WO2019063748A1 - Ror-gamma inhibitors - Google Patents

Ror-gamma inhibitors Download PDF

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Publication number
WO2019063748A1
WO2019063748A1 PCT/EP2018/076379 EP2018076379W WO2019063748A1 WO 2019063748 A1 WO2019063748 A1 WO 2019063748A1 EP 2018076379 W EP2018076379 W EP 2018076379W WO 2019063748 A1 WO2019063748 A1 WO 2019063748A1
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methyl
compound
chloro
pharmaceutically acceptable
trans
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PCT/EP2018/076379
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French (fr)
Inventor
Guillaume Barbe
Gary Bohnert
Nicholas CALANDRA
Millard Hurst Lambert Iii
Hongfu LU
Mercedes Lobera
Joshi Ramanjulu
Feng Ren
Ting Yang
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Glaxosmithkline Intellectual Property Development Limited
Glaxosmithkline (China) R&D Company Limited
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Publication of WO2019063748A1 publication Critical patent/WO2019063748A1/en

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    • 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
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • C07D213/82—Amides; Imides in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/50—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the nitrogen atom of at least one of the carboxamide groups quaternised
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C255/50—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton to carbon atoms of non-condensed six-membered aromatic rings
    • 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
    • C07D213/63—One oxygen atom
    • C07D213/65—One oxygen atom attached in position 3 or 5
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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

Definitions

  • the present invention relates to retinoid-related orphan receptor gamma (RORY) modulators and their use in the treatment of diseases mediated by RORy.
  • RORY retinoid-related orphan receptor gamma
  • RORs Retinoid-related orphan receptors
  • the ROR family consists of three members, ROR alpha (RORa), ROR beta (ROR3) and ROR gamma (RORy), each encoded by a separate gene (RORA, RORB and RORC, respectively).
  • RORs contain four principal domains shared by the majority of nuclear receptors: an N-terminal A/B domain, a DNA-binding domain, a hinge domain, and a ligand binding domain. Each ROR gene generates several isoforms which differ only in their N- terminal A/B domain.
  • RORyl and RORyt are two isoforms of RORy.
  • RORy is a term used to describe both RORyl and/or RORyt. While RORyl is expressed in a variety of tissues including thymus, muscle, kidney and liver, RORyt is exclusively expressed in the cells of the immune system. RORyt has been identified as a key regulator of Th17 cell differentiation. Th17 cells are a subset of T helper cells which produce IL-17 and other proinflammatory cytokines. Th17 cells have been shown to have key functions in several mouse autoimmune disease models including experimental autoimmune encephalomyelitis (EAE) and collagen-induced arthritis (CIA).
  • EAE experimental autoimmune encephalomyelitis
  • CIA collagen-induced arthritis
  • Th17 cells or their products have been shown to be associated with the pathology of a variety of human inflammatory and autoimmune disorders including multiple sclerosis, rheumatoid arthritis, psoriasis, ankylosing spondylitis, Crohn's disease, ulcerative colitis, primary Sjogren's Syndrome and asthma (Jetten (2009) Nucl.Recept.Signal.7: e003; Manel et al. (2008) Nat. /mmuno/.9:641 -649; Catana et al. (2015) World.J.Gastroenterol.21 (19)5823-5830; Mieliauskaite et al. (2012) Clin. Dev.
  • Th17 cells are activated during the disease process and are responsible for recruiting other inflammatory cells types, especially neutrophils, to mediate pathology in the target tissues (Korn et al. (2009) Annu. Rev. Immunol. 27:485-517).
  • Recent studies also show a role for RORy, Th17 cells and cytokines in colon cancer (Blatner et al. (2012) Sci.Transl.Med. 4(164):164ra159; McAllister et al. (2014) Cancer Cell. 25(5):621 -637; Tosolini et al. (201 1 ) Cancer.Res. 71 (4)1263-1271 ).
  • RORy+ Th17 cells represent a reservoir of active HIV that contributes to persistent infection (Wacleche et al. (2016) Retrovirology. 13(1 ):59).
  • R 1 is -Cy-(CH 2 ) n -COOH
  • Cy is C3-6 cycloalkyl, C3-6 cycloalkenyl or C3-6 heterocycloalkyl wherein Cy is optionally substituted with one or more substituents independently selected from the group consisting of halo, hydroxyland C1-3 alkyl;
  • n 0 or 1 ;
  • R 2 is H or C1-3 alkyl
  • X 1 is C or N
  • X 3 is C or N, with the proviso that when X 3 is N, X 1 is C;
  • X 2 is C-R 3 ;
  • R 3 is H, halo, C1-3 alkyl, CN or C1-3 haloalkyl;
  • Y is NH, CH 2 or O
  • R 4 is H, C3-6 cycloalkyl or C1-5 alkyl, wherein the C1-5 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of O-C1-5 alkyl and hydroxy I;
  • R 5 is phenyl or a six membered monocyclic heteroaryl, wherein R 5 is substituted with one to three substituents independently selected from the group consisting of:
  • O-C1-5 alkyl wherein one or more of the hydrogens on the alkyl are optionally deuterated or wherein the O-C1-5 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of halo, hydroxl and O-C1-3 alkyl;
  • a compound is selected from the group consisting of compounds 1 , 87, 90, 102, 136, 158, and 208 or pharmaceutically acceptable salts thereof.
  • the present invention provides a hydrochloride salt of Compound 1 .
  • the present invention provides a hydrochloride salt of Compound 136.
  • the present invention provides a pharmaceutical composition comprising a compound or pharmaceutically acceptable salt thereof of the invention, as defined above, and a pharmaceutically acceptable excipient.
  • the present invention provides a method of treatment of an inflammatory, metabolic or autoimmune disease mediated by RORy comprising administering to a subject in need thereof, a therapeutically effective amount of a compound as defined above, or a pharmaceutically acceptable salt thereof.
  • the present invention further provides, a method for the treatment of multiple sclerosis, psoriasis, Sjogren's syndrome, innflamatory bowel disease or ankylosing spondylitis in a human in need thereof comprising administering to said human a therapeutically effective amount of a compound or pharmaceutically acceptable salt thereof of the invention as defined in above.
  • the present invention provides a compound or pharmaceutically acceptable salt thereof as defined above for use in therapy.
  • the present invention provides a compound or pharmaceutically acceptable salt thereof of the invention as defined above for use in the treatment of multiple sclerosis, psoriasis, Sjogren's syndrome, innflamatory bowel disease or ankylosing spondylitis.
  • the present invention provides use of a compound or pharmaceutically acceptable salt thereof of the invention as defined in above, in the manufacture of a medicament for use in the treatment of multiple sclerosis, psoriasis, Sjogren's syndrome, innflamatory bowel disease or ankylosing spondylitis.
  • the present invention may be advantageous in a number of respects.
  • the compounds of the invention may be used in the treatment of diseases mediated by RORy. Examples of such diseases include autoimmune or inflammatory diseases such as multiple sclerosis, rheumatoid arthritis, psoriasis and ankylosing spondylitis.
  • cycloalkyl refers to a saturated hydrocarbon ring having the specified number of member atoms. Cycloalkyl groups are monocyclic ring systems or are fused or bridged bicyclic ring systems. For example, C3-6 cycloalkyl refers to a cycloalkyl group having from 3 to 6 member atoms. Cycloalkyl groups may be optionally substituted with one or more substituents as defined herein. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • heteroaryl refers to an aromatic ring containing from 1 to 4 heteroatoms as member atoms in the ring. Heteroaryl groups containing more than one heteroatom may contain different heteroatoms. Heteroaryl groups may be optionally substituted with one or more substituent as defined herein. Heteroaryl groups are monocyclic ring systems or are fused or bridged bicyclic ring systems. Monocyclic heteroaryl rings have from 5 to 7 member atoms. Bicyclic heteroaryl rings have from 7 to 1 1 member atoms.
  • Bicyclic heteroaryl rings include those rings wherein phenyl and a monocyclic heterocycloalkyl ring are attached forming a fused, spiro, or bridged bicyclic ring system, and those rings wherein a monocyclic heteroaryl ring and a monocyclic cycloalkyl, cycloalkenyl, heterocycloalkyl, or heteroaryl ring are attached forming a fused, spiro, or bridged bicyclic ring system.
  • heteroaryl examples include pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, furanyl, furazanyl, thienyl, triazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, tetrazinyl, tetrazolyl, indolyl, isoindolyl, indolizinyl, indazolyl, purinyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, pteridinyl, cinnolinyl, benzimidazolyl, furopyridinyl, and naphthyridinyl.
  • “six membered monocyclic heteroaryl” represents a group or moiety comprising an aromatic monovalent monocyclic radical, containing 6 ring atoms, including at least one carbon atom and 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • Selected 6-membered monocyclic heteroaryl groups contain 1 , 2, or 3 nitrogen ring heteroatoms.
  • Illustrative examples of 5 to 6 membered monocyclic heteroaryl groups useful in the present invention include, but are not limited to pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, tetrazinyl, and tetrazolyl.
  • cycloalkenyl refers to a partially saturated ring.
  • C3-6 cycloalkenyl refers to a partially saturated ring containing 3 to 6 carbon atoms.
  • Cycloalkenes are not aromatic. Examples of cycloalkenes include, but are not limited to, cyclopropane, cyclobutene, cyclopentane and cyclohexene.
  • heteroatom refers to a nitrogen, sulphur, or oxygen atom.
  • heterocycloalkyl refers to a saturated ring containing from 1 to 4 heteroatoms as member atoms in the ring.
  • heterocycloalkyl rings are not aromatic.
  • Heterocycloalkyl groups containing more than one heteroatom may contain different heteroatoms.
  • Heterocycloalkyl groups may be optionally substituted with one or more substituents as defined herein.
  • Heterocycloalkyl groups are monocyclic ring systems or are fused, spiro, or bridged bicyclic ring systems.
  • Monocyclic heterocycloalkyl rings have from 4 to 7 member atoms.
  • Bicyclic heterocycloalkyl rings have from 7 to 1 1 member atoms.
  • heterocycloalkyl examples include pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, pyranyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothienyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, piperidinyl, homopiperidinyl, piperazinyl, morpholinyl, thiamorpholinyl, azepinyl, 1 ,3- dioxolanyl, 1 ,3-dioxanyl, 1 ,3-oxathiolanyl, 1 ,3-dithianyl, azetidinyl, oxetanyl, azabicylo[3.2.1 ]octyl, and oxabicylo[2.2.1 ]heptyl.
  • halo refers to the halogen radicals fluoro, chloro, bromo, and iodo.
  • Hydoxyl refers to the hydroxyl radical OH.
  • alkyl refers to a monovalent saturated hydrocarbon chain having the specified number of member atoms.
  • C1-3 alkyl refers to an alkyl group having from 1 to 3 carbon atoms.
  • Alkyl groups may be optionally substituted with one or more substituent as defined herein.
  • Alkyl groups may be straight or branched. Representative branched alkyl groups have one, two, or three branches.
  • alkyl examples include methyl, ethyl, propyl (n-propyl and isopropyl), butyl (n-butyl, isobutyl, and t-butyl), pentyl (n-pentyl, isopentyl, and neopentyl), and hexyl.
  • haloalkyl refers to an alkyl, as defined herein, wherein one or more of the hydrogens on the hydrocarbon chain are substituted with a halo group.
  • C1-3 haloalkyl refers to an alkyl group having from 1 to 3 carbon atoms substituted with at least one halo group.
  • Representative haloalkyl groups include, but are not limited to, fluoromethyl, difluoromethyl and trifluoromethyl.
  • pICso refers to the negative log of IC50 value in molar.
  • IC50 refers to the half maximal inhibitory concentration. This is a measure of how much of a particular compound (in molar concentration) is needed to inhibit a given functional response by half.
  • member atoms refers to the atom or atoms that form a chain or ring. Where more than one member atom is present in a chain and within a ring, each member atom is covalently bound to an adjacent member atom in the chain or ring. Atoms that make up a substituent group on a chain or ring are not member atoms in the chain or ring.
  • the term "optionally substituted” indicates that a group, such as alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heteroaryl, may be unsubstituted, or the group may be substituted with one or more substituents as defined.
  • RORy refers to all isoforms encoded by the RORC gene which include RORyl and RORyt.
  • RORy modulator refers to a chemical compound that inhibits, either directly or indirectly, the activity of RORy.
  • RORy modulators include antagonists and inverse agonists of RORy.
  • substituted in reference to a group indicates that one or more hydrogen atom attached to a member atom within the group is replaced with a substituent selected from the group of defined substituents.
  • substituted includes the implicit provision that such substitution be in accordance with the permitted valence of the substituted atom and the substituent and that the substitution results in a stable compound (i.e. one that does not spontaneously undergo transformation such as by rearrangement, cyclization, or elimination and that is sufficiently robust to survive isolation from a reaction mixture).
  • a group may contain one or more substituent, one or more (as appropriate) member atom within the group may be substituted.
  • a single member atom within the group may be substituted with more than one substituent as long as such substitution is in accordance with the permitted valence of the atom.
  • the term "enantiomeric excess” or "ee” is the excess of one enantiomer over the other expressed as a percentage. As a result, since both enantiomers are present in equal amounts in a racemic mixture, the enantiomeric excess is zero (0% ee). However, if one enantiomer was enriched such that it constitutes 95% of the product, then the enantiomeric excess would be 90% ee (the amount of the enriched enantiomer, 95%, minus the amount of the other enantiomer, 5%). As used herein, the term “enantiomerically pure” refers to products whose enantiomeric excess is 99% ee or greater.
  • half-life refers to the time required for half of a quantity of a substance to be converted to another chemically distinct species in vitro or in vivo.
  • compounds of the invention as used herein means a compound of formula I or a pharmaceutically acceptable salt thereof.
  • a compound of the invention means any one of the compounds of the invention as defined above.
  • phrases such as "a compound of formula (I) or a pharmaceutically acceptable salt thereof or “compounds of the invention” are intended to encompass the compound of formula (I), a pharmaceutically acceptable salt or solvate of the compound of formula (I), or any pharmaceutically acceptable combination of these.
  • a compound of formula (I) or a pharmaceutically acceptable salt thereof encompasses a pharmaceutically acceptable salt of a compound of formula (I) which is present as a solvate, and this phrase also encompasses a mixture of a compound of Formula (I) and a pharmaceutically acceptable salt of a compound of Formula (I).
  • references herein to a compound of formula (I) or a pharmaceutically acceptable salt thereof includes a compound of formula (I) as a free base or as a pharmaceutically acceptable salt thereof.
  • the invention is directed to a compound of formula (I).
  • the invention may be directed to a pharmaceutically acceptable salt of a compound of formula (I).
  • pharmaceutically acceptable refers to those compounds (including salts), materials, compositions, and dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically-acceptable salts refers to salts that retain the desired biological activity of the subject compound and exhibit minimal undesired toxicological effects. These pharmaceutically-acceptable salts may be prepared in situ during the final isolation and purification of the compound, or by separately reacting the purified compound in its free acid or free base form with a suitable base or acid, respectively.
  • Pharmaceutically acceptable salts include, amongst others, those described in Berge, J. Pharm. Sci., 1977, 66, 1 -19, or those listed in P H Stahl and C G Wermuth, editors, Handbook of Pharmaceutical Salts; Properties, Selection and Use, Second Edition Stahl/Wermuth: Wiley- VCHA/HCA, 201 1 (see http://www.wilev.com/WilevCDA/WilevTitle/productCd- 3906390519.html).
  • Suitable pharmaceutically acceptable salts can include acid or base addition salts.
  • Representative pharmaceutically acceptable acid addition salts include, but are not limited to, 4-acetamidobenzoate, acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate (besylate), benzoate, bisulfate, bitartrate, butyrate, calcium edetate, camphorate, camphorsulfonate (camsylate), caprate (decanoate), caproate (hexanoate), caprylate (octanoate), cinnamate, citrate, cyclamate, digluconate, 2,5-dihydroxybenzoate, disuccinate, dodecylsulfate (estolate), edetate (ethylenediaminetetraacetate), estolate (lauryl sulfate), ethane-1 ,2-disulfonate (edisylate), ethanesulfonate (esylate), formate, fumarate, galactarate
  • Representative pharmaceutically acceptable base addition salts include, but are not limited to, aluminium, 2-amino-2-(hydroxymethyl)-1 ,3-propanediol (TRIS, tromethamine), arginine, benethamine (A/-benzylphenethylamine), benzathine (A/,A/-dibenzylethylenediamine), bis-(2- hydroxyethyl)amine, bismuth, calcium, chloroprocaine, choline, clemizole (1 -p chlorobenzyl- 2-pyrrolildine-1 -ylmethylbenzimidazole), cyclohexylamine, dibenzylethylenediamine, diethylamine, diethyltriamine, dimethylamine, dimethylethanolamine, dopamine, ethanolamine, ethylenediamine, L-histidine, iron, isoquinoline, lepidine, lithium, lysine, magnesium, meglumine (N-methylglucamine), piperazine, pipe
  • the term "therapeutically effective amount” means any amount which, as compared to a corresponding subject who has not received such amount, results in improved treatment, healing, prevention, or amelioration of a disease, disorder, or side effect, or a decrease in the rate of advancement of a disease or disorder.
  • the present invention provides a compound of formula I:
  • R 1 is -Cy-(CH 2 ) n -COOH
  • Cy is C3-6 cycloalkyl, C3-6 cycloalkenyl or C3-6 heterocycloalkyl wherein Cy is optionally substituted with one or more substituents independently selected from the group consisting of halo, hydroxyl and C1-3 alkyl;
  • n 0 or 1 ;
  • R 2 is H or C1-3 alkyl
  • X 1 is C or N
  • X 3 is C or N, with the proviso that when X 3 is N, X 1 is C;
  • X 2 is C-R 3 ;
  • R 3 is H, halo, C1-3 alkyl, CN or C1-3 haloalkyl;
  • Y is NH, CH 2 or O
  • R 4 is H, C3-6 cycloalkyl or C1-5 alkyl, wherein the C1-5 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of O-C1-5 alkyl and hydroxyl;
  • R 5 is phenyl or a six membered monocyclic heteroaryl, wherein R 5 is substituted with one to three substituents independently selected from the group consisting of:
  • O-C1-5 alkyl wherein one or more of the hydrogens on the alkyl are optionally deuterated or wherein the O-C1-5 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of halo, hydroxl and O-C1-3 alkyl; (ix) C1-5 haloalkyl; and
  • the compound or pharmaceutically acceptable salt thereof is:
  • the compound or pharmaceutically acceptable salt thereof is:
  • Cy (defined in R 1 ) is selected from the group consisting of C3-6 cycloalkyl, cyclohexene, tetrahydropyran, oxetane, morpholine, 1 ,4-dioxan and pipiridine. In some embodiments of the invention, Cy is selected from cyclohexyl, oxetane or cyclobutyl.
  • n 0.
  • V n indicates a linkage to the rest of the compound.
  • R 2 is H.
  • R 3 is halo or C1-3 haloalkyl. In some embodiments of the invention R 3 is C1-3 haloalkyl. In an embodiment of the invention R 3 is C1-3 haloalkyl and the halo is fluorine e.g. R 3 is CH2F, CHF2 or CF3. In a particular embodiment of the invention R 3 is CF3. In an alternative embodiment of the invention R 3 is halo e.g. R 3 is chlorine.
  • Y is O or NH. In an embodiment, Y is NH.
  • R 4 is C1-5 alkyl, wherein the C1-5 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of O-C1-5 alkyl and hydroxyl. In another embodiment of the invention R 4 is C1-5 alkyl. In another embodiment of the invention R 4 is CH3.
  • R 5 is phenyl, pyridinyl or pyrimidinyl optionally substituted with one to three substituents as set out above.
  • R 5 is phenyl substituted with two substituents independently selected from: halo; C1-5 alkyl optionally substituted with one or more hydroxyl groups; O-C1-5 alkyl wherein one or more of the hydrogens on the alkyl is optionally deuterated or wherein the O-C1-5 alkyl is optionally substituted with one or more substituents independently selected from halo, hydroxl and O-C1-3 alkyl; C1-5 haloalkyl and CN.
  • R 5 is phenyl substituted with O-C1-5 alkyl and at least one other group selected from: C1-5 alkyl optionally substituted with one or more hydroxyl groups; C1-5 haloalkyl and CN.
  • the O-C1-3 alkyl may be selected from O-CH3, O- CH2CH3 and 0-(CH2)2CH3.
  • R 5 is a phenyl substituted with O-C1-5 alkyl and at least one other substituent, independently selected from halo, C1-5 alkyl, C1-5 haloalkyl and CN.
  • R 5 is a phenyl substituted with O-C1-5 alkyl and CN.
  • R 2 is H
  • X 1 is N and X 3 is C;
  • R 3 is C1-3 haloalkyl wherein the halo may be fluorine
  • R 4 is C1-5 alkyi
  • R 5 is phenyl substituted with two substituents independently selected from the group consisting of: halo; C1-5 alkyi optionally substituted with one or more hydroxyl groups; O-C1-5 alkyi optionally wherein one or more of the hydrogens on the alkyi is deuterated or optionally wherein the O-C1-5 alkyi is substituted with one or more substituents selected from the group consisting of halo, hydroxl and O-C1-3 alkyi; C1-5 haloalkyl and CN .
  • R 2 is H
  • X 1 is N and X 3 is C;
  • R 3 is C1-3 haloalkyl wherein the halo is fluorine
  • Y is NH
  • R 4 is C1-5 alkyl
  • R 5 is phenyl substituted with O-C1-5 alkyl and at least one other group selected from the group consisting of C1-5 alkyl optionally substituted with one or more hydroxyl groups; C1-5 haloalkyl and CN.
  • the compound of Formula I is selected from the compounds in Table 1 or a pharmaceutically acceptable salt thereof:
  • the compound is selected from the group consisting of compound 1 , 87, 90, 102, 136, 158, and 208 and pharmaceutically acceptable salts thereof. In another embodiment, the compound is selected from the group consisting of compound 1 and compound 136 and pharmaceutically acceptable salts thereof.
  • the compound is Compound 136 or a pharmaceutically acceptable salt thereof. In another aspect, the compound is Compound 1 or a pharmaceutically acceptable salt thereof.
  • the compound is the hydrochloride salt or the hydrobromide salt of Compound 1 . In an embodiment the compound is the hydrochloride salt of Compound 1 . In an aspect of the invention the compound is the hydrochloride salt or the hydrobromide salt of Compound 136. In an embodiment the compound is the hydrochloride salt of Compound 136.
  • the compounds according to Formula I may contain one or more asymmetric center (also referred to as a chiral center) and may, therefore, exist as individual enantiomers, diastereomers, or other stereoisomeric forms, or as mixtures thereof.
  • Chiral centers such as chiral carbon atoms, may also be present in a substituent such as an alkyl group.
  • the stereochemistry of a chiral center present in Formula I, or in any chemical structure illustrated herein, is not specified the structure is intended to encompass all individual stereoisomers and all mixtures thereof.
  • compounds according to Formula I containing one or more chiral center may be used as racemic mixtures, enantiomerically enriched mixtures, or as enantiomerically pure individual stereoisomers.
  • Individual stereoisomers of a compound according to Formula I which contain one or more asymmetric center may be resolved by methods known to those skilled in the art. For example, such resolution may be carried out (1 ) by formation of diastereoisomeric salts, complexes or other derivatives; (2) by selective reaction with a stereoisomer-specific reagent, for example by enzamatic oxidation or reduction; or (3) by gas-liquid or liquid chromatography in a chiral enviornment, for example, on a chiral support such as silica with a bound chiral ligand or in the presence of a chiral solvent.
  • stereoisomers may be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by converting one enantiomer to the other by asymmetric transformation.
  • an enantiomer is represented and the absolute stereochemistry is unknown, the use of "or1 " or "or2" at the chiral centre denotes that the absolute stereochemistry of the particular compound is unknown, i.e. the compound as drawn may be either the R enantiomer or the S enantiomer.
