifluoromethyl)phenethyl)pyridin-4-ol,
2-((tetrahydro-2H-pyran-2-yl)methoxy)-6-(3-(trifluoromethyl)phenethyl)pyridin-4-ol,
2-(4-ethylphenethyl)-6-((tetrahydro-2H-pyran-2-yl)methoxy)pyridin-4-ol,
2-((l,4-dioxan-2-yl)methoxy)-6-(4-propylphenethyl)pyridin-4-ol,
2-((l,4-dioxan-2-yl)methoxy)-6-(4-ethoxyphenethyl)pyridin-4-ol,
2-((l,3-dioxan-2-yl)methoxy)-6-(4-propylphenethyl)pyridin-4-ol,
2-((2,3-dihydrobenzofuran-2-yl)methoxy)-6-(4-propylphenethyl)pyridin-4-ol,
2-((2,3-dihydrobenzo[b][l,4]dioxin-2-yl)methoxy)-6-(4-propylphenethyl)pyridin-4-ol,
2-(4-pentylphenyl)-6-((tetrahydro-2H-pyran-2-yl)methoxy)pyridin-4-ol,
2-((5-methyl-l,3-dioxan-2-yl)methoxy)-6-(4-propylphenethyl)pyridin-4-ol, 2-((4-methyl-l,3-dioxan-2-yl)methoxy)-6-(4-propylphenethyl)pyridin-4-ol,
2-(4-propylphenethyl)-6-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)pyridin-4-ol,
2-(((4-propylbenzyl)oxy)methyl)-6-((tetrahydro-2H-pyran-2-yl)methoxy)pyridin-4-ol,
2-((4-propylphenoxy)methyl)-6-((tetrahydro-2H-pyran-2-yl)methoxy)pyridin-4-ol, 2-(2-(6-ethoxypyridin-3-yl)ethyl)-6-((tetrahydro-2H-pyran-2-yl)methoxy)pyridin-4-ol
29. The compound according to any of paragraphs 1, wherein the compound is selected from the group consisting of 2-((3-methyltetrahydro-2H-pyran-2-yl)methoxy)-6-(4-propylphenethyl)pyridin-4-ol, 2-((2-methyltetrahydro-2H-pyran-2-yl)methoxy)-6-(4-propylphenethyl)pyridin-4-ol, 2-((4-methyltetrahydro-2H-pyran-2-yl)methoxy)-6-(4-propylphenethyl)pyridin-4-ol, 2-((6-methyltetrahydro-2H-pyran-2-yl)methoxy)-6-(4-propylphenethyl)pyridin-4-ol, 2-((5-methyltetrahydro-2H-pyran-2-yl)methoxy)-6-(4-propylphenethyl)pyridin-4-ol, 2-(isochroman-l-ylmethoxy)-6-(4-propylphenethyl)pyridin-4-ol, 2-(chroman-2-ylmethoxy)-6-(4-propylphenethyl)pyridin-4-ol, 2-(isochroman-3-ylmethoxy)-6-(4-propylphenethyl)pyridin-4-ol, 2-((2-methylchroman-2-yl)methoxy)-6-(4-propylphenethyl)pyridin-4-ol, 2-((2-ethylchroman-2-yl)methoxy)-6-(4-propylphenethyl)pyridin-4-ol, 2-((2-isopropylchroman-2-yl)methoxy)-6-(4-propylphenethyl)pyridin-4-ol, 2-((2-propylchroman-2-yl)methoxy)-6-(4-propylphenethyl)pyridin-4-ol, 2-(methyl((tetrahydro-2H-pyran-2-yl)methyl)amino)-6-(4-propylphenethyl)pyridin-4-ol,
(R)-2-(4-propylphenethyl)-6-((tetrahydro-2H-pyran-2-yl)methoxy)pyridin-4-ol,
(S)-2-(4-propylphenethyl)-6-((tetrahydro-2H-pyran-2-yl)methoxy)pyridin-4-ol, 2-(2-(6-propylpyridin-3-yl)ethyl)-6-((tetrahydro-2H-pyran-2-yl)methoxy)pyridin-4-ol, and 2-(2-(5-propylpyridin-2-yl)ethyl)-6-((tetrahydro-2H-pyran-2-yl)methoxy)pyridin-4-ol.
2-((l,3-oxathian-2-yl)methoxy)-6-(4-propylphenethyl)pyridin-4-ol,
2-((4, 6-dimethyl- l,3-dioxan-2-yl)methoxy)-6-(4-propylphenethyl)pyridin-4-ol, 2-((5-hydroxy-l,3-dioxan-2-yl)methoxy)-6-(4-propylphenethyl)pyridin-4-ol, 2-((5, 5-dimethyl- l,3-dioxan-2-yl)methoxy)-6-(4-propylphenethyl)pyridin-4-ol,
2-((2,4-dioxaspiro[5.5]undec-8-en-3-yl)methoxy)-6-(4-propylphenethyl)pyridin-4-ol,
2-(2-(3-propylphenoxy)ethyl)-6-((tetrahydro-2AY-pyran-2-yl)methoxy)pyridin-4-ol,
2-(2-((4-chloronaphthalen-l-yl)oxy)ethyl)-6-((tetrahydro-2AY-pyran-2-yl)methoxy)pyridin-4-ol,
2-(2-(naphthalen-2-yloxy)ethyl)-6-((tetrahydro-2Ay-pyran-2-yl)methoxy)pyridin-4-ol, 2-(2-(5-ethylpyridin-2-yl)ethyl)-6-((tetrahydro-2H-pyran-2-yl)methoxy)pyridin-4-ol,
2-(2-(6-ethylpyridin-3-yl)ethyl)-6-((tetrahydro-2H-pyran-2-yl)methoxy)pyridin-4-ol, 2-(2-(6-ethoxypyridin-3-yl)ethyl)-6-((tetrahydro-2H-pyran-2-yl)methoxy)pyridin-4-ol, 2-(2-(5-ethoxypyridin-2-yl)ethyl)-6-((tetrahydro-2H-pyran-2-yl)methoxy)pyridin-4-ol, 2-(2-(5-ethoxypyrazin-2-yl)ethyl)-6-((tetrahydro-2H-pyran-2-yl)methoxy)pyridin-4-ol, 2-(2-(5-propylpyrazin-2-yl)ethyl)-6-((tetrahydro-2H-pyran-2-yl)methoxy)pyridin-4-ol,
2-(2-(5-propylpyrimidin-2-yl)ethyl)-6-((tetrahydro-2H-pyran-2-yl)methoxy)pyridin-4-ol, 2-(2-(2-ethoxypyrimidin-5-yl)ethyl)-6-((tetrahydro-2H-pyran-2-yl)methoxy)pyridin-4-ol, 2-(2-(isoquinolin-l-yloxy)ethyl)-6-((tetrahydro-2H-pyran-2-yl)methoxy)pyridin-4-ol, 2-(2-(isoquinolin-4-yloxy)ethyl)-6-((tetrahydro-2H-pyran-2-yl)methoxy)pyridin-4-ol, 2-(2-(quinolin-4-yloxy)ethyl)-6-((tetrahydro-2H-pyran-2-yl)methoxy)pyridin-4-ol,
2-(2-(quinolin-5-yloxy)ethyl)-6-((tetrahydro-2H-pyran-2-yl)methoxy)pyridin-4-ol, 2-(2-(isoquinolin-5-yloxy)ethyl)-6-((tetrahydro-2H-pyran-2-yl)methoxy)pyridin-4-ol, 2-(2-(isoquinolin-8-yloxy)ethyl)-6-((tetrahydro-2H-pyran-2-yl)methoxy)pyridin-4-ol, 2-(2-(quinolin-8-yloxy)ethyl)-6-((tetrahydro-2H-pyran-2-yl)methoxy)pyridin-4-ol, 2-(2-(lH-indol-l-yl)ethyl)-6-((tetrahydro-2H-pyran-2-yl)methoxy)pyridin-4-ol, 2-(2-(5-methoxy-lH-indol-l-yl)ethyl)-6-((tetrahydro-2H-pyran-2-yl)methoxy)pyridin-4-ol,
2-(2-(5-(methylthio)-lH-indol-l-yl)ethyl)-6-((tetrahydro-2H-pyran-2-yl)methoxy)pyridin-4-ol,
2-(2-(5-methoxy-lH-pyrrolo[3,2-b]pyridin-l-yl)ethyl)-6-((tetrahydro-2H-pyran-2- yl)methoxy)pyridin-4-ol, 2-(2-(5-methoxy-lH-pyrrolo[2,3-c]pyridin-l-yl)ethyl)-6-((tetrahydro-2H-pyran-2- yl)methoxy)pyridin-4-ol,
2-(2-(2-(methylthio)-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethyl)-6-((tetrahydro-2H-pyran-2- yl)methoxy)pyridin-4-ol,
2-(2-(5-ethoxy-lH-pyrrolo[3,2-b]pyridin-l-yl)ethyl)-6-((tetrahydro-2H-pyran-2- yl)methoxy)pyridin-4-ol,
2-(2-(5-ethoxy-lH-indol-l-yl)ethyl)-6-((tetrahydro-2H-pyran-2-yl)methoxy)pyridin-4-ol,
2-(2-(4-ethylphenoxy)ethyl)-6-((tetrahydro-2H-pyran-2-yl)methoxy)pyridin-4-ol,
2-(2-(4-propylphenoxy)ethyl)-6-((tetrahydro-2H-pyran-2-yl)methoxy)pyridin-4-ol,
2-(4-ethyl-2-methylphenethyl)-6-((tetrahydro-2H-pyran-2-yl)methoxy)pyridin-4-ol, 2-(4-ethyl-3-methylphenethyl)-6-((tetrahydro-2H-pyran-2-yl)methoxy)pyridin-4-ol,
2-(4-ethyl-3-methoxyphenethyl)-6-((tetrahydro-2H-pyran-2-yl)methoxy)pyridin-4-ol,
2-(4-ethyl-2-methoxyphenethyl)-6-((tetrahydro-2H-pyran-2-yl)methoxy)pyridin-4-ol,
2-(3-chloro-4-ethylphenethyl)-6-((tetrahydro-2H-pyran-2-yl)methoxy)pyridin-4-ol and
2-(2-chloro-4-ethylphenethyl)-6-((tetrahydro-2H-pyran-2-yl)methoxy)pyridin-4-ol. 30. The compound according to paragraph 1 and 28-29, wherein the compound is 2-(4- propylphenethyl)-6-((tetrahydro-2Ay-pyran-2-yl)methoxy)pyridin-4-ol.
31. A pharmaceutical composition for use as a medicament, said pharmaceutical composition comprising a compound according to any of paragraphs 1-30 and a pharmaceutically acceptable carrier, excipient or diluent.
32. The pharmaceutical composition according to paragraph 31, wherein the composition is for use in the treatment of inflammatory or diabetic disease. 33. The pharmaceutical composition according to any of paragraph 31-32, wherein the composition is use in the treatment of fibrosis.
34. The pharmaceutical composition according to paragraph 33, wherein the composition is for use in treatment of fibrosis of an one of the kidney, liver, lung, pancreas
PHARMACEUTICAL COMPOSITIONS
The term "composition" as used herein is intended to encompass a product comprising the specified ingredients (and in the specified amounts, if indicated), as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
By "pharmaceutically acceptable" it is meant that the carrier, excipient, or diluent is compatible with the other ingredients of the formulation and is not deleterious to the recipient thereof.
Composition formulations may improve one or more pharmacokinetic properties (eg oral bioavailability, membrane permeability) of a compound of the invention (herein referred to as the active ingredient).
The pharmaceutical compositions for the administration of the compounds of this invention may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art. All methods include the step of bringing the active ingredient into association with the carrier which constitutes one or more accessory ingredients.
In general, the pharmaceutical compositions are prepared by uniformly and intimately bringing the active ingredient into association with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired formulation. In the pharmaceutical composition, the active object compound is included in an amount sufficient to produce the desired effect upon the process or condition of diseases.
The pharmaceutical compositions containing the active ingredient may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions. Such compositions may contain one or more agents selected from sweetening agents, flavouring agents, colouring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets may contain the active ingredient in admixture with other non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid, or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. They may also be coated by the techniques described in US Patent No. 4,256,108, 4,160,452, and 4,265,874 to form osmotic therapeutic tablets for control release.
Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate, or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxy-propylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxy-ethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl, p-hydroxybenzoate, one or more colouring agents, one or more flavouring agents, and one or more sweetening agents, such as sucrose or saccharin.
Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil, or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin, or cetyl alcohol.
Sweetening agents such as those set forth above, and flavouring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti oxidant such as ascorbic acid. Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavouring and colouring agents, may also be present.
The pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these. Suitable emulsifying agents may be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavouring agents.
Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, and flavouring and colouring agents. The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. 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-butane diol. Among the acceptable vehicles and solvents that may be employed are 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. In addition, fatty acids such as oleic acid find use in the preparation of injectables. The pharmaceutical compositions may also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials include, for example, cocoa butter and polyethylene glycols.
For topical use, creams, ointments, jellies, solutions, or suspensions etc containing the compounds of the invention are employed. As used herein, topical application is also meant to include the use of mouthwashes and gargles.
EXAMPLES
Aq Aqueous cAMP Cyclic adenosine monophosphate
DCM Dichloromethane
DEE Diethyl ether
DMF Dimethylformamide
DMSO Dimethylsulfoxide
EtOAc Ethyl acetate
FBS Fetal bovine serum
HEPES 4-(2-FlydroxyEthyl)-l-Piperazine EthaneSulfonic acid
HPLC Hig h Performance Liquid Chromatography
IBMX 3-Isobutyl-l-methylxanthine
MeCN Acetonitrile
MeOFI Methanol
MS Mass Spectrometry
MW Microwave
ND Not determined
NMR Nuclear Magnetic Resonance
PE Petroleum ether rt Room temperature
TFA Trifluoroacetic acid
THF Tetrahydrofuran
SYNTHETIC PROCEDURES
Chemicals were used without further purification. Anhydrous reactions were carried out in oven or flame-dried glassware under nitrogen atmosphere. Dry chromatographic grade DCM, TFIF and DMF were obtained from a Waters SG solvent purification system. MeCN was dried over molecular sieves (3A). Thin layer chromatography (TLC) Silica gel 60 F254, Merck pre-coated plates were used, visualized under UV light (254 or 365nm), developed in the system stated for each compound. Flash chromatography of compounds was performed using silica gel 60(40-64 pm), where loading of the compounds was done after dry mixing with Celite. Nuclear Magnetic Resonance (NMR) spectra were recorded on 400 or 600 MHz Bruker instruments. The obtained FID files were processed with Mnova 14 software. Signals are reported in ppm (<5) using the solvent as reference. Multiplet patterns are designated the following abbreviations, or combinations of these: m - multiplet, s - singlet, d - doublet, t - triplet, q - quartet, p - pentet, h - sextet. Signal assignments were made from chemical shifts. Mass spectrometry (MS) was performed on an Aquity UPLC instrument connected to an Aquity TUV detector and an Aquity QDa detector. Gradient: 100%A to 100% B over 5 min. Mobile phase A: MeCN 5%, Formic acid 0.1% in H O, Mobile Phase B: MeCN 99.9%, Formic acid 0.1%.. Flow rate: 0.5 ml/min. Samples used in this system were dissolved in 1: 1 MeCN, H O or MeOH. Analytical High- Performance Liquid Chromatography (HPLC) was performed on a Dionex UltiMate HPLC system consisting of an LPG-3400A pump (1 ml/min), a WPS-3000L autosampler and a DAD-3000D diode array detector (210, 254, 290, 365nm), using a Gemini-NX C18 column (4.6 x 250 mm, 3 pm, llOA); Mobile phase A: H20 : TFA ®· 100:0.1, v/v. Mobile phase B: MeCN : H20 : TFA ®· 90: 10:0.1, v/v/v. Data were acquired and processed using the Chromeleon Software v. 6.80.
Methods used for analysis
Method A: Gradient 0-15min, 50-100% Mobile phase B.
Method B: Gradient 0-15min, 30-100% Mobile phase B.
Method A is the default method, except if it is stated otherwise in the experimental procedures.
Mass analysis by matrix-assisted laser desorption/ionization high-resolution mass spectrometry (MALDI-HRMS) was performed on a QExactive Orbitrap mass spectrometer (Thermo Scientific, Bremen, Germany) equipped with a SMALDI5 ion source (TransMIT GmbH, Giessen, Germany). The sample was analyzed in the positive ion mode using a peak from the DHB matrix for internal mass calibration whereby a mass accuracy of 2 ppm or better was achieved. The samples (1 mg) were mixed with a 20 mg/mL solution of 2,5-dihydroxybenzoic acid in MeOH as MALDI matrix, 2 pL of the mixture was deposited on a 30 well glass plate (Electron Microscopy Sciences, Hatfield, PA, USA) and analysis followed upon evaporation. Infrared (IR) spectra were recorded neat on a Perkin-Elmer Spectrum One fourier-transform spectrometer with a universal ATR accesory. The signals (/ max) are reported in wavenumbers (cm 1). Peak intensity is designated the following abbreviations or combination of these: broad (br), weak (w), medium (m) and strong (s). Samples were dissolved in DCM, added dropwise onto the analysis plate and the spectra were recorded upon evaporation of the solvent. METHOD FOR PREPARING THE COMPOUNDS OF THE INVENTION
Synthetic Routes
Figure imgf000052_0001
Figure 1: i) Benzyl alcohol (for 2) or (4-Methoxyphenyl)methanol (for 9), NaH, DMF, 0 °C to rt, 23 h; ii) (tetrahydro-2H-pyran-2-yl)methanamine, Cul, H20, 185 °C, MW, 4 h; iii) (tetrahydro-2H- pyran-2-yl)methanol (6a) or (l,4-dioxan-2-yl)methanol (6b) or oxepan-2-ylmethanol (6c) or (Tetrahydrofuran-2-yl)methanol (6d) or pyridin-2-ylmethanol (10), NaH, THF, 0 °C to 100 °C, 3h; iv) PdCI2(MeCN)2, XPhos, Cs2C03, 1-nonyne (for 4, 7a-e) or l-ethynyl-4-propylbenzene (for 7f), MeCN, 90 °C, 18 h; v) Pd2(dba)3, XantPhos, tBuONa, octylamine, dioxane, 100 °C, 42 h; vi) 10% Pd-C, H2, 1 atm, MeOH:EtOAc (1:2), 4 h; vi) Fe(acac)3, nonylmagnesium bromide, THF:NMP (4: 1), rt, 3.5 h; viii) TFA in DCM, rt, 1 h.
Table 1: Supplementary table to Figure 1.
Figure imgf000053_0002
Cl OPMB OPMB OPMB OH
Figure imgf000053_0001
Figure 2: Reactants and conditions: i) (4-methoxyphenyl)methanol, NaH, DMF, 0 °C to rt, 23 h; ii) pyridin-3-ylmethanol, NaH, THF, 0 °C to 100 °C, 3h; iii) Fe(acac)3, nonylmagnesium bromide, THF:NMP (4: 1), rt, 3.5 h; iv) TFA in DCM, rt, 1 h.
Figure imgf000054_0001
Figure 3: Reagents and conditions: i) Benzyl alcohol (for 2) or (4-methoxyphenyl)methanol (for 9), NaH, DMF, 0 °C to rt, 23 h; ii) corresponding alcohol, NaH, THF, 0 °C to 100 °C, 3h; iii) propane-1, 3-diol, p-TsOH, DCM, rt, 7 h; iv) PdCI2(MeCN)2 XPhos, Cs2C03 corresponding alkyne, MeCN, 90 °C, 18 h ; v) (4-pentylphenyl)boronic acid (for 7s) or (4-phenoxyphenyl)boronic acid (for 7t), SPhos, PdCI2(MeCN)2, K3P04, toluene, 100 °C, 2 d ; vi) 10% Pd-C, H2, 1 atm, MeOH:EtOAc (1:2), 4 h; vi i) (4-propylphenyl)methanol (for lib) or (4- propylphenyl)methanamine (for 11c), tBuBrettPhos Pd G3, tBuONa, dioxane, 100 °C, 20.5 - 48 h; xi) Mel, NaH, DMF, 0 °C to rt, 2.5 d; viii) TFA in DCM, rt, 4.5 h. Table 2: Supplement to Figure 3.
Figure imgf000055_0003
Figure imgf000055_0002
Figure imgf000055_0001
Figure imgf000057_0001
Figure 6: Reagents and conditions: i) Benzyl bromide, Cs2C03, acetone, reflux, 5 h; ii) (tetrahydro-2H-pyran-2-yi)methanoi, NaH, THF, 0-100 °C, 24 h ; Hi) a) trimethylsilylacetylene, PdCI2(PPh3)2, TEA, Cul, THF, rt, 17 h; b) K2C03, MeOH, 0 °C to rt, 1 h; iv) 2-ethoxy -5- iodopyridine, Pd(PPh3)4, TEA, Cul, THF, rt, 17 h; v) H2, Pd/C, MeOH:EtOAc (1:2), rt, 6 h.
4-(Benzyloxy)-2,6-dichloropyridine (2). NaH (60% in mineral oil, 189.0 mg, 4.73 mmol) was added to a solution of 2,4,6-trichloropyridine (854.7 mg, 4.69 mmol) in DMF (5 mL) at 0 °C. Benzyl alcohol (0.49 mL, 4.71 mmol) was added dropwise during 5 min and the reaction was stirred at 0 °C for 3 h, then at room temperature (rt) for 20 h. Water (60 mL) was added and the mixture was extracted with EtOAc (3 x 20 mL). The combined organic phase was dried over Na2SC>4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (0-3% EtOAc in heptane) to afford 2 (923 mg, 78%) as white solid. Rf = 0.55 (PE: EtOAc, 7:3).
Figure imgf000057_0002
NMR (400 MHz, CDCI3) d 7.47 - 7.34 (m, 5H), 6.86 (s, 2H), 5.11 (s, 2H). 13C NMR (101 MHz, CDCI3) d 167.7, 151.5, 134.6, 129.1, 129.0, 127.7, 110.0, 71.1. 2,6-Dichloro-4-((4-methoxybenzyl)oxy)pyridine (9). NaH (60% in mineral oil, 105.5 mg, 2.64 mmol) was added to a solution of 2,4,6-trichloropyridine (458.2 mg, 2.51 mmol) in DMF (2.5 mL) at 0 °C. (4-Methoxyphenyl)methanol (0.31 mL, 2.50 mmol) was added dropwise during 5 min and the reaction was stirred at 0 °C for 3 h, then at rt for 17 h. Water (25 mL) was added and the mixture was extracted with EtOAc (3 x 15 mL). The combined organic phase was dried over Na2S04, filtered, concentrated in vacuo and the residue was purified by silica gel column chromatography (7% EtOAc in heptane) to afford 9 (532 mg, 75%) as white solid. Rf = 0.40 (PE: EtOAc, 8:2). *H NMR (600 MHz, CDCI3) d 7.33 - 7.28 (m, 2H), 6.96 - 6.91 (m, 2H), 6.84 (s, 2H), 5.03 (s, 2H), 3.83 (s, 3H). 13C NMR (151 MHz, CDCI3) d 167.8, 160.2, 151.4, 129.6, 126.5, 114.4, 110.0, 71.0, 55.5. 4-(Benzyloxy)-6-chloro-N-((tetrahydro-2H-pyran-2-yl)methyl)pyridin-2-amine (3). 2
(52.0 mg, 0.205 mmol), Cul (0.5 mg, 0.003 mmol) and H20 (5 pL) were treated with (tetrahydro-2H-pyran-2-yl)methanamine (70.5 mg, 0.612 mmol) and sealed in a 2mL microwave vial. The mixture was heated in the microwave reactor at 185 °C for 4 h. Then solid K2CO3 (56.6mg, 0.410mmol, 2eq) was added. The resulting mixture was diluted with H20 (5 mL) and extracted with EtOAc (3 x 5 mL). The combined organic layer was dried over Na2SC>4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (15% EtOAc in Heptane) to afford 3 (18 mg, 26 %) as colorless oil. Rf = 0.48 (PE:EtOAc, 7:3). JH NMR (600 MHz, CDCI3) d 7.43 - 7.30 (m, 5H), 6.27 (d, J = 1.8 Hz, 1H), 5.81 (d, J = 1.8 Hz, 1H), 5.03 (s, 2H), 5.01 - 4.96 (m, 1H), 4.01 - 3.94 (m, 1H), 3.48 - 3.35 (m, 3H), 3.11 (ddd, J = 13.1, 7.9, 4.0 Hz, 1H), 1.89 - 1.81 (m, 1H), 1.61 - 1.46 (m, 4H), 1.41 - 1.31 (m, 1H). 13C NMR (151 MHz, CDCI3) d 167.7, 160.0, 150.7, 135.9, 128.8, 128.5, 127.6, 100.7, 90.1, 76.3, 70.1, 68.5, 47.3,
29.4, 26.1, 23.2.