  • the bold or hashed wedge symbol (— 1 ) is used as appropriate, without the use of "or1 " or “or2” at the chiral centre.
  • the compounds according to Formula I may also contain double bonds or other centers of geometric asymmetry. Where the stereochemistry of a center of geometric asymmetry present in Formula I, or in any chemical structure illustrated herein, is not specified, the structure is intended to encompass the trans (E) geometric isomer, the cis (Z) geometric isomer, and all mixtures thereof. Likewise, all tautomeric forms are also included in Formula I whether such tautomers exist in equilibrium or predominately in one form.
  • compounds according to Formula I may be present as a free base or free acid.
  • compounds according to Formula I may contain an acidic functional group. In certain other embodiments, compounds according to Formula I may contain a basic functional group.
  • pharmaceutically-acceptable salts of the compounds according to Formula I may be prepared. Indeed, in certain embodiments of the invention, pharmaceutically-acceptable salts of the compounds according to Formula I may be preferred over the respective free base or free acid because such salts may impart greater stability or solubility to the molecule thereby facilitating formulation into a dosage form. Accordingly, the invention is further directed to the use of pharmaceutically-acceptable salts of the compounds according to Formula I.
  • salts which are not pharmaceutically acceptable, may be useful in the preparation of compounds of this invention and these should be considered to form a further aspect of the invention.
  • These salts such as trifluoroacetate, while not in themselves pharmaceutically acceptable, may be useful in the preparation of salts useful as intermediates in obtaining the compounds of the invention and their pharmaceutically acceptable salts.
  • a compound of the invention containing a basic amine or other basic functional group is isolated as a salt
  • the corresponding free base form of that compound may be prepared by any suitable method known to the art, including treatment of the salt with an inorganic or organic base, suitably an inorganic or organic base having a higher pK a than the free base form of the compound.
  • the corresponding free acid form of that compound may be prepared by any suitable method known to the art, including treatment of the salt with an inorganic or organic acid, suitably an inorganic or organic acid having a lower pK a than the free acid form of the compound.
  • the invention also includes various deuterated forms of the compounds of Formula I.
  • Each available hydrogen atom attached to a carbon atom may be independently replaced with a deuterium atom.
  • a person of ordinary skill in the art will know how to synthesize deuterated forms of the compounds of Formula (I).
  • Commercially available deuterated starting materials may be employed in the preparation of deuterated forms of the compounds of Formula (I), or they may be synthesized using conventional techniques employing deuterated reagents (e.g. lithium aluminum deuteride).
  • the compounds of the invention may exist in solid or liquid form. In the solid state, the compounds of the invention may exist in crystalline or noncrystalline form, or as a mixture thereof.
  • pharmaceutically-acceptable solvates may be formed wherein solvent molecules are incorporated into the crystalline lattice during crystallization. Solvates may involve nonaqueous solvents such as ethanol, isopropanol, DMSO, acetic acid, ethanolamine, and ethyl acetate, or they may involve water as the solvent that is incorporated into the crystalline lattice.
  • Solvates wherein water is the solvent that is incorporated into the crystalline lattice are typically referred to as "hydrates.” Hydrates include stoichiometric hydrates as well as compositions containing vaiable amounts of water. The invention includes all such solvates. The skilled artisan will further appreciate that certain compounds of the invention that exist in crystalline form, including the various solvates thereof, may exhibit polymorphism (i.e. the capacity to occur in different crystalline structures). These different crystalline forms are typically known as “polymorphs.” The invention includes all such polymorphs. Polymorphs have the same chemical composition but differ in packing, geometrical arrangement, and other descriptive properties of the crystalline solid state.
  • Polymorphs therefore, may have different physical properties such as shape, density, hardness, deformability, stability, and dissolution properties. Polymorphs typically exhibit different melting points, IR spectra, and X-ray powder diffraction patterns, which may be used for identification. The skilled artisan will appreciate that different polymorphs may be produced, for example, by changing or adjusting the reaction conditions or reagents, used in making the compound. For example, changes in temperature, pressure, or solvent may result in polymorphs. In addition, one polymorph may spontaneously convert to another polymorph under certain conditions.
  • a pharmaceutical composition comprising a compound or pharmaceutically acceptable salt thereof as defined above, and a pharmaceutically acceptable excipient.
  • the compound may be as described in any of the above embodiments.
  • the compound is any of the compounds in table 1 or a pharmaceutically acceptable salt thereof.
  • the compound is compound 1 or a pharmaceutically acceptable salt thereof.
  • the compound is compound 136 or a pharmaceutically acceptable salt thereof.
  • compositions of the invention will normally, but not necessarily, be formulated into pharmaceutical compositions prior to administration to an individual.
  • Pharmaceutical compositions of the invention may be prepared and packaged in bulk form wherein a safe and effective amount of a compound of the invention can be extracted and then given to the individual such as with powders or syrups.
  • the pharmaceutical compositions of the invention may be prepared and packaged in unit dosage form wherein each physically discrete unit contains a safe and effective amount of a compound of the invention.
  • the pharmaceutical compositions of the invention typically contain from 0.1 mg to 1000 mg.
  • the pharmaceutical compositions of the invention typically contain one compound of the invention. However, in certain embodiments, the pharmaceutical compositions of the invention contain more than one compound of the invention. For example, in certain embodiments the pharmaceutical compositions of the invention contain two compounds of the invention.
  • the pharmaceutical compositions of the invention may optionally further comprise one or more additional pharmaceutically active compounds.
  • pharmaceutically-acceptable excipient means a pharmaceutically acceptable material, composition or vehicle involved in giving form or consistency to the pharmaceutical composition.
  • Each excipient must be compatible with the other ingredients of the pharmaceutical composition when commingled such that interactions which would substantially reduce the efficacy of the compound of the invention when administered to an individual and interactions which would result in pharmaceutical compositions that are not pharmaceutically acceptable are avoided.
  • each excipient must of course be of sufficiently high purity to render it pharmaceutically-acceptable.
  • dosage forms include those adapted for (1 ) oral administration such as tablets, capsules, caplets, pills, troches, powders, syrups, elixers, suspensions, solutions, emulsions, sachets, and cachets; (2) parenteral administration such as sterile solutions, suspensions, and powders for reconstitution; (3) transdermal administration such as transdermal patches; (4) rectal administration such as suppositories; (5) inhalation such as dry powders, aerosols, suspensions, and solutions; and (6) topical administration such as creams, ointments, lotions, solutions, pastes, sprays, foams, and gels.
  • oral administration such as tablets, capsules, caplets, pills, troches, powders, syrups, elixers, suspensions, solutions, emulsions, sachets, and cachets
  • parenteral administration such as sterile solutions, suspensions, and powders for reconstitution
  • transdermal administration such as transdermal patches
  • rectal administration
  • Suitable pharmaceutically-acceptable excipients will vary depending upon the particular dosage form chosen.
  • suitable pharmaceutically-acceptable excipients may be chosen for a particular function that they may serve in the composition.
  • certain pharmaceutically-acceptable excipients may be chosen for their ability to facilitate the production of uniform dosage forms.
  • Certain pharmaceutically-acceptable excipients may be chosen for their ability to facilitate the production of stable dosage forms.
  • Certain pharmaceutically-acceptable excipients may be chosen for their ability to facilitate the carrying or transporting of the compound or compounds of the invention once administered to the individual from one organ, or portion of the body, to another organ, or portion of the body.
  • Certain pharmaceutically-acceptable excipients may be chosen for their ability to enhance compliance.
  • Suitable pharmaceutically-acceptable excipients include the following types of excipients: Diluents, fillers, binders, disintegrants, lubricants, glidants, granulating agents, coating agents, wetting agents, solvents, co-solvents, suspending agents, emulsifiers, sweetners, flavoring agents, flavor masking agents, coloring agents, anticaking agents, hemectants, chelating agents, plasticizers, viscosity increasing agents, antioxidants, preservatives, stabilizers, surfactants, and buffering agents.
  • excipients include the following types of excipients: Diluents, fillers, binders, disintegrants, lubricants, glidants, granulating agents, coating agents, wetting agents, solvents, co-solvents, suspending agents, emulsifiers, sweetners, flavoring agents, flavor masking agents, coloring agents, anticaking agents, hemectants, chelating agents
  • Skilled artisans possess the knowledge and skill in the art to enable them to select suitable pharmaceutically-acceptable excipients in appropriate amounts for use in the invention.
  • resources that are available to the skilled artisan which describe pharmaceutically-acceptable excipients and may be useful in selecting suitable pharmaceutically-acceptable excipients. Examples include Remington's Pharmaceutical Sciences (Mack Publishing Company), The Handbook of Pharmaceutical Additives (Gower Publishing Limited), and The Handbook of Pharmaceutical Excipients (the American Pharmaceutical Association and the Pharmaceutical Press).
  • the pharmaceutical compositions of the invention are prepared using techniques and methods known to those skilled in the art. Some of the methods commonly used in the art are described in Remington's Pharmaceutical Sciences (Mack Publishing Company).
  • the invention is directed to a solid oral dosage form such as a tablet or capsule comprising a safe and effective amount of a compound of the invention and a diluent or filler.
  • Suitable diluents and fillers include lactose, sucrose, dextrose, mannitol, sorbitol, starch (e.g. corn starch, potato starch, and pre-gelatinized starch), cellulose and its derivatives (e.g. microcrystalline cellulose), calcium sulfate, and dibasic calcium phosphate.
  • the oral solid dosage form may further comprise a binder. Suitable binders include starch (e.g.
  • the oral solid dosage form may further comprise a disintegrant. Suitable disintegrants include crospovidone, sodium starch glycolate, croscarmelose, alginic acid, and sodium carboxymethyl cellulose.
  • the oral solid dosage form may further comprise a lubricant. Suitable lubricants include stearic acid, magnesuim stearate, calcium stearate, and talc.
  • the compounds of Formula I are modulators of RORy and can be useful in the treatment of diseases mediated by RORy, particularly autoimmune or inflammatory diseases, oncology indications and HIV infection.
  • diseases mediated by RORy particularly autoimmune or inflammatory diseases, oncology indications and HIV infection.
  • inflammatory or autoimmune diseases of the invention include multiple sclerosis, rheumatoid arthritis, psoriasis, ankylosing spondylitis, Crohn's disease, inflammatory bowel disease, Sjogren's syndrome, optic neuritis, chronic obstructive pulmonary disease, asthma, type I diabetes, neuromyelitis optica, Myasthenia Gavis, uveitis, Guillain-Barre syndrome, psoriatic arthritis, Graves' disease and allergy.
  • oncology indications include colorectal and pancreatic cancers.
  • uses in HIV infection include persistence of viral infection and comorbidities in the gut. Accordingly, in another aspect the invention is directed to methods of treating autoimmune and inflammatory diseases mediated by RORy.
  • the present invention provides a compound of Formula I or pharmaceutically acceptable salt thereof as defined above for use in therapy.
  • the compound is any of the compounds in table 1 or a pharmaceutically acceptable salt thereof.
  • the compound is compound 1 or a pharmaceutically acceptable salt thereof.
  • the compound is compound 136 or a pharmaceutically acceptable salt thereof.
  • the present invention also provides a compound of Formula I, or a pharmaceutically acceptable salt thereof, for use in the treatment of inflammatory and autoimmune diseases mediated by RORy.
  • a compound or pharmaceutically acceptable salt thereof as described above for use in the treatment of multiple sclerosis, psoriasis, Sjogren's syndrome, inflammatory bowel disease or ankylosing spondylitis.
  • the disease mediated by RORy is multiple sclerosis.
  • the disease mediated by RORy is ankylosing spondylitis.
  • the disease is psoriasis.
  • the disease is Sjogren's syndrome.
  • the disease is inflammatory bowel disease
  • the compound is any of the compounds in table 1 or a pharmaceutically acceptable salt thereof.
  • the compound is compound 1 or a pharmaceutically acceptable salt thereof.
  • the compound is compound 136 or a pharmaceutically acceptable salt thereof.
  • the present invention is directed to a method of treatment of an inflammatory or autoimmune disease mediated by RORy, which comprises administering to a subject in need thereof, a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof.
  • the subject is a human.
  • the disease is multiple sclerosis, psoriasis, Sjogren's syndrome, inflammatory bowel disease or ankylosing spondylitis.
  • the disease mediated by RORy is multiple sclerosis.
  • the disease mediated by RORy is ankylosing spondylitis.
  • the disease is psoriasis.
  • the disease is Sjogren's syndrome.
  • the disease is inflammatory bowel disease
  • the compound is any of the compounds in table 1 or a pharmaceutically acceptable salt thereof.
  • the compound is compound 1 or a pharmaceutically acceptable salt thereof.
  • the compound is compound 136 or a pharmaceutically acceptable salt thereof.
  • the disease mediated by RORy is multiple sclerosis, psoriasis, Sjogren's syndrome, inflammatory bowel disease or ankylosing spondylitis.
  • the disease mediated by RORy is multiple sclerosis.
  • the disease mediated by RORy is ankylosing spondylitis.
  • the disease is psoriasis.
  • the disease is Sjogren's syndrome.
  • the disease is inflammatory bowel disease.
  • the compound is any of the compounds in table 1 or a pharmaceutically acceptable salt thereof.
  • the compound is compound 1 or a pharmaceutically acceptable salt thereof.
  • the compound is compound 136 or a pharmaceutically acceptable salt thereof.
  • treat in reference to a condition means: (1 ) to ameliorate or prevent the condition or one or more of the biological manifestations of the condition, (2) to interfere with (a) one or more points in the biological cascade that leads to or is responsible for the condition or (b) one or more of the biological manifestations of the condition, (3) to alleviate one or more of the symptoms or effects associated with the condition, or (4) to slow the progression of the condition or one or more of the biological manifestations of the condition.
  • prevention of a condition includes prevention of the condition.
  • prevention is not an absolute term. In medicine, “prevention” is understood to refer to the prophylactic administration of a drug to substantially diminish the likelihood or severity of a condition or biological manifestation thereof, or to delay the onset of such condition or biological manifestation thereof.
  • the compounds of the invention may be administered by any suitable route of administration, including both systemic administration and topical administration.
  • Systemic administration includes oral administration, parenteral administration, transdermal administration, rectal administration, and administration by inhalation.
  • Parenteral administration refers to routes of administration other than enteral, transdermal, or by inhalation, and is typically by injection or infusion.
  • Parenteral administration includes intravenous, intramuscular, and subcutaneous injection or infusion.
  • Inhalation refers to administration into the human lungs whether inhaled through the mouth or through the nasal passages.
  • Topical administration includes application to the skin as well as intraocular, otic, intravaginal, and intranasal administration.
  • the compounds of the invention may be administered once or according to a dosing regimen wherein a number of doses are administered at varying intervals of time for a given period of time. For example, doses may be administered one, two, three, or four times per day. Doses may be administered until the desired therapeutic effect is achieved or indefinitely to maintain the desired therapeutic effect. Suitable dosing regimens for a compound of the invention depend on the pharmacokinetic properties of that compound, such as absorption, distribution, and half-life, which can be determined by the skilled artisan.
  • suitable dosing regimens including the duration such regimens are administered, for a compound of the invention depend on the condition being treated, the severity of the condition being treated, the age and physical condition of the individual being treated, the medical history of the individual to be treated, the nature of concurrent therapy, the desired therapeutic effect, and like factors within the knowledge and expertise of the skilled artisan. It will be further understood by such skilled artisans that suitable dosing regimens may require adjustment given an individual's response to the dosing regimen or over time as individual needs change.
  • Typical daily dosages may vary depending upon the particular route of administration chosen. Typical daily dosages for oral administration range from 0.1 mg to 1000 mg. Typical daily dosages for topical administration range from about 0.001 % to about 10% w/w (weight percent) and preferably from about 0.01 % to about 1 % w/w.
  • a prodrug of a compound of the invention is a functional derivative of the compound which, upon administration to an individual, eventually liberates the compound of the invention in vivo.
  • Administration of a compound of the invention as a prodrug may enable the skilled artisan to do one or more of the following: (a) modify the onset of the compound in vivo; (b) modify the duration of action of the compound in vivo; (c) modify the transportation or distribution of the compound in vivo; (d) modify the solubility of the compound in vivo; and (e) overcome or overcome a side effect or other difficulty encountered with the compound.
  • Typical functional derivatives used to prepare prodrugs include modifications of the compound that are chemically or enzymatically cleaved in vivo. Such modifications, which include the preparation of phosphates, amides, esters, thioesters, carbonates, and carbamates, are well known to those skilled in the art.
  • Combination therapies according to the present invention thus comprise the administration of at least one compound of Formula I or a pharmaceutically acceptable salt thereof, and the use of at least one other therapeutically active agent.
  • a compound of Formula I or pharmaceutically acceptable salt thereof, and the other therapeutically active agent(s) may be administered together in a single pharmaceutical composition or separately and, when administered separately this may occur simultaneously or sequentially in any order.
  • a combination product comprising a compound of Formula I or a pharmaceutically acceptable salt thereof, together with one or more other therapeutically active agents, and optionally a pharmaceutically acceptable carrier or excipient.
  • Suitable other therapeutic agents include, but are not limited to, (1 ) TNF-alpha inhibitors; (2) non-selective COX-1 /COX-2 inhibitors; (3) COX-2 inhibitors; (4) other agents for treatment of inflammatory and autoimmune diseases including glucocorticoids, methotrexate, leflunomide, sulfasalazine, azathioprine, cyclosporin, tacrolimus, penicillamine, bucillamine, actarit, mizoribine, lobenzarit, ciclesonide, hydroxychloroquine, d-penicillamine, aurothiomalate, auranofin or parenteral or oral gold, cyclophosphamide, Lymphostat-B, BAFF/APRIL inhibitors, such as belimumab, and CTLA-4-lg or mimetics thereof; (5) leukotriene biosynthesis inhibitor, 5-lipoxygenase (5-LO) inhibitor or 5-lipoxygenase activating
  • the compounds according to Formula I may be prepared using conventional organic syntheses. Suitable synthetic routes are depicted below in the following general reaction scheme.
  • a substituent described herein is not compatible with the synthetic methods described herein, the substituent may be protected with a suitable protecting group that is stable to the reaction conditions.
  • the protecting group may be removed at a suitable point in the reaction sequence to provide a desired intermediate or target compound.
  • Suitable protecting groups and the methods for protecting and de- protecting different substituent using such suitable protecting groups are well known to those skilled in the art; examples of which may be found in T. Greene and P. Wuts, Protecting Groups in Chemical Synthesis (3 rd ed.), Wiley & Sons, NY (1999).
  • a substituent may be specifically selected to be reactive under the reaction conditions used. In these instances, the reaction conditions convert the selected substituent into another substituent that is either useful as an intermediate compound or is a desired substituent in a target compound.
  • Scheme 1 represents a general reaction scheme for preparing compounds of Formula I where R 1 to R 5 and X 1 , X 2 and X 3 are as defined above, and wherein Y is NH or O.
  • R 1 E and R 2E are esters of R 1 and R 2 .
  • the starting material or reagents described are either commercially available or made from commercially available starting materials using methods known to those skilled in the art.
  • Step (i) in Scheme 1 is carried out by reacting 1 with 2 using any appropriate reagents.
  • An example of an appropriate reagent is diisopropyl ethyl amine.
  • Step (i) may be carried out in any appropriate solvent, e.g. DMSO, and at any suitable temperature e.g. 80°C to 150°C to provide compound 3.
  • Step (ii) is carried out by reacting 3 with any suitable acid or base e.g. LiOH, NaOH, or hydrochloric acid and in any suitable solvent, e.g. MeOH or water, at any suitable temperature e.g. 20°C
  • Step(iii) is carried out using standard amide formation methods. 4 is reacted with 5 in the presence of any suitable reagent, e.g.
  • Step (iv) is be carried out by hydrolysing the ester 6 with a suitable reagent, such as LiOH or NaOH in a suitable solvent, such as THF/water, at a suitable temperature, e.g. 40°C, to provide Formula I.
  • a suitable reagent such as LiOH or NaOH in a suitable solvent, such as THF/water
  • Scheme 2 represents a general reaction scheme for preparing compounds of Formula I where R 1 to R 5 and X 1 , X 2 and X 3 are as defined above, and wherein Y is NH.
  • R 1E and R 2E are esters of R 1 and R 2 and Q is halo e.g. Br or CI.
  • the starting material or reagents described are either commercially available or made from commercially available starting materials using methods known to those skilled in the art.
  • Amide formation, step (i) may be carried out by reacting 1 with 2 using appropriate reagents, such as HATU, with an appropriate base, such as DIPEA or TEA, in an appropriate solvent, such as DMF, at any suitable temperatures, e.g. 23°C, to provide 3.
  • step (ii) may be carried out by reacting 3 with 4 using any suitable reagent, e.g. Pd 2 (dba)3, CS2CO3 or XantPhos, in any suitable solvent, e.g. DMF, at any suitable temperature, e.g.100 °C.
  • Ester hydrolysis, step (iii) may be carried out by reacting 5 with a suitable reagent such as LiOH or NaOH in a suitable solvent, e.g. THF, MeOH, or THF/H2O, at any suitable temperature, e.g. 23°C , to provide a compound of Formula I.
  • Scheme 3 represents a general reaction scheme for preparing compounds of Formula I where R 1 to R 5 and X 1 , X 2 and X 3 are as defined above, and wherein Y is O.
  • R 1E and R 2E are esters of R 1 and R 2 and Q is CN, C0 2 Me or C0 2 Eth.
  • the starting material or reagents described are either commercially available or made from commercially available starting materials using methods known to those skilled in the art.
  • Step (i) is carried out by reacting 1 with 2 using any appropriate reagents, such as triphenyl phosphine and DIAD, in an appropriate solvent, such as tetrahydrofuran, at any suitable temperatures e.g. 0-23°C to provide 3.
  • Step (ii) is be carried out reacting 3 with any suitable base, such as LiOH or NaOH, in a suitable solvent, such as MeOH or water/THF, at any suitable temperature e.g. 23°C.
  • Step(iii) is be carried out using standard amide formation methods reacting 4 with 5 in the presence of any suitable reagent, e.g.
  • Step (iv) is be carried out by hydrolysing the ester 6 with a suitable reagent, such as LiOH or NaOH, in any suitable solvent, such as methanol or water, at any suitable temperature e.g. 25°C, to provide a compound of Formula I.
  • a suitable reagent such as LiOH or NaOH
  • any suitable solvent such as methanol or water
  • reaction mixture was then concentrated directly in vacuo and water (20 mL) was added.
  • the pH of the resulting aqueous mixture was adjusted to 1 with 1 N aqueous HCI.
  • the acidified mixture was then extracted with with EtOAc (1 x 30 mL, 1 x 10 mL).

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Abstract

The present invention relates to compounds of formula I and pharmaceutical compositions comprising compounds of formula I. Compounds of Formula I are useful in treatment of inflammatory, metabolic or autoimmune diseases which are mediated by RORy.

Description

ROR-GAMMA INHIBITORS
Field of the invention
The present invention relates to retinoid-related orphan receptor gamma (RORY) modulators and their use in the treatment of diseases mediated by RORy. Background to the Invention
Retinoid-related orphan receptors (RORs) are transcription factors which belong to the steroid hormone nuclear receptor superfamily (Jetten & Joo (2006) Adv. Dev. Biol. 16:313- 355). The ROR family consists of three members, ROR alpha (RORa), ROR beta (ROR3) and ROR gamma (RORy), each encoded by a separate gene (RORA, RORB and RORC, respectively). RORs contain four principal domains shared by the majority of nuclear receptors: an N-terminal A/B domain, a DNA-binding domain, a hinge domain, and a ligand binding domain. Each ROR gene generates several isoforms which differ only in their N- terminal A/B domain. Two isoforms of RORy have been identified: RORyl and RORyt (also known as RORy2). RORy is a term used to describe both RORyl and/or RORyt. While RORyl is expressed in a variety of tissues including thymus, muscle, kidney and liver, RORyt is exclusively expressed in the cells of the immune system. RORyt has been identified as a key regulator of Th17 cell differentiation. Th17 cells are a subset of T helper cells which produce IL-17 and other proinflammatory cytokines. Th17 cells have been shown to have key functions in several mouse autoimmune disease models including experimental autoimmune encephalomyelitis (EAE) and collagen-induced arthritis (CIA). In addition, Th17 cells or their products have been shown to be associated with the pathology of a variety of human inflammatory and autoimmune disorders including multiple sclerosis, rheumatoid arthritis, psoriasis, ankylosing spondylitis, Crohn's disease, ulcerative colitis, primary Sjogren's Syndrome and asthma (Jetten (2009) Nucl.Recept.Signal.7: e003; Manel et al. (2008) Nat. /mmuno/.9:641 -649; Catana et al. (2015) World.J.Gastroenterol.21 (19)5823-5830; Mieliauskaite et al. (2012) Clin. Dev. Immunol.2012:187258; Miossec & Kolls (2012) Nat. Rev. Drug. Discov.10:763-776). The pathogenesis of chronic autoimmune diseases including multiple sclerosis and rheumatoid arthritis arises from the break in tolerance towards self-antigens and the development of auto-aggressive effector T cells infiltrating the target tissues. Studies have shown that Th17 cells are one of the important drivers of the inflammatory process in tissue-specific autoimmunity (Steinman (2008) J. Exp. Med. 205:1517-1522; Leung et al. (2010) Cell. Mol. Immunol. 7:182-189). There is evidence that Th17 cells are activated during the disease process and are responsible for recruiting other inflammatory cells types, especially neutrophils, to mediate pathology in the target tissues (Korn et al. (2009) Annu. Rev. Immunol. 27:485-517). Recent studies also show a role for RORy, Th17 cells and cytokines in colon cancer (Blatner et al. (2012) Sci.Transl.Med. 4(164):164ra159; McAllister et al. (2014) Cancer Cell. 25(5):621 -637; Tosolini et al. (201 1 ) Cancer.Res. 71 (4)1263-1271 ). Further studies have shown that RORy+ Th17 cells represent a reservoir of active HIV that contributes to persistent infection (Wacleche et al. (2016) Retrovirology. 13(1 ):59).
RORyt plays a critical role in the pathogenic responses of Th17 cells (Ivanov et al. (2006)
Cell 126:1 121 -1 133). RORyt deficient mice show very few Th17 cells. In addition, RORyt deficiency resulted in amelioration of EAE (Ivanov et al. (2006) Cell 126:1 121 -1 133). Support for the role of RORyt in the pathogensis of autoimmune or inflammatory diseases can be found in the following references: Jetten & Joo (2006) Adv. Dev. Biol.16:313-355; Meier et al.
(2007) Immunity 26:643-654; Aloisi & Pujol-Borrell (2006) Nat. Rev. Immunol. 6:205-217;
Jager et al. (2009) J. Immunol.183:7169-7177; Serafini et al. (2004) Brain Pathol.14: 164-174;
Magliozzi et al. (2007) Brain 130: 1089-1 104; Barnes (2008) Nat.Rev.lmmunol.8-A 83^ 92; Miossec & Kolls (2012) Nat.Rev.Drug.DiscovA 0:7Q3-77Q.
In light of the role RORy plays in the pathogenesis of diseases, it is desirable to prepare compounds that modulate RORy activity, which can be used in the treatment of diseases mediated by RORy.
Summary of the Invention
According to a first aspect of the invention, there is provided a compound of formula I
Figure imgf000003_0001
Formula I or a pharmaceutically acceptable salt thereof,
wherein
R1 is -Cy-(CH2)n-COOH;
Cy is C3-6 cycloalkyl, C3-6 cycloalkenyl or C3-6 heterocycloalkyl wherein Cy is optionally substituted with one or more substituents independently selected from the group consisting of halo, hydroxyland C1-3 alkyl;
n is 0 or 1 ;
R2 is H or C1-3 alkyl;
X1 is C or N;
X3 is C or N, with the proviso that when X3 is N, X1 is C;
X2 is C-R3;
R3 is H, halo, C1-3 alkyl, CN or C1-3 haloalkyl;
Y is NH, CH2 or O;
R4 is H, C3-6 cycloalkyl or C1-5 alkyl, wherein the C1-5 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of O-C1-5 alkyl and hydroxy I;
R5 is phenyl or a six membered monocyclic heteroaryl, wherein R5 is substituted with one to three substituents independently selected from the group consisting of:
(i) halo,
(ii) C1-5 alkyl optionally substituted with one or more hydroxyl groups,
(iii) O-C1-5 alkyl wherein one or more of the hydrogens on the alkyl are optionally deuterated or wherein the O-C1-5 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of halo, hydroxl and O-C1-3 alkyl;
(iv) C1-5 haloalkyl; and
(v) CN.
In a second aspect of the invention, there is a compound is selected from the group consisting of compounds 1 , 87, 90, 102, 136, 158, and 208 or pharmaceutically acceptable salts thereof.
In a third aspect, there is provided Compound 1 or a pharmaceutically acceptable salt thereof. In a third aspect there is provided Compound 136 or a pharmaceutically acceptable salt thereof.
In a fourth aspect the present invention provides a hydrochloride salt of Compound 1 .
In another aspect, the present invention provides a hydrochloride salt of Compound 136. In another aspect, the present invention provides a pharmaceutical composition comprising a compound or pharmaceutically acceptable salt thereof of the invention, as defined above, and a pharmaceutically acceptable excipient.
In a further aspect, the present invention provides a method of treatment of an inflammatory, metabolic or autoimmune disease mediated by RORy comprising administering to a subject in need thereof, a therapeutically effective amount of a compound as defined above, or a pharmaceutically acceptable salt thereof.
The present invention further provides, a method for the treatment of multiple sclerosis, psoriasis, Sjogren's syndrome, innflamatory bowel disease or ankylosing spondylitis in a human in need thereof comprising administering to said human a therapeutically effective amount of a compound or pharmaceutically acceptable salt thereof of the invention as defined in above. In a still further aspect, the present invention provides a compound or pharmaceutically acceptable salt thereof as defined above for use in therapy.
In a still further aspect, the present invention provides a compound or pharmaceutically acceptable salt thereof of the invention as defined above for use in the treatment of multiple sclerosis, psoriasis, Sjogren's syndrome, innflamatory bowel disease or ankylosing spondylitis.
In a still further aspect, the present invention provides use of a compound or pharmaceutically acceptable salt thereof of the invention as defined in above, in the manufacture of a medicament for use in the treatment of multiple sclerosis, psoriasis, Sjogren's syndrome, innflamatory bowel disease or ankylosing spondylitis. The present invention may be advantageous in a number of respects. The compounds of the invention may be used in the treatment of diseases mediated by RORy. Examples of such diseases include autoimmune or inflammatory diseases such as multiple sclerosis, rheumatoid arthritis, psoriasis and ankylosing spondylitis. Terms and Definitions
As used herein, the term "cycloalkyl" refers to a saturated hydrocarbon ring having the specified number of member atoms. Cycloalkyl groups are monocyclic ring systems or are fused or bridged bicyclic ring systems. For example, C3-6 cycloalkyl refers to a cycloalkyl group having from 3 to 6 member atoms. Cycloalkyl groups may be optionally substituted with one or more substituents as defined herein. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
As used herein, the term "heteroaryl" refers to an aromatic ring containing from 1 to 4 heteroatoms as member atoms in the ring. Heteroaryl groups containing more than one heteroatom may contain different heteroatoms. Heteroaryl groups may be optionally substituted with one or more substituent as defined herein. Heteroaryl groups are monocyclic ring systems or are fused or bridged bicyclic ring systems. Monocyclic heteroaryl rings have from 5 to 7 member atoms. Bicyclic heteroaryl rings have from 7 to 1 1 member atoms. Bicyclic heteroaryl rings include those rings wherein phenyl and a monocyclic heterocycloalkyl ring are attached forming a fused, spiro, or bridged bicyclic ring system, and those rings wherein a monocyclic heteroaryl ring and a monocyclic cycloalkyl, cycloalkenyl, heterocycloalkyl, or heteroaryl ring are attached forming a fused, spiro, or bridged bicyclic ring system. Examples of heteroaryl include pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, furanyl, furazanyl, thienyl, triazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, tetrazinyl, tetrazolyl, indolyl, isoindolyl, indolizinyl, indazolyl, purinyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, pteridinyl, cinnolinyl, benzimidazolyl, furopyridinyl, and naphthyridinyl. As used herein, "six membered monocyclic heteroaryl" represents a group or moiety comprising an aromatic monovalent monocyclic radical, containing 6 ring atoms, including at least one carbon atom and 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. Selected 6-membered monocyclic heteroaryl groups contain 1 , 2, or 3 nitrogen ring heteroatoms. Illustrative examples of 5 to 6 membered monocyclic heteroaryl groups useful in the present invention include, but are not limited to pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, tetrazinyl, and tetrazolyl.
As used herein, the term "cycloalkenyl" refers to a partially saturated ring. For example, C3-6 cycloalkenyl refers to a partially saturated ring containing 3 to 6 carbon atoms. Cycloalkenes are not aromatic. Examples of cycloalkenes include, but are not limited to, cyclopropane, cyclobutene, cyclopentane and cyclohexene.
As used herein, the term "heteroatom" refers to a nitrogen, sulphur, or oxygen atom.
As used herein, the term "heterocycloalkyl" refers to a saturated ring containing from 1 to 4 heteroatoms as member atoms in the ring. However, heterocycloalkyl rings are not aromatic. Heterocycloalkyl groups containing more than one heteroatom may contain different heteroatoms. Heterocycloalkyl groups may be optionally substituted with one or more substituents as defined herein. Heterocycloalkyl groups are monocyclic ring systems or are fused, spiro, or bridged bicyclic ring systems. Monocyclic heterocycloalkyl rings have from 4 to 7 member atoms. Bicyclic heterocycloalkyl rings have from 7 to 1 1 member atoms. Examples of heterocycloalkyl include pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, pyranyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothienyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, piperidinyl, homopiperidinyl, piperazinyl, morpholinyl, thiamorpholinyl, azepinyl, 1 ,3- dioxolanyl, 1 ,3-dioxanyl, 1 ,3-oxathiolanyl, 1 ,3-dithianyl, azetidinyl, oxetanyl, azabicylo[3.2.1 ]octyl, and oxabicylo[2.2.1 ]heptyl.
As used herein, the term "halo" refers to the halogen radicals fluoro, chloro, bromo, and iodo.
As used herein, the term "Hydoxyl" refers to the hydroxyl radical OH.
As used herein, the term "alkyl" refers to a monovalent saturated hydrocarbon chain having the specified number of member atoms. For example, C1-3 alkyl refers to an alkyl group having from 1 to 3 carbon atoms. Alkyl groups may be optionally substituted with one or more substituent as defined herein. Alkyl groups may be straight or branched. Representative branched alkyl groups have one, two, or three branches. Examples of alkyl include methyl, ethyl, propyl (n-propyl and isopropyl), butyl (n-butyl, isobutyl, and t-butyl), pentyl (n-pentyl, isopentyl, and neopentyl), and hexyl. As used herein, the term "haloalkyl" refers to an alkyl, as defined herein, wherein one or more of the hydrogens on the hydrocarbon chain are substituted with a halo group. For example, C1-3 haloalkyl refers to an alkyl group having from 1 to 3 carbon atoms substituted with at least one halo group. Representative haloalkyl groups include, but are not limited to, fluoromethyl, difluoromethyl and trifluoromethyl.
As used herein the term "pICso" refers to the negative log of IC50 value in molar.
As used herein, the term "IC50" refers to the half maximal inhibitory concentration. This is a measure of how much of a particular compound (in molar concentration) is needed to inhibit a given functional response by half.
As used herein, the term "member atoms" refers to the atom or atoms that form a chain or ring. Where more than one member atom is present in a chain and within a ring, each member atom is covalently bound to an adjacent member atom in the chain or ring. Atoms that make up a substituent group on a chain or ring are not member atoms in the chain or ring.
As used herein, the term "optionally substituted" indicates that a group, such as alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heteroaryl, may be unsubstituted, or the group may be substituted with one or more substituents as defined. As used herein, the term "RORy" refers to all isoforms encoded by the RORC gene which include RORyl and RORyt.
As used herein, the term "RORy modulator" refers to a chemical compound that inhibits, either directly or indirectly, the activity of RORy. RORy modulators include antagonists and inverse agonists of RORy.
As used herein, the term "substituted" in reference to a group indicates that one or more hydrogen atom attached to a member atom within the group is replaced with a substituent selected from the group of defined substituents. The term "substituted" includes the implicit provision that such substitution be in accordance with the permitted valence of the substituted atom and the substituent and that the substitution results in a stable compound (i.e. one that does not spontaneously undergo transformation such as by rearrangement, cyclization, or elimination and that is sufficiently robust to survive isolation from a reaction mixture). When it is stated that a group may contain one or more substituent, one or more (as appropriate) member atom within the group may be substituted. In addition, a single member atom within the group may be substituted with more than one substituent as long as such substitution is in accordance with the permitted valence of the atom.
As used herein, the term "enantiomeric excess" or "ee" is the excess of one enantiomer over the other expressed as a percentage. As a result, since both enantiomers are present in equal amounts in a racemic mixture, the enantiomeric excess is zero (0% ee). However, if one enantiomer was enriched such that it constitutes 95% of the product, then the enantiomeric excess would be 90% ee (the amount of the enriched enantiomer, 95%, minus the amount of the other enantiomer, 5%). As used herein, the term "enantiomerically pure" refers to products whose enantiomeric excess is 99% ee or greater.
As used herein, the term "half-life" refers to the time required for half of a quantity of a substance to be converted to another chemically distinct species in vitro or in vivo.
The term "compounds of the invention" as used herein means a compound of formula I or a pharmaceutically acceptable salt thereof. The term "a compound of the invention" means any one of the compounds of the invention as defined above.
Furthermore, it will be understood that phrases such as "a compound of formula (I) or a pharmaceutically acceptable salt thereof or "compounds of the invention" are intended to encompass the compound of formula (I), a pharmaceutically acceptable salt or solvate of the compound of formula (I), or any pharmaceutically acceptable combination of these. Thus by way of non-limiting example used here for illustrative purpose, "a compound of formula (I) or a pharmaceutically acceptable salt thereof encompasses a pharmaceutically acceptable salt of a compound of formula (I) which is present as a solvate, and this phrase also encompasses a mixture of a compound of Formula (I) and a pharmaceutically acceptable salt of a compound of Formula (I). It is to be understood that references herein to a compound of formula (I) or a pharmaceutically acceptable salt thereof includes a compound of formula (I) as a free base or as a pharmaceutically acceptable salt thereof. Thus, in one embodiment, the invention is directed to a compound of formula (I). In another embodiment, the invention may be directed to a pharmaceutically acceptable salt of a compound of formula (I).
The term "pharmaceutically acceptable" refers to those compounds (including salts), materials, compositions, and dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
As used herein, the term "pharmaceutically-acceptable salts" refers to salts that retain the desired biological activity of the subject compound and exhibit minimal undesired toxicological effects. These pharmaceutically-acceptable salts may be prepared in situ during the final isolation and purification of the compound, or by separately reacting the purified compound in its free acid or free base form with a suitable base or acid, respectively.
Pharmaceutically acceptable salts include, amongst others, those described in Berge, J. Pharm. Sci., 1977, 66, 1 -19, or those listed in P H Stahl and C G Wermuth, editors, Handbook of Pharmaceutical Salts; Properties, Selection and Use, Second Edition Stahl/Wermuth: Wiley- VCHA/HCA, 201 1 (see http://www.wilev.com/WilevCDA/WilevTitle/productCd- 3906390519.html).
Suitable pharmaceutically acceptable salts can include acid or base addition salts.
Representative pharmaceutically acceptable acid addition salts include, but are not limited to, 4-acetamidobenzoate, acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate (besylate), benzoate, bisulfate, bitartrate, butyrate, calcium edetate, camphorate, camphorsulfonate (camsylate), caprate (decanoate), caproate (hexanoate), caprylate (octanoate), cinnamate, citrate, cyclamate, digluconate, 2,5-dihydroxybenzoate, disuccinate, dodecylsulfate (estolate), edetate (ethylenediaminetetraacetate), estolate (lauryl sulfate), ethane-1 ,2-disulfonate (edisylate), ethanesulfonate (esylate), formate, fumarate, galactarate (mucate), gentisate (2,5-dihydroxybenzoate), glucoheptonate (gluceptate), gluconate, glucuronate, glutamate, glutarate, glycerophosphorate, glycolate, hexylresorcinate, hippurate, hydrabamine (A/,A/'-di(dehydroabietyl)-ethylenediamine), hydrobromide, hydrochloride, hydroiodide, hydroxynaphthoate, isobutyrate, lactate, lactobionate, laurate, malate, maleate, malonate, mandelate, methanesulfonate (mesylate), methylsulfate, mucate, naphthalene-1 ,5-disulfonate (napadisylate), naphthalene-2-sulfonate (napsylate), nicotinate, nitrate, oleate, palmitate, p-aminobenzenesulfonate, p-aminosalicyclate, pamoate (embonate), pantothenate, pectinate, persulfate, phenylacetate, phenylethylbarbiturate, phosphate, polygalacturonate, propionate, p-toluenesulfonate (tosylate), pyroglutamate, pyruvate, salicylate, sebacate, stearate, subacetate, succinate, sulfamate, sulfate, tannate, tartrate, teoclate (8-chlorotheophyllinate), thiocyanate, triethiodide, undecanoate, undecylenate, and valerate.
Representative pharmaceutically acceptable base addition salts include, but are not limited to, aluminium, 2-amino-2-(hydroxymethyl)-1 ,3-propanediol (TRIS, tromethamine), arginine, benethamine (A/-benzylphenethylamine), benzathine (A/,A/-dibenzylethylenediamine), bis-(2- hydroxyethyl)amine, bismuth, calcium, chloroprocaine, choline, clemizole (1 -p chlorobenzyl- 2-pyrrolildine-1 -ylmethylbenzimidazole), cyclohexylamine, dibenzylethylenediamine, diethylamine, diethyltriamine, dimethylamine, dimethylethanolamine, dopamine, ethanolamine, ethylenediamine, L-histidine, iron, isoquinoline, lepidine, lithium, lysine, magnesium, meglumine (N-methylglucamine), piperazine, piperidine, potassium, procaine, quinine, quinoline, sodium, strontium, f-butylamine, and zinc.
As used herein, the term "therapeutically effective amount" means any amount which, as compared to a corresponding subject who has not received such amount, results in improved treatment, healing, prevention, or amelioration of a disease, disorder, or side effect, or a decrease in the rate of advancement of a disease or disorder.
An appropriate "therapeutically effective amount" will depend upon a number of factors including, for example, the age and weight of the subject, the precise condition requiring treatment and its severity, the nature of the formulation, and the route of administration, and will ultimately be at the discretion of the attendant physician. Description of Various Embodiments Compounds
In a first aspect of the invention, the present invention provides a compound of formula I:
Figure imgf000012_0001
Formula I or a pharmaceutically acceptable salt thereof,
wherein
R1 is -Cy-(CH2)n-COOH;
Cy is C3-6 cycloalkyl, C3-6 cycloalkenyl or C3-6 heterocycloalkyl wherein Cy is optionally substituted with one or more substituents independently selected from the group consisting of halo, hydroxyl and C1-3 alkyl;
n is 0 or 1 ;
R2 is H or C1-3 alkyl;
X1 is C or N;
X3 is C or N, with the proviso that when X3 is N, X1 is C;
X2 is C-R3;
R3 is H, halo, C1-3 alkyl, CN or C1-3 haloalkyl;
Y is NH, CH2 or O;
R4 is H, C3-6 cycloalkyl or C1-5 alkyl, wherein the C1-5 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of O-C1-5 alkyl and hydroxyl;
R5 is phenyl or a six membered monocyclic heteroaryl, wherein R5 is substituted with one to three substituents independently selected from the group consisting of:
(vi) halo,
(vii) C1-5 alkyl optionally substituted with one or more hydroxyl groups,
(viii) O-C1-5 alkyl wherein one or more of the hydrogens on the alkyl are optionally deuterated or wherein the O-C1-5 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of halo, hydroxl and O-C1-3 alkyl; (ix) C1-5 haloalkyl; and
(x) CN.
In one embodiment of the invention, the compound or pharmaceutically acceptable salt thereof is:
Figure imgf000013_0001
In an alternative embodiment of the present invention, the compound or pharmaceutically acceptable salt thereof is:
Figure imgf000013_0002
In an embodiment of the invention Cy (defined in R1) is selected from the group consisting of C3-6 cycloalkyl, cyclohexene, tetrahydropyran, oxetane, morpholine, 1 ,4-dioxan and pipiridine. In some embodiments of the invention, Cy is selected from cyclohexyl, oxetane or cyclobutyl.
In an embodiment of the invention n is 0.
In an embodi
Figure imgf000013_0003
Wherein the use of the symbol V n indicates a linkage to the rest of the compound. In certain embodiments of the invention R1 is
Figure imgf000014_0001
In an embodiment of the invention R2 is H. In an embodiment R3 is halo or C1-3 haloalkyl. In some embodiments of the invention R3 is C1-3 haloalkyl. In an embodiment of the invention R3 is C1-3 haloalkyl and the halo is fluorine e.g. R3 is CH2F, CHF2 or CF3. In a particular embodiment of the invention R3 is CF3. In an alternative embodiment of the invention R3 is halo e.g. R3 is chlorine. In an embodiment of the invention Y is O or NH. In an embodiment, Y is NH.
In an embodiment of the invention R4 is C1-5 alkyl, wherein the C1-5 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of O-C1-5 alkyl and hydroxyl. In another embodiment of the invention R4 is C1-5 alkyl. In another embodiment of the invention R4 is CH3.
In an embodiment R5 is phenyl, pyridinyl or pyrimidinyl optionally substituted with one to three substituents as set out above. In another embodiment R5 is phenyl substituted with two substituents independently selected from: halo; C1-5 alkyl optionally substituted with one or more hydroxyl groups; O-C1-5 alkyl wherein one or more of the hydrogens on the alkyl is optionally deuterated or wherein the O-C1-5 alkyl is optionally substituted with one or more substituents independently selected from halo, hydroxl and O-C1-3 alkyl; C1-5 haloalkyl and CN. In another embodiment R5 is phenyl substituted with O-C1-5 alkyl and at least one other group selected from: C1-5 alkyl optionally substituted with one or more hydroxyl groups; C1-5 haloalkyl and CN. In this embodiment the O-C1-3 alkyl may be selected from O-CH3, O- CH2CH3 and 0-(CH2)2CH3. In one embodiment, R5 is a phenyl substituted with O-C1-5 alkyl and at least one other substituent, independently selected from halo, C1-5 alkyl, C1-5 haloalkyl and CN. In another embodiment, R5 is a phenyl substituted with O-C1-5 alkyl and CN.
Figure imgf000015_0001
It is envisaged that each of the above embodiments relating to compounds of formula I may be combined with any other embodiment relating to compounds of formula I.
In a particular embodiment of the invention:
1 is
Figure imgf000015_0002
R2 is H;
X1 is N and X3 is C;
R3 is C1-3 haloalkyl wherein the halo may be fluorine;
R4 is C1-5 alkyi; and
R5 is phenyl substituted with two substituents independently selected from the group consisting of: halo; C1-5 alkyi optionally substituted with one or more hydroxyl groups; O-C1-5 alkyi optionally wherein one or more of the hydrogens on the alkyi is deuterated or optionally wherein the O-C1-5 alkyi is substituted with one or more substituents selected from the group consisting of halo, hydroxl and O-C1-3 alkyi; C1-5 haloalkyl and CN .