General procedure for nucleophilic aromatic substitution for synthesis of compounds 6a-d, 10 as exemplified for compound 6a:
4-(Benzyloxy)-2-chloro-6-((tetrahydro-2H-pyran-2-yl)methoxy)pyridine (6a). NaH
(60% in mineral oil, 17.6 mg, 0.440 mmol) was added to a solution of (tetrahydro-2H-pyran-2- yl)methanol (0.05 mL, 0.442 mmol) in THF (0.5 mL) at 0 °C. The mixture was stirred for 15 min and 2 (101.9 mg, 0.401 mmol) in 1 mL THF was added, the tube was sealed and the temperature was set at 100 °C. After 2 h the mixture was allowed to cool to r.t., water (10 mL) was added and the mixture was extracted with DEE (3 x 10 mL). The combined organic phase was washed with brine (10 mL), dried over Na2SC>4, filtrated and concentrated in vacuo. The residue was purified by silica gel column chromatography (0-20% EtOAc in heptane) to afford 6a (114 mg, 85%) as white solid. Rf = 0.52 (PE:EtOAc, 7:3). JH NMR (600 MHz, CDCI3) d 7.42 - 7.31 (m, 5H), 6.57 (d, J = 1.9 Hz, 1H), 6.28 (d, J = 1.9 Hz, 1H), 5.03 (s, 2H), 4.31 (dd, J =
11.4, 3.0 Hz, 1H), 4.21 (dd, J = 11.4, 7.1 Hz, 1H), 4.08 - 4.01 (m, 1H), 3.67 (ddt, J = 11.1, 7.2, 2.7 Hz, 1H), 3.48 (td, J = 11.7, 2.2 Hz, 1H), 1.94 - 1.84 (m, 1H), 1.66 - 1.48 (m, 4H), 1.46 - 1.37 (m, 1H). 13C NMR (151 MHz, CDCI3) d 168.2, 164.8, 149.0, 135.4, 128.8, 128.6, 127.6, 106.0, 94.2, 75.9, 70.4, 69.9, 68.6, 27.9, 25.9, 23.2.
2-((l 4-Dioxan-2-yl)methoxy)-4-(benzyloxy)-6-chloropyridine (6b). The target compound was synthesized as described for 6a using l,4-dioxan-2-yl)methanol (117.1 mg, 0.991 mmol) to yield 223 mg (74%) white solid. Rf = 0.44 (PE:EtOAc, 6:4). *H NMR (400 MHz, CDCI3) d 7.50 - 7.30 (m, 5H), 6.59 (d, J = 1.8 Hz, 1H), 6.26 (d, J = 1.9 Hz, 1H), 5.05 (s, 2H), 4.29 (d, J = 5.0 Hz, 2H), 3.96 (dtd, J = 10.0, 5.0, 2.6 Hz, 1H), 3.88 - 3.61 (m, 5H), 3.49 (dd, J = 11.5, 10.1 Hz, 1H). 13C NMR (101 MHz, CDCI3) d 168.4, 164.4, 149.1, 135.4, 128.9, 128.7, 127.6, 106.3, 94.2, 73.7, 70.6, 68.3, 66.9, 66.6, 66.2.
4-(Benzyloxy)-2-chloro-6-(oxepan-2-ylmethoxy)pyridine (6c). The target compound was synthesized as described for 6a using oxepan-2-ylmethanol (80 mg, 0.615 mmol) and purified by silica gel column chromatography (5% EtOAc in heptane) to yield 77.3 mg (37%) colorless oil. Rf = 0.28 (PE:DEE, 8:2). JH NMR (600 MHz, CDCh) d 7.42 - 7.32 (m, 5H), 6.57 (d, J = 1.9 Hz, 1H), 6.26 (d, J = 1.9 Hz, 1H), 5.04 (s, 2H), 4.23 (d, J = 5.7 Hz, 2H), 3.94 - 3.86 (m, 2H), 3.59 (ddd, J = 12.4, 7.6, 3.7 Hz, 1H), 1.85 - 1.75 (m, 3H), 1.71 - 1.54 (m, 6H). 13C NMR (101 MHz, CDCh) d 168.3, 165.0, 149.1, 135.5, 128.9, 128.6, 127.6, 105.9, 94.2, 77.5, 70.5, 69.8, 68.9, 32.0, 31.3, 27.2, 25.7.
4-(Benzyloxy)-2-chloro-6-((tetrahydrofuran-2-yl)methoxy)pyridine (6d). The target compound was synthesized as described for 6a using (Tetrahydrofuran-2-yl)methanol (37.3 pL, 0.385 mmol) and purified by silica gel column chromatography (8% EtOAc in heptane) to yield 59 mg (53%) colorless oil. Rf = 0.25 (PE:EtOAc, 8:2). *H NMR (600 MHz, CDCh) d 7.41 - 7.33 (m, 5H), 6.57 (d, J = 1.9 Hz, 1H), 6.26 (d, J = 1.9 Hz, 1H), 5.04 (s, 2H), 4.37 (dd, J = 10.9, 3.1 Hz, 1H), 4.24 (qd, J = 7.1, 3.1 Hz, 1H), 4.19 (dd, J = 10.9, 7.3 Hz, 1H), 3.94 - 3.90 (m, 1H), 3.85 - 3.80 (m, 1H), 2.07 - 2.00 (m, 1H), 1.98 - 1.87 (m, 2H), 1.73 - 1.65 (m, 1H). 13C NMR (151 MHz, CDCh) d 168.3, 164.8, 149.0, 135.4, 128.9, 128.6, 127.6, 106.1, 94.2, 77.0, 70.5, 69.0, 68.6, 28.1, 25.8.
2-Chloro-4-((4-methoxybenzyl)oxy)-6-(pyridin-2-ylmethoxy)pyridine (10). The target compound was synthesized as described for 6a using pyridin-2-ylmethanol (0.06 mL, 0.622 mmol) and compound 9 (166.2 mg, 0.585 mmol) instead of 2 and purified by silica gel column chromatography (25% EtOAc in heptane) to yield 156 mg (75%) colorless oil. Rf = 0.22 (PE: EtOAc, 7:3). JH NMR (600 MHz, CDCh) d 8.61 (ddd, J = 4.9, 1.8, 1.0 Hz, 1H), 7.68 (td, J =
7.7, 1.8 Hz, 1H), 7.43 (d, J = 7.8 Hz, 1H), 7.32 - 7.28 (m, 2H), 7.21 (ddd, J = 7.6, 4.8, 1.2 Hz, 1H), 6.93 - 6.89 (m, 2H), 6.58 (d, J = 1.9 Hz, 1H), 6.31 (d, J = 1.9 Hz, 1H), 5.46 (s, 2H), 4.97 (s, 2H), 3.81 (s, 3H). 13C NMR (151 MHz, CDCh) d 168.5, 164.3, 159.9, 156.8, 149.5, 149.2,
136.7, 129.5, 127.3, 122.8, 122.2, 114.3, 106.2, 94.2, 70.4, 69.0, 55.4.
General procedure for Sonogashira coupling for synthesis of compounds 4 and 7a-e, as exemplified for compound 7a:
4-(Benzyloxy)-2-(non-l-yn-l-yl)-6-((tetrahydro-2H-pyran-2-yl)methoxy)pyridine (7a).
A vial was charged with PdCh(MeCN)2 (1.8 mg, 0.007 mmol), XPhos (9.8 mg, 0.021 mmol) and anhydrous CS2CO3 (290.1 mg, 0.890 mmol). The vial was evacuated and backfilled with Ar (x3) and the contents were suspended in anhydrous MeCN (0.2 ml). 1-nonyne (0.08 mL, 0.488 mmol) was added and the reaction was allowed to stir for 15 min after which a solution of 6a (114.3 mg, 0.342 mmol) in anhydrous MeCN (0.8 mL) was added to the yellow solution. The vial was capped and heated to 90 °C for 18 h. The reaction mixture was filtered over a Celite pad, washed with DEE, the solvents were concentrated in vacuo and the residue was purified by silica gel column chromatography (0-20% DEE in heptane) to give 7a as an orange oil (64mg, 44%). Rf = 0.10 (Et20:PE, 1 :9). JH NMR (600 MHz, CDCh) d 7.49 - 7.29 (m, 5H), 6.67 (d, J = 2.1 Hz, 1H), 6.30 (d, J = 2.1 Hz, 1H), 5.03 (s, 2H), 4.36 (dd, J = 11.4, 3.0 Hz, 1H), 4.23 (dd, J = 11.4, 7.1 Hz, 1H), 4.05 (ddt, J = 11.5, 4.0, 1.7 Hz, 1H), 3.67 (ddt, J = 12.1, 7.1, 2.6 Hz, 1H), 3.49 (td, J = 11.7, 2.2 Hz, 1H), 2.40 (t, J = 7.2 Hz, 2H), 1.91 - 1.85 (m, 1H), 1.64 - 1.50 (m, 6H), 1.48 - 1.39 (m, 3H), 1.37 - 1.25 (m, 6H), 0.89 (t, J = 6.9 Hz, 3H). 13C NMR (151 MHz, CDCh) d 166.9,
165.3, 141.3, 135.9, 128.8, 128.4, 127.6, 110.6, 95.2, 90.3, 80.5, 76.2, 70.0, 69.5, 68.6, 31.9, 29.1, 29.0, 28.5, 28.0, 26.0, 23.3, 22.8, 19.6, 14.2.
4-(Benzyloxy)-6-(non-l-yn-l-yl)-N-((tetrahydro-2H-pyran-2-yl)methyl)pyridin-2- amine (4). The target compound was synthesized as described for 7a using compound 3 (17.4 mg, 0.052 mmol) instead of 6a and purified by silica gel column chromatography (14-15% EtOAc in heptane) to yield 14.3 mg (65%) slightly yellow oil. Rf = 0.50 (EtOAcPE, 3:7). JH NMR (600 MHz, CDCh) d 7.45 - 7.36 (m, 4H), 7.36 - 7.31 (m, 1H), 6.41 (d, J = 2.1 Hz, 1H), 5.89 (s, 1H), 5.04 (s, 3H), 4.01 - 3.92 (m, 1H), 3.50 - 3.33 (m, 3H), 3.16 - 3.09 (m, 1H), 2.39 (t, J = 7.2 Hz, 2H), 1.89 - 1.80 (m, 1H), 1.61 - 1.26 (m, 15H), 0.88 (t, J = 6.9 Hz, 3H). 13C NMR (151 MHz, CDCh) d 166.5, 160.2, 142.8, 136.1, 128.8, 128.4, 127.6, 105.2, 91.2, 90.0, 80.6, 76.5, 69.9,
68.5, 47.5, 31.9, 29.4, 29.1, 29.0, 28.5, 26.1, 23.2, 22.8, 19.5, 14.2.
2-((l,4-Dioxan-2-yl)methoxy)-4-(benzyloxy)-6-(non-l-yn-l-yl)pyridine (7b). The target compound was synthesized as described for 7a using compound 6b (217.0 mg, 0.646 mmol) instead of 6a and purified by silica gel column chromatography (0-20% EtOAc in heptane) to yield 186 mg (68%) slightly yellow oil. Rf = 0.53 (EtOAc:PE 4:6). JH NMR (400 MHz, CDCh) d 7.50 - 7.29 (m, 5H), 6.69 (d, J = 2.1 Hz, 1H), 6.28 (d, J = 2.1 Hz, 1H), 5.04 (s, 2H), 4.38 - 4.25 (m, 2H), 3.96 (dddd, J = 10.1, 5.6, 4.5, 2.7 Hz, 1H), 3.89 - 3.60 (m, 5H), 3.50 (dd, J = 11.5, 10.1 Hz, 1H), 2.41 (t, J = 7.2 Hz, 2H), 1.64 - 1.56 (m, 2H), 1.48 - 1.38 (m, 2H), 1.38 - 1.20 (m, 6H), 0.96 - 0.82 (m, 3H). 13C NMR (101 MHz, CDCh) d 167.0, 164.9, 141.4, 135.8, 128.8,
128.5, 127.6, 110.7, 95.2, 90.6, 80.4, 74.0, 70.1, 68.4, 66.9, 66.6, 65.7, 31.9, 29.1, 28.9, 28.5, 22.8, 19.6, 14.2.
4-(Benzyloxy)-2-(non-l-yn-l-yl)-6-(oxepan-2-ylmethoxy)pyridine (7c). The target compound was synthesized as described for 7a using compound 6c (88.1 mg, 0.253 mmol) instead of 6a and purified by silica gel column chromatography (6% DEE in heptane) to yield 71 mg (73%) slightly yellow oil. Rf = 0.28 (DEE:PE, 2:8). JH NMR (600 MHz, CDCh) d 7.46 - 7.28 (m, 5H), 6.67 (d, J = 2.1 Hz, 1H), 6.28 (d, J = 2.1 Hz, 1H), 5.04 (s, 2H), 4.28 (dd, J = 11.1, 3.9 Hz, 1H), 4.24 (dd, J = 11.1, 7.2 Hz, 1H), 3.96 - 3.84 (m, 2H), 3.60 (ddd, J = 11.9, 7.6, 3.7 Hz, 1H), 2.40 (t, J = 7.2 Hz, 2H), 1.87 - 1.80 (m, 1H), 1.80 - 1.73 (m, 2H), 1.70 - 1.53 (m, 7H), 1.42 (p, J = 7.6 Hz, 2H), 1.35 - 1.24 (m, 6H), 0.89 (t, J = 6.8 Hz, 3H). 13C NMR (101 MHz, CDCh) d 166.9, 165.4, 141.4, 135.9, 128.8, 128.4, 127.6, 110.4, 95.2, 90.3, 80.6, 77.7, 70.0,
69.3, 68.8, 32.1, 31.9, 31.3, 29.1, 29.0, 28.6, 27.3, 25.7, 22.8, 19.6, 14.2. 4-(Benzyloxy)-2-((4-propylphenyl)ethynyl)-6-((tetrahydro-2H-pyran-2- yl)methoxy)pyridine (7d). The target compound was synthesized as described for 7a using 1- ethynyl-4-propylbenzene (40.1 mg, 0.28 mmol) instead of 1-nonyne and purified by silica gel column chromatography (50-70% DCM in heptane) to yield 49 mg (53%) slightly yellow oil. JH NMR (400 MHz, CDCI3) d 7.49 (d, 2H), 7.47 - 7.30 (m, 5H), 7.16 (d, J = 8.1 Hz, 2H), 6.82 (d, J = 2.1 Hz, 1H), 6.35 (d, J = 2.1 Hz, 1H), 5.07 (s, 2H), 4.41 (dd, J = 11.5, 3.1 Hz, 1H), 4.28 (dd, J = 11.5, 7.1 Hz, 1H), 4.14 - 4.00 (m, 1H), 3.78 - 3.64 (m, 1H), 3.50 (td, J = 11.5, 2.3 Hz, 1H), 2.60 (t, J = 7.6 Hz, 2H), 1.98 - 1.82 (m, 1H), 1.71 - 1.56 (m, 5H), 1.54 (ddt, J = 10.4, 7.2, 3.2 Hz, 2H), 1.51 - 1.37 (m, 1H), 0.94 (t, J = 7.4 Hz, 3H); 13C NMR (101 MHz, CDCI3) d 166.9,
165.4, 143.9, 141.0, 135.8, 132.1, 128.8, 128.6, 128.5, 127.6, 119.7, 110.9, 95.6, 88.7, 88.4,
76.2, 70.1, 69.6, 68.6, 38.1, 28.0, 26.0, 24.4, 23.3, 13.9.
4-(Benzyloxy)-2-(non-l-yn-l-yl)-6-((tetrahydrofuran-2-yl)methoxy)pyridine (7e). The target compound was synthesized as described for 7a using compound 6d (62.8 mg, 0.196 mmol) instead of 6a and purified by silica gel column chromatography (9% EtOAc in Heptane) to yield 57.4 mg (72%) slightly yellow oil. Rf = 0.16 (EtOAc:PE, 2:8). JH NMR (400 MHz, CDCI3) d 7.45 - 7.30 (m, 5H), 6.68 (d, J = 2.1 Hz, 1H), 6.28 (d, J = 2.1 Hz, 1H), 5.04 (s, 2H), 4.46 - 4.37 (m, 1H), 4.30 - 4.17 (m, 2H), 3.96 - 3.88 (m, 1H), 3.86 - 3.78 (m, 1H), 2.41 (t, J = 7.2 Hz, 2H), 2.08 - 1.84 (m, 3H), 1.75 - 1.56 (m, 3H), 1.49 - 1.39 (m, 2H), 1.39 - 1.20 (m, 6H), 0.89 (t, J = 6.7 Hz, 3H). 13C NMR (101 MHz, CDCI3) d 166.9, 165.3, 141.4, 135.9, 128.8, 128.4,
127.6, 110.6, 95.2, 90.4, 80.5, 77.2, 70.1, 68.6, 31.9, 29.1, 29.0, 28.5, 28.1, 25.8, 22.8, 19.6,
14.2.
4-(Benzyloxy)-N-octyl-6-((tetrahydro-2H-pyran-2-yl)methoxy)pyridin-2-amine (7f). In a microwave vial, octyl amine (35 mI, 0.21 mmol), 6a (69 mg, 0.21 mmol), and tBuONa (30.5 mg, 0.32 mmol) were suspended in anhydrous dioxane (0.2 ml). The mixture was evacuated and back-filled with argon (3x). Then, a solution of Pd3(dba)3 (9.5 mg, 10.4 mpioI) and XantPhos (6.1 mg, 10.5 mpioI) in 0.5 ml dioxane was added. The vial was capped and stirred at 100 °C for 43 h. The reaction mixture was vacuum-filtered through a thick bed of silica (EtOAc: heptane, 1: 1), concentrated onto Celite and purified by silica gel column chromatography (10% EtOAc in heptane) to afford 7f as a colorless oil (37 mg, 42%). Rf = 0.22 (EtOAc: heptane, 1:4); JH NMR
(600 MHz, CDC ) d 7.41 - 7.35 (m, 4H), 7.35 - 7.29 (m, 1H), 5.76 (d, J = 1.8 Hz, 1H), 5.55 (d,
J = 1.8 Hz, 1H), 5.01 (s, 2H), 4.45 - 4.24 (m, OH), 4.41 - 4.25 (m, 1H), 4.20 (dd, J = 11.1, 3.9 Hz, 1H), 4.16 (dd, J = 11.1, 6.6 Hz, 1H), 4.04 (ddt, J = 11.4, 3.9, 1.7 Hz, 1H), 3.66 (dddd, J = 10.8, 6.3, 4.0, 2.2 Hz, 1H), 3.48 (td, J = 11.8, 2.2 Hz, 1H), 3.13 (td, J = 7.3, 3.9 Hz, 2H), 1.93 - 1.83 (m, 1H), 1.68 - 1.61 (m, 2H), 1.61 - 1.55 (m, 3H), 1.54 - 1.48 (m, 2H), 1.45 - 1.34 (m,
3H), 1.33 - 1.23 (m, 8H), 0.88 (t, J = 7.0 Hz, 3H); 13C NMR (151 MHz, CDCI3) d 168.9, 164.6,
158.6, 136.6, 128.7, 128.2, 127.7, 85.0, 84.7, 76.2, 69.8, 69.0, 68.6, 42.7, 32.0, 29.7, 29.5,
29.4, 28.4, 27.3, 26.1, 23.3, 22.8, 14.2. General procedure for hydrogenolysis / hydrogenation for synthesis of compounds 5 and 8a-f as exemplified for compound 8a:
Example 2, 2-nonyl-6-((tetrahydro-2H-pyran-2-yl)methoxy)pyridin-4-ol (8a). 10% Pd-C (8.1 mg, 0.008 mmol) was added in a solution of 7a (64 mg, 0.152 mmol) in MeOH:EtOAc (1:2, 1.5ml). The suspension was first evacuated and backfilled with argon (x3), then evacuated and backfilled with H2 (x3) and left stirring at rt for 4 h. After removal of the H2, the reaction mixture was evaporated on Celite and purified by silica gel column chromatography (3-5% MeOH in DCM) to afford 8a (44mg, 86%) as a slightly yellow oil. Rf = 0.48 (DCM:MeOH, 9: 1), HPLC: 5.39 min, Purity: 97.69%. IR (neat) Amax 2923(s), 2852(m), 1610(s), 1587(s), 1488(m), 1440(s), 1225(m), 1160(s) cm 1. Ή NMR (600 MHz, DMSO) d 10.29 (s, 1H), 6.23 (d, J = 2.0 Hz, 1H), 5.89 (d, J = 1.9 Hz, 1H), 4.12 - 4.06 (m, 2H), 3.89 - 3.83 (m, 1H), 3.56 (dtd, J = 10.9, 5.2, 2.1 Hz, 1H), 3.36 - 3.32 (m, 1H), 2.47 (t, J = 7.5 Hz, 2H), 1.84 - 1.75 (m, 1H), 1.63 - 1.54 (m, 3H), 1.50 - 1.42 (m, 3H), 1.30 - 1.19 (m, 13H), 0.85 (t, J = 7.0 Hz, 3H). 13C NMR (151 MHz, DMSO) d 166.2, 164.2, 160.2, 104.9, 92.9, 75.3, 68.1, 67.2, 37.0, 31.3, 28.9, 28.9, 28.7, 28.6, 28.5, 27.8, 25.5, 22.6, 22.1, 13.9. HRMS (MALDI): m/z calcd for C20H33NO3 (M+H+) 336.2533, found 336.2534. HPLC: tR = 5.39 min, Purity: 97.69%.
Example 3, 2-nonyl-6-(((tetrahydro-2H-pyran-2-yl)methyl)amino)pyridin-4-ol (5). The target compound was synthesized as described for 8a using compound 4 (14.3 mg, 0.034 mmol) instead of 7a and purified by silica gel column chromatography (8-9% MeOH in DCM) to yield 9.7 mg (85%) colorless oil. Rf = 0.29 (DCM:MeOH, 9: 1), HPLC: 5.99 min, Purity: 99.9%. JH NMR (600 MHz, DMSO) d 10.94 (s, 1H), 6.51 (s, 1H), 5.90 (d, J = 1.9 Hz, 1H), 5.73 (d, J = 2.0 Hz, 1H), 3.91 - 3.83 (m, 1H), 3.43 - 3.36 (m, 1H), 3.37 - 3.28 (m, 1H), 3.26 - 3.18 (m, 1H), 3.16 - 3.07 (m, 1H), 2.42 (t, J = 7.6 Hz, 2H), 1.82 - 1.71 (m, 1H), 1.63 - 1.51 (m, 3H), 1.50 - 1.38 (m, 3H), 1.31 - 1.12 (m, 13H), 0.85 (t, J = 7.0 Hz, 3H). 13C NMR (151 MHz, DMSO) d 168.1, 157.5, 156.5, 102.1, 90.3, 75.8, 67.4, 46.3, 35.2, 31.3, 29.0, 28.9, 28.8, 28.7, 28.5, 28.4, 25.6,
22.6, 22.1, 13.9. HRMS (MALDI): m/z calcd for C20H34N2O2 (M+H+) 335.2693, found 335.2701. HPLC: tR = 5.99 min, Purity: 99.9%.
Example 1, 2-((l,4-dioxan-2-yl)methoxy)-6-nonylpyridin-4-ol (8b). The target compound was synthesized as described for 8a using compound 7b (190.0 mg, 0.449 mmol) instead of 7a and purified by silica gel column chromatography (10% MeOH in DCM) to yield 139 mg (92%) slightly yellow oil. Rf = 0.36 (DCM:MeOH, 9: 1), HPLC: 4.32 min, Purity: 98.3%. IR (neat) Amax 2923(m), 2853(m), 1611(s), 1588(m), 1489(m), 1448(m), 1222(m), 1129(s) cm 1. Ή NMR (600 MHz, DMSO) d 10.41 (s, 1H), 6.26 (d, J = 1.8 Hz, 1H), 5.92 (d, J = 1.9 Hz, 1H), 4.16 (dd, J = 11.4, 5.9 Hz, 1H), 4.11 (dd, J = 11.5, 4.4 Hz, 1H), 3.80 (dddd, J = 10.2, 5.9, 4.4, 2.6 Hz, 1H), 3.74 (td, J = 11.6, 2.7 Hz, 2H), 3.64 (dd, J = 11.5, 2.6 Hz, 1H), 3.58 (td, J = 11.3, 2.7 Hz, 1H), 3.47 (td, J = 11.2, 2.7 Hz, 1H), 3.33 (dd, J = 11.4, 10.0 Hz, 1H), 2.48 (t, J = 7.4 Hz, 2H), 1.59 (p, J = 7.3 Hz, 2H), 1.32 - 1.18 (m, 12H), 0.85 (t, J = 6.9 Hz, 3H). 13C NMR (151 MHz, DMSO) d 166.5, 163.9, 160.1, 105.2, 93.0, 73.3, 67.6, 65.8, 65.8, 64.7, 36.9, 31.3, 28.9, 28.9, 28.7, 28.6, 28.6, 22.1, 13.9. HRMS (MALDI): m/z calcd for CI9H3IN04 (M+H+) 338.2326, found 338.2327. HPLC: tR = 4.32 min, Purity: 98.3%.
Example 5, 2-nonyl-6-(oxepan-2-ylmethoxy)pyridin-4-ol (8c). The target compound was synthesized as described for 8a using compound 7c (70 mg, 0.161 mmol) instead of 7a and purified by silica gel column chromatography (4% MeOH in DCM) to yield 51 mg (91%) slightly yellow oil. Rf = 0.45 (DCM:MeOH, 9: 1), HPLC: 4.88 min, Purity: 99.57%. JH NMR (600 MHz, DMSO) d 10.28 (s, 1H), 6.23 (s, 1H), 5.88 (d, J = 1.9 Hz, 1H), 4.10 (dd, J = 11.0, 6.8 Hz, 1H), 4.03 (dd, J = 11.0, 4.7 Hz, 1H), 3.82 - 3.73 (m, 2H), 3.46 (ddd, J = 11.8, 7.5, 3.8 Hz, 1H), 2.47 (t, J = 7.5 Hz, 2H), 1.82 - 1.73 (m, 1H), 1.71 - 1.43 (m, 9H), 1.29 - 1.19 (m, 12H), 0.85 (t, J = 6.9 Hz, 3H). 13C NMR (151 MHz, DMSO) d 166.2, 164.3, 160.2, 104.9, 92.9, 76.8, 67.8, 67.6, 37.0, 31.5, 31.3, 30.7, 28.9, 28.9, 28.7, 28.6, 28.6, 26.5, 25.1, 22.1, 13.9. HRMS (MALDI): m/z calcd for C21H35NO3 (M+H+) 350.2690, found 350.2691. HPLC: tR = 4.88 min, Purity: 99.57%.
Example 4, 2-(4-propylphenethyl)-6-((tetrahydro-2H-pyran-2-yl)methoxy)pyridin-4-ol (8d). The target compound was synthesized as described for 8a using compound 7d (49 mg, 0.11 mmol) instead of 7a and purified by silica gel column chromatography (5-10% MeOH in DCM) to yield 39 mg (99%) slightly yellow oil. Rf = 0.49 (DCM:MeOH, 9.5:0.5), HPLC: 4.04 min, Purity: 99%. IR (neat) Amax 2930(m), 2858(m), 1610(s), 1587(s), 1512(m), 1488(m), 1439(s), 1225(m), 1160(s) cm 1. Ή NMR (600 MHz, DMSO) d 10.32 (s, 1H), 7.09 (d, J = 8.1 Hz, 2H), 7.06 (d, J = 8.1 Hz, 2H), 6.24 (d, J = 1.9 Hz, 1H), 5.91 (d, J = 1.9 Hz, 1H), 4.12 (d, J = 5.2 Hz, 2H), 3.87 (dt, J = 11.1, 2.2 Hz, 1H), 3.57 (dtd, J = 10.9, 5.2, 2.1 Hz, 1H), 3.35 (dd, J = 10.9, 3.5 Hz, 1H), 2.89 (t, J = 9.1, 6.5 Hz, 2H), 2.78 (t, J = 9.1, 6.5 Hz, 2H), 2.49 - 2.47 (m, 2H), 1.83 - 1.77 (m, 1H), 1.63 - 1.58 (m, 1H), 1.55 (h, 2H), 1.51 - 1.41 (m, 3H), 1.31 - 1.22 (m, 1H), 0.87 (t, J = 7.3 Hz, 3H). 13C NMR (151 MHz, DMSO-ds) d 166.3, 164.3, 159.3, 139.4, 138.7, 128.1, 128.1, 105.2, 93.1, 75.4, 68.2, 67.2, 38.7, 36.9, 34.0, 27.8, 25.5, 24.1, 22.6, 13.6; HRMS (MALDI): m/z calcd for C22H29NO3 (M+Na+) 378.2039, found 378.2039; HPLC: 4.04 min, Method A, Purity: 99.04%.
Example 9, 2-nonyl-6-((tetrahydrofuran-2-yl)methoxy)pyridin-4-ol (8e). The target compound was synthesized as described for 8a using compound 7e (57.4 mg, 0.141 mmol) instead of 7a and purified by silica gel column chromatography (5% MeOH in DCM) to yield 37.2 mg (82%) slightly yellow oil. Rf = 0.43 (DCM:MeOH, 9: 1), HPLC: 4.85 min, Purity: 99.9%. JH NMR (600 MHz, DMSO) d 10.31 (s, 1H), 6.24 (d, J = 1.9 Hz, 1H), 5.89 (d, J = 1.9 Hz, 1H), 4.17 - 4.06 (m, 3H), 3.79 - 3.72 (m, 1H), 3.67 - 3.61 (m, 1H), 2.47 (t, J = 7.5 Hz, 2H), 1.97 - 1.90 (m, 1H), 1.90 - 1.75 (m, 2H), 1.65 - 1.54 (m, 3H), 1.29 - 1.20 (m, 12H), 0.85 (t, J = 7.0 Hz, 3H). 13C NMR (151 MHz, DMSO) d 166.3, 164.3, 160.3, 105.0, 92.9, 76.4, 67.3, 67.2, 37.1, 31.3, 28.9, 28.9, 28.7, 28.6, 28.6, 27.7, 25.1, 22.1, 13.9. HRMS (MALDI): m/z calcd for C19H31NO3 (M+H+) 322.2377, found 322.2377. HPLC: tR = 4.85min, Purity: 99.99%.
Example 6, 2-(octylamino)-6-((tetrahydro-2H-pyran-2-yl)methoxy)pyridin-4-ol (8f).
The target compound was synthesized as described for 8a using compound 7f (37 mg, 0.09 mmol) instead of 7a and purified by silica gel column chromatography (3-5% MeOH in DCM) to yield 28 mg (96%) green oil that solidifies upon standing. Rf = 0.33 (DCM:MeOH, 9.5:0.5), HPLC: 4.15 min, Purity: 93%. IR (neat) Amax 3263(w), 3095(w), 2925(m), 2854(m), 1649(m), 1610(s), 1466(m), 1200(m), 1179(m) cm 1. JH NMR (600 MHz, CDCI3) d 5.65 (d, J = 1.7 Hz, 1H), 5.44 (d, J = 1.7 Hz, 1H), 4.17 (dd, J = 11.1, 3.5 Hz, 1H), 4.09 (dd, J = 11.2, 6.8 Hz, 1H), 4.06 - 4.00 (m, 1H), 3.69 (ddt, J = 12.7, 6.4, 2.8 Hz, 1H), 3.48 (td, J = 11.7, 2.2 Hz, 1H), 3.09 (t, J = 7.1 Hz, 2H), 1.87 (ddt, J = 13.5, 5.0, 2.7 Hz, 1H), 1.68 - 1.59 (m, 2H), 1.59 - 1.48 (m, 4H), 1.41 (qd, J = 12.4, 3.9 Hz, 1H), 1.37 - 1.31 (m, 2H), 1.31 - 1.21 (m, 8H), 0.88 (t, J = 6.9 Hz, 3H); 13C NMR (151 MHz, CDCI3) d 167.5, 163.8, 158.3, 86.2, 85.5, 76.4, 68.8, 68.4, 42.5, 31.8, 29.5,
29.4, 29.3, 28.0, 27.1, 25.9, 23.0, 22.7, 14.1. HRMS (MALDI): m/z calcd for C19H32N2O3 (M+H+) 337.2485, found 337.2478. HPLC: tR = 4.15 min, Purity: 93%.
4-((4-methoxybenzyl)oxy)-2-nonyl-6-(pyridin-2-ylmethoxy) pyridine (11). A flame dried flask was charged with Fe(acac)3 (5.7 mg, 0.016 mmol), and 10 (154. Omg, 0.432 mmol), then evacuated and backfilled with Ar(x3). THF:NMP (4: 1, 3.0 mL) was added, followed by dropwise addition of nonylmagnesium bromide (0.74 M in THF, 0.7 mL, 0.518 mmol). After 1 h, additional Grignard reagent (0.4 eq) was being added every 30 min for another 2 h. 30 min after the last addition saturated NH4CI (lOmL) was added and the mixture was extracted with EtOAc (3 x 15 mL). The combined organic phase was dried over Na2SC>4, filtrated and concentrated in vacuo. The residue was purified by silica gel column chromatography (20% EtOAc in Heptane) to afford 11 (114 mg, 59%) as colorless oil. Rf = 0.60 (EtOAc:PE, 5:5). JH NMR (600 MHz, CDCI3) d 8.62 - 8.57 (m, 1H), 7.66 (td, J = 7.7, 1.8 Hz, 1H), 7.45 (d, J = 7.8 Hz, 1H), 7.36 - 7.31 (m, 2H), 7.19 (ddd, J = 7.6, 4.8, 1.2 Hz, 1H), 6.94 - 6.89 (m, 2H), 6.38 (d, J = 2.0 Hz, 1H), 6.23 (d, J = 2.0 Hz, 1H), 5.50 (s, 2H), 4.97 (s, 2H), 3.82 (s, 3H), 2.57 (t, J = 7.7 Hz, 2H), 1.62 (p, J = 7.3 Hz, 2H), 1.31 - 1.21 (m, 12H), 0.88 (t, J = 7.0 Hz, 3H). 13C NMR (151 MHz, CDCI3) d 167.6, 164.5, 161.3, 159.8, 158.2, 149.3, 136.6, 129.5, 128.2, 122.4, 121.8, 114.2, 105.2, 92.2, 69.8, 68.3,
55.5, 38.1, 32.0, 29.7, 29.5, 29.4, 29.2, 22.8, 14.3.
Example 7, 2-Nonyl-6-(pyridin-2-ylmethoxy)pyridin-4-ol (12). To a solution of 11 (60.0 mg, 0.134 mmol) in DCM (1.5 mL) was added TFA (150 pL, 10% v/v). The mixture was stirred for 1 h at rt. Phosphate buffer (5 mL, pH 7.0, 0.1 M) was added, the phases were separated, and the aqueous (aq.) phase was extracted with DCM (2 x 5mL). The combined organic phase was dried over Na S0 , filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (10% MeOH in DCM) to afford 12 (42 mg, 96%) as colorless oil. Rf = 0.39 (DCM:MeOH, 9: 1), HPLC: 3.68 min, Purity: 98.73%. IR (neat) Amax 2923(m), 2853(m), 1611(m), 1587(s), 1436(m), 1160(s) cm 1. 1 H NMR (600 MHz, DMSO) d 10.39 (s, 1H), 8.55 - 8.49 (m, 1H), 7.76 (td, J = 7.7, 1.8 Hz, 1H), 7.38 (d, J = 7.8 Hz, 1H), 7.28 (ddd, J = 7.6, 4.9, 1.2 Hz, 1H), 6.27 (d, J = 1.9 Hz, 1H), 6.03 (d, J = 1.9 Hz, 1H), 5.35 (s, 2H), 2.46 (t, J = 7.5 Hz, 2H), 1.52 (p, J = 7.1 Hz, 2H), 1.27 - 1.17 (m, 12H), 0.84 (t, J = 7.0 Hz, 3H). 13C NMR (151 MHz, DMSO) d 166.4, 163.8, 160.3, 157.5, 148.9, 136.6, 122.5, 121.2, 105.3, 93.1, 67.2, 37.0, 31.3, 28.9, 28.8, 28.7, 28.5, 28.5, 22.1, 13.9. HRMS (MALDI): m/z calcd for C20H28N2O2 (M+H+) 329.2223, found 329.2223. HPLC: tR = 3.68 min, Purity: 98.73%.
Example 8, 2-nonyl-6-(pyridin-3-ylmethoxy)pyridin-4-ol (afforded as TFA salt) (12a).
The target compound was synthesized as described for 12 using compound 11a (55 mg, 0.123 mmol) instead of 11. Purification: 10-15% MeOH in DCM. Yield: 37mg, 68%, colorless oil. JH NMR (600 MHz, DMSO) d 8.78 (d, J = 2.2 Hz, 1H), 8.65 (dd, J = 5.1, 1.6 Hz, 1H), 8.10 (dt, J = 8.0, 1.9 Hz, 1H), 7.61 (dd, J = 7.9, 5.0 Hz, 1H), 6.41 (d, J = 1.9 Hz, 1H), 6.21 (d, J = 2.0 Hz, 1H), 5.40 (s, 2H), 2.54 (t, J = 7.6 Hz, 2H), 1.57 (p, J = 7.4 Hz, 2H), 1.29 - 1.17 (m, 12H), 0.84 (t, J = 6.9 Hz, 3H). 13C NMR (151 MHz, DMSO) d 168.4, 162.9, 159.0, 147.0, 146.9, 138.7,
133.8, 124.5, 105.8, 93.3, 65.2, 35.7, 31.3, 28.9, 28.8, 28.7, 28.5, 28.5, 22.1, 13.9. Rf = 0.35 (DCM:MeOH, 9: 1). HRMS (MALDI): m/z calcd for C20H28N2O2 (M + H+) 329.2223, found 329.2225.
2-Chloro-4-((4-methoxybenzyl)oxy)-6-(pyridin-3-ylmethoxy)pyridine (10a). The target compound was synthesized as described for 6a using pyridin-3-ylmethanol (0.03 mL, 0.309 mmol) instead of (tetrahydro-2H-pyran-2-yl)methanol and 9 (88.5 mg, 0.312 mmol) instead of 2 and purified by silica gel column chromatography (45% EtOAc in heptane) to yield 89 mg (80%) white solid. Rf = 0.13 (PE:EtOAc, 7:3). JH NMR (600 MHz, CDCI3) d 8.70 (d, J = 2.2 Hz, 1H), 8.57 (dd, J = 4.9, 1.6 Hz, 1H), 7.77 (dt, J = 7.8, 2.0 Hz, 1H), 7.33 - 7.27 (m, 3H), 6.95 - 6.89 (m, 2H), 6.60 (d, J = 1.9 Hz, 1H), 6.24 (d, J = 1.9 Hz, 1H), 5.36 (s, 2H), 4.98 (s, 2H), 3.82 (s, 3H). 13C NMR (151 MHz, CDCI3) d 168.5, 164.2, 160.0, 149.9, 149.6, 149.1, 136.1, 132.5, 129.5, 127.3, 123.5, 114.3, 106.4, 94.3, 70.5, 66.0, 55.5.
4-((4-Methoxybenzyl)oxy)-2-nonyl-6-(pyridin-3-ylmethoxy)pyridine (11a). The target compound was synthesized as described for 11 using 10a (86 mg, 0.241 mmol) instead of 10 and purified by silica gel column chromatography (40% EtOAc in heptane) to yield 55 mg (51%) colorless oil. Rf = 0.45 (EtOAc:PE, 5:5). JH NMR (600 MHz, CDCI3) d 8.71 (d, J = 2.2 Hz, 1H), 8.54 (dd, J = 4.9, 1.6 Hz, 1H), 7.78 (dt, J = 7.9, 2.0 Hz, 1H), 7.35 - 7.30 (m, 2H), 7.28 (dd, J =
7.8, 4.8 Hz, 1H), 6.94 - 6.88 (m, 2H), 6.39 (d, J = 2.0 Hz, 1H), 6.15 (d, J = 2.0 Hz, 1H), 5.39 (s, 2H), 4.96 (s, 2H), 3.81 (s, 3H), 2.60 (t, J = 7.6 Hz, 2H), 1.67 (p, J = 7.3 Hz, 2H), 1.36 - 1.21 (m, 12H), 0.88 (t, J = 7.2 Hz, 3H). 13C NMR (151 MHz, CDCI3) d 167.6, 164.4, 161.2, 159.8, 149.9, 149.2, 136.0, 133.6, 129.5, 128.1, 123.4, 114.2, 105.3, 92.3, 69.8, 65.0, 55.4, 38.1, 32.0, 29.7, 29.7, 29.5, 29.4, 29.3, 22.8, 14.3. 4-(Benzyloxy)-2-chloro-6-(2,2-dimethoxyethoxy)pyridine (6e). The target compound was synthesized as described for 6a using 2,2-dimethoxyethan-l-ol (38.0 pL, 0.376 mmol) and purified by silica gel column chromatography (8% EtOAc in heptane) to yield 63 mg (55%) colorless oil. Rf = 0.35 (PE:EtOAc, 8:2). JH NMR (600 MHz, CDCI3) d 7.47 - 7.30 (m, 5H), 6.59 (d, J = 1.9 Hz, 1H), 6.26 (d, J = 1.9 Hz, 1H), 5.05 (s, 2H), 4.70 (t, J = 5.2 Hz, 1H), 4.34 (d, J = 5.2 Hz, 2H), 3.44 (s, 6H). 13C NMR (151 MHz, CDCI3) d 168.4, 164.3, 149.1, 135.4, 128.9, 128.6, 127.6, 106.3, 101.8, 94.2, 70.5, 65.4, 54.1.
2-(Benzo[d][l,3]dioxol-2-ylmethoxy)-4-(benzyloxy)-6-chloropyridine (6f). The target compound was synthesized as described for 6a using benzo[d][l,3]dioxol-2-ylmethanol (77.8 mg, 0.51 mmol) and purified by silica gel column chromatography (5-7% DEE in heptane) to yield 188.1 mg (99%) colorless oil. Rf =0.5 (EtOAc: heptane, 1:4). *H NMR (400 MHz, CDC ) d 7.44 - 7.32 (m, 5H), 6.83 (s, 4H), 6.62 (d, J = 2.0 Hz, 1H), 6.43 (t, J = 4.2 Hz, 1H), 6.26 (d, J = 1.8 Hz, 1H), 5.05 (s, 2H), 4.60 (d, J = 4.1 Hz, 2H). 13C NMR (101 MHz, CDCI3) d 168.5, 163.9, 149.1, 147.3, 135.3, 128.9, 128.7, 127.7, 121.9, 108.9, 107.8, 106.7, 94.3, 70.6, 66.0.
4-(Benzyloxy)-2-chloro-6-((2,3-dihydrobenzofuran-2-yl)methoxy)pyridine (6g). The target compound was synthesized as described for 6a using (2,3-dihydrobenzofuran-2- yl)methanol (76.8 mg, 0.51 mmol) and purified by silica gel column chromatography (6% DEE in heptane) to yield 160.1 mg (85%) colorless oil. Rf =0.52 (EtOAc: heptane, 1:4). JH NMR (400 MHz, CDCI3) d 7.43 - 7.33 (m, 5H), 7.18 (d, J = 7.4 Hz, 1H), 7.12 (t, J = 7.7 Hz, 1H), 6.89 - 6.80 (m, 2H), 6.60 (d, J = 1.9 Hz, 1H), 6.28 (d, J = 1.9 Hz, 1H), 5.18 - 5.09 (m, 1H), 5.05 (s, 2H), 4.55 (dd, J = 11.6, 3.6 Hz, 1H), 4.45 (dd, J = 11.6, 7.2 Hz, 1H), 3.35 (dd, J = 15.7, 9.5 Hz, 1H), 3.07 (dd, J = 15.7, 7.5 Hz, 1H). 13C NMR (101 MHz, CDCI3) d 168.40, 164.53, 159.49, 149.08, 135.38, 128.93, 128.66, 128.28, 127.65, 126.16, 125.09, 120.75, 109.83, 106.39, 94.30, 80.59, 70.56, 68.38, 32.20.
4-(Benzyloxy)-2-chloro-6-((2,3-dihydrobenzo[b][l 4]dioxin-2-yl)methoxy)pyridine (6h). The target compound was synthesized as described for 6a using (2,3- dihydrobenzo[b][l,4]dioxin-2-yl)methanol (85 mg, 0.51 mmol) and purified by silica gel column chromatography (7% DEE in heptane) to yield 186.4 mg (94%) colorless oil. Rf =0.48 (EtOAc: heptane, 1:4). JH NMR (400 MHz, CDCI3) d 7.48 - 7.31 (m, 5H), 6.96 - 6.79 (m, 4H), 6.61 (d, J = 1.9 Hz, 1H), 6.26 (d, J = 1.9 Hz, 1H), 5.07 (s, 2H), 4.61 - 4.44 (m, 3H), 4.36 (dd, J = 11.5, 1.9 Hz, 1H), 4.19 - 4.11 (m, 1H). 13C NMR (101 MHz, CDCI3) d 168.5, 164.2, 149.2, 143.3, 143.1, 135.3, 129.0, 128.7, 127.7, 121.9, 121.6, 117.6, 117.3, 106.5, 94.3, 71.5, 70.6, 65.4, 65.0.
2-Chloro-4-((4-methoxybenzyl)oxy)-6-((tetrahydro-2H-pyran-2-yl)methoxy)pyridine (10b). The target compound was synthesized as described for 6a using (tetrahydro-2H-pyran-2- yl)methanol (0.2 mL, 1.77 mmol) and compound 10 (504 mg, 1.77 mmol) instead of 2 and purified by silica gel column chromatography (7% DEE in heptane) to yield 462.5 mg (72%) colorless oil. Rf =0.35 (EtOAc: heptane, 1:4). JH NMR (600 MHz, CDCh) d 7.32 - 7.28 (m, 2H), 6.94 - 6.89 (m, 2H), 6.55 (d, J = 1.8 Hz, 1H), 6.28 (d, J = 1.8 Hz, 1H), 4.96 (s, 2H), 4.31 (dd, J = 11.4, 3.0 Hz, 1H), 4.21 (dd, J = 11.4, 7.1 Hz, 1H), 4.09 - 4.02 (m, 1H), 3.82 (s, 3H), 3.71 - 3.65 (m, 1H), 3.49 (td, J = 11.7, 2.2 Hz, 1H), 1.93 - 1.86 (m, 1H), 1.66 - 1.56 (m, 2H), 1.55 - 1.50 (m, 2H), 1.42 (qd, 1H). 13C NMR (151 MHz, CDCh) d 168.3, 164.9, 160.0, 149.0, 129.5,
127.5, 114.3, 106.1, 94.2, 76.0, 70.4, 70.0, 68.6, 55.5, 28.0, 26.0, 23.2.
2-((l,3-Dioxan-2-yl)methoxy)-4-(benzyloxy)-6-chloropyridine (6i). To a solution of 6e (101.1 mg, 0.312 mmol) in DCM (1.6 mL) was added propane-1, 3-d iol (30 pL, 0.415 mmol) and para-toluenesulfonic acid (p-TsOH) (5.9 mg, 0.031 mmol) at rt. The mixture was stirred for 5 h, followed by quenching with triethylamine (TEA) (30 pL). The reaction mixture was concentrated in vacuo and purified by silica gel column chromatography (8-12 % EtOAc in heptane) to afford 7 (59 mg, 56 %) as colorless oil. Rf = 0.32 (PE:EtOAc, 7:3). JH NMR (400 MHz, CDCh) d 7.43 - 7.32 (m, 5H), 6.58 (d, J = 1.9 Hz, 1H), 6.29 (d, J = 1.8 Hz, 1H), 5.04 (s, 2H), 4.90 (t, J = 4.5
Hz, 1H), 4.33 (d, J = 4.4 Hz, 2H), 4.20 - 4.14 (m, 2H), 3.87 - 3.79 (m, 2H), 2.24 - 2.08 (m,
1H), 1.42 - 1.35 (m, 1H). 13C NMR (101 MHz, CDCh) d 168.3, 164.3, 149.1, 135.4, 128.9, 128.6,
127.6, 106.4, 99.1, 94.3, 70.5, 67.4, 67.1, 25.9.
4-(Benzyloxy)-2-((4-butylphenyl)ethynyl)-6-((tetrahydro-2H-pyran-2- yl)methoxy)pyridine (7g). The target compound was synthesized as described for 7a using 1- butyl-4-ethynylbenzene (34 mg, 0.21 mmol) instead of 1-nonyne and purified by silica gel column chromatography (70-100% DCM in heptane) to yield 36 mg (53%, slightly impure) slightly yellow oil. Rf = 0.38 (EtOAc: heptane, 1:4). *H NMR (600 MHz, CDCh) d 7.48 (d, J = 7.9 Hz, 2H), 7.39 (d, J = 4.3 Hz, 4H), 7.35 (h, J = 4.5, 4.0, 3.8 Hz, 1H), 7.16 (d, J = 7.9 Hz, 2H),
6.82 (d, J = 2.0 Hz, 1H), 6.35 (d, J = 2.0 Hz, 1H), 5.06 (s, 2H), 4.41 (dd, J = 11.4, 3.1 Hz, 1H),
4.28 (dd, J = 11.4, 7.1 Hz, 1H), 4.10 - 4.03 (m, 1H), 3.75 - 3.65 (m, 1H), 3.50 (td, J = 11.7, 2.1 Hz, 1H), 2.62 (t, J = 7.8 Hz, 2H), 1.95 - 1.82 (m, 1H), 1.67 - 1.57 (m, 4H), 1.57 - 1.50 (m, 2H), 1.45 (qd, J = 11.9, 3.7 Hz, 1H), 1.35 (h, J = 7.4 Hz, 2H), 0.93 (t, J = 7.4, 0.9 Hz, 3H). 13C NMR (151 MHz, CDCh) d 166.9, 165.4, 144.2, 141.0, 135.8, 132.1, 128.8, 128.6, 128.5, 127.6,
119.7, 110.9, 95.6, 88.7, 88.4, 76.2, 70.1, 69.6, 68.6, 35.8, 33.5, 28.0, 26.0, 23.3, 22.4, 14.0.