In another embodiment, the invention related to compounds of Formula I wherein:
R1 is
Figure imgf000016_0001
R2 is H;
X1 is N and X3 is C;
R3 is C1-3 haloalkyl wherein the halo is fluorine;
Y is NH;
R4 is C1-5 alkyl; and
R5 is phenyl substituted with O-C1-5 alkyl and at least one other group selected from the group consisting of C1-5 alkyl optionally substituted with one or more hydroxyl groups; C1-5 haloalkyl and CN.
In an embodiment of the invention, the compound of Formula I is selected from the compounds in Table 1 or a pharmaceutically acceptable salt thereof:
Figure imgf000016_0002
trans-4-((5-chloro-6-(((S)-1 -(2- methoxyphenyl)ethyl)amino)nicotinamido)methyl)cyclohexanecarboxy lie acid
(S)-4-((5-chloro-6-((1 -(5-cyano-2- methoxyphenyl)ethyl)amino)nicotinamido)methyl)-1 - methylcyclohexanecarboxylic acid
(S)-2-(1 -((5-chloro-6-((1 -(5-cyano-2- methoxyphenyl)ethyl)amino)nicotinamido)methyl)cyclohexyl)acetic acid
(S)-2-(4-((5-chloro-6-((1 -(5-cyano-2- methoxyphenyl)ethyl)amino)nicotinamido)methyl)tetrahydro-2H- pyran-4-yl)acetic acid
(S)-2-(3-((5-chloro-6-((1 -(5-cyano-2- methoxyphenyl)ethyl)amino)nicotinamido)methyl)oxetan-3-yl)acetic acid
Figure imgf000018_0001
c acid
Figure imgf000019_0001
Figure imgf000020_0001
Figure imgf000021_0001
yl)ethyl)amino)nicotinamido)methyl)cyclohexanecarboxylic acid
Figure imgf000022_0001
trans-4-((6-(((S)-1 -(5-bromo-2-(2- methoxyethoxy)phenyl)ethyl)amino)-5- chloronicotinamido)methyl)cyclohexanecarboxylic acid
o 0H
trans-4-((6-(((R)-1 -(5-bromo-2-methoxyphenyl)-2-hydroxy-2- methylpropyl)amino)-5- chloronicotinamido)methyl)cyclohexanecarboxylic acid
trans-4-((6-(((S)-1 -(5-bromo-2-methoxyphenyl)-3-hydroxy-3- methylbutyl)amino)-5- chloronicotinamido)methyl)cyclohexanecarboxylic acid
o
trans-4-((6-(((S)-1 -(5-cyano-2- methoxyphenyl)ethyl)amino)nicotinamido)methyl)cyclohexanecarboxy lie acid
trans-4-((6-(((S)-1 -(5-bromo-2-(2-hydroxyethoxy)phenyl)ethyl)amino)- 5-chloronicotinamido)methyl)cyclohexanecarboxylic acid
o
trans-4-((6-(((S)-1 -(5-cyano-2-methoxyphenyl)ethyl)amino)-5- (difluoromethyl)nicotinamido)methyl)cyclohexanecarboxylic acid
Figure imgf000024_0001
Figure imgf000025_0001
Figure imgf000026_0001
methylnicotinamido)methyl)cyclohexanecarboxylic acid trans-4-((5-chloro-6-(((R)-1 -(5-fluoro-2-methoxyphenyl)-2- methoxyethyl)amino)nicotinamido)methyl)cyclohexanecarboxylic acid
trans-4-((5-chloro-6-(((5-cyano-2- methoxyphenyl)(cyclopropyl)methyl)amino)nicotinamido)methyl)cyclo hexanecarboxylic acid
trans-4-((5-chloro-6-(((5-cyano-2- methoxyphenyl)(cyclopropyl)methyl)amino)nicotinamido)methyl)cyclo hexanecarboxylic acid
trans-4-((5-chloro-6-((1 -(5-cyano-2-methoxyphenyl)-2- methoxyethyl)amino)nicotinamido)methyl)cyclohexanecarboxylic acid
trans-4-((5-chloro-6-((1 -(5-cyano-2-methoxyphenyl)-2- methoxyethyl)amino)nicotinamido)methyl)cyclohexanecarboxylic acid trans-4-((3-cyano-4-(((S)-1 -(5-methoxy-2-(tnfluoromethyl)pyridin-4- yl)ethyl)amino)benzamido)methyl)cyclohexanecarboxylic acid
o
trans-4-((3-cyano-4-(((S)-1 -(3-methoxy-6-(trifluoromethyl)pyndin-2- yl)ethyl)amino)benzamido)methyl)cyclohexanecarboxylic acid
o I
trans-4-((5-chloro-6-((1 -(5-chloro-2-methoxyphenyl)-2- methoxyethyl)amino)nicotinamido)methyl)cyclohexanecarboxylic acid
trans-4-((5-chloro-6-((1 -(5-chloro-2-methoxyphenyl)-2- methoxyethyl)amino)nicotinamido)methyl)cyclohexanecarboxylic acid
trans-4-((5-bromo-6-(((S)-1 -(5-chloro-2- methoxyphenyl)ethyl)amino)nicotinamido)methyl)cyclohexanecarboxy lie acid
trans-4-((5-chloro-6-((2-methoxy-1 -(5-methoxy-2- (trifluoromethyl)pyridin-4- yl)ethyl)amino)nicotinamido)methyl)cyclohexanecarboxylic acid
Figure imgf000029_0001
Figure imgf000030_0001
Figure imgf000031_0001
yl)ethyl)amino)benzamido)methyl)oxetan-3-yl)acetic acid
Figure imgf000032_0001
Figure imgf000033_0001
yl)ethyl)amino)benzamido)methyl)oxetan-3-yl)acetic acid 97
(S)-2-(3-((3-chloro-4-((1 -(6-ethyl-3-methoxypyridin-2- yl)ethyl)amino)benzamido)methyl)oxetan-3-yl)acetic acid
98
(S)-2-(3-((3-chloro-4-((1 -(3-methoxy-6-(trifluoroinethyl)pyridin-2- yl)ethyl)amino)benzamido)methyl)oxetan-3-yl)acetic acid
99
°
rac-trans-4-((3-chloro-4-((2-ethoxy-1 -(5-fluoro-2- methoxyphenyl)ethyl)amino)benzamido)methyl)cyclohexanecarboxyli c acid
100 ^
trans-4-((3-chloro-4-(((S)-1 -(2-ethyl-5-methoxypyridin-4- yl)ethyl)amino)benzamido)methyl)cyclohexanecarboxylic acid
101 trans-4-((3-chloro-4-(((S)-1 -(6-ethyl-3-methoxypyridin-2- yl)ethyl)amino)benzamido)methyl)cyclohexanecarboxylic acid
102 o
trans-4-((3-chloro-4-(((S)-1 -(5-methoxy-2-(trifluoromethyl)pyridiri-4- yl)ethyl)amino)benzamido)methyl)cyclohexanecarboxylic acid
Figure imgf000035_0001
(trifluoromethyl)benzamido)methyl)cyclohexanecarboxylic acid
Figure imgf000036_0001
Figure imgf000037_0001
Figure imgf000038_0001
Figure imgf000039_0001
c acid
Figure imgf000040_0001
(trifluoromethyl)nicotinamido)methyl)cyclohexanecarboxylic acid
Figure imgf000041_0001
Figure imgf000042_0001
(trifluoromethyl)nicotinamido)methyl)cyclohexanecarboxylic acid
Figure imgf000043_0001
Figure imgf000044_0001
trans-4-((6-(((S)-1 -(5-chloro-2-methoxyphenyl)ethyl)amino)-5- cyanonicotinamido)methyl)cyclohexanecarboxylic acid
158 o trans-4-((3-chloro-4-((1 -(5-cyano-2-methoxyphenyl)-2- methoxyethyl)amino)benzamido)methyl)cyclohexanecarboxylic acid
159 o ' trans-4-((3-chloro-4-((1 -(5-cyano-2-methoxyphenyl)-2- methoxyethyl)amino)benzamido)methyl)cyclohexanecarboxylic acid
160 o trans-4-((6-(((R)-1 -(5-chloro-2-methoxyphenyl)-2- methoxyethyl)amino)-5- cyanonicotinamido)methyl)cyclohexanecarboxylic acid
161 o trans-4-((4-((1 -(5-cyano-2-methoxyphenyl)-2-methoxyethyl)amino)-3- (trifluoromethyl)benzamido)methyl)cyclohexanecarboxylic acid
162 o 1
trans-4-((4-((1 -(5-cyano-2-methoxyphenyl)-2-methoxyethyl)amino)-3- (trifluoromethyl)benzamido)methyl)cyclohexanecarboxylic acid
Figure imgf000046_0001
methylbenzamido)methyl)cyclohexanecarboxylic acid
Figure imgf000047_0001
3-methylbenzamido)methyl)cyclohexanecarboxylic acid 175
trans-4-((4-(((S)-1 -(5-chloro-2-methoxyphenyl)ethyl)amino)-3- methylbenzamido)methyl)cyclohexanecarboxylic acid
176
trans-4-((4-((1 -(5-chloro-2-methoxyphenyl)-2-methoxyethyl)amino)-3- methylbenzamido)methyl)cyclohexanecarboxylic acid
177
trans-4-((4-((1 -(5-chloro-2-methoxyphenyl)-2-methoxyethyl)amino)-3- methylbenzamido)methyl)cyclohexanecarboxylic acid
178
trans-4-((4-(((S)-1 -(2-chloro-5-fluorophenyl)ethyl)amino)-3- methylbenzamido)methyl)cyclohexanecarboxylic acid
179
trans-4-((4-(((S)-1 -(5-cyano-2-methoxyphenyl)ethyl)amino)-3- methylbenzamido)methyl)cyclohexanecarboxylic acid
180
trans-4-((5-(((S)-1 -(5-cyano-2-methoxyphenyl)ethyl)amino)-4- methylpicolinamido)methyl)cyclohexanecarboxylic acid
Figure imgf000049_0001
Figure imgf000050_0001
Figure imgf000051_0001
Figure imgf000052_0001
Figure imgf000053_0001
yl)ethoxy)benzamido)methyl)cyclohexanecarboxylic acid
Figure imgf000054_0001
acid
Figure imgf000055_0001
Figure imgf000056_0001
Figure imgf000057_0001
(t fluoromethyl)benzamido)methyl)cyclohexanecarboxylic acid
Figure imgf000058_0001
methoxyethoxy)benzamido)methyl)cyclohexanecarboxylic acid
Figure imgf000059_0001
Table 1
In another embodiment, the compound is selected from the group consisting of compound 1 , 87, 90, 102, 136, 158, and 208 and pharmaceutically acceptable salts thereof. In another embodiment, the compound is selected from the group consisting of compound 1 and compound 136 and pharmaceutically acceptable salts thereof.
In one aspect, the compound is Compound 136 or a pharmaceutically acceptable salt thereof. In another aspect, the compound is Compound 1 or a pharmaceutically acceptable salt thereof.
In an aspect of the invention the compound is the hydrochloride salt or the hydrobromide salt of Compound 1 . In an embodiment the compound is the hydrochloride salt of Compound 1 . In an aspect of the invention the compound is the hydrochloride salt or the hydrobromide salt of Compound 136. In an embodiment the compound is the hydrochloride salt of Compound 136.
The compounds according to Formula I may contain one or more asymmetric center (also referred to as a chiral center) and may, therefore, exist as individual enantiomers, diastereomers, or other stereoisomeric forms, or as mixtures thereof. Chiral centers, such as chiral carbon atoms, may also be present in a substituent such as an alkyl group. Where the stereochemistry of a chiral center present in Formula I, or in any chemical structure illustrated herein, is not specified the structure is intended to encompass all individual stereoisomers and all mixtures thereof. Thus, compounds according to Formula I containing one or more chiral center may be used as racemic mixtures, enantiomerically enriched mixtures, or as enantiomerically pure individual stereoisomers.
Individual stereoisomers of a compound according to Formula I which contain one or more asymmetric center may be resolved by methods known to those skilled in the art. For example, such resolution may be carried out (1 ) by formation of diastereoisomeric salts, complexes or other derivatives; (2) by selective reaction with a stereoisomer-specific reagent, for example by enzamatic oxidation or reduction; or (3) by gas-liquid or liquid chromatography in a chiral enviornment, for example, on a chiral support such as silica with a bound chiral ligand or in the presence of a chiral solvent. The skilled artisan will appreciate that where the desired stereoisomer is converted into another chemical entity by one of the separation procedures described above, a further step is required to liberate the desired form. Alternatively, specific stereoisomers may be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by converting one enantiomer to the other by asymmetric transformation. Where an enantiomer is represented and the absolute stereochemistry is unknown, the use of "or1 " or "or2" at the chiral centre denotes that the absolute stereochemistry of the particular compound is unknown, i.e. the compound as drawn may be either the R enantiomer or the S enantiomer. Where the absolute stereochemistry is known and the compound is a single enantiomer, the bold or hashed wedge symbol (— 1 ) is used as appropriate, without the use of "or1 " or "or2" at the chiral centre.
The compounds according to Formula I may also contain double bonds or other centers of geometric asymmetry. Where the stereochemistry of a center of geometric asymmetry present in Formula I, or in any chemical structure illustrated herein, is not specified, the structure is intended to encompass the trans (E) geometric isomer, the cis (Z) geometric isomer, and all mixtures thereof. Likewise, all tautomeric forms are also included in Formula I whether such tautomers exist in equilibrium or predominately in one form.
In certain embodiments, compounds according to Formula I may be present as a free base or free acid.
In certain embodiments, compounds according to Formula I may contain an acidic functional group. In certain other embodiments, compounds according to Formula I may contain a basic functional group. Thus, the skilled artisan will appreciate that pharmaceutically-acceptable salts of the compounds according to Formula I may be prepared. Indeed, in certain embodiments of the invention, pharmaceutically-acceptable salts of the compounds according to Formula I may be preferred over the respective free base or free acid because such salts may impart greater stability or solubility to the molecule thereby facilitating formulation into a dosage form. Accordingly, the invention is further directed to the use of pharmaceutically-acceptable salts of the compounds according to Formula I.
Other salts, which are not pharmaceutically acceptable, may be useful in the preparation of compounds of this invention and these should be considered to form a further aspect of the invention. These salts, such as trifluoroacetate, while not in themselves pharmaceutically acceptable, may be useful in the preparation of salts useful as intermediates in obtaining the compounds of the invention and their pharmaceutically acceptable salts.
If a compound of the invention containing a basic amine or other basic functional group is isolated as a salt, the corresponding free base form of that compound may be prepared by any suitable method known to the art, including treatment of the salt with an inorganic or organic base, suitably an inorganic or organic base having a higher pKa than the free base form of the compound. Similarly, if a compound of the invention containing an acidic functional group is isolated as a salt, the corresponding free acid form of that compound may be prepared by any suitable method known to the art, including treatment of the salt with an inorganic or organic acid, suitably an inorganic or organic acid having a lower pKa than the free acid form of the compound.
The invention also includes various deuterated forms of the compounds of Formula I. Each available hydrogen atom attached to a carbon atom may be independently replaced with a deuterium atom. A person of ordinary skill in the art will know how to synthesize deuterated forms of the compounds of Formula (I). Commercially available deuterated starting materials may be employed in the preparation of deuterated forms of the compounds of Formula (I), or they may be synthesized using conventional techniques employing deuterated reagents (e.g. lithium aluminum deuteride).
The compounds of the invention may exist in solid or liquid form. In the solid state, the compounds of the invention may exist in crystalline or noncrystalline form, or as a mixture thereof. For compounds of the invention that are in crystalline form, the skilled artisan will appreciate that pharmaceutically-acceptable solvates may be formed wherein solvent molecules are incorporated into the crystalline lattice during crystallization. Solvates may involve nonaqueous solvents such as ethanol, isopropanol, DMSO, acetic acid, ethanolamine, and ethyl acetate, or they may involve water as the solvent that is incorporated into the crystalline lattice. Solvates wherein water is the solvent that is incorporated into the crystalline lattice are typically referred to as "hydrates." Hydrates include stoichiometric hydrates as well as compositions containing vaiable amounts of water. The invention includes all such solvates. The skilled artisan will further appreciate that certain compounds of the invention that exist in crystalline form, including the various solvates thereof, may exhibit polymorphism (i.e. the capacity to occur in different crystalline structures). These different crystalline forms are typically known as "polymorphs." The invention includes all such polymorphs. Polymorphs have the same chemical composition but differ in packing, geometrical arrangement, and other descriptive properties of the crystalline solid state. Polymorphs, therefore, may have different physical properties such as shape, density, hardness, deformability, stability, and dissolution properties. Polymorphs typically exhibit different melting points, IR spectra, and X-ray powder diffraction patterns, which may be used for identification. The skilled artisan will appreciate that different polymorphs may be produced, for example, by changing or adjusting the reaction conditions or reagents, used in making the compound. For example, changes in temperature, pressure, or solvent may result in polymorphs. In addition, one polymorph may spontaneously convert to another polymorph under certain conditions. In another aspect there is provided a pharmaceutical composition comprising a compound or pharmaceutically acceptable salt thereof as defined above, and a pharmaceutically acceptable excipient. The compound may be as described in any of the above embodiments. In one embodiment, the compound is any of the compounds in table 1 or a pharmaceutically acceptable salt thereof. In another embodiment, the compound is compound 1 or a pharmaceutically acceptable salt thereof. In a further embodiment, the compound is compound 136 or a pharmaceutically acceptable salt thereof.
Compounds of the invention will normally, but not necessarily, be formulated into pharmaceutical compositions prior to administration to an individual. Pharmaceutical compositions of the invention may be prepared and packaged in bulk form wherein a safe and effective amount of a compound of the invention can be extracted and then given to the individual such as with powders or syrups. Alternatively, the pharmaceutical compositions of the invention may be prepared and packaged in unit dosage form wherein each physically discrete unit contains a safe and effective amount of a compound of the invention. When prepared in unit dosage form, the pharmaceutical compositions of the invention typically contain from 0.1 mg to 1000 mg. The pharmaceutical compositions of the invention typically contain one compound of the invention. However, in certain embodiments, the pharmaceutical compositions of the invention contain more than one compound of the invention. For example, in certain embodiments the pharmaceutical compositions of the invention contain two compounds of the invention. In addition, the pharmaceutical compositions of the invention may optionally further comprise one or more additional pharmaceutically active compounds.
As used herein, "pharmaceutically-acceptable excipient" means a pharmaceutically acceptable material, composition or vehicle involved in giving form or consistency to the pharmaceutical composition. Each excipient must be compatible with the other ingredients of the pharmaceutical composition when commingled such that interactions which would substantially reduce the efficacy of the compound of the invention when administered to an individual and interactions which would result in pharmaceutical compositions that are not pharmaceutically acceptable are avoided. In addition, each excipient must of course be of sufficiently high purity to render it pharmaceutically-acceptable.
The compound of the invention and the pharmaceutically-acceptable excipient or excipients will typically be formulated into a dosage form adapted for administration to the individual by the desired route of administration. For example, dosage forms include those adapted for (1 ) oral administration such as tablets, capsules, caplets, pills, troches, powders, syrups, elixers, suspensions, solutions, emulsions, sachets, and cachets; (2) parenteral administration such as sterile solutions, suspensions, and powders for reconstitution; (3) transdermal administration such as transdermal patches; (4) rectal administration such as suppositories; (5) inhalation such as dry powders, aerosols, suspensions, and solutions; and (6) topical administration such as creams, ointments, lotions, solutions, pastes, sprays, foams, and gels.
Suitable pharmaceutically-acceptable excipients will vary depending upon the particular dosage form chosen. In addition, suitable pharmaceutically-acceptable excipients may be chosen for a particular function that they may serve in the composition. For example, certain pharmaceutically-acceptable excipients may be chosen for their ability to facilitate the production of uniform dosage forms. Certain pharmaceutically-acceptable excipients may be chosen for their ability to facilitate the production of stable dosage forms. Certain pharmaceutically-acceptable excipients may be chosen for their ability to facilitate the carrying or transporting of the compound or compounds of the invention once administered to the individual from one organ, or portion of the body, to another organ, or portion of the body. Certain pharmaceutically-acceptable excipients may be chosen for their ability to enhance compliance.
Suitable pharmaceutically-acceptable excipients include the following types of excipients: Diluents, fillers, binders, disintegrants, lubricants, glidants, granulating agents, coating agents, wetting agents, solvents, co-solvents, suspending agents, emulsifiers, sweetners, flavoring agents, flavor masking agents, coloring agents, anticaking agents, hemectants, chelating agents, plasticizers, viscosity increasing agents, antioxidants, preservatives, stabilizers, surfactants, and buffering agents. The skilled artisan will appreciate that certain pharmaceutically-acceptable excipients may serve more than one function and may serve alternative functions depending on how much of the excipient is present in the formulation and what other ingredients are present in the formulation.
Skilled artisans possess the knowledge and skill in the art to enable them to select suitable pharmaceutically-acceptable excipients in appropriate amounts for use in the invention. In addition, there are a number of resources that are available to the skilled artisan which describe pharmaceutically-acceptable excipients and may be useful in selecting suitable pharmaceutically-acceptable excipients. Examples include Remington's Pharmaceutical Sciences (Mack Publishing Company), The Handbook of Pharmaceutical Additives (Gower Publishing Limited), and The Handbook of Pharmaceutical Excipients (the American Pharmaceutical Association and the Pharmaceutical Press). The pharmaceutical compositions of the invention are prepared using techniques and methods known to those skilled in the art. Some of the methods commonly used in the art are described in Remington's Pharmaceutical Sciences (Mack Publishing Company).
In one aspect, the invention is directed to a solid oral dosage form such as a tablet or capsule comprising a safe and effective amount of a compound of the invention and a diluent or filler. Suitable diluents and fillers include lactose, sucrose, dextrose, mannitol, sorbitol, starch (e.g. corn starch, potato starch, and pre-gelatinized starch), cellulose and its derivatives (e.g. microcrystalline cellulose), calcium sulfate, and dibasic calcium phosphate. The oral solid dosage form may further comprise a binder. Suitable binders include starch (e.g. corn starch, potato starch, and pre-gelatinized starch), gelatin, acacia, sodium alginate, alginic acid, tragacanth, guar gum, povidone, and cellulose and its derivatives (e.g. microcrystalline cellulose). The oral solid dosage form may further comprise a disintegrant. Suitable disintegrants include crospovidone, sodium starch glycolate, croscarmelose, alginic acid, and sodium carboxymethyl cellulose. The oral solid dosage form may further comprise a lubricant. Suitable lubricants include stearic acid, magnesuim stearate, calcium stearate, and talc.
Methods of use
The compounds of Formula I are modulators of RORy and can be useful in the treatment of diseases mediated by RORy, particularly autoimmune or inflammatory diseases, oncology indications and HIV infection. Examples of the inflammatory or autoimmune diseases of the invention include multiple sclerosis, rheumatoid arthritis, psoriasis, ankylosing spondylitis, Crohn's disease, inflammatory bowel disease, Sjogren's syndrome, optic neuritis, chronic obstructive pulmonary disease, asthma, type I diabetes, neuromyelitis optica, Myasthenia Gavis, uveitis, Guillain-Barre syndrome, psoriatic arthritis, Graves' disease and allergy. Examples of oncology indications include colorectal and pancreatic cancers. Examples of uses in HIV infection include persistence of viral infection and comorbidities in the gut. Accordingly, in another aspect the invention is directed to methods of treating autoimmune and inflammatory diseases mediated by RORy.
In one aspect, the present invention provides a compound of Formula I or pharmaceutically acceptable salt thereof as defined above for use in therapy. In one embodiment, the compound is any of the compounds in table 1 or a pharmaceutically acceptable salt thereof. In another embodiment, the compound is compound 1 or a pharmaceutically acceptable salt thereof. In a further embodiment, the compound is compound 136 or a pharmaceutically acceptable salt thereof.
In a further aspect, the present invention also provides a compound of Formula I, or a pharmaceutically acceptable salt thereof, for use in the treatment of inflammatory and autoimmune diseases mediated by RORy. In one embodiment, there is provided a compound or pharmaceutically acceptable salt thereof as described above for use in the treatment of multiple sclerosis, psoriasis, Sjogren's syndrome, inflammatory bowel disease or ankylosing spondylitis. In one embodiment the disease mediated by RORy is multiple sclerosis. In another embodiment the disease mediated by RORy is ankylosing spondylitis. In another embodiment, the disease is psoriasis. In another embodiment, the disease is Sjogren's syndrome. In another embodiment, the disease is inflammatory bowel disease In an embodiment, the compound is any of the compounds in table 1 or a pharmaceutically acceptable salt thereof. In another embodiment, the compound is compound 1 or a pharmaceutically acceptable salt thereof. In a further embodiment, the compound is compound 136 or a pharmaceutically acceptable salt thereof.
In a further aspect, the present invention is directed to a method of treatment of an inflammatory or autoimmune disease mediated by RORy, which comprises administering to a subject in need thereof, a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof. In one embodiment the subject is a human. In one embodiment, the disease is multiple sclerosis, psoriasis, Sjogren's syndrome, inflammatory bowel disease or ankylosing spondylitis. In one embodiment the disease mediated by RORy is multiple sclerosis. In another embodiment the disease mediated by RORy is ankylosing spondylitis. In another embodiment, the disease is psoriasis. In another embodiment, the disease is Sjogren's syndrome. In another embodiment, the disease is inflammatory bowel disease In an embodiment, the compound is any of the compounds in table 1 or a pharmaceutically acceptable salt thereof. In another embodiment, the compound is compound 1 or a pharmaceutically acceptable salt thereof. In a further embodiment, the compound is compound 136 or a pharmaceutically acceptable salt thereof.
In a further aspect of the invention, there is provided use of a compound or pharmaceutically acceptable salt thereof as defined above, in the manufacture of a medicament for use in the treatment of an inflammatory or autoimmune disease mediated by RORy. In one embodiment, the disease mediated by RORy is multiple sclerosis, psoriasis, Sjogren's syndrome, inflammatory bowel disease or ankylosing spondylitis. In one embodiment the disease mediated by RORy is multiple sclerosis. In another embodiment the disease mediated by RORy is ankylosing spondylitis. In another embodiment, the disease is psoriasis. In another embodiment, the disease is Sjogren's syndrome. In another embodiment, the disease is inflammatory bowel disease. In an embodiment, the compound is any of the compounds in table 1 or a pharmaceutically acceptable salt thereof. In another embodiment, the compound is compound 1 or a pharmaceutically acceptable salt thereof. In a further embodiment, the compound is compound 136 or a pharmaceutically acceptable salt thereof.
As used herein, "treat" in reference to a condition means: (1 ) to ameliorate or prevent the condition or one or more of the biological manifestations of the condition, (2) to interfere with (a) one or more points in the biological cascade that leads to or is responsible for the condition or (b) one or more of the biological manifestations of the condition, (3) to alleviate one or more of the symptoms or effects associated with the condition, or (4) to slow the progression of the condition or one or more of the biological manifestations of the condition.
As indicated above, "treatment" of a condition includes prevention of the condition. The skilled artisan will appreciate that "prevention" is not an absolute term. In medicine, "prevention" is understood to refer to the prophylactic administration of a drug to substantially diminish the likelihood or severity of a condition or biological manifestation thereof, or to delay the onset of such condition or biological manifestation thereof.
The compounds of the invention may be administered by any suitable route of administration, including both systemic administration and topical administration. Systemic administration includes oral administration, parenteral administration, transdermal administration, rectal administration, and administration by inhalation. Parenteral administration refers to routes of administration other than enteral, transdermal, or by inhalation, and is typically by injection or infusion. Parenteral administration includes intravenous, intramuscular, and subcutaneous injection or infusion. Inhalation refers to administration into the human lungs whether inhaled through the mouth or through the nasal passages. Topical administration includes application to the skin as well as intraocular, otic, intravaginal, and intranasal administration.
The compounds of the invention may be administered once or according to a dosing regimen wherein a number of doses are administered at varying intervals of time for a given period of time. For example, doses may be administered one, two, three, or four times per day. Doses may be administered until the desired therapeutic effect is achieved or indefinitely to maintain the desired therapeutic effect. Suitable dosing regimens for a compound of the invention depend on the pharmacokinetic properties of that compound, such as absorption, distribution, and half-life, which can be determined by the skilled artisan. In addition, suitable dosing regimens, including the duration such regimens are administered, for a compound of the invention depend on the condition being treated, the severity of the condition being treated, the age and physical condition of the individual being treated, the medical history of the individual to be treated, the nature of concurrent therapy, the desired therapeutic effect, and like factors within the knowledge and expertise of the skilled artisan. It will be further understood by such skilled artisans that suitable dosing regimens may require adjustment given an individual's response to the dosing regimen or over time as individual needs change.
Typical daily dosages may vary depending upon the particular route of administration chosen. Typical daily dosages for oral administration range from 0.1 mg to 1000 mg. Typical daily dosages for topical administration range from about 0.001 % to about 10% w/w (weight percent) and preferably from about 0.01 % to about 1 % w/w.
Additionally, the compounds of the invention may be administered as prodrugs. As used herein, a "prodrug" of a compound of the invention is a functional derivative of the compound which, upon administration to an individual, eventually liberates the compound of the invention in vivo. Administration of a compound of the invention as a prodrug may enable the skilled artisan to do one or more of the following: (a) modify the onset of the compound in vivo; (b) modify the duration of action of the compound in vivo; (c) modify the transportation or distribution of the compound in vivo; (d) modify the solubility of the compound in vivo; and (e) overcome or overcome a side effect or other difficulty encountered with the compound. Typical functional derivatives used to prepare prodrugs include modifications of the compound that are chemically or enzymatically cleaved in vivo. Such modifications, which include the preparation of phosphates, amides, esters, thioesters, carbonates, and carbamates, are well known to those skilled in the art.
The compounds of Formula I and pharmaceutically acceptable salts thereof may be employed alone or in combination with other therapeutic agents. Combination therapies according to the present invention thus comprise the administration of at least one compound of Formula I or a pharmaceutically acceptable salt thereof, and the use of at least one other therapeutically active agent. A compound of Formula I or pharmaceutically acceptable salt thereof, and the other therapeutically active agent(s) may be administered together in a single pharmaceutical composition or separately and, when administered separately this may occur simultaneously or sequentially in any order.
In a further aspect, there is provided a combination product comprising a compound of Formula I or a pharmaceutically acceptable salt thereof, together with one or more other therapeutically active agents, and optionally a pharmaceutically acceptable carrier or excipient.
Suitable other therapeutic agents include, but are not limited to, (1 ) TNF-alpha inhibitors; (2) non-selective COX-1 /COX-2 inhibitors; (3) COX-2 inhibitors; (4) other agents for treatment of inflammatory and autoimmune diseases including glucocorticoids, methotrexate, leflunomide, sulfasalazine, azathioprine, cyclosporin, tacrolimus, penicillamine, bucillamine, actarit, mizoribine, lobenzarit, ciclesonide, hydroxychloroquine, d-penicillamine, aurothiomalate, auranofin or parenteral or oral gold, cyclophosphamide, Lymphostat-B, BAFF/APRIL inhibitors, such as belimumab, and CTLA-4-lg or mimetics thereof; (5) leukotriene biosynthesis inhibitor, 5-lipoxygenase (5-LO) inhibitor or 5-lipoxygenase activating protein (FLAP) antagonist; (6) LTD4 receptor antagonist; (7) PDE4 inhibitor; (8) antihistamine H1 receptor antagonists; (9) a1 - and a2-adrenoceptor agonist; (10) anticholinergic agents; (1 1 ) β-adrenoceptor agonists; (12) insulin-like growth factor type I (IGF-1 ) mimetic; (13) glucocorticosteroids; (14) kinase inhibitors such as inhibitors of the Janus Kinases (JAK 1 and/or JAK2 and/or JAK 3 and/or TYK2), p38 MAPK and IKK2; (15) B-cell targeting biologies such as rituximab; (16) selective costimulation modulators such as abatacept; (17) interleukin inhibitors, such as IL-1 inhibitor anakinra, IL-6 inhibitors tocilizumab or sirukumab, IL-12/IL- 23 inhibitor ustekinumab, IL-23 inhibitor guselkumab, and IL-17 inhibitor secukinumab; (18) anti-GM-CSF antibodies; (19) checkpoint blockade and other immunotherapies, such as anti- PD-1/anti-PD-L1 antibodies, including pembrolizumab and nivolumab, and anti-CTLA4 antibodies, including ipilimumab; (20) BET inhibitors, such as GSK525762; and (21 ) other oncology agents, such as fluorouracil, bevacizumab, irinotecan hydrochloride, capecitabine, cetuximab, ramucirumab, oxaliplatin, leucovorin calcium, panitumumab, regorafenib, ziv- aflibercept, trastuzumab, imatinib mesylate, sunitinib malate, sorafenib tosylate, paclitaxel, everolimus, erlotinib hydrochloride, gemcitabine hydrochloride, mitomycin C, dabrafenib, trametinib, lapatinib, ofatumumab, topotecan, doxorubicin hydrochloride, and ibrutinib. Compound preparation
The compounds according to Formula I may be prepared using conventional organic syntheses. Suitable synthetic routes are depicted below in the following general reaction scheme.
The skilled artisan will appreciate that if a substituent described herein is not compatible with the synthetic methods described herein, the substituent may be protected with a suitable protecting group that is stable to the reaction conditions. The protecting group may be removed at a suitable point in the reaction sequence to provide a desired intermediate or target compound. Suitable protecting groups and the methods for protecting and de- protecting different substituent using such suitable protecting groups are well known to those skilled in the art; examples of which may be found in T. Greene and P. Wuts, Protecting Groups in Chemical Synthesis (3rd ed.), Wiley & Sons, NY (1999). In some instances, a substituent may be specifically selected to be reactive under the reaction conditions used. In these instances, the reaction conditions convert the selected substituent into another substituent that is either useful as an intermediate compound or is a desired substituent in a target compound.
Compounds of the invention may be prepared by any of Schemes 1 , 2 or 3 as set out below.
Figure imgf000071_0001
Figure imgf000071_0002
Scheme 1 represents a general reaction scheme for preparing compounds of Formula I where R1 to R5 and X1, X2 and X3 are as defined above, and wherein Y is NH or O. R1 E and R2E are esters of R1 and R2. The starting material or reagents described are either commercially available or made from commercially available starting materials using methods known to those skilled in the art.
Step (i) in Scheme 1 is carried out by reacting 1 with 2 using any appropriate reagents. An example of an appropriate reagent is diisopropyl ethyl amine. Step (i) may be carried out in any appropriate solvent, e.g. DMSO, and at any suitable temperature e.g. 80°C to 150°C to provide compound 3. Step (ii) is carried out by reacting 3 with any suitable acid or base e.g. LiOH, NaOH, or hydrochloric acid and in any suitable solvent, e.g. MeOH or water, at any suitable temperature e.g. 20°C Step(iii) is carried out using standard amide formation methods. 4 is reacted with 5 in the presence of any suitable reagent, e.g. HATU, in any suitable solvent, e.g. DMF, at any suitable temperature, e.g. 23°C. Step (iv) is be carried out by hydrolysing the ester 6 with a suitable reagent, such as LiOH or NaOH in a suitable solvent, such as THF/water, at a suitable temperature, e.g. 40°C, to provide Formula I.
Figure imgf000072_0001
Formula I
Scheme 2
Scheme 2 represents a general reaction scheme for preparing compounds of Formula I where R1 to R5 and X1 , X2 and X3 are as defined above, and wherein Y is NH. R1E and R2E are esters of R1 and R2 and Q is halo e.g. Br or CI. The starting material or reagents described are either commercially available or made from commercially available starting materials using methods known to those skilled in the art. Amide formation, step (i), may be carried out by reacting 1 with 2 using appropriate reagents, such as HATU, with an appropriate base, such as DIPEA or TEA, in an appropriate solvent, such as DMF, at any suitable temperatures, e.g. 23°C, to provide 3. The Buchwald-Hartwig amination reaction, step (ii) may be carried out by reacting 3 with 4 using any suitable reagent, e.g. Pd2(dba)3, CS2CO3 or XantPhos, in any suitable solvent, e.g. DMF, at any suitable temperature, e.g.100 °C. Ester hydrolysis, step (iii) may be carried out by reacting 5 with a suitable reagent such as LiOH or NaOH in a suitable solvent, e.g. THF, MeOH, or THF/H2O, at any suitable temperature, e.g. 23°C , to provide a compound of Formula I.
Figure imgf000073_0001
Figure imgf000073_0002
5 6 Formula I
LiOH
HATU, DIPEA
Scheme 3
Scheme 3 represents a general reaction scheme for preparing compounds of Formula I where R1 to R5 and X1, X2 and X3 are as defined above, and wherein Y is O. R1E and R2E are esters of R1 and R2 and Q is CN, C02Me or C02Eth. The starting material or reagents described are either commercially available or made from commercially available starting materials using methods known to those skilled in the art.
Step (i) is carried out by reacting 1 with 2 using any appropriate reagents, such as triphenyl phosphine and DIAD, in an appropriate solvent, such as tetrahydrofuran, at any suitable temperatures e.g. 0-23°C to provide 3. Step (ii) is be carried out reacting 3 with any suitable base, such as LiOH or NaOH, in a suitable solvent, such as MeOH or water/THF, at any suitable temperature e.g. 23°C. Step(iii) is be carried out using standard amide formation methods reacting 4 with 5 in the presence of any suitable reagent, e.g. HATU with diisopropyl amine or triethylamine, in any suitable solvent, such as DMF, at any suitable temperature e.g. 23°C. Step (iv) is be carried out by hydrolysing the ester 6 with a suitable reagent, such as LiOH or NaOH, in any suitable solvent, such as methanol or water, at any suitable temperature e.g. 25°C, to provide a compound of Formula I. The following non-limiting examples illustrate the present invention.
Examples
Abbreviations
DAST (Diethylamino)sulfur trifluoride
DBA Bis-dibenzylideneacetone
DCM dichloromethane
DEAD Diethoxycarbonyldiazene solution
DIPEA A/,A/-diisopropylethylamine
DIAD Diisopropyl azodicarboxylate
DMAP A/,A/-dimethylpyridin-4-amine
DMF A/,A/-dimethylformamide
DMS dimethylsufide
DMSO dimethylsulfoxide
DPPF 1 ,1 -Ferrocenediyl-bis(diphenylphosphine)
DTT DL-Dithiothreitol
EA or EtOAc ethyl acetate
EDTA Ethylenediaminetetraacetic acid
ESI electrospray ionization
FBS fetal bovine serum
HATU 0-(7-azabenzotriazol-1 -yl)-A/,A/,A/',A/'-tetramethyluronium
hexafluorophosphate
HOBt hydroxybenzotriazole
HPLC high-performance liquid chromatography
LBD ligand binding domain
LCMS liquid chromatography mass spectrometry
MsCI methanesulfonyl chloride
MS mass spectrometry NMP A/-methyl-2-pyrrolidone
PBS phosphate buffered saline
PE petroleum ether
PBMC Peripheral blood mononuclear cell
PCC pyridinium chlorochromate
PG protecting group
RT room temperature
sat. saturated
SM starting material
TBAF Tetrabutylammonium fluoride hydrate
TBME tert-butylmethyl ether
TBS Tris Buffered Saline
TEA triethylamine
TEMPO 2,2,6,6-Tetramethyl-1 -piperidinyloxy, free radical
TFA trifluoroacetic acid
THF tetrahydrofuran
TMS trimethylsilyl
XantPhos 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene
XantPhos-Pd-G3 [(4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene)-2-(2'-amino-1 , 1 '- biphenyl)]palladium(ll) methanesulfonate
Xphos-Pd-G3 2-Dicyclohexylphosphino-2',4',6'-triisopropyl-1 ,1 '-biphenyl)[2-(2'-amino-
1 ,1 '-biphenyl)]palladium(ll) methanesulfonate
Chromatography
Unless stated otherwise, all chromatography was carried out using silica columns.
LCMS Conditions:
1 ) Acidic conditions:
Mobile phase: water containing 0.05 % TFA / acetonitrile
Column: Agilent SB-C18 4.6x30 mm 1 .8m;
Detection: MS and photodiode array detector (PDA)
2) Basic conditions:
Mobile phase: 10mM NH4HC03 aqueous / acetonitrile Column: Waters XBridge C18 4.6x50 mm 3.5m;
Detection: MS and photodiode array detector (PDA)
Example 1 : Preparation of Compound 1
Figure imgf000076_0001
Intermediate 223: (S)-methyl 5-chloro-6-((1 -(5-cyano-2- methoxyphenyl)ethyl)amino)nicotinate
Figure imgf000076_0002
A 250ml_ round bottomed flask was charged with methyl 5,6-dichloronicotinate (5g, 24.27 mmol, 1 equiv) and (S)-3-(1-aminoethyl)-4-methoxybenzonitrile (4.70 g, 26.7 mmol, 1 .1 equiv). DMSO (15ml_, 3 vol) was then added followed by W-ethyl-N-isopropylpropan-2-amine (10.57 ml, 60.7 mmol, 2.5 equiv). The flask was then sealed under positive pressure of N2 and the contents heated to 100 °C with stirring for 18 h. The product solution was then allowed to cool to 20 °C. The cooled solution was then added dropwise over 30 minutes to a rapidly stirring 1 M aq. HCI solution (100 ml_, 20 vol). The resulting slurry was allowed to stir an additional 10 minutes at 20 °C and then filtered. The filtered solid was washed with water (2 x 10 vol) and then allowed to dry 1 hour on filter pad. The resulting light brown solid was carried on directly to the following reaction without further purification, m/z: [M + H]+ Calcd for C17H17CIN3O3 346.1 ; Found 345.9. Intermediate 224: (S)-5-chloro-6-((1 -(5-cyano-2-methoxyphenyl)ethyl)amino)nicotinic acid
Figure imgf000077_0001
To a solution of (S)-methyl 5-chloro-6-((1 -(5-cyano-2-methoxyphenyl)ethyl)amino)nicotinate (carried on directly from the previous reaction assuming 100% recovery) in THF (100 mL, 20 vol) and water (50ml_, 10 vol) was added lithium hydroxide (7.0 g, 12 equiv) and the reaction allowed to stir at 40 °C for 36 h. Following completion of the reaction, THF was removed by rotary evaporation. Aqueous hydrochloric acid (1 N) was then added until a pH of 1 was achieved. The resulting slurry was then filtered and the filtered solid washed with water (2 x 10 vol) and then allowed to dry on filter pad. The dried solid was then collected to provide the desired product as a beige solid (7.0g, 87% over 2 steps), m/z: [M + H]+ Calcd for C16H15CIN3O3 332.2; Found 331 .9.
Intermediate 225: trans-methyl 4-((5-chloro-6-(((S)-1 -(5-cyano-2- methoxyphenyl)ethyl)amino)nicotinamido)methyl)cyclohexanecarboxylate
Figure imgf000077_0002
(S)-5-chloro-6-((1 -(5-cyano-2-methoxyphenyl)ethyl)amino)nicotinic acid (800 mg, 1 equiv) was dissolved in DMF (2.4ml_, 3 vol) and HATU (1 .1 g, 1 .2 equiv) was added. Reaction allowed to stir 30 minutes at 20 °C. trans-methyl 4-(aminomethyl)cyclohexanecarboxylate hydrochloride (551 mg, 1 .1 equiv) and DIPEA (1 .1 mL, 2.5 equiv) then added and reaction allowed to stir 3 h at 20 °C. Upon complete consumption of starting material, the reaction mixture was diluted with ethyl acetate (4.8 mL, 6 vol). The organic layer was then washed with 1 M aq. HCI (3.2 mL, 4 vol), then sat. aqueous sodium chloride solution (2 x 4 vol). The organic layer was then concentrated directly by rotary evaporation. The resulting gummy solid (1 .15 g, 98% yield) was carried on directly to the following reaction without further purification, m/z: [M + H]+ Calcd for C25H3oCIN404 485.2; Found 484.9.
Compound 1 : trans-4-((5-chloro-6-(((S)-1 -(5-cyano-2- methoxyphenyl)ethyl)amino)nicotinamido)methyl)cyclohexanecarboxylic acid
Figure imgf000078_0001
To a solution of trans-methyl 4-((5-chloro-6-(((S)-1 -(5-cyano-2- methoxyphenyl)ethyl)amino)nicotinamido)methyl)cyclohexanecarboxylate (1 g, 1 equiv) in THF (12 mL, 12 vol) was added a solution of lithium hydroxide (123 mg, 2.5 equiv) in water (4 mL, 4 vol). The resulting mixture was stirred at 40 °C for 16h. Following completion of the reaction, the THF was removed by rotary evaporation and the aqueous solution of product was further diluted with water (5ml, 5 vol). Aqueous 1 M hydrochloric acid was then added until a pH of 1 was achieved. The resulting slurry was then filtered and the filtered solid washed with water (2 x 10 vol). The isolated solid was then recrystallized from methanol (5 mL, 5 vol) at 40 °C for 3 h, then stirred at 20 °C for 16 h. The recrystallized solid was then filtered and washed with methanol (2 ml, 2 vol) and allowed to dry on filter pad. The solid was then collected to provide the desired product as a white solid, m/z: [M + H]+ Calcd for C24H28CIN404 471 .2; Found 470.9. 1H NMR (400 MHz, DMSO-cfe) δ ppm 0.66 - 0.99 (2 H, m), 1 .17 - 1 .30 (2 H, m), 1 .44 (4 H, d, J=6.84 Hz), 1 .59 - 1 .96 (4 H, m), 1 .99 - 2.19 (1 H, m), 3.03 (2 H, t, J=6.10 Hz), 3.93 (3 H, s), 5.58 (1 H, quin, J=7.20 Hz), 7.03 - 7.31 (2 H, m), 7.60 - 7.77 (2 H, m), 8.02 (1 H, d, J=1 .95 Hz), 8.22 (1 H, t, J=5.49 Hz), 8.37 (1 H, d, J=1 .95 Hz).
The following compounds were synthesized using a similar procedure to that described in Example 1 for Compound 1 .
The following acronyms are used in the below table: CN - Compound number/SM - Starting material.