4-(Benzyloxy)-2-((4-isobutylphenyl)ethynyl)-6-((tetrahydro-2H-pyran-2- yl)methoxy)pyridine (7h). The target compound was synthesized as described for 7a using 1- ethynyl-4-isobutylbenzene (30 mg, 0.19 mmol) instead of 1-nonyne and purified by silica gel column chromatography (70-100% DCM in heptane) to yield 40 mg (59%) yellow oil. Rf = 0.34 (EtOAc: heptane, 1:4). *H NMR (600 MHz, CDCh) d 7.49 (d, J = 8.0 Hz, 2H), 7.39 (d, J = 4.4 Hz, 4H), 7.35 (h, J = 4.7, 3.9, 3.9 Hz, 1H), 7.13 (d, J = 7.9 Hz, 2H), 6.82 (d, J = 2.1 Hz, 1H), 6.35 (d, J = 2.1 Hz, 1H), 5.06 (s, 2H), 4.41 (dd, J = 11.4, 3.0 Hz, 1H), 4.28 (dd, J = 11.4, 7.1 Hz, 1H), 4.11 - 4.03 (m, 1H), 3.75 - 3.66 (m, 1H), 3.50 (td, J = 11.7, 2.1 Hz, 1H), 2.48 (d, J = 7.2 Hz, 2H), 1.93 - 1.83 (m, 2H), 1.67 - 1.60 (m, 2H), 1.60 - 1.50 (m, 2H), 1.45 (qd, J = 12.0, 3.7 Hz, 1H), 0.90 (d, J = 6.6 Hz, 6H). 13C NMR (151 MHz, CDCh) d 166.9, 165.4, 143.0, 141.0, 135.8, 131.9, 129.2, 128.8, 128.4, 127.6, 119.7, 110.9, 95.6, 88.7, 88.5, 76.2, 70.1, 69.6, 68.6,
45.5, 30.3, 28.0, 26.0, 23.3, 22.4.
4-(Benzyloxy)-2-((4-ethoxyphenyl)ethynyl)-6-((tetrahydro-2H-pyran-2- yl)methoxy)pyridine (7i). The target compound was synthesized as described for 7a using 1- ethoxy-4-ethynylbenzene (28 mg, 0.19 mmol) instead of 1-nonyne and purified by silica gel column chromatography (20% EtOAc in heptane) to yield 50 mg (80%) slightly yellow oil. Rf = 0.49 (EtOAc: heptane, 2:3). JH NMR (600 MHz, CDCh) d 7.54 - 7.47 (m, 2H), 7.39 (d, J = 4.4 Hz, 4H), 7.37 - 7.31 (m, 1H), 6.90 - 6.83 (m, 2H), 6.80 (d, J = 2.1 Hz, 1H), 6.34 (d, J = 2.1 Hz, 1H), 5.06 (s, 2H), 4.41 (dd, J = 11.4, 3.0 Hz, 1H), 4.28 (dd, J = 11.4, 7.1 Hz, 1H), 4.10 - 4.00 (m, 3H), 3.75 - 3.65 (m, 1H), 3.50 (td, J = 11.7, 2.1 Hz, 1H), 1.92 - 1.86 (m, 1H), 1.67 - 1.57 (m, 2H), 1.57 - 1.49 (m, 2H), 1.48 - 1.43 (m, 1H), 1.42 (t, J = 7.0 Hz, 3H). 13C NMR (151 MHz, CDCh) d 166.8, 165.4, 159.6, 141.1, 135.8, 133.7, 128.8, 128.4, 127.6, 114.6, 114.4, 110.7,
95.5, 88.7, 87.8, 76.2, 70.1, 69.5, 68.6, 63.6, 28.0, 26.0, 23.2, 14.9.
4-(Benzyloxy)-2-((tetrahydro-2H-pyran-2-yl)methoxy)-6-((4-
(trifluoromethyl)phenyl)ethynyl)pyridine (7j). The target compound was synthesized as described for 7a using l-trifluoromethyl-4-ethynylbenzene (50 m!_, 0.31 mmol) instead of 1- nonyne and purified by silica gel column chromatography (5-10% EtOAc in heptane) to yield 72 mg (74%) brown oil. Rf = 0.4 (EtOAc: heptane, 1 :4). JH NMR (400 MHz, CDCh) d 7.68 (d, J = 8.2 Hz, 2H), 7.61 (d, J = 8.3 Hz, 2H), 7.44 - 7.31 (m, 5H), 6.85 (d, J = 2.0 Hz, 1H), 6.39 (d, J = 2.1 Hz, 1H), 5.08 (s, 2H), 4.40 (dd, J = 11.4, 3.1 Hz, 1H), 4.29 (dd, J = 11.4, 7.0 Hz, 1H), 4.11 - 4.02 (m, 1H), 3.75 - 3.65 (m, 1H), 3.51 (td, J = 11.6, 2.4 Hz, 1H), 1.96 - 1.85 (m, 1H), 1.68 - 1.40 (m, 5H).. 13C NMR (151 MHz, CDCh) d 166.9, 165.6, 140.1, 135.7, 132.4, 130.6 (q, J = 32.8 Hz), 128.9, 128.5, 127.6, 126.5, 125.4 (q, J = 3.7 Hz), 124.1 (q, J = 272.0 Hz), 111.5, 96.2, 91.1, 86.6, 76.1, 70.2, 69.7, 68.6, 28.1, 26.0, 23.3.
4-(Benzyloxy)-2-((tetrahydro-2H-pyran-2-yl)methoxy)-6-((3-
(trifluoromethyl)phenyl)ethynyl)pyridine (7k). The target compound was synthesized as described for 7a using l-ethynyl-3-(trifluoromethyl)benzene (50 pL, 0.34 mmol) instead of 1- nonyne and purified by silica gel column chromatography (8% EtOAc in heptane) to yield 71 mg (73%) brown oil. Rf = 0.36 (EtOAc: heptane, 1 :4). *H NMR (400 MHz, CDCh) d 7.84 (d, J = 2.0 Hz, 1H), 7.74 (d, J = 7.7 Hz, 1H), 7.63 - 7.58 (m, 1H), 7.48 (t, J = 7.8 Hz, 1H), 7.42 - 7.32 (m, 5H), 6.84 (d, J = 2.1 Hz, 1H), 6.38 (d, J = 2.1 Hz, 1H), 5.08 (s, 2H), 4.40 (dd, J = 11.4, 3.0 Hz, 1H), 4.28 (dd, J = 11.4, 7.1 Hz, 1H), 4.12 - 4.02 (m, 1H), 3.76 - 3.64 (m, 1H), 3.50 (td, J =
11.6, 2.3 Hz, 1H), 1.96 - 1.83 (m, 1H), 1.67 - 1.40 (m, 5H). 13C NMR (101 MHz, CDCh) d 166.9,
165.6, 140.2, 135.7, 135.2, 131.3, 131.0, 129.0, 129.0, 128.9, 128.5, 127.6, 125.5 (q, J = 3.8 Hz), 123.6, 111.4, 96.2, 90.3, 86.5, 76.1, 70.2, 69.7, 68.6, 28.1, 26.0, 23.3. 4-(Benzyloxy)-2-((4-ethylphenyl)ethynyl)-6-((tetrahydro-2H-pyran-2- yl)methoxy)pyridine (71). The target compound was synthesized as described for 7a using 1- ethyl-4-ethynylbenzene (50 pL, 0.36 mmol) instead of 1-nonyne and purified by silica gel column chromatography (8% EtOAc in heptane) to yield 85 mg (89%) brown oil. Rf = 0.39 (EtOAc: heptane, 1:4). *H NMR (600 MHz, CDCI3) d 7.49 (d, J = 8.1 Hz, 2H), 7.40 (d, J = 4.4 Hz, 4H), 7.37 - 7.32 (m, 1H), 7.18 (d, J = 8.1 Hz, 2H), 6.82 (d, J = 2.1 Hz, 1H), 6.35 (d, J = 2.1 Hz, 1H), 5.07 (s, 2H), 4.41 (dd, J = 11.4, 3.0 Hz, 1H), 4.28 (dd, J = 11.4, 7.1 Hz, 1H), 4.09 - 4.04 (m, 1H), 3.72 - 3.67 (m, 1H), 3.50 (td, J = 11.7, 2.1 Hz, 1H), 2.66 (q, J = 7.6 Hz, 2H), 1.93 - 1.86 (m, 1H), 1.67 - 1.51 (m, 4H), 1.45 (qd, J = 12.3, 3.8 Hz, 1H), 1.24 (t, J = 7.6 Hz, 3H). 13C NMR (151 MHz, CDC ) d 166.9, 165.4, 145.4, 141.0, 135.8, 132.2, 128.8, 128. 5, 128.0, 127.6, 119.7, 110.9, 95.6, 88.7, 88.4, 76.2, 70.1, 69.6, 68.6, 29.0, 28.1, 26.0, 23.3, 15.4.
2-((l,4-Dioxan-2-yl)methoxy)-4-(benzyloxy)-6-((4-propylphenyl)ethynyl)pyridine (7m). The target compound was synthesized as described for 7a using 6b instead of 6a and 1- ethynyl-4-propylbenzene (60 pL, 0.379 mmol) instead of 1-nonyne and purified by silica gel column chromatography (14-16% EtOAc in heptane) to yield 90 mg (71%) orange oil. Rf = 0.29 (PE: EtOAc, 7:3). JH NMR (600 MHz, CDCh) d 7.51 - 7.45 (m, 2H), 7.42 - 7.33 (m, 5H), 7.18 - 7.13 (m, 2H), 6.83 (d, J = 2.1 Hz, 1H), 6.32 (d, J = 2.1 Hz, 1H), 5.08 (s, 2H), 4.40 - 4.33 (m, 2H), 3.99 (dddd, J = 10.1, 5.8, 4.3, 2.6 Hz, 1H), 3.89 - 3.84 (m, 2H), 3.80 (ddd, J = 11.8, 10.9, 2.8 Hz, 1H), 3.76 - 3.70 (m, 1H), 3.70 - 3.63 (m, 1H), 3.52 (dd, J = 11.5, 10.1 Hz, 1H), 2.60 (t, J = 7.7 Hz, 2H), 1.65 (h, J = 7.3 Hz, 2H), 0.94 (t, J = 7.4 Hz, 3H). 13C NMR (151 MHz, CDCI3) d 167.0, 165.0, 144.0, 141.1, 135.7, 132.1, 128.9, 128.7, 128.5, 127.6, 119.6, 111.0, 95.6, 88.9, 88.3, 74.0, 70.2, 68.4, 66.9, 66.6, 65.8, 38.1, 24.4, 13.9.
2-((l,4-Dioxan-2-yl)methoxy)-4-(benzyloxy)-6-((4-ethoxyphenyl)ethynyl)pyridine (7n). The target compound was synthesized as described for 7a using 6b instead of 6a and 1- ethoxy-4-ethynylbenzene (45 pL, 0.31 mmol) instead of 1-nonyne and purified by silica gel column chromatography (20-30% EtOAc in heptane) to yield 34.5 mg (39%) brown oil. Rf = 0.16 (EtOAc: heptane, 1:9). JH NMR (600 MHz, CDCh) d 7.52 - 7.48 (m, 2H), 7.43 - 7.32 (m, 6H), 6.89 - 6.82 (m, 2H), 6.81 (d, J = 2.0 Hz, 1H), 6.31 (d, J = 2.1 Hz, 1H), 5.07 (s, 2H), 4.41 - 4.30 (m, 2H), 4.05 (q, J = 7.0 Hz, 2H), 4.02 - 3.95 (m, 1H), 3.86 (dd, J = 11.6, 2.7 Hz, 2H), 3.80 (td, J = 11.3, 2.8 Hz, 1H), 3.73 (dd, J = 11.6, 2.5 Hz, 1H), 3.66 (td, J = 11.3, 2.9 Hz, 1H), 3.52 (dd, J = 11.5, 10.1 Hz, 1H), 1.42 (t, J = 7.0 Hz, 3H). 13C NMR (151 MHz, CDCI3) d 166.9, 164.8, 159.5, 141.1, 135.6, 133.6, 128.7, 128.4, 127.5, 114.5, 114.2, 110.7, 95.3, 88.8, 87.5, 73.8, 70.0, 68.3, 66.8, 66.5, 65.7, 63.5, 14.8.
2-((l,3-Dioxan-2-yl)methoxy)-4-(benzyloxy)-6-((4-propylphenyl)ethynyl)pyridine (7o). The target compound was synthesized as described for 7a using compound 6i (59 mg, 0.176 mmol) instead of 6a and l-ethynyl-4-propylbenzene (40 pL, 0.250 mmol) instead of 1- nonyne and purified by silica gel column chromatography (10-12% EtOAc in heptane) to yield 49 mg (63%) orange oil. Rf = 0.30 (PE:EtOAc, 7:3). NMR (600 MHz, CDCI3) d 7.53 - 7.47 (m, 2H), 7.43 - 7.32 (m, 5H), 7.20 - 7.14 (m, 2H), 6.82 (d, J = 2.1 Hz, 1H), 6.35 (d, J = 2.0 Hz, 1H), 5.06 (s, 2H), 4.93 (t, J = 4.5 Hz, 1H), 4.41 (d, J = 4.5 Hz, 2H), 4.21 - 4.16 (m, 2H), 3.88 - 3.82 (m, 2H), 2.60 (t, J = 7.5 Hz, 2H), 2.21 - 2.12 (m, 1H), 1.65 (h, J = 7.4 Hz, 2H), 1.41 - 1.36 (m, 1H), 0.94 (t, J = 7.3 Hz, 3H). 13C NMR (151 MHz, CDCh) d 167.0, 164.9, 144.0, 141.0, 135.8, 132.1, 128.9, 128.7, 128.5, 127.6, 119.7, 111.1, 99.4, 95.6, 88.8, 88.4, 70.2, 67.1, 67.1, 38.2, 25.9, 24.4, 13.9.
2-(Benzo[d][l,3]dioxol-2-ylmethoxy)-4-(benzyloxy)-6-((4- propylphenyl)ethynyl)pyridine (7p). The target compound was synthesized as described for 7a using compound 6f (107.8 mg, 0.29 mmol) instead of 6a and l-ethynyl-4-propylbenzene (60 pL, 0.38 mmol) instead of 1-nonyne and purified by silica gel column chromatography (6% DEE in heptane) to yield 80.5 mg (58%) yellow oil. Rf =0.30 (DEE:heptane, 1:9). JH NMR (400 MHz, CDCh) d 7.35 (d, J = 7.9 Hz, 2H), 7.30 - 7.19 (m, 5H), 7.03 (d, J = 8.1 Hz, 2H), 6.72 (d, J = 2.1 Hz, 1H), 6.70 (s, 4H), 6.33 (t, J = 4.2 Hz, 1H), 6.18 (d, J = 2.1 Hz, 1H), 4.94 (s, 2H), 4.54 (d, J = 4.3 Hz, 2H), 2.47 (t, J = 7.9, 7.1 Hz, 2H), 1.51 (h, J = 7.4 Hz, 2H), 0.81 (t, J = 7.3 Hz, 3H). 13C NMR (101 MHz, CDCh) d 167.2, 164.5, 147.4, 144.1, 141.1, 135.7, 132.1, 128.9, 128.7, 128.6, 127.6, 121.8, 119.6, 111.3, 108.9, 108.1, 95.6, 89.1, 88.1, 70.3, 65.7, 38.2, 24.4, 13.9.
4-(Benzyloxy)-2-((2,3-dihydrobenzofuran-2-yl)methoxy)-6-((4- propylphenyl)ethynyl)pyridine (7q). The target compound was synthesized as described for 7a using compound 6g (132.0 mg, 0.36 mmol) instead of 6a and l-ethynyl-4-propylbenzene (80 pL, 0.50 mmol) instead of 1-nonyne and purified by silica gel column chromatography (6% DEE in heptane) to yield 146.9 mg (86%) yellow oil. Rf = 0.20 (DEE:heptane, 1:9). JH NMR (400 MHz, CDCh) d 7.49 (d, J = 8.2 Hz, 2H), 7.44 - 7.32 (m, 5H), 7.21 - 7.09 (m, 4H), 6.89 - 6.81 (m, 3H), 6.34 (d, J = 2.1 Hz, 1H), 5.23 - 5.12 (m, 1H), 5.08 (s, 2H), 4.63 (dd, J = 11.6, 3.7 Hz, 1H), 4.53 (dd, J = 11.6, 7.2 Hz, 1H), 3.36 (dd, J = 15.7, 9.4 Hz, 1H), 3.10 (dd, J = 15.7, 7.5 Hz, 1H), 2.60 (t, J = 7.6 Hz, 2H), 1.64 (h, J = 7.5 Hz, 2H), 0.94 (t, J = 7.4 Hz, 3H). 13C NMR (101 MHz, CDCh) d 167.1, 165.1, 159.6, 144.0, 141.0, 135.7, 132.1, 128.9, 128.6, 128.5, 128.2, 127.6, 126.3, 125.1, 120.7, 119.6, 111.1, 109.8, 95.6, 89.0, 88.2, 80.9, 70.2, 68.0, 38.1, 32.3, 24.4, 13.9.
4-(Benzyloxy)-2-((2,3-dihydrobenzo[b][l 4]dioxin-2-yl)methoxy)-6-((4- propylphenyl)ethynyl)pyridine (7r). The target compound was synthesized as described for 7a using compound 6h (114.9 mg, 0.30 mmol) instead of 6a and l-ethynyl-4-propylbenzene (60 pL, 0.38 mmol) instead of 1-nonyne and purified by silica gel column chromatography (5-6% DEE in heptane) to yield 12 mg (8%) yellow oil. Rf = 0.24 (DEE:heptane, 1:9). JH NMR (600 MHz, CDCh) d 7.49 (d, J = 8.3 Hz, 2H), 7.41 (d, J = 4.4 Hz, 4H), 7.38 - 7.34 (m, 1H), 7.17 (d, J = 7.9 Hz, 2H), 6.96 - 6.92 (m, 1H), 6.92 - 6.88 (m, 1H), 6.88 - 6.82 (m, 3H), 6.32 (d, J = 2.0 Hz, 1H), 5.09 (s, 2H), 4.68 - 4.63 (m, 1H), 4.60 - 4.54 (m, 2H), 4.38 (dd, J = 11.3, 2.0 Hz, 1H), 4.17 (dd, J = 11.4, 6.6 Hz, 1H), 2.61 (t, J = 7.6 Hz, 2H), 1.66 (h, J = 7.8, 7.2, 6.8 Hz, 2H), 0.95 (t, J = 7.3 Hz, 3H). 13C NMR (151 MHz, CDCh) d 167.1, 164.7, 144.1, 143.3, 143.2, 141.2,
135.7, 132.1, 128.9, 128.7, 128.6, 127.6, 121.8, 121.6, 119.6, 117.6, 117.3, 111.1, 95.5, 89.1,
88.2, 71.7, 70.3, 65.5, 64.7, 38.1, 24.4, 13.9.
General procedure for Suzuki coupling for synthesis of compounds 7s-t as exemplified for compound 7s.
4-(Benzyloxy)-2-(4-pentylphenyl)-6-((tetrahydro-2H-pyran-2-yl)methoxy)pyridine (7s). A flame-dried MW vial was charged with (4-pentylphenyl)boronic acid (80.6 mg, 0.42 mmol, 2.0 eq), 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (SPhos, 8.6 mg, 0.021 mmol, 0.1 eq), Pd(MeCN)2Cl2 (2.7 mg, 0.01 mmol, 0.05 eq), and K3P0 (89 mg, 0.42 mmol, 2.0 eq). The vial was evacuated and backfilled with Ar (x 3). Then, a solution of 6a (70.1 mg, 0.21 mmol) in anhydrous toluene (2.1 mL) was added. The vial was sealed and stirred at 100 °C for 2 d. The cooled reaction mixture was diluted with 10 mL water and extracted with DCM (3 x 10 mL). The organic phase was dried over anhydrous Na2S0 , evaporated onto Celite, and purified by flash chromatography (2-7% EtOAc in heptane) to afford 7s as a colorless oil (80 mg, 85%). Rf = 0.5 (EtOAc: heptane, 1:4). *H NMR (400 MHz, CDCh) d 7.89 (d, J = 8.2 Hz, 2H), 7.46 - 7.32 (m, 5H), 7.24 (d, J = 8.1 Hz, 2H), 6.98 (d, J = 1.9 Hz, 1H), 6.31 (d, J = 1.9 Hz, 1H), 5.10 (s, 2H), 4.48 (dd, J = 11.4, 3.5 Hz, 1H), 4.37 (dd, J = 11.4, 6.7 Hz, 1H), 4.13 - 4.04 (m, 1H), 3.81 - 3.70 (m, 1H), 3.51 (td, J = 11.6, 2.3 Hz, 1H), 2.64 (t, 2H), 1.95 - 1.87 (m, 1H), 1.73 - 1.42 (m, 7H), 1.40 - 1.29 (m, 4H), 0.89 (t, 3H). 13C NMR (101 MHz, CDCh) d 167.8, 165.2, 155.5, 144.1, 136.6, 136.2, 128.8, 128.8, 128.4, 127.7, 126.7, 103.0, 93.5, 76.3, 70.1, 69.2, 68.7, 35.9, 31.6,
31.2, 28.4, 26.1, 23.3, 22.7, 14.2.
4-(Benzyloxy)-2-(4-phenoxyphenyl)-6-((tetrahydro-2H-pyran-2-yl)methoxy)pyridine (7t). The target compound was synthesized as described for 7s using compound (4- phenoxyphenyl)boronic acid (89.8 mg, 0.42 mmol) instead of (4-pentylphenyl)boronic acid and purified by silica gel column chromatography (10% EtOAc in heptane) to yield 85.5 mg (87%) colorless oil. Rf = 0.20 (EtOAc: heptane, 1:9). JH NMR (600 MHz, CDCh) d 7.96 (d, J = 8.7 Hz, 2H), 7.45 - 7.38 (m, 4H), 7.38 - 7.33 (m, 3H), 7.13 (t, J = 7.4, 1.2 Hz, 1H), 7.08 - 7.03 (m, 4H), 6.96 (d, J = 1.9 Hz, 1H), 6.31 (d, J = 1.9 Hz, 1H), 5.10 (s, 2H), 4.46 (dd, J = 11.4, 3.5 Hz, 1H), 4.37 (dd, J = 11.4, 6.8 Hz, 1H), 4.11 - 4.04 (m, 1H), 3.78 - 3.71 (m, 1H), 3.51 (td, J =
11.7, 2.1 Hz, 1H), 1.95 - 1.86 (m, 1H), 1.72 - 1.67 (m, 1H), 1.67 - 1.58 (m, 1H), 1.58 - 1.51 (m, 2H), 1.46 (qd, J = 12.3, 3.7 Hz, 1H). 13C NMR (151 MHz, CDCh) d 167.8, 165.2, 158.3, 157.1, 154.8, 136.1, 134.2, 130.0, 128.9, 128.4, 128.3, 127.7, 123.7, 119.3, 118.7, 102.9, 93.4, 76.3, 70.1, 69.3, 68.7, 28.3, 26.1, 23.3.
Example 10, 2-(4-butylphenethyl)-6-((tetrahydro-2H-pyran-2-yl)methoxy)pyridin-4-ol (8g). The target compound was synthesized as described for 8a using compound 7g (36 mg, 0.08 mmol) instead of 7a and purified by silica gel column chromatography (3% MeOH in DCM) to yield 25 mg (86%) slightly yellow oil. Rf = 0.28 (MeOH:DCM, 5:95).