Figure imgf000078_0002
J=6.84 Hz, 1H), 7.16 (d,
J=8.30 Hz, 1H), 5.51 - 5.59 (m, 1H), 3.93 (s, 3H), 3.00-3.06 (m, 2H), 2.05- 2.14 (m, 1H), 1.82- 1.91 (m, 2H), 1.72 (dd, J=12.70, 2.93 Hz, 2H), 1.40 (d, J=6.84 Hz, 3H), 1.17- 1.28 (m, 2H), 0.84-0.97 (m, 2H) ppm methyl 5,6- (1S)-1-(2- trans-methyl 4- 44 1H NMR(500 MHz, dichloronicotinat methoxyphenyl)et aminomethyl- 6 MeOD) δ 8.44 (d, J = 2.0 e han-1-amine cyclohexanecar Hz, 1H), 7.98 (d, J = 2.0 boxylate Hz, 1H), 7.24 (dd, J =
13.3, 7.5 Hz, 2H), 7.01 (d, J = 8.3 Hz, 1H), 6.90 (t, J = 7.3 Hz, 1H), 5.57 (d, J = 6.8 Hz, 1H), 3.93 (s, 3H),
3.20 (d, J = 7.0 Hz, 2H), 2.23 (s, 1H), 2.02 (d, J = 11.9 Hz, 2H), 1.87 (d, J = 12.7 Hz, 2H), 1.60 (s, 1H),
1.55 (d, J = 6.9 Hz, 3H),
1.42 (d, J = 9.8 Hz, 2H), 1.04 (d, J = 13.2 Hz, 2H). methyl 5,6- (S)-3-(1- 4- 48
dichloronicotinat aminoethyl)-4- (aminomethyl)- 5
e methoxybenzonitri 1- le methylcyclohex
anecarboxylic
acid methyl 5,6- (S)-3-(1- ethyl 2-[1- 48
dichloronicotinat aminoethyl)-4- (aminomethyl)c 5
e methoxybenzonitri yclohexyl]aceta
le te methyl 5,6- (S)-3-(1- ethyl 2-[4- 48
dichloronicotinat aminoethyl)-4- (aminomethyl)o 7
e methoxybenzonitri xan-4- le yl]acetate methyl 5,6- (S)-3-(1- ethyl 2-(3- 45 1H NMR(500 MHz, dichloronicotinat aminoethyl)-4- (aminomethyl)o 8.8 MeOD) δ= 8.41 (d, J = 2.1 e methoxybenzonitri xetan-3- Hz, 1H), 8.02 (d, J = 2.1 le yl)acetate Hz, 1H), 7.69-7.54 (m,
2H), 7.16 (d, J = 8.5 Hz,
1H), 5.61 (q, J = 6.9 Hz,
1H), 4.59 (dd, J = 14.1, 6.5
Hz, 4H), 4.01 (s, 3H), 3.77
(s, 2H), 2.78 (s, 2H), 1.56
(d, J = 7.0 Hz, 3H). methyl 5,6- (S)-3-(1- methyl 2-[3- 45 : 1H NMR (500 MHz, dichloronicotinat aminoethyl)-4- (aminomethyl)c 7.0 MeOD) 5=8.38 (s, 1H), e methoxybenzonitri yclobutyl]acetat 7.99 (s, 1H), 7.69-7.55 le e (m, 1H), 7.16 (d, J = 8.5
Hz, 1H), 5.61 (d, J = 7.2
Hz, 1H), 4.01 (s, 2H), 3.27
(m, 3H), 2.35 (m, 3H), 1.89
(d, J = 8.9 Hz, 2H), 1.80-
1.64 (m, 2H), 1.56 (d, J =
6.9 Hz, 2H). methyl 5,6- 5-(1-aminoethyl)- trans-methyl 4- 47
dichloronicotinat 6- aminomethyl- 2.2
e methoxynicotinonit cyclohexanecar
rile boxylate methyl 5,6- 5-(1-aminoethyl)- trans-methyl 4- 47
dichloronicotinat 6- aminomethyl- 2.2
e methoxynicotinonit cyclohexanecar
rile boxylate methyl 5,6- 1-(5-ethyl-2- trans-methyl 4- 47 1H NMR(500 MHz, dichloronicotinat methoxyphenyl)et aminomethyl- 3.7 MeOD) 5=8.40 (s, 1H), e hanamine cyclohexanecar 7.28 (m, 1H), 7.09-7.08 boxylate (m, 2H), 6.87 (d, J = 10.5
Hz, 1H), 6.50 (d, J = 10.5
Hz, 1H), 6.03 (b, 1H), 5.51
(m, 1H), 3.92 (s, 3H), 3.30
(t, J = 7.5 Hz, 2H), 2.59 (q,
J = 9.5 Hz, 2H), 2.33-2.27
(m ,1H), 2.09-2.06 (m,
2H), 1.91-1.88 (m, 2H),
1.58-1.50 (m, 4H), 1.48-
1.41 (m, 2H), 1.21 (t, J =
8.5 Hz, 3H), 1.09-1.01 (m,
2H). methyl 5,6- (S)-1-(3-methoxy- trans-methyl 4- 46 1H NMR(500 MHz, dichloronicotinat 2- aminomethyl- 0 MeOD) δ 8.41 (d, J = 2.0 e methylphenyl)etha cyclohexanecar Hz, 1H), 8.00 (d, J = 2.0 namine boxylate Hz, 1H), 7.13 (t, J = 8.1
Hz, 1H), 7.00 (d, J = 7.6
Hz, 1H), 6.82 (d, J = 8.1
Hz, 1H), 5.55 (q, J = 6.9
Hz, 1H), 3.83 (s, 3H), 3.19 (d, J = 6.9 Hz, 2H), 2.28
(s, 3H), 2.23 (d, J = 12.2 Hz, 1H), 2.02 (d, J = 10.9 Hz, 2H), 1.87 (d, J = 11.5 Hz, 2H), 1.59 (s, 1H), 1.55 (d, J = 6.9 Hz, 3H), 1.41 (dd, J = 24.4, 11.5 Hz, 2H), 1.04 (dd, J = 23.8, 11.5 Hz, 2H). methyl 5,6- (S)-1-(2-ethyl-5- trans-methyl 4- 47
dichloronicotinat methoxypyridin-4- aminomethyl- 5.1
e yl)ethanamine cyclohexanecar
boxylate methyl 5,6- (S)-1-(6-ethyl-3- trans-methyl 4- 47 1H NMR(400 MHz, d6- dichloronicotinat methoxypyridin-2- aminomethyl- 5 DMSO)511.99 (s, 1H), e yl)ethanamine cyclohexanecar 8.55 (s, 1H), 8.31 -8.28 boxylate (m, 1H), 8.09 (s, 1H), 7.44
-7.41 (m, 2H), 7.20 (d, J = 8.1 Hz, 1H), 5.53-5.45 (m, 1H), 3.87 (s, 3H), 3.09 -3.07 (m, 2H), 2.74 (d, J = 7.3 Hz, 2H), 2.12 (t, J = 10.8 Hz, 1H), 1.90 (d, J = 11.0 Hz, 2H), 1.76 (d, J = 11.8 Hz, 2H), 1.47 (s, 1H), 1.38 (d, J = 5.6 Hz, 3H), 1.32-1.17 (m, 5H), 1.01 - 0.90 (m, 2H). methyl 5,6- (S)-1-(6-ethyl-3- ethyl 2-[3- 46 1H NMR(400 MHz, dichloronicotinat methoxypyridin-2- (aminomethyl)o 3 DMSO) 58.54 (s, 1H), e yl)ethanamine 8.46-8.43 (m, 1H), 8.08 xetan-3- (s, 1H), 7.48-7.42 (m, yl]acetate 2H), 7.20 (d, J = 8.2 Hz,
1H), 5.54-5.46 (m, 1H), 5.07-5.05 (m, 1H), 4.17 (d, J = 8.9 Hz, 1H), 4.10 (d, J = 8.9 Hz, 1H), 3.87 (s, 3H), 3.40-3.39 (m, 4H), 2.74 (dd, J = 14.1, 6.8 Hz, 2H), 2.39 (d, J = 17.6 Hz, 1H), 1.39 (d, J = 5.8 Hz, 3H), 1.25 (t, J = 7.2 Hz, 3H). methyl 5,6- 1-(3-chloro-5- trans-methyl 4- 48
dichloronicotinat methoxyphenyl)et aminomethyl- 0.0
e hanamine cyclohexanecar
boxylate methyl 5,6- (S)-1-(5-chloro-2- trans-methyl 4- 48 1H NMR(400 MHz, dichloronicotinat methoxyphenyl)et aminomethyl- 0 MeOD) δ 8.42 (d, J = 2.0 e hanamine cyclohexanecar Hz, 1H), 7.99 (d, J = 2.0 boxylate Hz, 1H), 7.24 (d, J = 2.4
Hz, 1H), 7.21 -7.13 (m, 1H), 6.98 (d, J = 8.7 Hz, 1H), 5.55 (q, J = 6.8 Hz, 1H), 3.92 (s, 3H), 3.19 (d, J = 6.8 Hz, 2H), 2.21 (t, J = 12.1 Hz, 1H), 2.01 (d, J = 12.3 Hz, 2H), 1.87 (d, J
= 12.7 Hz, 2H), 1.62- 1.48 (m, 4H), 1.41 (dd, J = 25.5, 13.1 Hz, 2H), 1.03 (dd, J = 25.2, 12.8 Hz,
2H). methyl 5,6- (S)-1 -(2,5- trans-methyl 4- 48
dichloronicotinat dichlorophenyl)eth aminomethyl- 4
e anamine cyclohexanecar
boxylate methyl 5,6- (S)-1 -(2,3- trans-methyl 4- 48 1H NMR (500 MHz, dichloronicotinat dichlorophenyl)eth aminomethyl- 4 MeOD) 8.37 (s, 1 H), 7.98 e anamine cyclohexanecar (s, 1 H), 7.39 (t, J = 7.3 Hz, boxylate 2H), 7.22 (t, J = 7.8 Hz,
1 H), 5.68 (d, J = 6.9 Hz, 1 H), 3.18 (d, J = 6.7 Hz, 2H), 2.22 (s, 1 H), 2.00 (d, J = 13.2 Hz, 2H), 1 .86 (d, J = 12.5 Hz, 2H), 1 .60 (d, J = 7.0 Hz, 4H), 1 .46 - 1 .30 (m, 2H), 1 .03 (dd, J = 25.0, 12.1 Hz, 2H). methyl 5,6- (S)-1 -(3-methoxy- trans-methyl 4- 45
dichloronicotinat 6-methylpyridin-2- aminomethyl- 1
e yl)ethanamine cyclohexanecar
boxylate methyl 5,6- (S)-1 -(3-methoxy- trans-methyl 4- 45
dichloronicotinat 6-methylpyridin-2- aminomethyl- 1
e yl)ethanamine cyclohexanecar
boxylate methyl 5,6- (S)-1 -(5-methoxy- trans-methyl 4- 46 1H NMR (500 MHz, dichloronicotinat 2-methylpyrimidin- aminomethyl- 2 MeOD) |A 8.48 (d, J = 2.0 e 4-yl)ethanamine cyclohexanecar Hz, 1 H), 8.37 (s, 1 H), 8.02 boxylate (d, J = 2.0 Hz, 1 H), 5.67 (q, J = 6.7 Hz, 1H), 4.04
(s, 3H), 3.20 (d, J = 6.9 Hz, 2H), 2.64 (s, 3H), 2.17 (t, J = 12.2 Hz, 1H), 2.01 (t, J = 11.3 Hz, 2H), 1.87 (d, J = 10.9 Hz, 2H), 1.61 (s, 1H), 1.51 (d, J = 6.7 Hz, 3H), 1.46 "C 1.38 (m, 2H), 1.04 (dd, J = 23.6, 11.4 Hz, 2H). methyl 5,6- (S)-3-(1- trans-methyl 4- dichloronicotinat aminoethyl)-5- aminomethyl- e chloro-2- cyclohexanecar
methoxybenzonitri boxylate
le methyl 5,6- (S)-1-(5-fluoro-2- trans-methyl 4- 46 1H NMR(400 MHz, dichloronicotinat methoxyphenyl)et aminomethyl- 4 CDCI3) δ 8.27 (s, 1H), e hanamine cyclohexanecar 7.85 (s, 1H), 6.93-6.69 boxylate (m, 3H), 6.07 (d, J = 8.3
Hz, 1H), 5.89 (s, 1H), 5.52 -5.29 (m, 1H), 3.82 (s, 3H), 3.21 (s, 2H), 2.20 (s, 1H), 1.97 (s, 2H), 1.80 (d, J = 11.1 Hz, 2H), 1.47 (d, J = 6.8 Hz, 3H), 1.36 (d, J = 12.3 Hz, 2H), 1.18 (s, 1H), 0.96 (d, J = 11.6 Hz, 2H). methyl 5,6- (S)-3-(1-amino- trans-methyl 4- 51 1H NMR(500 MHz, dichloronicotinat 2,2- aminomethyl- 3 MeOD) δ 8.42 (s, 1H), e dimethylpropyl)-4- cyclohexanecar 8.00 (d, J = 1.8 Hz, 1H), boxylate 7.65 (d, J = 11.7 Hz, 2H), methoxybenzonitri 7.19 (d, J = 8.4 Hz, 1H), le 5.58 (s, 1H), 4.00 (s, 3H),
3.19 (d, J = 6.9 Hz, 2H), 2.24 (t, J = 12.2 Hz, 1H), 2.02 (d, J = 11.2 Hz, 2H), 1.87 (d, J = 11.5 Hz, 2H),
1.59 (s, 1H), 1.47 C1.33 (m, 2H), 1.04 (d, J = 14.4
Hz, 11H). methyl 5,6- (S)-1-(5-methoxy- trans-methyl 4- 51 1H NMR(400 MHz, d6- dichloronicotinat 2- aminomethyl- 5 DMSO) 58.51 (s, 1H), e (trifluoromethyl)py cyclohexanecar 8.37 (d, J = 1.9 Hz, 1H), ridin-4- boxylate 8.24 (t, J = 5.6 Hz, 1H), yl)ethanamine 8.04 (d, J = 1.9 Hz, 1H),
7.78 (s, 1H), 7.40 (d, J = 8.0 Hz, 1H), 5.65-5.56 (m, 1H), 4.08 (s, 3H), 3.04 (t, J = 6.2 Hz, 2H), 2.69 (q, J = 7.1 Hz, 3H), 2.09 (t, J = 11.7 Hz, 1H), 1.87 (d, J = 10.7 Hz, 2H), 1.73 (d, J
= 11.4 Hz, 2H), 1.47- 1.43 (m, 4H), 1.29-1.17 (m, 2H), 1.07 (t, J = 7.2 Hz, 3H), 0.97-0.83 (m,
2H). methyl 5,6- (S)-1-(5-methoxy- ethyl 2-(3- 50 1H NMR(400 MHz, d6- dichloronicotinat 2- (aminomethyl)o 3 DMSO) 58.51 (s, 1H), e (trifluoromethyl)py xetan-3- 8.43-8.32 (m, 2H), 8.03 ridin-4- yl)acetate (d, J = 1.7 Hz, 1H), 7.78 yl)ethanamine (s, 1H), 7.46 (d, J = 7.9 Hz, 1H), 5.67-5.55 (m,
1H), 4.18-4.03 (m, 5H), 3.37-3.35 (m, 4H), 2.41 (dd, J = 38.7, 9.7 Hz, 2H),
1.49 (d, J = 7.0 Hz, 3H). methyl 5,6- (S)-1-(3-methoxy- trans-methyl 4- 51 1H NMR(400 MHz,d6- dichloronicotinat 6- aminomethyl- 5 DMSO) 58.50 (s, 1H), e (trifluoromethyl)py cyclohexanecar 8.29-8.28 (m, 1H), 8.09 ridin-2- boxylate (s, 1H), 7.85 (d, J = 8.5 yl)ethanamine Hz, 1H), 7.68 (d, J = 8.5
Hz, 1H), 7.04 (d, J = 7.4 Hz, 1H), 5.69-5.59 (m, 1H), 4.00 (s, 3H), 3.07 (d,
J = 5.3 Hz, 2H), 2.16 - 2.13 (m, 1H), 1.89 (d, J = 12.4 Hz, 2H), 1.76 (d, J = 12.0 Hz, 2H), 1.45-1.41 (m, 4H), 1.24 - 1.21 (m, 2H), 1.00-0.82 (m, 2H). methyl 5,6- (S)-1-(3-methoxy- ethyl 2-(3- 50 1H NMR(400 MHz, d6- dichloronicotinat 6- (aminomethyl)o 3 DMSO) 58.49 -8.43 (m, e (trifluoromethyl)py xetan-3- 2H), 8.07 (s, 1H), 7.85 (d, ridin-2- yl)acetate J = 8.4 Hz, 1H), 7.68 (d, J yl)ethanamine = 8.4 Hz, 1H), 7.09 (d, J =
6.9 Hz, 1H), 5.64 (d, J = 6.2 Hz, 1H), 4.12 (dd, J = 28.9, 8.9 Hz, 2H), 3.99 (s, 3H), 3.39-3.37 (m, 4H), 2.38 (d, J = 17.6 Hz, 2H),
1.45 (d, J = 6.1 Hz, 3H). methyl 5,6- (S)-1 -(2,3,5- trans-methyl 4- 52 1H NMR(500 MHz, dichloronicotinat trichlorophenyl)eth aminomethyl- 0 MeOD) 8.37 (s, 1H), 8.00 e anamine cyclohexanecar (s, 1H), 7.50 "C7.34 (m, boxylate 2H), 5.63 (q, J = 7.0 Hz,
1H), 3.18 (d, J = 6.7 Hz, 2H), 2.20 (s, 1H), 2.00 (d, J = 12.9 Hz, 2H), 1.86 (d, J = 12.3 Hz, 2H), 1.59 (d, J = 7.0 Hz, 4H), 1.41 (dd, J = 24.8, 13.2 Hz, 2H), 1.03 (dd, J = 24.0, 11.5 Hz,
2H). methyl 5,6- (S)-1-(5-bromo-2- trans-methyl 4- 53 1H NMR(400 MHz, dichloronicotinat ethoxyphenyl)etha aminomethyl- 8 DMSO) 58.42 (d, J = 2.0 e namine cyclohexanecar Hz, 1H), 8.25 (m, J = 5.6 boxylate Hz, 1H), 8.04 (d, J = 2.0
Hz, 1H), 7.42 (d, J = 2.5 Hz, 1H), 7.33 (dd, J = 8.7, 2.5 Hz, 1H), 7.12 (d, J = 8.4 Hz, 1H), 6.95 (d, J = 8.8 Hz, 1H), 5.64-5.51 (m, 1H), 4.10 (q, J = 6.9 Hz, 2H), 3.05 (t, J = 6.3 Hz, 2H), 2.11 (ddd, J = 12.2, 7.8, 3.4 Hz, 1H), 1.88 (d, J = 10.6 Hz, 2H), 1.75 (dd, J = 8.3, 4.7 Hz, 2H), 1.46 (d, J = 6.9 Hz, 4H), 1.37 (t, J = 6.9 Hz, 3H), 1.30- 1.18 (m,2H), 0.99-0.86 (m, 2H). methyl 5,6- (S)-1-(5-bromo-2- trans-methyl 4- 55 1H NMR(400 MHz, dichloronicotinat isopropoxyphenyl) aminomethyl- 2 DMSO) 58.42 (d, J = 1.8 e ethanamine cyclohexanecar Hz, 1H), 8.26 (m, J = 5.5 boxylate Hz, 1H), 8.04 (d, J = 1.8
Hz, 1H), 7.43 (d, J = 2.4 Hz, 1H), 7.31 (dd, J = 8.7,
2.5 Hz, 1H), 7.08 (d, J = 8.4 Hz, 1H), 6.98 (d, J =
8.8 Hz, 1H), 5.56 (dd, J = 14.7, 7.3 Hz, 1H), 4.69 (dt, J = 12.0, 6.0 Hz, 1H), 3.05
(t, J = 6.1 Hz, 2H), 2.19-
2.06 (m, 1H), 1.88 (d, J = 10.9 Hz, 2H), 1.74 (d, J = 11.0 Hz, 2H), 1.45 (d, J =
6.9 Hz, 4H), 1.31 (d, J = 6.0 Hz, 6H), 1.24 (dd, J = 18.0, 7.2 Hz, 2H), 0.98-
0.86 (m, 2H). methyl 5,6- 3-amino-3-(5- trans-methyl 4- 50 1H NMR(500 MHz, dichloronicotinat bromo-2- aminomethyl- 1 MeOD) δ 8.40 (d, J = 2.0 e methoxyphenyl)pr cyclohexanecar Hz, 1H), 7.99 (d, J = 2.0 opan-1-ol boxylate Hz, 1H), 7.43-7.22 (m,
2H), 6.95 (d, J = 8.7 Hz,
1H), 5.72-5.54 (m, 1H),
3.92 (s, 3H), 3.63 (dt, J =
18.9, 8.1 Hz, 2H), 3.19 (d,
J = 6.8 Hz, 2H), 2.15 (ddd,
J = 21.0, 17.3, 13.0 Hz,
3H), 2.01 (d, J = 11.9 Hz,
2H), 1.87 (d, J = 11.0 Hz,
2H), 1.59 (s, 1H), 1.42 (q, J = 12.5 Hz, 2H), 1.16—
0.92 (m, 2H). methyl 5,6- (S)-1-(5-bromo-2- trans-methyl 4- 56 H NMR (400 MHz, CDCI3) dichloronicotinat (2- aminomethyl- 8 58.45 (s, 1H), 8.02 (s, e methoxyethoxy)ph cyclohexanecar 1H), 7.40 (d, J = 2.3 Hz, enyl)ethanamine boxylate 1H), 7.33 (dd, J = 8.7, 2.4
Hz, 1H), 6.80 (d, J = 8.7
Hz, 1H), 6.43-6.22 (m,
2H), 5.55-5.44 (m, 1H),
4.19 (dd, J = 8.9, 4.3 Hz,
2H), 3.82 (t, J = 4.1 Hz,
2H), 3.46 (s, 3H), 3.31 (t, J
= 6.1 Hz, 2H), 2.30 (t, J =
12.1 Hz, 1H), 2.06 (d, J =
11.6 Hz, 2H), 1.89 (d, J =
11.7 Hz, 2H), 1.60 (d, J =
6.8 Hz, 4H), 1.54-1.37
(m, 2H), 1.05 (dd, J = 23.4,
12.2 Hz, 2H) methyl 5,6- (R)-1-amino-1-(5- trans-methyl 4- 56
dichloronicotinat bromo-2- aminomethyl- 8
e methoxyphenyl)-2- cyclohexanecar
methylpropan-2-ol boxylate methyl 5,6- (S)-4-amino-4-(5- trans-methyl 4- 58 1H NMR (500 MHz, dichloronicotinat bromo-2- aminomethyl- 2 MeOD) |A8.37 (d, J = 2.0 e methoxyphenyl)-2- cyclohexanecar Hz, 1H), 7.99 (d, J = 2.1 methylbutan-2-ol boxylate Hz, 1H), 7.37 "C 7.27 (m,
2H), 6.93 (d, J = 8.7 Hz,
1H), 5.60 "C5.48 (m, 1H),
3.93 (s, 3H), 3.19 (d, J =
6.9 Hz, 2H), 2.24 (s, 1H), 2.00 (t, J = 6.8 Hz, 4H),
1.87 (d, J = 13.3 Hz, 2H), 1.58 (s, 1H), 1.41 (d, J = 12.8 Hz, 2H), 1.28 (d, J = 12.7 Hz, 6H), 1.04 (d, J = 15.1 Hz, 2H) methyl 6- (S)-3-(1- trans-methyl 4- 43 1H NMR(500 MHz, chloronicotinate aminoethyl)-4- aminomethyl- 6 MeOD) δ 8.41 (d, J = 2.2 methoxybenzonitri cyclohexanecar Hz, 1H), 7.83 (dd, J = 8.9, le boxylate 2.3 Hz, 1H), 7.60 (d, J =
8.9 Hz, 2H), 7.16 (d, J = 8.5 Hz, 1H), 6.54 (d, J = 8.8 Hz, 1H), 5.33 (d, J = 6.7 Hz, 1H), 4.01 (s, 3H), 3.20 (d, J = 6.9 Hz, 2H), 2.23 (s, 1H), 2.02 (d, J = 10.0 Hz, 2H), 1.88 (d, J = 11.5 Hz, 2H), 1.60 (s, 1H),
1.50 (d, J = 6.8 Hz, 3H), 1.41 (d, J = 13.2 Hz, 2H),
1.04 (d, J = 12.8 Hz, 2H). methyl 5,6- (S)-2-(2-(1- trans-methyl 4- 55 1H NMR(400 MHz, dichloronicotinat aminoethyl)-4- aminomethyl- 4 DMSO) 58.41 (d, J = 1.9 e bromophenoxy)et cyclohexanecar Hz, 1H), 8.25 (m, J = 5.6 hanol boxylate Hz, 1H), 8.03 (d, J = 2.0
Hz, 1H), 7.41 (d, J = 2.5 Hz, 1H), 7.33 (dd, J = 8.7, 2.5 Hz, 1H), 7.13 (d, J = 8.4 Hz, 1H), 6.97 (d, J = 8.8 Hz, 1H), 5.60-5.54 (m, 1H), 4.07 (dd, J = 9.4, 4.7 Hz, 2H), 3.77 (t, J =
5.0 Hz, 2H), 3.05 (t, J = 6.2 Hz, 2H), 2.12 (dd, J =
13.7, 10.4 Hz, 1H), 1.88 (d, J = 10.8 Hz, 2H), 1.74 (d, J = 10.5 Hz, 2H), 1.48
(d, J = 6.9 Hz, 3H), 1.24 (q, J = 13.1 Hz, 3H), 0.92 (dd, J = 25.0, 10.2 Hz,