Figure imgf000072_0001
NMR (600 MHz, DMSO) d 10.31 (s, 1H), 7.09 (d, J = 8.1 Hz, 2H), 7.06 (d, J = 8.1 Hz, 2H), 6.24 (s, 1H), 5.91 (d, J = 1.9 Hz, 1H), 4.11 (d, 2H), 3.91 - 3.82 (m, 1H), 3.62 - 3.54 (m, 1H), 3.38 - 3.33 (m, 1H), 2.91 - 2.85 (m, 2H), 2.80 - 2.74 (m, 2H), 2.53 - 2.51 (m, 2H), 1.84 - 1.75 (m, 1H), 1.63 - 1.56 (m, 1H), 1.54 - 1.48 (m, 2H), 1.48 - 1.42 (m, 3H), 1.31 - 1.23 (m, 3H), 0.88 (t, J = 7.4 Hz, 3H); 13C NMR (151 MHz, DMSO-ds) d 166.7, 164.7, 159.8, 140.0, 139.1, 128.6, 128.6, 105.7, 93.6, 75.9, 68.7, 67.7, 39.2, 34.9, 34.5, 33.7, 28.2, 26.0, 23.1, 22.2, 14.2; HRMS (MALDI) : m/z calcd for C23H31NO3 (M + Na+) 392.2196, found 392.2195. HPLC: tR = 4.62 min, Purity: 99.36%.
Example 11, 2-(4-isobutylphenethyl)-6-((tetrahydro-2H-pyran-2-yl)methoxy)pyridin- 4-ol (8h). The target compound was synthesized as described for 8a using compound 7h (30 mg, 0.07 mmol) instead of 7a and purified by silica gel column chromatography (3% MeOH in DCM) to yield 23 mg (95%) slightly yellow oil. Rf = 0.28 (MeOH:DCM, 5:95). JH NMR (600 MHz, DMSO) d 10.31 (s, 1H), 7.09 (d, J = 7.9 Hz, 2H), 7.03 (d, J = 8.0 Hz, 2H), 6.24 (d, J = 1.9 Hz, 1H), 5.91 (d, J = 1.9 Hz, 1H), 4.12 (d, J = 5.2 Hz, 2H), 3.90 - 3.85 (m, 1H), 3.60 - 3.54 (m, 1H), 3.37 - 3.33 (m, 1H), 2.92 - 2.85 (m, 2H), 2.81 - 2.76 (m, 2H), 2.39 (d, J = 7.1 Hz, 2H), 1.84 - 1.73 (m, 2H), 1.63 - 1.56 (m, 1H), 1.52 - 1.41 (m, 3H), 1.31 - 1.22 (m, 1H), 0.86 - 0.81 (m, 6H). 13C NMR (151 MHz, DMSO-ds) d 166.7, 164.8, 159.8, 139.2, 138.8, 129.2, 128.5, 105.6, 93.6, 75.9, 68.7, 67.7, 44.7, 39.2, 34.5, 30.1, 28.2, 26.0, 23.1, 22.6; HRMS (MALDI) : m/z calcd for C23H31NO3 (M+H+) 370.2377, found 370.2377. HPLC: tR = 4.56 min, Purity: 98.36%.
Example 12, 2-(4-ethoxyphenethyl)-6-((tetrahydro-2H-pyran-2-yl)methoxy)pyridin-4- ol (8i). The target compound was synthesized as described for 8a using compound 7i (39 mg, 0.088 mmol) instead of 7a and purified by silica gel column chromatography (3-10% MeOH in DCM) to yield 29.7 mg (95%) slightly yellow oil. Rf = 0.22 (MeOH:DCM, 5:95). IR (neat) Amax 2935(w), 2853(w), 1610(s), 1586(w), 1510(s), 1478(m), 1440(m), 1227(s), 1160(m) cm 1. Ή NMR (400 MHz, DMSO) d 10.30 (s, 1H), 7.07 (d, J = 8.6 Hz, 2H), 6.79 (d, J = 8.6 Hz, 2H), 6.22 (d, J = 1.9 Hz, 1H), 5.90 (d, J = 1.8 Hz, 1H), 4.11 (d, J = 5.2 Hz, 2H), 3.96 (q, J = 7.0 Hz, 2H), 3.90 - 3.84 (m, 1H), 3.61 - 3.53 (m, 1H), 3.39 - 3.33 (m, 1H), 2.89 - 2.81 (m, 2H), 2.79 - 2.72 (m, 2H), 1.84 - 1.76 (m, 1H), 1.63 - 1.56 (m, 1H), 1.52 - 1.43 (m, 3H), 1.29 (t, J = 6.9 Hz, 3H), 1.27 - 1.15 (m, 1H). 13C NMR (151 MHz, DMSO) d 166.2, 164.3, 159.3, 156.6, 133.2, 129.2, 114.1, 105.2, 93.1, 75.4, 68.2, 67.2, 62.8, 39.4 (masked by solvent peak), 33.6, 27.7, 25.5, 22.6, 14.7. HRMS (MALDI) : m/z calcd for C21H27NO4 (M+H+) 358.2013, found 358.2010. HPLC: tR = 3.42 min, Purity: 99.99%.
Example 13, 2-((tetrahydro-2H-pyran-2-yl)methoxy)-6-(4-(trifluoromethyl)- phenethyl)pyridin-4-ol (8j). The target compound was synthesized as described for 8a using compound 7j (61 mg, 0.13 mmol) instead of 7a and purified by silica gel column chromatography (3-6% MeOH in DCM) to yield 32.8 mg (66%) slightly yellow oil. Rf = 0.16 (MeOH:DCM, 5:95). IR (neat) Amax 2940(w), 2854(w), 1612(m), 1589(m), 1488(m), 1441(s), 1325(s), 1226(w), 1160(m), 1066(s) cm 1. 1 H NMR (600 MHz, DMSO) d 10.33 (s, 1H), 7.60 (d, J = 8.1 Hz, 2H), 7.42 (d, J = 8.0 Hz, 2H), 6.24 (s, 1H), 5.91 (s, 1H), 4.09 (d, J = 5.2 Hz, 2H), 3.90 - 3.83 (m, 1H), 3.59 - 3.51 (m, 1H), 3.37 - 3.33 (m, 1H), 3.03 (t, J = 7.6 Hz, 2H), 2.85 (t, J = 8.0, 7.3 Hz, 2H), 1.83 - 1.75 (m, 1H), 1.61 - 1.55 (m, 1H), 1.52 - 1.42 (m, 3H), 1.31 - 1.21 (m, 1H). 13C NMR (151 MHz, DMSO) d 166.3, 164.3, 158.7, 146.5, 129.1, 126.5 (q, J = 31.5 Hz), 125.0 (q, J = 3.8 Hz), 124.4 (q), 105.3, 93.3, 75.3, 68.2, 67.2, 38.0, 34.0, 27.7, 25.5, 22.6. HRMS (MALDI): m/z calcd for C20H22F3NO3 (M+H+) 382.1624, found 382.1623. HPLC: tR = 3.59 min, Purity: 99.99%.
Example 14, 2-((tetrahydro-2H-pyran-2-yl)methoxy)-6-(3-(trifluoromethyl)- phenethyl)pyridin-4-ol (8k). The target compound was synthesized as described for 8a using compound 7k (61 mg, 0.13 mmol) instead of 7a and purified by silica gel column chromatography (6% MeOH in DCM) to yield 28.1 mg (56%) slightly yellow oil. Rf = 0.17 (MeOH:DCM, 5:95). JH NMR (600 MHz, DMSO) d 10.33 (s, 1H), 7.54 - 7.46 (m, 4H), 6.24 (s, 1H), 5.91 (s, 1H), 4.10 (d, J = 5.2 Hz, 2H), 3.90 - 3.83 (m, 1H), 3.59 - 3.52 (m, 1H), 3.38 - 3.33 (m, 1H), 3.04 (t, J = 8.5, 6.8 Hz, 2H), 2.85 (t, J = 8.5, 6.8 Hz, 2H), 1.83 - 1.74 (m, 1H), 1.62 - 1.55 (m, 1H), 1.51 - 1.41 (m, 3H), 1.31 - 1.21 (m, 1H). 13C NMR (151 MHz, DMSO) d 166.29, 164.30, 158.73, 142.98, 132.55, 129.12, 128.89 (q, J = 31.2 Hz), 124.86 (q, J = 3.7 Hz), 124.33 (q, J = 272.3 Hz), 122.50 (q, J = 3.9 Hz), 105.36, 93.23, 75.36, 68.18, 67.21, 38.12, 33.92, 27.73, 25.54, 22.61. HRMS (MALDI): m/z calcd for C20H22F3NO3 (M+H+) 382.1624, found 382.1623. HPLC: tR = 3.56 min, Purity: 99.59%.
Example 15, 2-(4-ethylphenethyl)-6-((tetrahydro-2H-pyran-2-yl)methoxy)pyridin-4-ol (81). The target compound was synthesized as described for 8a using compound 71 (78 mg, 0.18 mmol) instead of 7a and purified by silica gel column chromatography (6% MeOH in DCM) to yield 42 mg (67%) slightly yellow oil. Rf = 0.15 (MeOH:DCM, 5:95). JH NMR (600 MHz, DMSO) d 10.31 (s, 1H), 7.11 - 7.07 (m, 4H), 6.24 (s, 1H), 5.91 (d, J = 1.9 Hz, 1H), 4.12 (d, J = 5.2 Hz, 2H), 3.90 - 3.83 (m, 1H), 3.61 - 3.53 (m, 1H), 3.38 - 3.33 (m, 1H), 2.92 - 2.86 (m, 2H), 2.80 - 2.76 (m, 2H), 2.54 (q, J = 7.6 Hz, 2H), 1.84 - 1.77 (m, 1H), 1.63 - 1.57 (m, 1H), 1.52 - 1.42 (m, 3H), 1.32 - 1.22 (m, 1H), 1.15 (t, J = 7.6 Hz, 3H). 13C NMR (151 MHz, DMSO) d 166.7, 164.8, 159.8, 141.5, 139.2, 128.7, 128.0, 105.7, 93.6, 75.9, 68.7, 67.7, 39.2, 34.5, 28.2, 28.2, 26.0, 23.1, 16.1. HRMS (MALDI): m/z calcd for C21H27NO3 (M+H+) 342.2064, found 342.2065. HPLC: tR = 3.67 min, Purity: 99.87%.
Example 16, 2-((l,4-dioxan-2-yl)methoxy)-6-(4-propylphenethyl)pyridin-4-ol (8m).
The target compound was synthesized as described for 8a using compound 7m (90 mg, 0.203 mmol) instead of 7a and purified by silica gel column chromatography (5% MeOH in DCM) to yield 64 mg (88%) slightly yellow oil. Rf = 0.46 (DCM:MeOH, 9: 1). JH NMR (600 MHz, DMSO) d 10.38 (s, 1H), 7.10 (d, J = 8.1 Hz, 2H), 7.06 (d, J = 8.1 Hz, 2H), 6.26 (d, J = 1.9 Hz, 1H), 5.93 (d, J = 1.9 Hz, 1H), 4.18 (dd, J = 11.5, 5.9 Hz, 1H), 4.14 (dd, J = 11.5, 4.3 Hz, 1H), 3.82 (dddd, J = 10.1, 5.9, 4.3, 2.6 Hz, 1H), 3.77 (dd, J = 11.4, 2.7 Hz, 1H), 3.76 - 3.72 (m, 1H), 3.65 (dd, J = 11.3, 2.6 Hz, 1H), 3.59 (td, J = 11.3, 2.6 Hz, 1H), 3.48 (td, J = 11.2, 2.7 Hz, 1H), 3.35 (dd, J = 11.4, 9.9 Hz, 1H), 2.89 (dd, J = 9.1, 6.5 Hz, 2H), 2.79 (dd, J = 9.2, 6.4 Hz, 2H), 2.48 (t, J = 7.1 Hz, 2H), 1.55 (h, J = 7.3 Hz, 2H), 0.87 (t, J = 7.3 Hz, 3H). 13C NMR (151 MHz, DMSO) d 166.5, 163.9, 159.2, 139.4, 138.6, 128.1, 128.1, 105.4, 93.2, 73.3, 67.6, 65.8, 65.8, 64.7, 38.6, 36.9, 34.1, 24.1, 13.6. HRMS (MALDI) : m/z calcd for C21H27NO4 (M+H+) 358.2013, found
358.2012. HPLC: tR = 3.73 min, Purity: 99.99%.
Example 17, 2-((l,4-dioxan-2-yl)methoxy)-6-(4-ethoxyphenethyl)pyridin-4-ol (8n).
The target compound was synthesized as described for 8a using compound 7n (34.5 mg, 0.077 mmol) instead of 7a and purified by silica gel column chromatography (1-6% MeOH in DCM) to yield 20.2 mg (73%) colorless oil. Rf = 0.60 (EtOAcDCM, 1 :9). IR (neat) Amax 2915(w), 2856(m), 1610(s), 1587(m), 1510(s), 1479(m), 1444(m), 1241(s), 1162(m) cm 1. JH NMR (600 MHz, CDCI3) d 7.08 - 7.03 (m, 2H), 6.81 - 6.77 (m, 2H), 6.25 (d, J = 1.9 Hz, 1H), 6.00 (d, J = 1.9 Hz, 1H), 4.16 (qd, J = 11.1, 5.0 Hz, 2H), 3.99 (q, J = 7.0 Hz, 2H), 3.96 - 3.91 (m, 1H), 3.82 (td, J = 11.3, 2.8 Hz, 2H), 3.78 - 3.67 (m, 2H), 3.62 (td, J = 11.3, 3.0 Hz, 1H), 3.47 (dd, J = 11.6, 10.0 Hz, 1H), 2.92 - 2.86 (m, 2H), 2.83 - 2.77 (m, 2H), 1.39 (t, J = 7.0 Hz, 3H). 13C NMR (151 MHz, CDCI3) d 174.1, 163.0, 157.4, 133.2, 129.4, 107.6, 94.1, 73.7, 68.3, 66.5, 63.6, 38.5, 34.4, 15.0. HPLC: tR = 8.22 min, Purity: 97.09%.
Example 18, 2-((l,3-dioxan-2-yl)methoxy)-6-(4-propylphenethyl)pyridin-4-ol (80). The target compound was synthesized as described for 8a using compound 7o (48 mg, 0.111 mmol) instead of 7a and purified by silica gel column chromatography (5% MeOH in DCM) to yield 31 mg (79%) slightly yellow oil. Rf = 0.55 (DCM :MeOH, 9: 1). IR (neat) Amax 2927(w), 2859(w), 1612(m), 1590(m), 1513(m), 1488(m), 1440(s), 1227(m), 1160(s) cm 1. JH NMR (600 MHz, DMSO) d 10.46 (s, 1H), 7.10 (d, J = 8.1 Hz, 2H), 7.06 (d, J = 8.0 Hz, 2H), 6.29 (s, 1H), 5.96 (s, 1H), 4.86 (t, J = 4.6 Hz, 1H), 4.15 (d, J = 4.6 Hz, 2H), 4.06 - 4.00 (m, 2H), 3.75 (td, J = 12.2, 2.4 Hz, 2H), 2.89 (t, J = 7.2 Hz, 2H), 2.80 (t, J = 7.8 Hz, 2H), 2.49 (t, J = 7.3 Hz, 2H), 1.92 (qt, J = 12.6, 5.0 Hz, 1H), 1.55 (h, J = 7.3 Hz, 2H), 1.40 - 1.35 (m, 1H), 0.87 (t, J = 7.3 Hz, 3H). 13C NMR (151 MHz, DMSO) d 167.3, 164.0, 159.4, 139.9, 139.0, 128.6, 128.6, 106.1, 99.1, 93.7, 66.7, 66.4, 38.9, 37.3, 34.4, 25.8, 24.6, 14.1. HRMS (MALDI) : m/z calcd for C21H27NO4 (M+H+)
358.2013, found 358.2013. HPLC: tR = 4.00 min, Purity: 99.22%.
Example 19, 2-(benzo[d][l,3]dioxol-2-ylmethoxy)-6-(4-propylphenethyl)pyridin-4-ol (8p). The target compound was synthesized as described for 8a using compound 7p (69.2 mg, 0.14 mmol) instead of 7a and purified by silica gel column chromatography (6% MeOH in DCM) to yield 52.4 mg (92%) yellow oil. Rf =0.3 (MeOH:DCM, 5:95). JH NMR (400 MHz, DMSO) d 10.44 (s, 1H), 7.11 - 7.03 (m, 4H), 6.93 - 6.88 (m, 2H), 6.87 - 6.81 (m, 2H), 6.50 (t, J = 3.8 Hz, 1H), 6.30 (s, 1H), 5.92 (s, 1H), 4.54 (d, J = 3.8 Hz, 2H), 2.92 - 2.85 (m, 2H), 2.84 - 2.74 (m, 2H), 2.48 - 2.43 (m, 2H), 1.54 (h, J = 7.4 Hz, 2H), 0.86 (t, J = 7.3 Hz, 3H). 13C NMR (101 MHz, DMSO) d 166.6, 163.4, 159.4, 146.9, 139.4, 138.6, 128.1, 128.1, 121.6, 108.4, 107.8, 105.8,
93.2, 64.2, 38.6, 36.8, 34.0, 24.1, 13.6. HRMS (MALDI): m/z calcd for C24H25NO4 (M+H+) 392.1856, found 392.1855. HPLC: tR = 4.22 min, Purity: 99.04%.
Example 20, 2-((2,3-dihydrobenzofuran-2-yl)methoxy)-6-(4-propylphenethyl)pyridin- 4-ol (8q). The target compound was synthesized as described for 8a using compound 7q (97 mg, 0.20 mmol) instead of 7a and purified by silica gel column chromatography (6% MeOH in DCM) to yield 77.2 mg (97%) yellow oil. Rf =0.31 (MeOH:DCM, 5:95). JH NMR (400 MHz, DMSO) d 10.37 (s, 1H), 7.21 (d, J = 7.3 Hz, 1H), 7.12 - 7.00 (m, 5H), 6.86 - 6.79 (m, 1H), 6.76 (d, J =
7.9 Hz, 1H), 6.28 (d, J = 1.9 Hz, 1H), 5.93 (d, J = 1.9 Hz, 1H), 5.13 - 5.02 (m, 1H), 4.45 - 4.31
(m, 2H), 3.30 - 3.24 (m, 1H), 3.03 (dd, J = 15.9, 7.5 Hz, 1H), 2.92 - 2.85 (m, 2H), 2.83 - 2.75
(m, 2H), 2.48 - 2.41 (m, 2H), 1.53 (h, J = 7.6, 7.2, 6.9 Hz, 2H), 0.86 (t, J = 7.3 Hz, 3H). 13C
NMR (101 MHz, DMSO) d 166.4, 164.0, 159.4, 159.0, 139.4, 138.7, 128.1, 127.8, 126.5, 125.1,
120.2, 109.0, 105.5, 93.2, 80.5, 66.7, 38.7, 36.8, 34.1, 31.3, 24.1, 13.6. HRMS (MALDI): m/z calcd for C25H27NO3 (M+H+) 390.2064, found 390.2063. HPLC: tR = 3.63 min, Purity: 99.70%.
Example 21, 2-((2,3-dihydrobenzo[b][l,4]dioxin-2-yl)methoxy)-6-(4-propyl- phenethyl)pyridin-4-ol (8r). The target compound was synthesized as described for 8a using compound 7r (12 mg, 0.024 mmol) instead of 7a and purified by silica gel column chromatography (6% MeOH in DCM) to yield 8.3 mg (84%) slightly yellow oil. Rf =0.31 (MeOH:DCM, 5:95). IR (neat) Amax 2928(w), 2870(w), 1610(m), 1592(m), 1512(w), 1490(s), 1441(m), 1265(m), 1159(m) cm 1. JH NMR (600 MHz, DMSO) d 10.43 (s, 1H), 7.10 (d, J = 8.0 Hz, 2H), 7.05 (d, J = 8.0 Hz, 2H), 6.93 - 6.86 (m, 2H), 6.86 - 6.80 (m, 2H), 6.30 (s, 1H), 5.99 (s, 1H), 4.57 - 4.50 (m, 1H), 4.47 (dd, J = 11.6, 5.7 Hz, 1H), 4.43 (dd, J = 11.7, 4.5 Hz, 1H), 4.38 (dd, J = 11.5, 2.4 Hz, 1H), 4.10 (dd, J = 11.5, 7.1 Hz, 1H), 2.92 - 2.86 (m, 2H), 2.83 - 2.78 (m, 2H), 2.50 - 2.46 (m, 2H), 1.55 (h, J = 7.4 Hz, 2H), 0.87 (t, J = 7.3 Hz, 3H). 13C NMR (151 MHz, DMSO) d 166.5, 163.7, 159.3, 142.9, 142.7, 139.4, 138.6, 128.1, 128.1, 121.5,
121.2, 117.1, 116.9, 105.7, 93.3, 71.4, 64.7, 63.6, 38.6, 36.9, 34.0, 24.1, 13.6. HRMS (MALDI): m/z calcd for C25H27NO4 (M+H+) 406.2013, found 406.2013. HPLC: tR = 5.01 min, Purity: 99.23%.
Example 22, 2-(4-pentylphenyl)-6-((tetrahydro-2H-pyran-2-yl)methoxy)pyridin-4-ol (8s). The target compound was synthesized as described for 8a using compound 7s (63 mg, 0.14 mmol) instead of 7a and purified by silica gel column chromatography (6% MeOH in DCM) to yield 18.9 mg (38%) white powder. Rf = 0.32 (MeOH:DCM, 5:95). IR (neat) Amax 2929(m), 2856(m), 1606(s), 1588(s), 1512(m), 1488(m), 1438(s), 1162(s) cm 1. Ή NMR (400 MHz, DMSO) d 10.56 (s, 1H), 7.87 (d, J = 8.1 Hz, 2H), 7.26 (d, J = 8.0 Hz, 2H), 6.90 (d, J = 1.8 Hz, 1H), 6.06 (d, J = 1.7 Hz, 1H), 4.25 (d, J = 5.1 Hz, 2H), 3.92 - 3.85 (m, 1H), 3.67 - 3.59 (m, 1H), 3.41 - 3.33 (m, 1H), 2.60 (t, J = 7.6 Hz, 2H), 1.86 - 1.78 (m, 1H), 1.68 - 1.54 (m, 3H), 1.53 - 1.42 (m, 3H), 1.37 - 1.22 (m, 5H), 0.86 (t, J = 6.8 Hz, 3H). 13C NMR (101 MHz, DMSO) d 166.9, 164.4, 154.6, 143.3, 136.0, 128.5, 126.2, 102.4, 94.3, 75.4, 68.3, 67.2, 34.8, 30.8, 30.5, 27.8, 25.5, 22.6, 21.9, 13.9. HRMS (MALDI) : m/z calcd for C22H29NO3 (M+H+) 356.2200, found 356.2222. HPLC: tR = 5.76 min, Purity: 99.99%.
Example 23, 2-(4-phenoxyphenyl)-6-((tetrahydro-2H-pyran-2-yl)methoxy)pyridin-4-ol (8t). The target compound was synthesized as described for 8a using compound 7t (65 mg, 0.14 mmol) instead of 7a and purified by silica gel column chromatography (5% MeOH in DCM) to yield 15.7 mg (30%) white powder. Rf =0.18 (MeOH:DCM, 5:95). JH NMR (400 MHz, DMSO) d 10.58 (s, 1H), 7.99 (d, J = 9.0 Hz, 2H), 7.42 (t, 2H), 7.18 (t, J = 7.4 Hz, 1H), 7.10 - 7.02 (m, 4H), 6.91 (d, J = 1.7 Hz, 1H), 6.07 (d, J = 1.7 Hz, 1H), 4.25 (d, J = 5.1 Hz, 2H), 3.92 - 3.83 (m, 1H), 3.66 - 3.58 (m, 1H), 3.41 - 3.33 (m, 1H), 1.84 - 1.74 (m, 1H), 1.67 - 1.59 (m, 1H), 1.54 - 1.42 (m, 3H), 1.30 (qd, J = 12.2, 3.9 Hz, 1H). 13C NMR (101 MHz, DMSO) d 166.9, 164.5, 157.5, 156.2, 153.9, 133.6, 130.1, 128.0, 123.8, 119.0, 118.3, 102.4, 94.2, 75.4, 68.3, 67.2, 27.8, 25.5, 22.6. HRMS (MALDI) : m/z calcd for C23H23NO4 (M+H+) 378.1700, found 378.1694. HPLC: tR = 4.74 min, Purity: 99.72%.
4-((4-Methoxybenzyl)oxy)-2-((4-propylbenzyl)oxy)-6-((tetrahydro-2H-pyran-2- yl)methoxy)pyridine (lib). A flame-dried vial equipped with a magnetic stirbar was charged with 10b (70 mg, 0.19 mmol), (4-propylphenyl)methanol (62 mg, 0.41 mmol), tBuONa (22.2 mg, 0.23 mmol), and [(2-di-tert-butylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-l,l'- biphenyl)-2-(2'-amino-l,l'-biphenyl)]palladium(II) methanesulfonate (tBuBrettPhos Pd G3, 3.3 mg, 3.86 pmol). The vial was capped, the septum was pierced with a needle attached to a Schlenk line, and the vial was evacuated and backfilled with Ar (x 3). Then anhydrous dioxane (190 pL) was added via a syringe. The reaction mixture was stirred at 100 °C for 2 d. The cooled reaction mixture was filtered through a Celite pad (eluent: EtOAc). The filtrate was evaporated onto Celite and purified by flash chromatography (5-6% EtOAc in heptane) to afford lib as a colorless oil (34 mg, 37%). Rf =0.36 (EtOAc: heptane, 1 :4). *H NMR (400 MHz, CDCI3) d 7.32 (t, J = 8.1 Hz, 4H), 7.19 - 7.14 (m, 2H), 6.93 - 6.88 (m, 2H), 6.01 (d, J = 1.8 Hz, 1H), 5.97 (d, J = 1.8 Hz, 1H), 5.27 (s, 2H), 4.94 (s, 2H), 4.27 - 4.18 (m, 2H), 4.08 - 4.02 (m, 1H), 3.81 (s, 3H), 3.70 - 3.62 (m, 1H), 3.48 (td, J = 11.6, 2.3 Hz, 1H), 2.58 (t, J = 7.9, 7.3 Hz, 2H), 1.92 - 1.84 (m, 1H), 1.70 - 1.46 (m, 6H), 1.45 - 1.33 (m, 1H), 0.94 (t, J = 7.3 Hz, 3H). 13C NMR (101 MHz, CDCI3) d 169.4, 163.7, 163.6, 159.8, 142.4, 134.9, 129.4, 128.7, 128.3, 128.0, 114.2, 89.2, 89.2, 76.1, 70.0, 69.4, 68.6, 67.9, 55.5, 37.9, 28.4, 26.1, 24.7, 23.3, 14.0.
4-((4-Methoxybenzyl)oxy)-N-(4-propylbenzyl)-6-((tetrahydro-2H-pyran-2- yl)methoxy)pyridin-2-amine (11c). A flame-dried vial equipped with a magnetic stirbar was charged with 10b (100 mg, 0.27 mmol), (4-propylphenyl)methanamine (61.5 mg, 0.41 mmol), tBuONa (31.7 mg, 0.33 mmol) and tBuBrettPhos Pd G3 (4.7 mg, 5.5 pmol). The vial was capped, the septum was pierced with a needle attached to a Schlenk line, and the vial was evacuated and backfilled with Ar (x 3). Then anhydrous dioxane (270 pL) was added via a syringe. The reaction mixture was stirred at 100 °C for 20.5 h. The cooled reaction mixture was filtered through a Celite pad (eluent: EtOAc). The filtrate was evaporated onto Celite and purified by flash chromatography (7-11% EtOAc in heptane) to afford 11c as a colorless oil (80.7 mg, 62%). Rf = 0.26 (EtOAc: heptane, 1 :4). *H NMR (400 MHz, CDCI3) d 7.29 (d, J = 8.6 Hz, 2H), 7.24 (d, J = 8.0 Hz, 2H), 7.13 (d, J = 7.9 Hz, 2H), 6.93 - 6.86 (m, 2H), 5.78 (d, J = 1.8 Hz, 1H), 5.57 (d, J = 1.8 Hz, 1H), 4.91 (s, 2H), 4.68 (s, 1H), 4.36 (d, J = 5.4 Hz, 2H), 4.21 (dd, J = 11.2, 3.9 Hz, 1H), 4.15 (dd, J = 11.2, 6.5 Hz, 1H), 4.06 - 3.99 (m, 1H), 3.81 (s, 3H), 3.69 - 3.61 (m, 1H), 3.46 (td, J = 11.6, 2.3 Hz, 1H), 2.57 (t, J = 8.1, 7.3 Hz, 2H), 1.91 - 1.81 (m, 1H), 1.68 - 1.43 (m, 6H), 1.43 - 1.31 (m, 1H), 0.94 (t, J = 7.3 Hz, 3H). 13C NMR (151 MHz, CDCI3) d 169.0, 165.3, 159.7, 158.2, 141.8, 136.6, 129.5, 128.8, 128.5, 127.5, 114.2, 85.6, 85.2, 76.2, 69.7, 69.1, 68.6, 55.5, 46.5, 37.8, 28.3, 26.1, 24.7, 23.3, 14.0.
4-((4-Methoxybenzyl)oxy)-N-methyl-N-(4-propylbenzyl)-6-((tetrahydro-2H-pyran-2- yl)methoxy)pyridin-2-amine (lid). NaH (60% dispersion in mineral oil, 17 mg, 0.42 mmol, 3.0 eq) was added to a solution of 11c (67.5 mg, 0.14 mmol) in anhydrous DMF (1.8 mL) to 0 °C and stirred for 15 min under an Ar atmosphere. Then, Mel (30 pL, 0.28 mmol) was added and stirred at rt. After 17 h, additional NaH (17 mg) and Mel (30 pL) were added and stirred for 24 h. Saturated NH4CI (10 mL) was added and the mixture was extracted with DCM (3 x 10 mL). The combined organic phase was dried over anhydrous Na2S0 , filtered, evaporated onto Celite, and purified by flash chromatography (5-10% EtOAc in heptane) to afford lid as colorless oil (29.7 mg, 43%). Rf =0.43 (EtOAc: heptane, 1 :4). JH NMR (600 MHz, CDCI3) d 7.33 - 7.29 (m, 2H), 7.13 - 7.07 (m, 4H), 6.92 - 6.88 (m, 2H), 5.79 (d, J = 1.7 Hz, 1H), 5.66 (d, J = 1.7 Hz, 1H), 4.94 (s, 2H), 4.72 (q, J = 15.7 Hz, 2H), 4.25 (dd, J = 11.3, 3.8 Hz, 1H), 4.16 (dd, J = 11.3, 6.6 Hz, 1H), 4.03 - 3.99 (m, 1H), 3.81 (s, 3H), 3.66 - 3.61 (m, 1H), 3.42 (td, J = 11.8, 2.3 Hz, 1H), 2.93 (s, 3H), 2.55 (t, J = 7.8 Hz, 2H), 1.85 - 1.78 (m, 1H), 1.66 - 1.55 (m, 4H), 1.51 - 1.46 (m, 1H), 1.43 (tt, J = 12.7, 3.8 Hz, 1H), 1.37 - 1.30 (m, 1H), 0.93 (t, J = 7.3 Hz, 3H). 13C NMR (151 MHz, CDC ) d 169.0, 164.1, 159.7, 158.5, 141.3, 136.5, 129.5, 128.7, 128.6, 127.3, 114.2, 85.2, 83.9, 76.3, 69.6, 68.9, 68.6, 55.5, 53.0, 37.9, 36.2, 28.4, 26.1, 24.7, 23.3, 14.0.
General procedure for PMB deprotection for synthesis of compounds 12b-d as exemplified for compound 12b.
Example 24, 2-((4-propylbenzyl)oxy)-6-((tetrahydro-2H-pyran-2-yl)methoxy)pyridin- 4-ol (12b). TFA (90 pL, 1.18 mmol) was added to a solution of lib (22.3 mg, 46.7 pmol) and 1,3-dimethoxybenzene (310 pL, 2.36 mmol) in DCM (470 pL) and stirred at rt for 4.5 h. The reaction mixture was brought to basic pH by addition of Na2C03 and extracted with DCM (3 x 10 mL). The combined organic phase was dried over anhydrous Na2S0 , filtered, evaporated onto Celite, purified by flash chromatography (3% MeOH in DCM) and further purified by preparative HPLC (50-70% solvent B in 15 min) to afford 12b as a colorless oil (8.2 mg, 69%). Rf = 0.16 (EtOAc: heptane, 1:4). IR (neat) Amax 3241(w, br), 2933(m), 2861(w), 1615(s), 1594(s), 1437(s), 1266(w), 1156(s) cm 1. JH NMR (600 MHz, DMSO) d 10.44 (s, 1H), 7.30 (d, J = 8.3 Hz, 2H), 7.17 (d, J = 8.0 Hz, 2H), 5.78 (d, J = 1.6 Hz, 1H), 5.74 (d, J = 1.6 Hz, 1H), 5.24 - 5.17 (m, 2H), 4.11
- 4.04 (m, 2H), 3.88 - 3.83 (m, 1H), 3.57 - 3.49 (m, 1H), 3.36 - 3.27 (m, 1H), 2.54 (t, J = 7.7 Hz, 2H), 1.81 - 1.72 (m, 1H), 1.62 - 1.53 (m, 3H), 1.50 - 1.40 (m, 3H), 1.27 - 1.19 (m, 1H), 0.88 (t, J = 7.3 Hz, 3H). 13C NMR (151 MHz, DMSO) d 168.3, 163.1, 162.9, 141.5, 134.9, 128.2, 127.7, 89.2, 89.2, 75.2, 68.5, 67.2, 66.7, 36.9, 27.7, 25.5, 24.1, 22.5, 13.6. HRMS (MALDI): m/z calcd for C21H27NO4 (M+H+) 358.2013, found 358.2016. HPLC: tR = 8.67 min, Purity: 99.99%.
Example 25, 2-((4-propylbenzyl)amino)-6-((tetrahydro-2H-pyran-2-yl)methoxy)- pyridin-4-ol (12c). The target compound was synthesized as described for 12b using compound 11c (70 mg, 0.161 mmol) instead of lib and purified by silica gel column chromatography (5% MeOH in DCM) and further purified by prep HPLC (40-60% solvent B in 15 min) to yield 4.2 mg (45%) slightly yellow oil. Rf = 0.25 (MeOH:DCM, 5:95). IR (neat) Amax 3101(w), 2925(m), 2855(w), 1674(s), 1634(s), 1512(m), 1200 (s), 1138(m) cm 1. Ή NMR (600 MHz, CDCI3) d 7.76 (br s, 1H), 7.13 - 7.07 (m, 4H), 5.68 (s, 1H), 5.66 (s, 1H), 4.16 (s, 2H), 3.95
- 3.87 (m, 2H), 3.85 (dd, J = 10.3, 3.3 Hz, 1H), 3.62 - 3.56 (m, 1H), 3.39 (dt, J = 11.6, 5.9 Hz, 1H), 2.51 (t, J = 8.7, 7.4 Hz, 2H), 1.88 - 1.83 (m, 1H), 1.62 - 1.45 (m, 6H), 1.37 - 1.29 (m, 1H), 0.90 (t, J = 7.3 Hz, 3H). 13C NMR (151 MHz, CDCI3) d 173.5, 158.9, 153.3, 142.7, 133.2, 129.1, 127.2, 86.5, 84.8, 75.1, 73.1, 68.5, 46.2, 37.8, 27.6, 25.6, 24.6, 22.9, 13.9. HRMS (MALDI): m/z calcd for C21H28N2O3 (M+H+) 357.2172, found 357.2174. HPLC: tR = 4.01 min, Purity: 96.38%.
Example 26, 2-(methyl(4-propylbenzyl)amino)-6-((tetrahydro-2H-pyran-2-yl)- methoxy)pyridin-4-ol (12d). The target compound was synthesized as described for 12b using compound lid (23.2 mg, 47.3 pmol) instead of lib and purified by silica gel column chromatography (5% MeOH in DCM) and further purified by prep HPLC (45% solvent B) to yield 9.1 mg (52%) colorless oil. Rf = 0.4 (MeOH:DCM, 5:95). IR (neat) Amax 2935(w), 2860(w), 1672(m), 1621(s), 1180(s), 1135(m) cm 1. Ή NMR (600 MHz, CDCI3) d 7.91 (br s, 1H), 7.14 (d, J = 7.8 Hz, 2H), 7.07 (d, J = 7.8 Hz, 2H), 5.76 (s, 1H), 5.74 (s, 1H), 4.51 (s, 2H), 3.97 - 3.88 (m, 3H), 3.67 - 3.61 (m, 1H), 3.43 (td, J = 11.4, 2.9 Hz, 1H), 3.08 (s, 3H), 2.53 (t, J = 7.7 Hz, 2H), 1.91 - 1.83 (m, 1H), 1.64 - 1.56 (m, 3H), 1.56 - 1.46 (m, 3H), 1.35 (qd, J = 12.1, 3.9 Hz, 1H), 0.92 (t, J = 7.3 Hz, 3H). 13C NMR (151 MHz, CDCI3) d 172.7, 159.6, 153.5, 142.8, 132.5, 129.3, 126.9, 88.1, 85.9, 75.4, 73.1, 68.6, 55.1, 37.9, 37.7, 27.6, 25.7, 24.6, 22.9, 13.9. HRMS (MALDI): m/z calcd for C22H30N2O3 (M+H+) 371.2329, found 371.2329. HPLC: tR = 4.61 min, Purity: 97.41%. 4-(Benzyloxy)-2-chloro-6-((4-methoxybenzyl)oxy)pyridine (13). To a solution of (4- methoxyphenyl)methanol (0.32 mL, 2.56 mmol) in THF (3.5 mL) at 0 °C was added NaH (60% in paraffine oil, 122.8 mg, 3.07 mmol). The mixture was stirred for 30 min and 2 (650.0 mg, 2.56 mmol) in THF (6.5 mL) was added, then the tube was sealed and the temperature was set at 100 °C. After 1.5 h, the mixture was allowed to cool to rt, water (15 mL) was added and was extracted with EtOAc (3 x 10 mL). The combined extracts were washed with brine, dried over Na2S04, filtered and the solvents were evaporated under reduced pressure. The residue was purified by silica gel column chromatography (3-5% EtOAc in heptane) to afford 13 as a white solid (767.2 mg, 84%). Rf = 0.57 (EtOAc: heptane, 1 :4). *H NMR (600 MHz, CDCh) d 7.48 - 7.33 (m, 7H), 6.95 - 6.88 (m, 2H), 6.62 - 6.58 (m, 1H), 6.25 - 6.20 (m, 1H), 5.28 (dd, J = 4.3, 2.0 Hz, 2H), 5.03 (s, 2H), 3.81 (s, 3H). ). 13C NMR (101 MHz, CDCh) d 168.2, 164.7, 159.6, 149.0,
135.3, 130.1, 128.8, 128.5, 127.5, 113.9, 105.9, 94.1, 70.4, 68.3, 55.3.
4-(Benzyloxy)-2-((4-methoxybenzyl)oxy)-6-((4-propylphenyl)ethynyl)pyridine (14). A vial was charged with PdCl2(MeCN)2 (57.08 mg, 0.120 mmol), XPhos (57.1 mg, 0.120 mmol) and anhydrous Cs2C03 (1.69 g, 5.19 mmol). The vial was evacuated and backfilled with Ar and the contents were suspended in anhydrous MeCN (2.3 mL). l-Ethynyl-4-propylbenzene (0.41 mL, 2.6 mmol) was added and the reaction was allowed to stir for 15 min after which 13 (710.0 mg, 2.00 mmol) was added to the yellow solution. The vial was capped and heated to 90 °C for 18 h. The reaction mixture was then filtered via Celite and washed with DCM (50 mL). The reaction mixture was evaporated onto Celite and purified by column chromatography (4-7% EtOAc in heptane) to give 14 as a brown oil (608.0 mg, 66%). Rf = 0.45 (EtOAc: heptane, 3: 17). JH NMR (600 MHz, CDCh) d 7.58 - 7.49 (m, 2H), 7.46 - 7.30 (m, 6H), 7.20 - 7.15 (m, 2H), 6.95 - 6.89 (m, 2H), 6.86 (d, J = 2.0 Hz, 1H), 6.29 (d, J = 2.1 Hz, 1H), 5.35 (s, 2H), 5.07 (s, 2H), 3.82 (s, 3H), 2.61 (t, 2H), 1.71 - 1.62 (m, 2H), 0.95 (t, J = 7.3 Hz, 3H). ). 13C NMR (151 MHz, CDCh) d 167.0,
165.4, 159.6, 144.0, 141.1, 135.8, 132.1, 130.2, 129.4, 128.8, 128.6, 128.5, 127.6, 119.7, 114.0, 110.8, 95.6, 88.9, 88.4, 70.1, 68.1, 55.4, 38.1, 24.4, 13.9.
4-(Benzyloxy)-6-((4-propylphenyl)ethynyl)pyridin-2-ol (15). To a solution of 14 (608.0 mg, 1.31 mmol) and anisole (1.45 mL, 13.1 mmol) in DCM (12.2 mL) was added TFA (1.60 mL, 12% final solution). The mixture was stirred for 1 h at rt. Phosphate buffer (pH 7.0, 0.1 M, 15 mL) and Na2C03 were added until pH around 7, the phases were separated and the aq. phase was extracted with DCM (3 x 15 mL). The combined organic phase was dried over Na2SC>4, filtered and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (3-6% MeOH in DCM) to afford 15 as a yellow solid (374.2 mg, 83%). Rf = 0.57 (MeOH:DCM, 1 :9). JH NMR (600 MHz, CDCh) d 11.29 (s, 1H), 7.50 - 7.46 (m, 2H), 7.43 - 7.32 (m, 1H), 7.20 - 7.15 (m, 2H), 6.23 (d, J = 2.3 Hz, 1H), 6.01 (d, J = 2.3 Hz, 1H), 5.02 (s, 2H), 2.61 (t, 2H), 1.69 - 1.60 (m, 2H), 0.94 (t, J = 7.3 Hz, 3H). 13C NMR (151 MHz, CDCh) d 168.1, 166.0, 144.9, 135.4, 132.2, 129.5, 128.9, 128.8, 128.8, 128.6, 127.8, 118.4, 105.7, 99.1, 94.6, 81.6, 70.4, 38.2, 24.4, 13.9. 4-(Benzyloxy)-2-(2,2-dimethoxyethoxy)-6-((4-propylphenyl)ethynyl)pyridine (16). To a solution of 15 (370.0 mg, 1.08 mmol) in DMF (7 mL) were added CS2CO3 (1.05 g, 3.23 mmol) and KI (9.0 mg, 0.54 mmol). The mixture was stirred for 5 min in rt, after which 2-chloro-l,l- dimethoxyethane (0.37 mL, 3.2 mmol) was added. The mixture was stirred at 100 °C for 24 h. The mixture was allowed to cool to rt, water (30 mL) was added, and was extracted with EtOAc (3 x 30 mL). The combined extracts were washed with saturated CaCI2 (30 mL), dried over Na2S0 , filtered and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (15-20% EtOAc in heptane) to afford 16 as a yellow oil (145.7 mg, 31%). Rf = 0.46 (EtOAc: heptane, 1 :4). JH NMR (600 MHz, CDCI3) d 7.49 (d, 2H), 7.45 - 7.31 (m, 4H), 7.16 (d, J = 8.0 Hz, 2H), 6.83 (d, J = 2.1 Hz, 1H), 6.32 (d, J = 2.1 Hz, 1H), 5.08 (s, 2H), 4.74 (t, J = 5.2 Hz, 1H), 4.42 (d, J = 5.2 Hz, 2H), 3.45 (s, 6H), 2.60 (t, 2H), 1.65 (h, J = 7.4 Hz, 2H), 0.94 (t, J = 7.3 Hz, 3H). 13C NMR (151 MHz, CDCI3) d 167.0, 164.9, 144.0, 141.1, 135.7,
132.1, 128.9, 128.7, 128.5, 127.6, 119.7, 111.0, 102.0, 95.6, 88.9, 88.3, 70.2, 65.2, 54.0, 38.1, 24.4, 13.9.
4-(Benzyloxy)-2-((5-methyl-l,3-dioxan-2-yl)methoxy)-6-((4-propylphenyl)ethynyl)- pyridine (17a). To a solution 16 (51.0 mg, 0.12 mmol) and catalytical amount of 4- toluenesulfonic acid in toluene (3.5 mL) was added 2-methylpropane-l,3-diol (0.02 mL, 0.13 mmol). The mixture was heated at 90 °C for 24 h in the uncapped vial, after which it was neutralized by the addition of aq. NaOH (1 M, 5 mL), water (5 mL) was added and the mixture was extracted with EtOAc (3 x 10 mL). The combined extracts were washed with saturated CaCI2 (10 mL), dried over Na2S0 , filtered and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (15% EtOAc in heptane) to afford 17a as a yellow oil (40.9 mg, 76%). Rf = 0.42 (EtOAc: heptane, 1 :3). JH NMR (600 MHz, CDCI3) d 7.51 - 7.47 (m, 2H), 7.39 (d, J = 3.8 Hz, 4H), 7.18 - 7.14 (m, 2H), 6.83 (d, J = 2.0 Hz, 1H), 6.34 (dd, J = 5.1, 2.0 Hz, 1H), 5.06 (s, 2H), 4.94 (t, J = 4.6 Hz, OH), 4.84 (t, J = 4.5 Hz, 1H), 4.43 (dd, J = 4.6, 1.6 Hz, 2H), 4.12 - 4.06 (m, 2H), 3.99 (dd, J = 11.8, 2.6 Hz, 1H), 3.90 - 3.85 (m, 1H), 3.39 - 3.31 (m, 2H), 2.63 - 2.57 (m, 2H), 2.16 (dtd, J = 11.2, 6.7, 4.6 Hz, 1H), 1.64 (dt, J = 14.7, 7.5 Hz, 2H), 1.31 (d, J = 7.0 Hz, 1H), 1.29 - 1.23 (m, 1H), 0.94 (t, J = 7.3 Hz, 3H), 0.72 (d, J = 6.7 Hz, 2H). 13C NMR (151 MHz, CDCI3) d 166.9, 164.8, 164.8, 143.9, 141.0, 135.8, 132.1, 128.8, 128.6, 128.5, 127.6, 119.7, 111.0, 111.0, 98.9, 95.6, 88.8, 88.8, 88.3, 73.3, 71.9, 70.1, 66.9,
38.1, 29.5, 24.4, 13.9, 12.4.
4-(Benzyloxy)-2-((4-methyl-l,3-dioxan-2-yl)methoxy)-6-((4-propylphenyl)ethynyl)- pyridine (17b). The target compound was synthesized as described for 17a using butane-1, 3- diol (0.02 mL, 0.13 mmol) instead of 2-methylpropane-l,3-diol, stirred for 18 h and purified by silica gel column chromatography (10-15% EtOAc in heptane) to yield 43.9 mg (82%) yellow oil. Rf = 0.39 (EtOAc: heptane, 1 :3). JH NMR (600 MHz, CDCI3) d 7.49 (d, 2H), 7.43 - 7.31 (m, 5H), 7.16 (d, J = 8.0 Hz, 2H), 6.83 (d, J = 2.1 Hz, 1H), 6.34 (d, J = 2.0 Hz, 1H), 5.06 (s, 2H), 4.94 (t, J = 4.6 Hz, 1H), 4.50 - 4.34 (m, 2H), 4.17 (dd, J = 11.4, 5.0, 1.3 Hz, 1H), 3.86 - 3.77 (m, 2H), 2.60 (t, J = 7.6 Hz, 2H), 1.74 (tdd, J = 12.8, 11.1, 5.0 Hz, 1H), 1.65 (h, J = 7.4 Hz, 2H), 1.50 - 1.43 (m, 1H), 1.27 (d, J = 6.2 Hz, 3H), 0.95 (t, J = 7.3 Hz, 3H). 13C NMR (151 MHz, CDCh) d 166.9, 164.9, 143.9, 141.0, 135.8, 132.0, 128.8, 128.6, 128.4, 127.6, 119.7, 110.9, 99.1, 95.6, 88.7, 88.4, 73.0, 70.1, 67.2, 66.7, 38.1, 33.2, 24.4, 21.8, 13.9.