2H) methyl 6-chloro- (S)-3-(1- trans-methyl 4- 48 1H NMR (400 MHz,
5- aminoethyl)-4- aminomethyl- 6.9 DMSO-cf) δ ppm 12.0 (1H,
(difluoromethyl)ni methoxybenzonitri cyclohexanecar brs), 8.53 (1H, br s), 8.28 cotinate le boxylate (1H, t, J=6.4 Hz), 8.10 (1H, brs), 7.70 (1H, dd, J=8.8, 2 Hz), 7.66 (1H, d, J=2 Hz), 7.31 (1H,t, J=55 Hz), 7.18 (1H, d, J=8.8 Hz), 7.18 (1H, d, J=7.6 Hz), 5.62 (1H, t, J=8 Hz), 3.94 (3H, s), 3.03-3.08 (2H, m), 2.06-2.15 (1H, m), 1.84- 1.90 (2H, m), 1.70-1.76 (2H, m), 1.42 (3H, d, 6.4 Hz), 1.17-1.28 (2H, m), 0.84-0.97 (3H, m)
methyl 6-chloro- (S)-1-(2-chloro-5- trans-methyl 4- 50 1H NMR (400 MHz, 5- fluorophenyl)ethan aminomethyl- 2 CDCI3) δ 8.44 (s, 1H),
(trifluoromethyl)n amine cyclohexanecar 8.10 (s, 1H), 7.29-7.20 icotinate boxylate (m, 1H), 6.93 (dd, J = 9.3, 3.0 Hz, 1H), 6.81 (t, J =
6.9 Hz, 1H), 5.90 (s, 1H),
5.50 (dd, J = 20.4, 14.0
Hz, 2H), 3.22 (s, 2H), 2.21
(s, 1H), 1.98 (d, J = 11.0
Hz, 2H), 1.79 (d, J = 12.1
Hz, 2H), 1.50 (d, J = 6.8
Hz, 3H), 1.46-1.23 (m,
3H), 0.96 (d, J = 12.3 Hz,
2H). methyl 6-chloro- (S)-3-(1- methyl 4- 52 1H NMR(400 MHz,
5- aminoethyl)-4- (aminomethyl)- 3 MeOD) δ 8.69 (d, J = 2.1
(trifluoromethyl)n methoxybenzonitri 4- Hz, 1H), 8.24 (d, J = 1.8 icotinate le fluorocyclohexa Hz, 1H), 7.68-7.57 (m, necarboxylate 2H), 7.17 (d, J = 8.5 Hz,
1H), 5.73 (q, J = 6.9 Hz, 1H), 4.00 (s, 3H), 3.61 (d, J = 21.8 Hz, 2H), 2.58- 2.52 (m, 1H), 1.99-1.64 (m, 8H), 1.57 (d, J = 7.0 Hz, 3H). methyl 6-chloro- (S)-3-(1- methyl 6- 50 1H NMR(400 MHz,
5- aminoethyl)-4- (aminomethyl) 8 MeOD) δ 8.70 (s, 1H),
(thfluoromethyl)n methoxybenzonitri morpholine-3- 8.25 (s, 1H), 7.68-7.53 icotinate le carboxylate (m, 2H), 7.17 (d, J = 8.4
Hz, 1H), 5.72 (dd, J = 13.9, 6.9 Hz, 1H), 5.41 - 5.32 (m, 1H), 3.98 (d, J = 22.2 Hz, 4H), 3.58-3.39 (m, 2H), 2.42 (d, J = 30.2 Hz, 2H), 2.25-2.16 (m, 1H), 2.11 - 1.98 (m, 2H),
1.56 (d, J = 7.0 Hz, 3H). methyl 6-chloro- (S)-3-(1- methyl 4- 53 1H), 6.95 (dd, J = 8.2, 3.8
5- aminoethyl)-4- (aminomethyl)- 5 Hz, 1H), 5.75-5.71 (m,
(trifluoromethyl)n methoxybenzonitri 4- 1H), 4.12 (s, 1H), 3.94 (s, icotinate le hydroxycyclohe 3H), 3.90 (q, J = 7.8 Hz, xanecarboxylat 1H), 2.10-2.04 (m, 1H), e 1.66- 1.56 (m, 6H), 1.47
(d, J = 7.8 Hz, 3H), 1.29- 1.23 (m, 2H), 1.06 (dd, J = 8.2, 3.6 Hz, 3H). methyl 6-chloro- (S)-3-(1- methyl 4- 50 1H), 5.82-5.65 (m, 1H),
5- aminoethyl)-4- (aminomethyl)( 6 3.94 (s, 3H), 3.13-2.97
(trifluoromethyl)n methoxybenzonitri 4- (m, 1H), 2.41 (s, 1H), 2.21 icotinate le 2H)cyclohexane -2.04 (m, 1H), 1.87 (d, J =
-1-carboxylate 13.5 Hz, 2H), 1.73 (d, J =
13.1 Hz, 1H), 1.46 (d, J = 6.9 Hz, 4H), 1.31 -1.11 (m, 2H), 1.00-0.85 (m,
1H) methyl 6-chloro- (S)-3-(1- methyl 4-(1- 51 1H NMR(400 MHz,
5- aminoethyl)-4- aminoethyl)cycl 9 DMSO)512.02 (s, 1H),
(trifluoromethyl)n methoxybenzonitri ohexanecarbox 8.67 (d, J = 6.0 Hz, 1H), icotinate le ylate 8.22 (s, 1H), 8.07 (d, J =
8.7 Hz, 1H), 7.83-7.60 (m, 2H), 7.20 (d, J = 8.6 Hz, 1H), 6.96 (d, J = 7.8 Hz, 1H), 5.79-5.68 (m, 1H), 3.95 (s, 3H), 3.90- 3.84 (m, 1H), 2.08 (s, 1H), 1.90 (s, 2H), 1.76 (s, 1H),
1.66-0.83 (m, 12H). methyl 6-chloro- (S)-3-(1- methyl 4- 51 1H NMR(400 MHz,
5- aminoethyl)-4- (aminomethyl)- 9 CDCI3) δ 8.57 (s, 1H),
(trifluoromethyl)n methoxybenzonitri 1- 8.12 (s, 1H), 7.55-7.51 icotinate le methylcyclohex (m, 2H), 6.94 (d, J = 8.5 anecarboxylate Hz, 1H), 6.29 (s, 1H), 5.99
(d, J = 7.4 Hz, 1H), 5.60-
5.52 (m, 1H), 3.95 (s, 3H),
3.30-3.21 (m, 2H), 2.21
(d, J = 9.0 Hz, 2H), 1.74-
1.67 (m, 2H), 1.60-1.51
(m, 4H), 1.20 (s, 3H), 1.16
- 1.08 (m, 4H). methyl 6-chloro- (S)-4-(1- trans-methyl 4- 50 1H NMR(500 MHz,
5- aminoethyl)-3- aminomethyl- 5.1 MeOD) 5=8.65 (d, J = 1.6
(trifluoromethyl)n methoxybenzonitri cyclohexanecar Hz, 1H), 8.22 (s, 1H), 7.42 icotinate le boxylate (d, J = 7.8 Hz, 1H), 7.36
(s, 1H), 7.28 (d, J = 7.7
Hz, 1H), 5.73 (q, J = 6.8
Hz, 1H), 4.00 (s, 3H), 3.21
(d, J = 6.9 Hz, 2H), 2.24 (t,
J = 12.1 Hz, 1H), 2.02 (d, J
= 13.0 Hz, 2H), 1.87 (d, J
= 12.7 Hz, 2H), 1.56 (m,
4H), 1.41 (dd, J = 24.3,
11.6 Hz, 2H), 1.05 (dd, J =
23.9, 11.6 Hz, 2H). methyl 6-chloro- (S)-1-(5-chloro-2- trans-methyl 4- 51 1H NMR(400 MHz,
5- ethylphenyl)ethan aminomethyl- 2 CDCI3) δ 8.54 (s, 1H), amine 8.11 (s, 1H), 7.25 (d, J = (trifluoromethyl)n cyclohexanecar 1.7 Hz, 1H), 7.17-7.07 icotinate boxylate (m, 2H), 6.02 (s, 1H), 5.60
-5.48 (m, 1H), 5.40 (d, J =
6.0 Hz, 1H), 3.65 (s, 1H),
3.28 (s, 2H), 2.76 (q, J =
7.5 Hz, 2H), 2.27 (s, 1H),
2.04 (d, J = 10.8 Hz, 2H),
1.86 (d, J = 12.3 Hz, 2H),
1.54 (d, J = 6.7 Hz, 3H),
1.42 (d, J = 12.3 Hz, 2H),
1.28 (t, J = 7.5 Hz, 3H),
1.17-0.93 (m, 2H). methyl 6-chloro- (S)-1-(2,5- trans-methyl 4- 51 1H NMR(400 MHz,
5- dichlorophenyl)eth aminomethyl- 8 CDCI3) δ 8.52 (s, 1H),
(trifluoromethyl)n anamine cyclohexanecar 8.17 (s, 1H), 7.28 (t, J = icotinate boxylate 5.7 Hz, 1H), 7.14 (dd, J =
8.5, 2.4 Hz, 1H), 6.01 (s,
1H), 5.67-5.39 (m, 2H),
3.28 (s, 2H), 2.91 (s, 2H),
2.27 (s, 1H), 2.04 (d, J =
11.8 Hz, 2H), 1.86 (d, J =
11.5 Hz, 2H), 1.57 (d, J =
6.8 Hz, 3H), 1.38 (t, J =
23.4 Hz, 2H), 1.02 (d, J =
12.3 Hz, 2H). methyl 6-chloro- (S)-3-(1- methyl 4- 52 1H NMR(400 MHz,
5- aminoethyl)-4- (aminomethyl)- 1 DMSO)511.95 (s, 1H),
(trifluoromethyl)n methoxybenzonitri 4- 8.70 (s, 1H), 8.31 -8.17 icotinate le hydroxycyclohe (m, 2H), 7.71 (dd, J = 9.6, xanecarboxylat 7.8 Hz, 2H), 7.20 (d, J = e 8.6 Hz, 1H), 6.96 (d, J = 8.0 Hz, 1H), 5.75 (dd, J =
14.3, 7.0 Hz, 1H), 4.30 (s, 1H), 3.95 (s, 3H), 3.20 (d, J = 3.4 Hz, 2H), 2.11 (dd, J = 10.2, 5.0 Hz, 1H), 1.64 (t, J = 10.3 Hz, 4H), 1.50 (dd, J = 15.4, 10.3 Hz, 5H), 1.28 (d, J = 8.0 Hz,
2H). methyl 6-chloro- (S)-1-(5-fluoro-2- trans-methyl 4- 49 1H NMR(400 MHz, 5- methoxyphenyl)et aminomethyl- 8 DMSO) 58.68 (d, J = 1.4
(trifluoromethyl)n hanamine cyclohexanecar Hz, 1H), 8.38 (t, J = 5.6 icotinate boxylate Hz, 1H), 8.22 (d, J = 1.6
Hz, 1H), 7.10 (d, J = 8.7 Hz, 1H), 7.01 (dd, J = 6.9, 1.8 Hz, 2H), 6.94 (d, J = 8.1 Hz, 1H), 5.70 (p, J = 7.0 Hz, 1H), 3.85 (s, 3H), 3.07 (t, J = 5.7 Hz, 2H), 2.10 (t, J = 12.0 Hz, 1H), 1.84 (t, J = 22.7 Hz, 2H), 1.74 (d, J = 11.1 Hz, 2H), 1.46 (d, J = 6.9 Hz, 4H), 1.23 (q, J = 12.3 Hz, 2H), 0.92 (q, J = 11.9 Hz, 2H). methyl 5,6- (S)-1-(2-ethyl-5- ethyl 2-(3- 46
dichloronicotinat methoxypyridin-4- (aminomethyl)o 3
e yl)ethanamine xetan-3- yl)acetate methyl 5,6- 1-(3,5-difluoro-2- trans-methyl 4- 48
dichloronicotinat methoxyphenyl)et aminomethyl- 2.1
e hanamine cyclohexanecar
boxylate methyl 6-chloro- (S)-3-(1- 2-(3- 43 1H NMR (500 MHz,
5- aminoethyl)-4- (aminomethyl)o 9. MeOD) δ 8.34 (s, 1H), methylnicotinate methoxybenzonitri xetan-3- 2 7.75 (s, 1H), 7.64-7.52 le yl)acetic acid (m, 2H), 7.14 (d, J = 8.6
Hz, 1H), 5.58 (d, J = 6.8
Hz, 1H), 4.58 (dd, J =
13.0, 6.2 Hz, 4H), 4.00 (s,
3H), 3.76 (s, 2H), 2.70 (s,
2H), 2.29 (s, 3H), 1.54 (d,
J = 6.9 Hz, 3H). methyl 6-chloro- (S)-3-(1- trans-methyl 4- 45 1H NMR (400 MHz,
5- aminoethyl)-4- aminomethyl- 1.2 CDCI3) δ 8.29 (s, 1H), methylnicotinate methoxybenzonitri cyclohexanecar 7.70 (s, 1H), 7.57-7.47 le boxylate (m, 2H), 6.96 (t, J = 14.1
Hz, 1H), 5.96 (s, 1H), 5.61
-5.46 (m, 1H), 5.00 (d, J =
7.1 Hz, 1H), 3.97 (s, 3H),
3.28 (t, J = 6.2 Hz, 2H),
2.27 (d, J = 12.2 Hz, 2H),
2.18 (s, 3H), 2.05 (d, J =
12.3 Hz, 2H), 1.88 (d, J =
12.1 Hz, 2H), 1.54 (d, J =
6.9 Hz, 3H), 1.44 (d, J =
12.2 Hz, 3H), 1.11 -0.98
(m, 2H). methyl 4-chloro- (S)-1-(5-chloro-2- trans-methyl 4- 45 1H NMR (400 MHz,
3- ethylphenyl)ethan aminomethyl- 8.2 CDCI3) δ 8.33 (s, 1H), methylbenzoate amine cyclohexanecar 7.68 (s, 1H), 7.28 (d, J = boxylate 14.6 Hz, 1H), 7.14 (q, J =
8.5 Hz, 2H), 6.07 (s, 1H),
5.61 -5.40 (m, 1H), 4.64
(d, J = 5.4 Hz, 1H), 3.26
(s, 3H), 2.87-2.62 (m,
2H), 2.25 (s, 1H), 2.18-
2.07 (m, 3H), 2.03 (d, J =
10.8 Hz, 2H), 1.86 (d, J =
11.1 Hz, 2H), 1.53 (d, J =
6.6 Hz, 3H), 1.41 (d, J =
12.3 Hz, 2H), 1.25 (t, J =
7.5 Hz, 3H), 1.01 (d, J =
12.0 Hz, 2H). methyl 5,6- (R)-1-(5-fluoro-2- trans-methyl 4- 49
dichloronicotinat methoxyphenyl)-2- aminomethyl- 4.2
e methoxyethanami cyclohexanecar
ne boxylate
methyl 5,6- 3- trans-methyl 4- 49 1H NMR (500 MHz, dichloronicotinat (amino(cyclopropy aminomethyl- 7.3 MeOD) 5=8.39 (d, J = 2.0 e l)methyl)-4- cyclohexanecar Hz, 1H), 7.98 (d, J = 2.0 methoxybenzonitri boxylate Hz, 1H), 7.72 (d, J = 2.0 le Hz, 1H), 7.63 (dd, J = 8.6,
2.0 Hz, 1H), 7.15 (t, J =
12.3 Hz, 1H), 3.99 (s, 3H),
3.19 (d, J = 6.9 Hz, 2H),
2.37-2.20 (m, 1H), 2.10-
1.95 (m, 2H), 1.87 (d, J = 10.8 Hz, 2H), 1.59 (s, 1H),
1.45 (m, 3H), 1.12-1.01 (m, 2H), 0.73-0.38 (m, 4H). methyl 5,6- 3- trans-methyl 4- 49 1H NMR (500 MHz, dichloronicotinat (amino(cyclopropy aminomethyl- 7.2 MeOD) δ= 8.39 (d, J = 2.0 e l)methyl)-4- cyclohexanecar Hz, 1H), 7.98 (d, J = 2.0 methoxybenzonitri boxylate Hz, 1H), 7.72 (d, J = 2.0 le Hz, 1H), 7.63 (dd, J = 8.6,
2.0 Hz, 1H), 7.15 (t, J = 12.3 Hz, 1H), 3.99 (s, 3H), 3.19 (d, J = 6.9 Hz, 2H), 2.37-2.20 (m, 1H), 2.10- 1.95 (m, 2H), 1.87 (d, J = 10.8 Hz, 2H), 1.59 (s, 1H), 1.45 (m, 3H), 1.12-1.01 (m, 2H), 0.73-0.38 (m, 4H). methyl 5,6- 3-(1-amino-2- trans-methyl 4- 50 1H NMR (500 MHz, dichloronicotinat methoxyethyl)-4- aminomethyl- 1.1 CDCI3) δ= 8.30 (s, 1H), e methoxybenzonitri cyclohexanecar 7.89 (s, 1H), 7.55 (d, J = le boxylate 8.6 Hz, 1H), 7.51 (s, 1H),
6.95 (d, J = 8.5 Hz, 1H), 6.25 (d, J = 7.3 Hz, 1H), 6.11 (s, 1H), 5.76-5.56 (m, 1H), 3.97 (s, 3H), 3.80 -3.64 (m, 2H), 3.36 (s, 3H), 3.25 (b, 2H), 2.21 (d, J = 32.4 Hz, 1H), 2.01 (b, 2H), 1.84 (d, J = 10.2 Hz, 2H), 1.54 (m, 1H), 1.46- 1.33 (m, 2H), 0.97 (t, J =
27.3 Hz, 2H). methyl 5,6- 3-(1-amino-2- trans-methyl 4- 50 1H NMR (500 MHz, dichloronicotinat methoxyethyl)-4- aminomethyl- 1.1 CDCI3) δ= 8.30 (s, 1H), e methoxybenzonitri cyclohexanecar 7.89 (s, 1H), 7.55 (d, J = le boxylate 8.6 Hz, 1H), 7.51 (s, 1H),
6.95 (d, J = 8.5 Hz, 1H), 6.25 (d, J = 7.3 Hz, 1H), 6.11 (s, 1H), 5.76-5.56 (m, 1H), 3.97 (s, 3H), 3.80 -3.64 (m, 2H), 3.36 (s, 3H), 3.25 (b, 2H), 2.21 (d, J = 32.4 Hz, 1H), 2.01 (b, 2H), 1.84 (d, J = 10.2 Hz, 2H), 1.54 (m, 1H), 1.46- 1.33 (m, 2H), 0.97 (t, J = 27.3 Hz, 2H). methyl 3-cyano- (S)-1-(5-methoxy- trans-methyl 4- 50 1H NMR (400 MHz, d6- -fluorobenzoate 2- aminomethyl- 4.6 DMSO) δ 11.36 (s, 1H),
(trifluoromethyl)py cyclohexanecar 8.57 (s, 1H), 8.23 (d, J = ridin-4- boxylate 5.2 Hz, 1H), 8.04 (s, 1H), yl)ethanamine 7.93 (s, 1H), 7.80 (d, J =
8.9 Hz, 1H), 7.03 (d, J = 7.9 Hz, 1H), 6.45 (d, J = 9.1 Hz, 1H), 5.07-4.97 (m, 1H), 4.12 (s, 3H), 3.04 (t, J = 6.0 Hz, 2H), 2.11 (t, J = 12.0 Hz, 1H), 1.88 (d, J = 11.6 Hz, 2H), 1.74 (d, J = 11.2 Hz, 2H), 1.53 (d, J = 6.7 Hz, 3H), 1.42 (s, 1H), 1.23 (dd, J = 23.4, 11.6
Hz, 2H), 0.92 (dd, J = 23.2, 12.2 Hz, 2H). methyl 6-chloro- (S)-1-(3-methoxy- trans-methyl 4- 50 1H NMR (400 MHz, d6- 5- 6- aminomethyl- 6 DMSO)512.10 (s, 1H), cyanonicotinate (trifluoromethyl)py cyclohexanecar 8.71 (s, 1H), 8.42-8.36 ridin-2- boxylate (m, 1H), 8.36-8.29 (m, yl)ethanamine 1H), 7.85 (d, J = 8.5 Hz,
1H), 7.68 (d, J = 8.5 Hz, 1H), 7.53 (d, J = 7.1 Hz, 1H), 5.71 -5.62 (m, 1H), 3.98 (s, 3H), 3.09-3.06 (m, 2H), 2.11 (t, J = 11.5 Hz, 1H), 1.89 (d, J = 12.0 Hz, 2H), 1.76 (d, J = 11.9 Hz, 2H), 1.46 (d, J = 6.5 Hz, 4H), 1.25 (dd, J = 24.4, 12.2 Hz, 2H), 0.94 (dd, J = 24.0, 11.8 Hz, 2H). methyl 5,6- 1-(5-chloro-2- trans-methyl 4- 51 1H NMR (400 MHz, dichloronicotinat methoxyphenyl)-2- aminomethyl- 0.1 MeOD) δ 8.41 (d, J = 2 Hz, e methoxyethanami cyclohexanecar 1H), 8.02(d, J=1.8Hz, 1H), ne boxylate 7.21-7.24 (m, 2H), 7.00 (s,
J=8.4Hz, 1H), 5.73 (t, J= 5.2Hz, 1H), 3.94 (s, 3H), 3.72(d, J = 6Hz, 2H), 3.33(s, 3H), 3.13 (d, 7.2Hz, 2H), 3.06 (dd, J = 7.21, 14.4Hz, 2H), 2.01- 2.12 (m, 1H) 1.99(d, J = 12.4, 2H), 1.86 (d, J =
11.6Hz, 2H), 1.55-1.61 (m), 1.37-1.45(m, 2H), 0.92- 1.308(m, 2H)ppm 1H) ppm methyl 5,6- 1-(5-chloro-2- trans-methyl 4- 51 1H NMR (400 MHz, dichloronicotinat methoxyphenyl)-2- aminomethyl- 0.1 MeOD) δ 8.41 (d, J = 2 Hz, e methoxyethanami cyclohexanecar 1H), 8.02(d, J=1.8Hz, 1H), ne boxylate 7.21-7.24 (m, 2H), 7.00 (s,
J=8.4Hz, 1H), 5.73 (t, J= 5.2Hz, 1H), 3.94 (s, 3H), 3.72(d, J = 6Hz, 2H), 3.33(s, 3H), 3.13 (d, 7.2Hz, 2H), 3.06 (dd, J = 7.21, 14.4Hz, 2H), 2.01- 2.12 (m, 1H) 1.99(d, J = 12.4, 2H), 1.86 (d, J = 11.6Hz, 2H), 1.55-1.61 (m), 1.37-1.45(m, 2H), 0.92- 1.308(m, 2H)ppm 1H) ppm methyl 5-bromo- (S)-1-(5-chloro-2- trans-methyl 4- 52 1HNMR(500MHz, DMSO) 6- methoxyphenyl)et aminomethyl- 4.1 58.43 (d,J = 2.0Hz, 1H), chloronicotinate hanamine cyclohexanecar 8.22 (t,J = 5.7Hz, 1H), boxylate 8.18 (d,J = 2.0Hz, 1H),
7.31 (d,J = 2.7Hz, 1H),
7.23 (dd,J = 8.7, 2.7Hz, 1H), 7.02 (d,J = 8.8Hz, 1H), 6.90 (d,J = 8.3Hz, 1H), 5.58-5.47 (m, 1H), 3.86 (s, 3H), 3.05 (t,J = 5.9Hz, 2H), 2.10 (s, 1 H),
1.87 (d,J = 1 1.0Hz, 2H), 1.73 (d,J = 10.3Hz, 2H), 1.45 (d,J = 6.9Hz, 4H), 1.23 (dd,J = 12.7, 2.8Hz, 2H), 0.91 (d,J = 12.7Hz, 2H). ethyl 5,6- 2-methoxy-1-(5- trans-methyl 4- 54 1H NMR (500 MHz, dichloronicotinat methoxy-2- aminomethyl- 5.1 MeOD) δ= 8.45 (s, 1 H), e (trifluoromethyl)py cyclohexanecar 8.37 (d, J = 2.0 Hz, 1 H), ridin-4- boxylate 8.04 (d, J = 2.0 Hz, 1 H), yl)ethanamine 7.65 (s, 1 H), 5.86 - 5.75
(m, 1 H), 4.15 (s, 3H), 3.91 - 3.72 (m, 2H), 3.40 (s, 3H), 3.18 (d, J = 6.9 Hz, 2H), 2.15 (t, J = 12.1 Hz, 1 H), 1.99 (d, J = 10.7 Hz, 2H), 1.85 (d, J = 1 1.2 Hz, 2H), 1.59 (s, 1 H), 1.51 - 1.36 (m, 2H), 1.02 (dd, J = 23.8, 1 1.3 Hz, 2H). ethyl 5,6- 2-methoxy-1-(3- trans-methyl 4- 54 1H NMR (500 MHz, dichloronicotinat methoxy-6- aminomethyl- 5.2 CDCI3) 5= 8.41 (s, 1 H), e (trifluoromethyl)py cyclohexanecar 7.90 (d, J = 1.8 Hz, 1 H), ridin-2- boxylate 7.60 (d, J = 8.5 Hz, 1 H), yl)ethanamine 6.94 (d, J = 8.2 Hz, 1 H),
6.00 (dt, J = 12.0, 5.5 Hz, 2H), 4.1 1 (dt, J = 10.3, 6.9 Hz, 1 H), 3.97 (s, 3H), 3.80 (qd, J = 9.9, 5.2 Hz, 2H), 3.33 (s, 3H), 3.29 (t, J = 6.4 Hz, 2H), 2.29 (t, J =
12.3 Hz, 1H), 2.15-2.02 (m, 3H), 1.89 (d, J = 11.2
Hz, 2H), 1.44 (dd, J = 24.2, 11.5 Hz, 2H), 1.26 (t, J = 7.1 Hz, 2H), 1.10- 0.98 (m, 2H).