Example 27, 2-((5-methyl-l,3-dioxan-2-yl)methoxy)-6-(4-propylphenethyl)pyridin-4- ol (18a). The target compound was synthesized as described for 8a using compound 17a (40.9 mg, 89.4 pmol) instead of 7a, stirred for 2.5 h and purified by silica gel column chromatography (6% MeOH in DCM) to yield 26.4 mg (80%) colorless oil. Rf = 0.26 (MeOH:DCM, 7:93). JH NMR (600 MHz, CDCh) d 7.11 - 7.05 (m, 4H), 6.28 (s, 1H), 6.04 (s, 1H), 4.89 (t, J = 4.6 Hz, OH), 4.80 (t, J = 4.5 Hz, 1H), 4.22 (d, J = 4.5 Hz, 2H), 4.08 - 4.02 (m, 2H), 3.94 (dd, J = 11.8, 2.7 Hz, 1H), 3.83 (dd, 1H), 3.32 (t, 2H), 2.92 (dd, J = 9.8, 6.3 Hz, 2H), 2.81 (dd, J = 9.8, 6.3 Hz, 2H), 2.54 (t, 2H), 2.17 - 2.08 (m, 1H), 1.61 (h, 2H), 1.30 - 1.24 (m, 1H), 0.93 (t, J = 7.3 Hz, 3H), 0.70 (d, J = 6.8 Hz, 2H). 13C NMR (151 MHz, CDCI3) d 171.4, 162.8, 156.6, 140.5, 128.6,
128.4, 107.7, 99.3, 98.8, 94.2, 73.2, 71.9, 67.8, 38.3, 37.8, 34.8, 29.5, 29.2, 24.7, 16.0, 14.0,
12.4. HPLC: tR = 4.07 min, Purity: 99.0%.
Example 28, 2-((4-methyl-l,3-dioxan-2-yl)methoxy)-6-(4-propylphenethyl)pyridin-4- ol (18b). The target compound was synthesized as described for 8a using compound 17b (43.9 mg, 95.9 pmol) instead of 7a, stirred for 3 h and purified by silica gel column chromatography (6-7% MeOH in DCM) to yield 26.6 mg (75%) colorless oil. Rf = 0.46 (MeOH:DCM, 7:93). JH NMR (600 MHz, CDCh) d 7.11 - 7.05 (m, 4H), 6.28 (d, J = 1.9 Hz, 1H), 6.03 (d, J = 2.0 Hz, 1H), 4.89 (t, J = 4.5 Hz, 1H), 4.25 - 4.15 (m, 2H), 4.14 - 4.09 (m, 1H), 3.96 (dd, J = 8.3, 3.1 Hz, OH), 3.83 - 3.72 (m, 2H), 2.92 (dd, J = 9.8, 6.3 Hz, 2H), 2.81 (dd, J = 9.7, 6.3 Hz, 2H), 2.54 (t, J = 8.5, 6.8 Hz, 2H), 1.70 (tdd, J = 12.8, 11.2, 5.0 Hz, 1H), 1.61 (h, J = 7.6 Hz, 2H), 1.48 - 1.42 (m, 1H), 1.35 (d, J = 6.8 Hz, OH), 1.24 (d, J = 6.2 Hz, 4H), 0.93 (t, J = 7.3 Hz, 3H). 13C NMR (151 MHz, CDCh) d 171.7, 162.8, 156.6, 140.5, 138.5, 128.6, 128.3, 107.8, 98.9, 94.2, 73.2, 68.2, 66.7, 38.2, 37.8, 34.8, 33.1, 24.7, 21.7, 14.0. HPLC: tR = 3.98 min, Purity: 97.32%.
(4,6-Dichloropyridin-2-yl)methanol (20). Thionyl chloride (0.27 mL, 3.70 mmol) was added to a solution of 4,6-dichloropicolinic acid (500 mg, 2.60 mmol) in MeOH (5 mL) at 0 °C and the reaction mixture was warmed to 65 °C under reflux conditions. After 1 h sat. aq. NaHC03 solution (20 mL) was added, the mixture was extracted with EtOAc (3 x 20 mL) and the combined organic phase was dried over Na2S0 , filtered and the solvents were evaporated under reduced pressure to afford methyl 4,6-dichloropicolinate (511 mg, 95%) as white solid. Rf = 0.61 (PE:EtOAc, 8:2). *H NMR (400 MHz, CDCh) d 8.06 (d, J = 1.7 Hz, 1H), 7.55 (d, J = 1.7 Hz, 1H), 4.01 (s, 3H). 13C NMR (101 MHz, CDCh) d 163.8, 152.4, 149.1, 147.1, 127.8, 124.6, 53.6. NaBH4 (187.7 mg, 4.96 mmol) was added in two portions to a solution of methyl 4,6-dichloropicolinate (511 mg, 2.48 mmol) in MeOH (10 mL) at 0 °C and the reaction mixture was allowed to reach rt. After stirring for 2 h, brine (10 mL) and water (2 mL) were added and the mixture was extracted with EtOAc (3 x 10 mL). The organic phase was dried over Na2SC>4, filtered and the solvents were evaporated under reduced pressure to afford 20 (436 mg, 99%) as white solid. Rf = 0.38 (PE: EtOAc, 8:2). JH NMR (400 MHz, CDCI3) d 7.31 (d, J = 1.6 Hz, 1H), 7.27 (d, J = 1.6 Hz, 1H), 4.74 (s, 2H), 2.87 (s, 1H). 13C NMR (101 MHz, CDCI3) d 162.2, 151.7, 146.8, 123.0, 119.8, 64.4.
2,4-Dichloro-6-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)pyridine (21). To a solution of 20 (436 mg, 2.73 mmol) in DCM (3.5 mL), 3,4-dihydro-2H-pyran (0.76 mL, 8.33 mmol) and pyridin-l-ium 4-methylbenzenesulfonate (34.3 mg, 0.137 mmol) were added and the mixture was stirred at rt for 22 h. Then water (5 mL) and brine (5 mL) were added and the mixture was extracted with DCM (3 x 10 mL). The combined organic phase was dried over Na2S04, filtered and the solvents were evaporated under reduced pressure. The residue was purified by silica gel column chromatography (7-9% EtOAc in heptane) to afford 21 (681 mg, 95%) as colorless oil. JH NMR (400 MHz, CDCI3) d 7.44 (d, J = 1.7 Hz, 1H), 7.24 (d, J = 1.7 Hz, 1H), 4.83 (d, J = 14.7 Hz, 1H), 4.75 (t, J = 3.6 Hz, 1H), 4.58 (d, J = 14.7 Hz, 1H), 3.89 - 3.83 (m, 1H), 3.58 - 3.52 (m, 1H), 1.90 - 1.53 (m, 6H). 13C NMR (101 MHz, CDCI3) d 161.3, 151.3, 146.5, 122.7, 120.3, 98.8, 68.8, 62.5, 30.6, 25.4, 19.5.
2-Chloro-4-((4-methoxybenzyl)oxy)-6-(((tetrahydro-2H-pyran-2- yl)oxy)methyl)pyridine (22). NaH (60% in mineral oil, 124.7 mg, 3.12 mmol) was added to a solution of 21 (681 mg, 2.60 mmol) in DMF (2.6 mL) at 0 °C. Then (4-methoxyphenyl)methanol (0.33 mL, 2.66 mmol) was added at the same temperature and the mixture was stirred at 0 °C for 30 min, then at rt for 1.5 h. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (3 x 10 mL). The combined organic phase was dried over Na2S04, filtered and the solvents were evaporated under reduced pressure. The residue was purified by silica gel column chromatography (20 % EtOAc in heptane) to afford 22 (753 mg, 80%) as colorless oil. Rf = 0.20 (PE: EtOAc, 9: 1). JH NMR (400 MHz, CDCI3) d 7.45 - 7.27 (m, 2H), 7.02 (d, J = 2.1 Hz, 1H), 6.96 - 6.84 (m, 2H), 6.78 (d, J = 2.1 Hz, 1H), 5.04 (s, 2H), 4.79 (d, J = 14.4 Hz, 1H), 4.72 (t, J = 3.6 Hz, 1H), 4.55 (d, J = 14.4 Hz, 1H), 3.89 - 3.78 (m, 4H), 3.59 - 3.49 (m, 1H), 1.93 - 1.51 (m, 6H). 13C NMR (101 MHz, CDCI3) d 167.2, 161.0, 160.0, 151.7, 129.6, 127.3, 114.3, 108.7, 107.4, 98.6, 70.4, 69.1, 62.4, 55.4, 30.6, 25.5, 19.5.
4-((4-Methoxybenzyl)oxy)-2-((4-propylphenyl)ethynyl)-6-(((tetrahydro-2H-pyran-2- yl)oxy)methyl)pyridine (23). A vial was charged with PdCI2(MeCN)2 (1.3 mg, 5.0 pmol), XPhos (6.9 mg, 14.5 pmol) and Cs2C03 (136.0 mg, 0.417 mmol). The vial was capped, evacuated and backfilled with Ar (x 3) and the contents were suspended in anhydrous and degassed MeCN (0.2 mL). l-Ethynyl-4-propylbenzene (0.9 mg, 0.193 mmol) was added and the reaction was allowed to stir for 15 min after which a solution of 22 (58.4 mg, 0.161 mmol) in anhydrous and degassed MeCN (0.4 mL) was added. The vial was heated to 80 °C for 9 h. The reaction mixture was filtered through a Celite pad, washed with DEE (15 mL), the solvents were evaporated under reduced pressure and the residue was purified by silica gel column chromatography (17-23% EtOAc in heptane) to afford slightly impure 23 (58.0 mg, 77 %) as a yellow oil, which was subjected to the next reaction without further purification. Rf = 0.27 (EtOAc:PE, 2:8).
Example 29, 2-(4-propylphenethyl)-6-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)pyridin- 4-ol (24). The target compound was synthesized as described for 8a using compound 23 (55.8 mg, 0.118 mmol) instead of 7a and purified by silica gel column chromatography (5-7% MeOH in DCM) to yield 28.4 mg (68%) colorless oil. Rf = 0.48 (DCM :MeOH, 9: 1). IR (neat) Amax 2929(m), 2869(w), 1623(s), 1510(s), 1200(w), 1123(m) cm 1. 1 H NMR (600 MHz, CDCI3) d 11.45 (s, 1H), 7.06 (s, 4H), 6.29 (d, J = 60.2 Hz, 2H), 4.64 - 4.57 (m, 2H), 4.49 (d, J = 13.7 Hz, 1H), 3.90 - 3.85 (m, 1H), 3.53 - 3.49 (m, 1H), 2.93 - 2.89 (m, 2H), 2.84 - 2.79 (m, 2H), 2.52 (t, J = 7.6 Hz, 2H), 1.85 - 1.79 (m, 1H), 1.76 - 1.70 (m, 1H), 1.62 - 1.48 (m, 6H), 0.91 (t, J = 7.3 Hz, 3H). 13C NMR (151 MHz, CDCI3) d 180.5, 151.7, 148.2, 140.9, 137.4, 128.7, 128.2, 115.0, 113.6, 99.9, 66.4, 63.4, 37.7, 35.7, 34.7, 30.6, 25.3, 24.6, 19.8, 13.9. HPLC: tR = 4.15 min, Purity: 99.99%.
4-((4-Methoxybenzyl)oxy)-2-((tetrahydro-2H-pyran-2-yl)methoxy)-6-(((tetrahydro- 2H-pyran-2-yl)oxy)methyl)pyridine (25). NaH (60% in mineral oil, 106.4 mg, 2.66 mmol) was added to a solution of 22 (691 mg, 1.90 mmol) and (tetrahydro-2H-pyran-2-yl)methanol (0.3 mL, 2.65 mmol) in THF (6 mL) at 0 °C and the reaction was stirred at the same temperature for 30 min before moving the vial to a heating block at 100 °C. After 16 h the mixture was allowed to cool to rt, water (5 mL) and brine (5 mL) were added and the mixture was extracted with EtOAc (3 x 10 mL). The combined organic phase was dried over Na2S04, filtered and the solvents were evaporated under reduced pressure. The residue was purified by silica gel column chromatography (18-25% EtOAc in heptane) to afford 25 (777 mg, 92%) as colorless oil. Rf = 0.31 (PE: EtOAc, 8:2). JH NMR (400 MHz, CDCI3) d 7.34 - 7.29 (m, 2H), 6.93 - 6.89 (m, 2H), 6.68 (d, J = 2.0 Hz, 1H), 6.23 (d, J = 2.0 Hz, 1H), 4.97 (s, 2H), 4.76 - 4.74 (m, 1H), 4.69 (d, J = 14.0 Hz, 1H), 4.46 (d, J = 14.0 Hz, 1H), 4.30 (dd, J = 11.4, 3.4 Hz, 1H), 4.21 (dd, J = 11.4, 7.0 Hz, 1H), 4.07 - 4.02 (m, 1H), 3.93 - 3.86 (m, 1H), 3.81 (s, 3H), 3.70 - 3.64 (m, 1H), 3.56 - 3.41 (m, 3H), 1.92 - 1.83 (m, 2H), 1.79 - 1.39 (m, 10H). 13C NMR (101 MHz, CDCI3) d 167.7, 165.1, 159.8, 157.3, 129.5, 128.1, 114.2, 103.7 (d, J = 2.0 Hz), 98.2 (d, J = 2.9 Hz), 93.5, 76.2, 69.8, 69.3, 69.3, 68.6, 62.1 (d, J = 2.4 Hz), 55.4, 30.7, 28.2, 26.1, 25.6, 23.3, 19.4 (d, J = 1.8 Hz).
(4-((4-Methoxybenzyl)oxy)-6-((tetrahydro-2H-pyran-2-yl)methoxy)pyridin-2- yl)methanol (26). 25 (777.0 mg, 1.75 mmol) was dissolved in MeOH (5 mL), then p- toluenesulfonic acid monohydrate (349.9 mg, 1.84 mmol) was added and the reaction mixture was stirred at rt for 1.5 h. Then sat. NaHC03 (10 mL) and water (5 mL) were added and the mixture was extracted with DCM (3 x 15 mL). The combined organic phase was dried over Na S0 , filtered and the solvents were evaporated under reduced pressure. The residue was purified by silica gel column chromatography (30-40% EtOAc in heptane) to afford 26 (439 mg, 70%) as colorless oil. Rf = 0.25 (PE:EtOAc, 6:4). JH NMR (400 MHz, CDCI3) d 7.33 - 7.28 (m, 2H), 6.93 - 6.89 (m, 2H), 6.44 (d, J = 1.9 Hz, 1H), 6.25 (d, J = 2.0 Hz, 1H), 4.96 (s, 2H), 4.56 (s, 2H), 4.33 - 4.21 (m, 2H), 4.08 - 4.02 (m, 1H), 3.81 (s, 3H), 3.72 - 3.65 (m, 1H), 3.53 - 3.30 (m, 2H), 1.92 - 1.85 (m, 1H), 1.67 - 1.37 (m, 5H). 13C NMR (101 MHz, CDCI3) d 167.8,
165.1, 159.8, 157.7, 129.4, 127.9, 114.2, 102.6, 93.9, 76.1, 69.9, 69.4, 68.6, 64.0, 55.4, 28.2, 26.0, 23.2.
4-((4-Methoxybenzyl)oxy)-2-(((4-propylbenzyl)oxy)methyl)-6-((tetrahydro-2H-pyran- 2-yl)methoxy)pyridine (27). NaH (60% in mineral oil, 7.9 mg, 0.198 mmol) was added to a solution of 26 (50.7 mg, 0.141 mmol) in THF (0.2 mL) at 0 °C and the mixture was allowed to warm to rt. Then a solution of l-(bromomethyl)-4-propylbenzene (30.7 mg, 0.144 mmol) in THF (0.3 mL) was added and the mixture was stirred at rt for 21 h. Then sat. NH4CI (10 mL) was added and the mixture was extracted with EtOAc (3 x 10 mL). The combined organic phase was dried over Na2S0 , filtered and the solvents were evaporated under reduced pressure. The residue was purified by silica gel column chromatography (7-10% EtOAc in heptane) to afford 27 (33.0 mg, 48%) as colorless oil. Rf = 0.40 (PE:EtOAc, 8:2). JH NMR (400 MHz, CDCI3) d 7.34 - 7.26 (m, 4H), 7.16 (d, J = 7.8 Hz, 2H), 6.91 (d, J = 8.8 Hz, 2H), 6.73 (d, J = 2.0 Hz, 1H), 6.24 (d, J = 2.0 Hz, 1H), 4.98 (s, 2H), 4.59 (s, 2H), 4.49 (s, 2H), 4.30 (dd, J = 11.3, 3.5 Hz, 1H), 4.22 (dd, J = 11.3, 6.8 Hz, 1H), 4.09 - 4.02 (m, 1H), 3.82 (s, 3H), 3.71 - 3.65 (m, 1H), 3.49 (td, J = 11.6, 2.3 Hz, 1H), 2.59 (t, J = 7.6 Hz, 2H), 1.93 - 1.84 (m, 1H), 1.69 - 1.39 (m, 7H), 0.94 (t, J = 7.3 Hz, 3H). 13C NMR (101 MHz, CDCI3) d 167.8, 165.1, 159.8, 157.3, 142.3, 135.5, 129.4, 128.6, 128.2, 127.9, 114.2, 103.7, 93.8, 76.2, 72.8, 72.7, 69.8, 69.3, 68.6, 55.4, 37.9, 28.2, 26.1, 24.7, 23.3, 14.0.
Example 30, 2-(((4-propylbenzyl)oxy)methyl)-6-((tetrahydro-2H-pyran-2-yl)- methoxy)pyridin-4-ol (28). To a solution of 27 (33.0 mg, 0.067 mmol) and 1,3- dimethoxybenzene (0.09 mL, 0.687 mmol) in DCM (0.7 mL) was added TFA (70 pL, 10% final solution) and the mixture was stirred at rt for 1.5 h. Then phosphate buffer (pH 7.0, 0.1 M, 10 mL) was added, the mixture was neutralized with Na2C03 and the phases were separated. The aq. phase was further extracted with DCM (2 x 10 mL). The combined organic phase was dried over Na2S0 , filtered and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (0-8% MeOH in DCM) to afford 28 (17.2 mg, 69%) as colorless oil. Rf = 0.69 (DCM:MeOH, 9: 1). IR (neat) Amax 2931(m), 2859(w), 1610(m), 1590(m), 1439(m), 1227(m), 1158(s) cm 1. Ή NMR (600 MHz, CDCI3) d 7.25 (d, J = 7.9 Hz, 2H), 7.15 (d, J = 7.9 Hz, 2H), 6.48 (s, 1H), 6.10 (d, J = 2.0 Hz, 1H), 4.55 (s, 2H), 4.43 (s, 2H), 4.17 (dd, J = 11.1, 3.2 Hz, 1H), 4.10 (dd, J = 11.1, 6.8 Hz, 1H), 4.03 - 3.98 (m, 1H), 3.70 - 3.66 (m, 1H), 3.46 (td, J = 11.7, 2.2 Hz, 1H), 2.57 (t, J = 7.8 Hz, 2H), 1.90 - 1.85 (m, 1H), 1.66 - 1.48 (m, 6H), 1.44 - 1.37 (m, 1H), 0.93 (t, J = 7.3 Hz, 3H). 13C NMR (151 MHz, CDCI3) d 171.8,
163.1, 153.1, 142.6, 134.9, 128.7, 128.1, 106.5, 95.5, 76.1, 72.9, 70.7, 70.5, 68.5, 37.9, 27.9, 25.9, 24.7, 23.1, 13.9. HPLC: tR = 4.22 min, Purity: 99.99%. 4-((4-Methoxybenzyl)oxy)-2-((4-propylphenoxy)methyl)-6-((tetrahydro-2H-pyran-2- yl)methoxy)pyridine (29). To a solution of 4-propylphenol (14.6 mg, 0.107 mmol), triphenylphosphine (PPh ) (28.0 mg, 0.107 mmol) and 26 (25.6 mg, 0.071 mmol) in anhydrous THF (0.2 mL), diisopropyl azodicarboxylate (0.03 mL, 0.152 mmol) was added dropwise at 0 °C. The reaction mixture was stirred at 0 °C for 30 min and then at rt for 24 h. The mixture was then diluted with EtOAc (10 mL), water (5 mL) and brine (5 mL), the phases were separated and the aq. phase was further extracted with EtOAc (2 x 10 mL). The combined organic phase was dried over Na2S0 , filtered and the solvents were evaporated under reduced pressure. The residue was purified by silica gel column chromatography (7-9% EtOAc in heptane) to afford 29 (28.4 mg, 84%) as colorless oil. Rf = 0.41 (PE:EtOAc, 8:2). JH NMR (400 MHz, CDCI3) d 7.35 - 7.28 (m, 2H), 7.10 - 7.05 (m, 2H), 6.93 - 6.85 (m, 4H), 6.77 - 6.74 (m, 1H), 6.26 (d, J = 2.1 Hz, 1H), 4.97 (d, J = 11.4 Hz, 4H), 4.32 (dd, J = 11.3, 3.5 Hz, 1H), 4.25 (dd, J = 11.3, 6.7 Hz, 1H), 4.10 - 4.03 (m, 1H), 3.81 (s, 3H), 3.73 - 3.66 (m, 1H), 3.50 (td, J = 11.6, 2.3 Hz, 1H), 2.52 (t, J = 7.8 Hz, 2H), 1.93 - 1.85 (m, 1H), 1.67 - 1.40 (m, 7H), 0.93 (t, J = 7.3 Hz, 3H). 13C NMR (101 MHz, CDCI3) d 167.7, 165.1, 159.7, 156.6, 156.0, 135.2, 129.4, 129.3, 127.9, 114.6, 114.1, 103.7, 93.7, 76.1, 70.3, 69.7, 69.3, 68.5, 55.3, 37.2, 28.1, 25.9, 24.7, 23.2, 13.8.
Example 31, 2-((4-propylphenoxy)methyl)-6-((tetrahydro-2H-pyran-2-yl)methoxy)- pyridin-4-ol (30). The target compound was synthesized as described for 28 using compound 29 (28.4 mg, 59.5 pmol) instead of 27 and purified initially by silica gel column chromatography (0-10% MeOH in DCM) and subsequently by preparative HPLC (30-70% solvent B in 15 min) to yield 17.7 mg (83%) colorless oil. Rf = 0.70 (DCM:MeOH, 9: 1). IR (neat) Amax 2930(w), 2860(w), 1668(m), 1625(m), 1611(m), 1240(m), 1180(s) cm 1. JH NMR (600 MHz, CDCI3) d 9.14 (s, 1H), 7.10 - 7.07 (m, 2H), 6.87 (d, J = 2.0 Hz, 1H), 6.85 - 6.80 (m, 2H), 6.54 (d, J = 2.1 Hz, 1H), 5.06 (s, 2H), 4.15 - 4.08 (m, 2H), 4.00 - 3.95 (m, 1H), 3.70 - 3.65 (m, 1H), 3.44 (td, J = 11.3, 3.1 Hz, 1H), 2.51 (t, J = 7.7 Hz, 2H), 1.91 - 1.87 (m, 1H), 1.62 - 1.47 (m, 6H), 1.41 - 1.34 (m, 1H), 0.91 (t, J = 7.3 Hz, 3H). 13C NMR (151 MHz, CDCI3) d 175.5, 161.5, 155.3, 149.3, 137.0, 129.8, 114.7, 107.0, 95.9, 75.4, 74.5, 68.7, 65.3, 37.2, 27.3, 25.5, 24.8, 22.8, 13.9. HPLC: tR = 4.56 min, Purity: 99.99%.
4-(Benzyloxy)-2,6-dibromopyridine (32). A suspension of 2,6-dibromopyridin-4-ol (300.0 mg, 1.19 mmol) and Cs2C03 (576.1 mg, 1.77 mmol) in acetone (5 mL) was stirred for 15 min before the addition of benzyl bromide (0.14 mL, 1.18 mmol) at rt and the mixture was set under reflux conditions. After 5 h the solvent was evaporated, and the residue was partitioned between water (5 mL), brine (5 mL) and EtOAc (10 mL) and the phases were separated. The aq. phase was further extracted with EtOAc (2 x 10 mL), and the combined organic phase was washed with NaOH (1 M, 2 x 10 mL), dried over Na2S04, filtered and concentrated under reduced pressure to afford 32 (394 mg, 98%) as a white solid. Rf = 0.58 (PE: EtOAc, 9: 1). JH NMR (400 MHz, CDCI3) d 7.45 - 7.36 (m, 5H), 7.05 (s, 2H), 5.09 (s, 2H). 13C NMR (101 MHz, CDCI3) d 166.8, 141.3, 134.6, 129.1, 129.0, 127.8, 114.2, 71.0. 4-(Benzyloxy)-2-bromo-6-((tetrahydro-2H-pyran-2-yl)methoxy)pyridine (33). NaH
(60% in mineral oil, 55.1 mg, 1.38 mmol) was added to a solution of 32 (394 mg, 1.15 mmol) and (tetrahydro-2H-pyran-2-yl)methanol (0.13 mL, 1.15 mmol) in THF (3.5 mL) at 0 °C and the reaction was stirred at the same temperature for 30 min before moving the vial to a heating block at 100 °C. After 24 h the mixture was allowed to cool to rt, water (5 mL) and brine (5 mL) were added and the mixture was extracted with EtOAc (3 x 10 mL). The combined organic phase was dried over Na2S04, filtered and the solvents were evaporated under reduced pressure. The residue was purified by silica gel column chromatography (7-9% EtOAc in heptane) to afford 33 (282 mg, 65%) as colorless oil. Rf = 0.44 (PE:EtOAc, 9: 1).
Figure imgf000086_0001
NMR (400 MHz, CDC ) d 7.41 - 7.33 (m, 5H), 6.74 (d, J = 1.9 Hz, 1H), 6.30 (d, J = 1.9 Hz, 1H), 5.03 (s, 2H), 4.31 (dd, J = 11.4, 3.1 Hz, 1H), 4.21 (dd, J = 11.4, 7.0 Hz, 1H), 4.07 - 4.02 (m, 1H), 3.70 - 3.64 (m, 1H), 3.48 (td, J = 11.5, 2.3 Hz, 1H), 1.92 - 1.86 (m, 1H), 1.67 - 1.37 (m, 6H). 13C NMR (101 MHz, CDCh) d 167.9, 164.8, 139.0, 135.4, 128.9, 128.6, 127.6, 110.0, 94.6, 75.9, 70.4, 70.0, 68.6, 28.0, 26.0, 23.2.
4-(Benzyloxy)-2-ethynyl-6-((tetrahydro-2H-pyran-2-yl)methoxy)pyridine (34). A vial was charged with 33 (260 mg, 0.687 mmol), Pd(PPh3)2Cl2 (24.1 mg, 0.034 mmol) and copper(I) iodide (10.5 mg, 0.055 mmol), the vial was capped, then evacuated and filled with Ar (x 3). Degassed THF (3.4 mL), TEA (0.19 mL, 1.36 mmol) and ethynyltrimethylsilane (0.19 mL, 1.37 mmol) were added successively and the suspension was stirred at rt for 17 h. The reaction mixture was filtered through a pad of Celite and eluted with DEE (20 mL). The solvents were evaporated under reduced pressure and the crude material was subjected to the next reaction without further purification. The crude residue was suspended in MeOH (3.4 mL) and K2CO3 was added at 0 °C. The reaction was stirred at the same temperature for 30 min, then allowed to warm to rt and stirred for another 30 min. The reaction mixture was diluted with EtOAc (10 mL) and water (10 mL) was added. The phases were separated and the aq. phase was further extracted with EtOAc (2 x 10 mL). The combined organic phase was dried over Na2S04, filtered and the solvents were evaporated under reduced pressure. The residue purified by silica gel column chromatography (10-14% EtOAc in heptane) to afford 34 (190.8 mg, 86% over 2 steps) as slightly yellow oil. Rf = 0.27 (PE:EtOAc, 9: 1). JH NMR (400 MHz, CDCI3) d 7.42 - 7.32 (m, 5H), 6.78 (d, J = 2.1 Hz, 1H), 6.37 (d, J = 2.1 Hz, 1H), 5.04 (s, 2H), 4.36 (dd, J = 11.5, 2.9 Hz, 1H), 4.24 (dd, J = 11.5, 7.2 Hz, 1H), 4.08 - 4.02 (m, 1H), 3.72 - 3.65 (m, 1H), 3.49 (td, J =
11.6, 2.3 Hz, 1H), 3.06 (s, 1H), 1.91 - 1.84 (m, 1H), 1.64 - 1.38 (m, 5H). 13C NMR (101 MHz, CDCI3) d 166.8, 165.4, 139.5, 135.6, 128.9, 128.5, 127.6, 111.6, 96.4, 83.0, 76.2, 76.1, 70.2,
69.6, 68.6, 28.0, 26.0, 23.3.
4-(Benzyloxy)-2-((6-ethoxypyridin-3-yl)ethynyl)-6-((tetrahydro-2H-pyran-2-yl)- methoxy)pyridine (35). A vial was charged with 2-ethoxy-5-iodopyridine (27.2 mg, 0.109 mmol), Pd(PPh3)4 (6.3 mg, 0.005 mmol) and copper(I) iodide (2.1 mg, 0.011 mmol), the vial was capped, then evacuated and filled with Ar (x 3). Degassed TEA (0.8 mL) and a solution of 34 (35.3 mg, 0.109 mmol) in dry and degassed THF (0.8 mL) were added successively and the suspension was stirred at rt for 16 h. The reaction mixture was filtered through a pad of Celite and washed with DEE (20 mL). The solvents were evaporated and the residue was purified by silica gel column chromatography (15-16% EtOAc in heptane) to afford 35 (39.8 mg, 82%) as slightly yellow oil. Rf = 0.48 (PE:EtOAc, 8:2). JH NMR (400 MHz, CDCI3) d 8.37 (d, J = 2.3 Hz, 1H), 7.71 (dd, J = 8.6, 2.4 Hz, 1H), 7.40 - 7.33 (m, 5H), 6.81 (d, J = 2.0 Hz, 1H), 6.70 (d, J = 8.6 Hz, 1H), 6.35 (d, J = 2.1 Hz, 1H), 5.07 (s, 2H), 4.42 - 4.35 (m, 3H), 4.27 (dd, J = 11.4, 7.1 Hz, 1H), 4.09 - 4.03 (m, 1H), 3.72 - 3.66 (m, 1H), 3.50 (td, J = 11.6, 2.3 Hz, 1H), 1.92 - 1.86 (m, 1H), 1.65 - 1.37 (m, 8H). 13C NMR (101 MHz, CDCI3) d 166.9, 165.5, 163.6, 150.8, 141.6, 140.6, 135.7, 128.8, 128.5, 127.6, 112.2, 111.0, 111.0, 95.8, 90.3, 85.5, 76.1, 70.2, 69.6, 68.6,
62.3, 28.0, 26.0, 23.3, 14.7.
Example 32, 2-(2-(6-ethoxypyridin-3-yl)ethyl)-6-((tetrahydro-2H-pyran-2-yl)- methoxy)pyridin-4-ol (36). The target compound was synthesized as described for 8a using compound 35 (39.8 mg, 0.090 mmol) instead of 7a, stirred for 6 h and purified by silica gel column chromatography (5-7% MeOH in DCM) to yield 23.9 mg (75%) colorless oil. Rf = 0.51 (DCM:MeOH, 9: 1). IR (neat) Amax 2937(m), 2858(w), 1608(s), 1588(m), 1491(s), 1440(m), 1253(m), 1160(m), 1045(s) cm 1. Ή NMR (600 MHz, CDCI3) d 7.85 (d, J = 2.4 Hz, 1H), 7.40 (dd, J = 8.5, 2.5 Hz, 1H), 6.63 (d, J = 8.4 Hz, 1H), 6.20 (d, J = 1.9 Hz, 1H), 6.01 (d, J = 1.9 Hz, 1H), 4.27 (q, J = 7.1 Hz, 2H), 4.20 (dd, J = 11.2, 3.4 Hz, 1H), 4.12 (dd, J = 11.2, 6.8 Hz, 1H), 4.04 - 3.97 (m, 1H), 3.72 - 3.65 (m, 1H), 3.47 (td, J = 11.7, 2.4 Hz, 1H), 2.91 (dt, J = 10.3, 7.3 Hz, 2H), 2.81 (t, J = 7.6 Hz, 2H), 1.92 - 1.85 (m, 1H), 1.66 - 1.46 (m, 4H), 1.45 - 1.32 (m, 4H). 13C NMR (151 MHz, CDCI3) d 169.6, 163.8, 162.6, 156.7, 146.0, 139.4, 129.3, 110.8, 107.2,
94.3, 76.2, 70.0, 68.5, 61.9, 38.3, 31.4, 28.0, 25.9, 23.1, 14.8. HPLC: tR = 3.30 min, Method B, Purity: 95.70%.
IN VITRO PHARMACOLOGICAL ASSAYS
Assay I: PRESTO-Tango b-arrestin recruitment assay
PRESTO-Tango b-arrestin recruitment assay (W.K. Kroeze et al., 2015). HTLA cells (a HEK293 cell line stably expressing a tTA-dependent luciferase reporter and a 3-arrestin2-TEV fusion gene) were maintained in Dulbecco's Modified Eagle's Medium (DMEM) supplemented with 10% Fetal Bovine Serum (dFBS), 100 U/ml penicillin and 100 pg/ml streptomycin, 2 pg/ml puromycin and 100 pg/ml hygromycin B in a humidified atmosphere at 37 °C in 5% CO2. For transfection, cells were plated at 9 x 106 to 10 x 106 cells per 15-cm cell-culture dish (day 1). The following day (day 2), cells were transfected by adding 5pg DNA and 15pg polyethylenimine (PEI) diluted in lmL Opti-MEM (Reduced Serum Medium supplied by ThermoFisher). On day 3, transfected cells were transferred at 25000 cells per well in 40 pi of medium into poly-l-lysine-coated and rinsed 384-well white, clear-bottomed cell-culture plates (Greiner Bio-One). On day 4, dilutions of the ligands to be tested were prepared in 1% dFBS DMEM and 10pL were added to each well. On day 5, 20 pi per well of Bright-Glo solution (Promega) diluted 10-fold in assay buffer (Hanks' Balanced Salt Solution [HBSS], 20mM HEPES, ImM CaCI2, ImM MgC , pH adjusted to 7.4 by 5M NaOH) was added to each well. After incubation for 20 min at room temperature, luminescence was counted in an Enspire luminescence counter at 384nm. Results in the form of relative luminescence units (RLU) were exported into Excel spreadsheets, and GraphPad Prism was used for analysis of data. To measure constitutive activity, no ligand was added on day 4. GPR84 antagonistic activity
The GPR84 antagonistic activity of compounds 1-34 was determined using the PRESTO-Tango b- arrestin2 recruitment assay (Assay I, see assays above), from which the concentration of each compound required for 50% inhibition (IC5o) of the response from the agonist ZQ-16 (100 nM) was determined. The antagonistic activity for each compound is given in Table 3 as the pIC5o, which is the negative log of the IC50 value when converted to molar.
GPR84 agonist activity
The GPR84 antagonistic activity of compounds 1-34 was determined using the PRESTO-Tango □- arrestin2 recruitment assay (Assay I, see assays above), from which the concentration of each compound required for 50% of maximal activation (EC50) was determined. Maximal activation is indicated as Emax in % relative to the maximal activation of ZQ16. Thus, Emax values between 0% and 100%, preferably below 50% indicate partial agonism, and negative Emax values indicate inverse agonism, i.e. a more efficient receptor inhibition than classical antagonists. The potency of the agonistic activity for each compound in the Table is stated as pEC50, denoting the negative loglO of the molar EC50 value. TABLE 3:
Figure imgf000088_0001
Figure imgf000089_0001
Figure imgf000090_0001
Figure imgf000091_0001
Figure imgf000092_0001
Figure imgf000093_0001
Assay II: CAMP
The cAMP assay kit from CisBio (cat. No. : 62AM4PEC) was used for performing the assay. A Flp-In 293 T-REx cell line with a stably integrated gene for GPR84-Gai fusion receptor was grown in 10cm dishes and induced with doxycycline (1 pL / 10 mL growth medium*) when confluency reached -60%. The next day, dilutions of the compounds (x 2.5) to be tested and agonist EC80 solution (x 4) were prepared in the stimulation buffer provided with the kit. Then 4 pL of the dilution solutions were transferred to the final 384 well plate (PerkinElmer, cat. No. 6008289) in triplicate. The growth medium of the cells was discarded, and the dishes were washed with 10 mL 1% PBS. The cells were detached by adding 1 mL Versene to the dishes and they were transferred to a 50 mL falcon tube with the addition of 3 mL stimulation buffer per dish. The cells were counted, and the tube was centrifuged at 1500 rpm for 5min. The supernatant liquid was decanted, and a precise amount of stimulation buffer was added to result in a concentration of 2*106 cells / mL. A certain amount of cell suspension that it will be added to the final plate was transferred to a vial and a DMSO solution of IBMX was added to a final concentration 0.5 mM. Immediately after, 2.5 pL of cell suspension was added with a repeater to the 384-well plate (~5000cells/well). Then 2.5 pL of agonist solution was added and the plates were incubated for 15 min at rt. 1 pL of 10 pM solution of forskolin in stimulation buffer was then added to all the wells with a repeater. After 45 min incubation at rt, 5 pL of cAMP-Cryptate conjugate and 5 pL of Anti-cAMP-d2 conjugate solution in lysis buffer, provided with the kit, were added successively. After incubation for 1 h at rt the plates were counted in an Envision plate reader using a Time Resolved Fluorescence protocol, measuring the light emission at 620 and 665 nm. The results were exported in Excel files and the ratio (signal at 665 nm)/(signal at 620 nm) x 104 was calculated and plotted versus the compound concentrations using the GraphPad prism software. ^Medium used: Dulbecco's Modified Eagle Medium lx (DMEM): + 4.5 g/L glucose, + l-glutamine, - pyruvate, 10% v/v FBS , penicillin/streptomycin (100 units/mL / 100 mg/mL respectively), 5 mg/mL blasticidin, 1 pg/mL hygromycin B.
Assay III: GTPyS
The compounds' dilutions (x 10) and agonist EC80 concentration (x 10) were prepared in Buffer A (20 mM HEPES, 5 mM MgC , 160 mM NaCI, 0.05% BSA). In deep 96-well plates were added sequentially 40 pL Buffer A, 20 pL from the compounds' dilutions, 20 pL agonist solution, 20 pL membrane preparation (3 pg) originating from cells expressing GPR84-Gai fusion protein and 100 pL Buffer B (Buffer A, 0.2nM GTP-y-35S, 2pM GDP). The plates were incubated for 1 h at 37°C, then filtered through Unifilter plates (Perkin Elmer, cat no. : 6005174) using a 96-well Unifilter harvester (Perkin Elmer) and washed (x 3) with distilled water. The filter plates were left to dry for 3 h, then 50 pL scintillation liquid (Microscint-20, PerkinElmer, cat. No.: 6013621) was added to all the filters and the plates were transferred to a topcount scintillation counter. The results were exported to an excel file and further analysed by GraphPad Prism software to result in concentration-response curves.
IN VIVO PHARMACOLOGICAL ASSAYS
CCI4-induced liver fibrosis
Sprague Dawley rats are orally administered with 0.25 pL/g carbon tetrachloride (CCU) in olive oil solution, starting from day 0, 3 times per week for 6 weeks. Animals are sacrificed 48 hours after the last CCI4 administration. The test compound is given by oral gavage after 3 weeks of CCI4 administration and continued throughout the remainder of the study at 3 mg/kg, 10 mg/kg or 30 mg/kg once a day. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels are assessed in the plasma. One lobe of the liver tissue are fixed in 10% formalin, stained for Sirius red and the percentage coverage area is measured.
NASH-induced liver disease
Non-alcoholic steatohepatitis (NASH) is established in male C57/BL6 mice by a single subcutaneous injection of 200 pg streptozotocin after birth and with a high fat diet ad libitum from 4 until 14 weeks of age. Mice are orally administered with the test compound (3, 10 or 30 mg/kg once daily) from 8 to 14 weeks of age. Plasma ALT levels are determined. One lobe of the liver tissue was fixed in 10% formalin, stained for Sirius red and the percentage coverage area is measured. Hematoxylin and eosin (HE) staining is performed to estimate non-alcoholic fatty liver disease (NAFLD) activity score according to the criteria of Kleiner et al (2005).
Bleomycin-Induced Mouse Model of Pulmonary Fibrosis
The bleomycin-induced model of pulmonary fibrosis is performed essentially as described by Gagnon et al (2018). Briefly, 10-week old C57BL/6 mice are intratracheally instilled with bleomycin (0.025 U per mouse). Mice are grouped according to their body weight loss and treated with test compound (3, 10 or 30 mg/kg per day) or vehicle from day 7 to day 20 via gastric gavage. On day 21, lungs are prepared for histologic assessment of lesions with Masson's trichrome staining.
Adenine-induced tubulointerstitial nephritis mouse model
The study is performed essentially as described by Tamura et al (2009). Briefly, mice are fed either standard chow with or without supplement of 0.25% adenine ad libitum for 4 weeks. After 1 week of adenine administration, mice were given either vehicle or test compound (3, 10 or 30 mg/kg per day) by gastric gavage for 3 weeks. Kidney sections were stained with Masson' s trichrome for histologic evaluation of tubulointerstitial fibrosis and cystic lesions scores.
Doxorubicin mouse model of nephropathy
The doxorubicin nephropathy mouse model was performed as described by Gagnon et al. (2018). Briefly, nephrotoxicity was induced in 6-10 weeks old mice by i.v. injection of doxorubicin (10 mg/kg) on day 0. Test compound (3, 10 or 30 mg/kg per day) or vehicle was administered from day -3 to -1 and day 1 to day 10, and mice were sacrificed on the following day. Kidneys were prepared for histologic assessment of glomerular and tubular lesions with hematoxylin and eosin staining.
REFERENCES
W.K. Kroeze et al., 2015 PRESTO-TANGO: an open-source resource for interrogation of the druggable human GPCR-ome in Nat Struct Mol Biol. 2015 May; 22(5): 362-369.
Mahmud et al. (2017) Three classes of ligands each bind to distinct sites on the orphan G protein- coupled receptor GPR84, Scientific reports, 2017, 7: 17953
Gagnon et al. (2018) A Newly Discovered Antifibrotic Pathway Regulated by Two Fatty Acid Receptors: GPR40 and GPR84, Am. J. Pathol. 2018, 188(5): 1132-1148
Lynch 8i Wang (2016) G Protein-Coupled Receptor Signaling in Stem Cells and Cancer. Int J Mol Sci. 17(5): 707
Miyamoto et al (2017) Anti-Inflammatory and Insulin-Sensitizing Effects of Free Fatty Acid Receptors. Handb. Exp. Pharmacol. 236: 221-231.
Milligan et al (2017) Complex pharmacology of free fatty acid receptors. 117(1): 67-110.
Suckow 8i Briscoe (2017) Key questions for translation of FFA receptors: From pharmacology to medicines. 236: 101-131. Pillaiyar et at. (2017) Diindolylmethane Derivatives: Potent Agonists of the Immunostimulatory Orphan G Protein-Coupled Receptor GPR84. J. Med. Chem. 60(9): 3636-3655.
Pillaiyar et al. (2018) 6-(Ar)Alkylamino-Substituted Uracil Derivatives: Lipid Mimetics with Potent Activity at the Orphan G Protein-Coupled Receptor 84 (GPR84). ACS Omega 3(3): 3365-3383. Kose et al. (2019) An agonist radioligand for the proinflammatory lipid-activated G protein- coupled receptor GPR84 providing structural insights. J. Med. Chem. DIO: 10.1021/acs.jmedchem.9b01339
Kleiner et al. (2005) Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology 41(6): 1313-1321. Tamura et al. (2009) Progressive renal dysfunction and macrophage infiltration in interstitial fibrosis in an adenine-induced tubulointerstitial nephritis mouse model. Histochem. Cell Biol. 131(4): 483-490.
Liu et al. (2016) Design and synthesis of 2-alkylpyrimidine-4,6-diol and 6-alkylpyridine-2,4-diol as potent GPR84 agonists. ACS Med. Chem. Lett. 7(6): 579-583.

Claims

A compound of the formula I:
(formula I)
Figure imgf000097_0001
X is -NH-, -0-, -S- or is absent;
A is -(Al)j-(Bl)k-(A2)r
(B2)m-H, wherein
A1 and A2 independently are C1-7 alkylene, C2-7 alkenylene, C2-7 alkynylene, or C1-7 heteroalkylene, optionally substituted with one or two of independently selected Ul;
B1 and B2 are independently an aliphatic ring, an aromatic ring or a fused ring, optionally substituted with one or two of independently selected U2; H is hydrogen; j, k, I, and m are independently 0 or 1, wherein at least one of j, k, I and m is 1;
Y is -OCH2-, -N(R')CH2-, -CH2-, or -0-, where R' is hydrogen or C1-C3 alkyl; and
R is an aromatic ring, an aliphatic ring or a fused ring, optionally substituted with one, two or three of independently selected U3;
Ul, U2 and U3 are independently hydrogen, C1-3 alkyl, C1-3 haloalkyl, C2-4 heteroalkyl, halogen, hydroxyl, =0, =NR' =N-OR' -NR'R", -SR', -CN, C2-5 alkynyl, C2-5 alkenyl, C3-5 cycloalkyl, C3-5 heterocycloalkyl or -NO2, where R', R", R'" and R"" independently refer to hydrogen, unsubstituted C1-3 alkyl and C2-3 heteroalkyl that can be connected by bonds to form rings, cycloalkyl or heterocycloalkyl; or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a solvate of the pharmaceutically acceptable salt thereof.
The compound according to claim 1, which compound is of the formula I:
Figure imgf000097_0002
(formula I) wherein X is -NH-, -0-, -S- or is absent;
A is
• -A1-B1-A2-B2-H;
• -A1-B1-A2-H;
• -B1-A2-H;
• -A1-B2-H; or
• -A1-A2-H; where A1 and A2 are independently C1-7 alkylene, C1-7 alkenylene, C1-7 alkynylene or C1-7 heteroalkylene; B1 and B2 are independently an aliphatic ring, an aromatic ring or a fused ring, and H is hydrogen;
Y is -OCH2-, -N(R')CH2-, -CH2-, or -0-, where R' is hydrogen or C1-C3 alkyl; and R is
• an aromatic ring comprising nitrogen, an aliphatic ring or a fused ring, where the ring is optionally substituted with -CF3, C1-3 alkyl or C2-4 heteroalkyl, or
Figure imgf000098_0001
the ring is optionally substituted with -CF3, C1-3 alkyl or C2-4 heteroalkyl, o wherein Z is -0-, -CH2-, -NH- or N-(CH2)0-2-CH3, o W is -0- or -CH2-; and o n is 0, 1 or 2; or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a solvate of the pharmaceutically acceptable salt thereof.
3. The compound according to claim 1 or 2, wherein X is absent.
4. The compound according to any of the preceding claims, wherein A is A1-A2-H, where A1 and A2 are C1-5 alkylene or C1-5 alkenylene.
5. The compound according to claims 1-3, wherein X is absent and A is A1-B1-A2-H, where A1 and A2 are Ci-5 alkylene, and B1 is -(C6H4)-.
6. The compound according to claim 5, wherein -X-A-H is -(CH2)2-(C6H4)-(CH2)2-CH3.
7. The compound according to any of the preceding claims, wherein Y is -NHCH2- or -OCH2-.
8. The compound according to any of the preceding claims, wherein R is
Figure imgf000099_0001
9. The compound according to claim 8, wherein n = l.
10. The compound according to claim 8 or 9, wherein Z=0.
11. The compound according to any of the preceding claims, wherein the compound is selected from the group consisting of:
2-((l,4-dioxan-2-yl)methoxy)-6-nonylpyridin-4-ol,
2-nonyl-6-((tetrahydro-2H-pyran-2-yl)methoxy)pyridin-4-ol,
2-nonyl-6-(((tetrahydro-2H-pyran-2-yl)methyl)amino)pyridin-4-ol,
2-(4-propylphenethyl)-6-((tetrahydro-2H-pyran-2-yl)methoxy)pyridin-4-ol,
2-((3-methyltetrahydro-2H-pyran-2-yl)methoxy)-6-(4-propylphenethyl)pyridin-4-ol,
2-((2-methyltetrahydro-2H-pyran-2-yl)methoxy)-6-(4-propylphenethyl)pyridin-4-ol,
2-((4-methyltetrahydro-2H-pyran-2-yl)methoxy)-6-(4-propylphenethyl)pyridin-4-ol,
2-((6-methyltetrahydro-2H-pyran-2-yl)methoxy)-6-(4-propylphenethyl)pyridin-4-ol,
2-((5-methyltetrahydro-2H-pyran-2-yl)methoxy)-6-(4-propylphenethyl)pyridin-4-ol,
2-(isochroman-l-ylmethoxy)-6-(4-propylphenethyl)pyridin-4-ol,
2-(chroman-2-ylmethoxy)-6-(4-propylphenethyl)pyridin-4-ol,
2-(isochroman-3-ylmethoxy)-6-(4-propylphenethyl)pyridin-4-ol,
2-((2-methylchroman-2-yl)methoxy)-6-(4-propylphenethyl)pyridin-4-ol,
2-((2-ethylchroman-2-yl)methoxy)-6-(4-propylphenethyl)pyridin-4-ol,
2-((2-isopropylchroman-2-yl)methoxy)-6-(4-propylphenethyl)pyridin-4-ol,
2-((2-propylchroman-2-yl)methoxy)-6-(4-propylphenethyl)pyridin-4-ol,
2-(methyl((tetrahydro-2H-pyran-2-yl)methyl)amino)-6-(4-propylphenethyl)pyridin-4-ol,
(R)-2-(4-propylphenethyl)-6-((tetrahydro-2H-pyran-2-yl)methoxy)pyridin-4-ol,
(S)-2-(4-propylphenethyl)-6-((tetrahydro-2H-pyran-2-yl)methoxy)pyridin-4-ol, 2-(2-(6-propylpyridin-3-yl)ethyl)-6-((tetrahydro-2H-pyran-2-yl)methoxy)pyridin-4-ol, and 2-(2-(5-propylpyridin-2-yl)ethyl)-6-((tetrahydro-2H-pyran-2-yl)methoxy)pyridin-4-ol.
12. A pharmaceutical composition for use as a medicament, said pharmaceutical composition comprising a compound according to any of claims 1-11 and a pharmaceutically acceptable carrier, excipient or diluent.
13. The pharmaceutical composition according to claim 12, wherein the composition is for use in the treatment of fibrotic, inflammatory, diabetic or cognitive disease.
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