ethyl 5,6- 2-methoxy-1-(3- trans-methyl 4- 1H NMR (500 MHz, dichloronicotinat methoxy-6- aminomethyl- CDCI3)5= 8.41 (s, 1H),
54
e (trifluoromethyl)py cyclohexanecar 7.90 (d, J = 1.8 Hz, 1H),
5.2
ridin-2- boxylate 7.60 (d, J = 8.5 Hz, 1H), yl)ethanamine 6.94 (d, J = 8.2 Hz, 1H),
6.00 (dt, J = 12.0, 5.5 Hz, 2H), 4.11 (dt, J = 10.3, 6.9 Hz, 1H), 3.97 (s, 3H), 3.80 (qd, J = 9.9, 5.2 Hz, 2H), 3.33 (s, 3H), 3.29 (t, J = 6.4 Hz, 2H), 2.29 (t, J = 12.3 Hz, 1H), 2.15-2.02 (m, 3H), 1.89 (d, J = 11.2
Hz, 2H), 1.44 (dd, J = 24.2, 11.5 Hz, 2H), 1.26 (t, J = 7.1 Hz, 2H), 1.10- 0.98 (m, 2H).
methyl 5,6- 1-(2-ethyl-5- trans-methyl 4- 50 H NMR (500 MHz, MeOD) dichloronicotinat methoxypyridin-4- aminomethyl- 5 58.39 (d, J = 2.0 Hz, 1H), e yl)-2- cyclohexanecar 8.14 (s, 1H), 8.03 (d, J = boxylate 2.0 Hz, 1H), 7.18 (s, 1H),
5.75 (t, J = 5.5 Hz, 1H), methoxyethanami 4.03 (s, 3H), 3.82-3.69 ne (m, 2H), 3.39 (s, 3H), 3.19
(d, J = 6.9 Hz, 2H), 2.70 (q, J = 7.6 Hz, 2H), 2.20 (d, J = 26.1 Hz, 1H), 2.01 (d, J = 10.9 Hz, 2H), 1.87 (d, J = 10.9 Hz, 2H), 1.59 (s, 1H), 1.49- 1.35 (m, 2H), 1.20 (t, J = 7.6 Hz, 3H), 1.04 (dd, J = 24.1, 11.3 Hz, 2H).
71 methyl 5,6- 1-(2-ethyl-5- trans-methyl 4- 50 H NMR (500 MHz, MeOD) dichloronicotinat methoxypyridin-4- aminomethyl- 5 58.39 (d, J = 2.0 Hz, 1H), e yl)-2- cyclohexanecar 8.14 (s, 1H), 8.03 (d, J = methoxyethanami boxylate 2.0 Hz, 1H), 7.18 (s, 1H), ne 5.75 (t, J = 5.5 Hz, 1H),
4.03 (s, 3H), 3.82-3.69 (m, 2H), 3.39 (s, 3H), 3.19 (d, J = 6.9 Hz, 2H), 2.70 (q, J = 7.6 Hz, 2H), 2.20 (d, J = 26.1 Hz, 1H), 2.01 (d, J = 10.9 Hz, 2H), 1.87 (d, J = 10.9 Hz, 2H), 1.59 (s, 1H), 1.49- 1.35 (m, 2H), 1.20 (t, J = 7.6 Hz, 3H), 1.04 (dd, J = 24.1, 11.3 Hz, 2H).
72 methyl 5,6- 1-(6-ethyl-3- trans-methyl 4- 50 1H NMR (500 MHz, dichloronicotinat methoxypyridin-2- aminomethyl- 5 MeOD) 8.50 (s, 1H), 8.02 e yl)-2- cyclohexanecar (s, 1H), 7.37 (d, J = 8.4 boxylate Hz, 1H), 7.17 (d, J = 8.4 methoxyethanami Hz, 1 H), 5.92 (t, J = 4.9 ne Hz, 1 H), 3.93 (s, 2H), 3.80
(s, 2H), 3.31 (s, 3H), 3.21 (d, J = 6.8 Hz, 2H), 2.78 (d, J = 5.2 Hz, 2H), 2.25 (s, 1 H), 2.03 (d, J = 13.1 Hz, 2H), 1.89 (d, J = 12.8 Hz, 2H), 1.61 (s, 1 H), 1.43 (d, J = 12.7 Hz, 2H), 1.30 (t, J = 7.5 Hz, 3H), 1.06 (d, J = 12.3 Hz, 2H).
73 methyl 5,6- 1 -(6-ethyl-3- trans-methyl 4- 50 1H NMR (500 MHz, dichloronicotinat methoxypyridin-2- aminomethyl- 5 MeOD) 8.50 (s, 1 H), 8.02 e yl)-2- cyclohexanecar (s, 1 H), 7.36 (d, J = 8.4 methoxyethanami boxylate Hz, 1 H), 7.17 (d, J = 8.4 ne Hz, 1 H), 5.92 (t, J = 5.0
Hz, 1 H), 3.93 (s, 3H), 3.80 (d, J = 5.2 Hz, 2H), 3.31 (s, 3H), 3.21 (d, J = 6.8 Hz, 2H), 2.78 (dt, J = 7.4, 4.8 Hz, 2H), 2.24 (s, 1 H), 2.03 (d, J = 12.6 Hz, 2H), 1.89 (d, J = 12.2 Hz, 2H), 1.61 (s, 1 H), 1.43 (dd, J = 23.9, 12.2 Hz, 2H), 1.30 (t, J = 7.6 Hz, 3H), 1.06 (dd, J = 24.3, 1 1.4 Hz, 2H).
74 methyl 4-chloro- (S)-1-(5-chloro-2- trans-methyl 4- 51 1H NMR (400 MHz,
3- ethylphenyl)ethan aminomethyl- 1 CDCI3) δ 7.82 (s, 1 H),
(trifluoromethyl)b amine cyclohexanecar 7.50 (t, J = 18.0 Hz, 1 H), enzoate boxylate 7.10 (s, 2H), 6.25 (d, J = 8.8 Hz, 1H), 5.93 (s, 1H),
4.86 (s, 1H), 4.79-4.62 (m, 1H), 3.20 (s, 2H), 2.68 (ddd, J = 26.9, 14.7, 7.2 Hz, 2H), 2.19 (s, 1H), 1.97 (d, J = 11.8 Hz, 3H), 1.79 (d, J = 10.8 Hz, 3H), 1.48 (d, J = 6.5 Hz, 3H), 1.40- 1.30 (m, 2H), 1.25 (t, J = 7.5 Hz, 3H), 0.95 (d, J = 12.2 Hz, 2H).
75 methyl 4-chloro- (S)-1-(2-chloro-5- trans-methyl 4- 50 1H NMR(400 MHz,
3- fluorophenyl)ethan aminomethyl- 1 CDCI3) δ 7.91 (s, 1H),
(trifluoromethyl)b amine cyclohexanecar 7.61 (d, J = 8.6 Hz, 1H), enzoate boxylate 7.36 (dd, J = 8.8, 5.0 Hz,
1H), 7.02 (dd, J = 9.3, 2.9 Hz, 1H), 6.94-6.85 (m, 1H), 6.29 (d, J = 8.7 Hz, 1H), 5.98 (s, 1H), 4.97 (dd, J = 12.0, 6.0 Hz, 2H), 3.27 (s, 2H), 2.27 (t, J = 12.4 Hz, 1H), 2.04 (d, J = 11.7 Hz, 2H), 1.86 (d, J = 11.7 Hz, 2H), 1.57 (d, J = 6.4 Hz, 4H), 1.45- 1.35 (m, 2H), 1.02 (dd, J = 24.3, 11.2 Hz, 2H).
76 methyl 3-cyano- (S)-1-(5-chloro-2- trans-methyl 4- 47 1H NMR(500 MHz, 4-fluorobenzoate methoxyphenyl)et aminomethyl- 0 MeOD) 5=7.94 (d, J = 2 hanamine cyclohexanecar Hz, 1H), 7.76 (dd, J = 2, boxylate 10.5 Hz, 1H), 7.27 (d, J = 3 Hz, 1H), 7.21 (dd, J = 3,
10.5 Hz, 1H), 7.04 (d, J = 11 Hz, 1H), 6.55 (d, J = 11 Hz, 1H), 5.00 (q, J = 8.5 Hz, 1H), 3.94 (s, 3H), 3.17(d, J = 8.5 Hz, 2H), 2.26-2.20 (m, 1H), 2.04- 1.99 (m, 2H), 1.87-1.84 (m, 2H), 1.59-1.55 (m, 4H), 1.45-1.35 (m, 2H), 1.08-1.01 (m, 2H). methyl 3-cyano- (S)-1-(5-fluoro-2- trans-methyl 4- 45 1H NMR(500 MHz, -fluorobenzoate methoxyphenyl)et aminomethyl- 4.1 MeOD) 5=7.95 (d, J = 2 hanamine cyclohexanecar Hz, 1H), 7.75 (dd, J = 2, boxylate 10.5 Hz, 1H), 7.05-6.94
(m, 3H), 6.56 (d, J = 11 Hz, 1H), 5.00 (q, J = 8.5 Hz, 1H), 3.93 (s, 3H), 3.17(d, J = 8.5 Hz, 2H), 2.263-2.19 (m, 1H), 2.02- 1.98 (m, 2H), 1.87-1.84 (m, 2H), 1.57-1.55 (m, 4H), 1.42-1.38 (m, 2H), 1.08-1.01 (m, 2H). methyl 5-bromo- (S)-3-(1- trans-methyl 4- 46 11H NMR(500 MHz, 6- aminoethyl)-4- aminomethyl- 2.3 MeOD) δ 8.65 (d, J = 2.4 chloronicotinate methoxybenzonitri cyclohexanecar Hz, 1H), 8.25 (d, J = 2.4 le boxylate Hz, 1H), 7.68 "C7.60 (m,
2H), 7.17 (d, J = 9.2 Hz, 1H), 5.67 (q, J = 7.0 Hz, 1H), 4.01 (s, 3H), 3.20 (d, J = 6.9 Hz, 2H), 2.27 "C
2.15 (m, 1H), 2.02 (d, J =
10.9 Hz, 2H), 1.87 (d, J = 11.0 Hz, 2H), 1.60 (s, 1H),
1.57 (d, J = 7.0 Hz, 3H), 1.42 (dt, J = 12.9, 10.1 Hz, 2H), 1.04 (dd, J = 25.2, 9.8
Hz, 2H).
79 methyl 3-cyano- (S)-3-(1- trans-methyl 4- 46 1H NMR(400 MHz, 4-fluorobenzoate aminoethyl)-4- aminomethyl- 1.3 MeOD) δ 7.97 (d, J=1.6Hz, methoxybenzonitri cyclohexanecar 1H), 7.77 (dd, J = 1.6, le boxylate 7.2Hz, 1H), 7.64-7.67 (m,
2H), 7.20 (d, J = 7.2Hz, 1H), 6.55 (d, J = 7.2Hz, 1H), 5.06-5.09- (m, 1H), 4.04 (s, 3H), 3.19 (d, J = 5.6Hz, 2H), 2.20-2.25 (m, 1H), 2.01 (d, J = 8.8Hz, 2H), 1.86 (d, J = 8.8Hz, 2H), 1.59 (d, J = 5.2Hz, 4H), 1.43-1.48 (m, 2H), 1.02-1.06 (m, 2H)ppm
80 methyl 3-cyano- (R)-1-(5-fluoro-2- trans-methyl 4- 48
4-fluorobenzoate methoxyphenyl)-2- aminomethyl- 4.1
methoxyethanami cyclohexanecar
ne boxylate
81 methyl 3-cyano- (S)-1-(3-methoxy- ethyl 2-(3- 49 1H NMR(400 MHz, 4-fluorobenzoate 6- (aminomethyl)o 3.1 CDCI3) δ 7.99 (d, J = 1.9
(trifluoromethyl)py xetan-3- Hz, 1H), 7.95 (d, J = 8.9 ridin-2- yl)acetate Hz, 1H), 7.64 (d, J = 8.5 yl)ethanamine Hz, 1H), 7.32 (d, J = 8.5 Hz, 1H), 7.20-7.19 (m,
1H), 6.84 (d, J = 9.0 Hz, 1H), 5.21 -5.16 (m, 1H), 4.23 (ddd, J = 13.3, 9.7, 2.8 Hz, 2H), 4.00 (s, 3H), 3.74 (dd, J = 14.4, 5.6 Hz, 1H), 3.54-3.44 (m, 3H), 2.56-2.40 (m, 2H), 2.03 (s, 3H), 1.58 (d, J = 6.6 Hz, 3H).
82 methyl 3-cyano- (S)-1-(6-ethyl-3- ethyl 2-(3- 45 1H NMR(400 MHz, d6- 4-fluorobenzoate methoxypyridin-2- (aminomethyl)o 3.2 DMSO) 58.44 -8.41 (m, yl)ethanamine xetan-3- 1H), 8.06 (s, 1H), 7.93 (d, yl)acetate J = 8.5 Hz, 1H), 7.47 (d, J
= 8.1 Hz, 1H), 7.24 (d, J = 8.1 Hz, 1H), 7.11 (s, 1H), 6.97 (d, J = 8.8 Hz, 1H), 5.10-5.07 (m, 1H), 4.17 (d, J = 8.8 Hz, 1H), 4.09 (d, J = 8.9 Hz, 1H), 3.89 (s, 3H), 3.39-3.38 (m, 4H), 2.77-2.69 (m, 2H), 2.52 (s, 1H), 2.38 (d, J = 17.5 Hz, 1H), 1.41 (d, J = 5.6 Hz, 3H), 1.25 (t, J = 7.2 Hz, 3H).
83 vmethyl 3-cyano- (S)-1-(2-ethyl-5- ethyl 2-(3- 45 1H NMR(400 MHz, d6- 4-fluorobenzoate methoxypyridin-4- (aminomethyl)o 3.2 DMSO) 58.47 (s, 1H), yl)ethanamine xetan-3- 8.43-8.39 (m, 1H), 8.05 yl)acetate (d, J = 2.1 Hz, 1H), 7.81 - 7.72 (m, 2H), 7.04 (d, J = 7.6 Hz, 1H), 6.47 (d, J =
9.1 Hz, 1H), 5.11 -5.00 (m, 2H), 4.18-4.08 (m, 1H), 4.07 (s, 3H), 3.36 (d, J = 6.7 Hz, 4H), 2.83 (dd, J = 15.1, 7.6 Hz, 2H), 2.41 (dd, J = 34.4, 9.9 Hz, 2H), 1.55 (d, J = 6.8 Hz, 3H), 1.22-1.13 (m, 3H).
84 methyl 3-cyano- (S)-1-(5-methoxy- ethyl 2-(3- 49 1H NMR (400 MHz, d6- 4-fluorobenzoate 2- (aminomethyl)o 3.1 DMSO) 58.57 (s, 1H),
(trifluoromethyl)py xetan-3- 8.40 (dd, J = 21.1, 14.9 ridin-4- yl)acetate Hz, 1H), 8.06-8.01 (m, yl)ethanamine 1H), 7.93 (d, J = 4.1 Hz,
1H), 7.82-7.75 (m, 1H), 7.09 (dd, J = 7.8, 3.3 Hz, 1H), 6.46 (d, J = 9.1 Hz, 1H), 5.07-4.98 (m, 1H), 4.38 (d, J = 2.1 Hz, 1H), 4.22 (dd, J = 21.2, 9.5 Hz, 1H), 4.17-4.02 (m, 4H), 3.45 (s, 1H), 3.35 (d, J = 8.2 Hz, 2H), 2.64 (dd, J = 25.8, 7.9 Hz, 1H), 2.46- 2.31 (m, 1H), 1.53 (d, J = 6.7 Hz, 3H).
85 methyl 3-cyano- (S)-1-(2-ethyl-5- trans-methyl 4- 46
4-fluorobenzoate methoxypyridin-4- aminomethyl- 5.2
yl)ethanamine cyclohexanecar
boxylate 86 methyl 3-cyano- (S)-1-(6-ethyl-3- trans-methyl 4- 46 1H NMR(400 MHz, d6- 4-fluorobenzoate methoxypyridin-2- aminomethyl- 5.2 DMSO) 58.28 -8.26 (m, yl)ethanamine cyclohexanecar 1H), 8.06 (s, 1H), 7.95 (d, boxylate J = 8.5 Hz, 1H), 7.47 (d, J
= 6.7 Hz, 1H), 7.23 (d, J = 7.6 Hz, 1H), 7.05 (s, 1H), 6.94 (d, J = 8.7 Hz, 1H), 5.08 (s, 1H), 3.89 (s, 3H), 3.14-3.06 (m, 2H), 2.76- 2.67 (m, 2H), 2.11 (dd, J = 21.7, 9.7 Hz, 1H), 1.89 (d, J = 12.1 Hz, 2H), 1.76 (d, J
= 11.8 Hz, 2H), 1.46 (s,
1H), 1.41 (d, J = 5.4 Hz, 3H), 1.29-1.21 (m, 5H),
0.94 (dd, J = 23.4, 11.8 Hz, 2H).
87 methyl 3-cyano- (S)-1-(3-methoxy- trans-methyl 4- 50 1H NMR(400 MHz, d6- 4-fluorobenzoate 6- aminomethyl- 5 DMSO)511.99 (s, 1H),
(trifluoromethyl)py cyclohexanecar 8.26 (s, 1H), 8.05 (s, 1H), ridin-2- boxylate 7.89 (dd, J = 14.4, 8.8 Hz, yl)ethanamine 2H), 7.71 (d, J = 8.7 Hz,
1H), 6.90 (d, J = 9.2 Hz, 1H), 6.64 (d, J = 7.9 Hz, 1H), 5.25- 5.16 (m, 1H), 4.00 (s, 3H), 3.07 (t, J = 5.9 Hz, 2H), 2.13 (m, 1H), 1.90 (d, J = 3.7 Hz, 2H), 1.76 (d, J = 11.2 Hz, 2H), 1.48 (d, J = 6.5 Hz, 4H), 1.24 (t, J = 11.3 Hz, 2H),
0.99-0.87 (m, 2H).
88 methyl 4-fluoro- (S)-3-(1- trans-methyl 4- 50 1H NMR(400 MHz,
3- aminoethyl)-4- (aminomethyl)c 4 CDCI3) δ 7.80 (s, 1H),
(trifluoromethyl)b methoxybenzonitri yclohexanecarb 7.57 (d, J = 8.3 Hz, 1H), enzoate le oxylate 7.48 (d, J = 8.5 Hz, 1H),
7.41 (s, 1H), 6.90 (d, J = 8.6 Hz, 1H), 6.27 (d, J = 8.9 Hz, 1H), 5.97 (s, 1H), 4.98 (s, 1H), 4.89-4.77 (m, 1H), 3.91 (s, 3H), 3.20 (s, 2H), 2.19 (s, 1H), 1.96 (d, J = 13.5 Hz, 2H), 1.79 (d, J = 11.1 Hz, 2H), 1.47 (d, J = 6.4 Hz, 3H), 1.34 (d, J = 11.7 Hz, 2H), 1.18 (s, 1H), 0.95 (d, J = 11.1 Hz, 2H).
Example 2: Preparation of Compound 89
Figure imgf000115_0001
Figure imgf000115_0002
Intermediate 226: (S)-methyl 6-((1 -(5-bromo-2-methoxyphenyl)ethyl)
(trifluoromethyl)nicotinate
Figure imgf000115_0003
To a solution of (S)-1 -(5-bromo-2-methoxyphenyl)ethanamine hydrochloride (5 g, 15.01 mmol) in Dimethyl Sulfoxide (25 mL) at rt was added methyl 6-chloro-5- (trifluoromethyl)nicotinate (4.67 g, 19.51 mmol) and DIPEA (25 mL, 143 mmol). The resulting mixture was stirred at 120 °C for 16 h. Water was then added to the reaction mixture and the resulting aqueous mixture was extracted with EtOAc (1 x 100 mL, 1 x 20 mL). The combined organic phases were dried over sodium sulphate, filtered, and evaporated in vacuo to provide the crude product that was purified by flash chromatography on silica gel (PE/EtOAc = 8/1 ) to provide the desired product (S)-methyl 6-((1 -(5-bromo-2-methoxyphenyl)ethyl)amino)-5- (trifluoromethyl)nicotinate (5.9 g, 12.26 mmol, 82% yield), m/z: [M + H]+ Calcd for Ci7Hi7BrF3N203 433.0; Found 433.
Intermediate 227: (S)-methyl 6-((1 -(5-cyano-2-methoxyphenyl)ethyl)amino)-5- (trifluoromethyl)nicotinate
Figure imgf000116_0001
To a solution of (S)-methyl 6-((1 -(5-bromo-2-methoxyphenyl)ethyl)amino)-5- (trifluoromethyl)nicotinate (5.9 g, 13.62 mmol) in A/,A/-Dimethylformamide (20 mL) at rt was added dicyanozinc (3.20 g, 27.2 mmol) and Pd(PPh3)4 (1.574 g, 1 .362 mmol). The reaction mixture was stirred at 120 °C 16 h. The reaction mixture was then allowed to cool to rt and water (100 mL) was added. The resulting aqueous mixture was extracted with EtOAc (1 x 80 mL, 1 x 10 mL). The combined organic phases were dried over sodium sulphate, filtered, and evaporated in vacuo to provide the crude product that was purified by flash chromatography on silica gel (PE/EtOAc = 4/1 ) to provide the desired product (S)-methyl 6-((1 -(5-cyano-2- methoxyphenyl)ethyl)amino)-5- (trifluoromethyl)nicotinate (4.5 g, 1 1 .27 mmol, 83% yield) as a yellow solid, m/z: [M + H]+ Calcd for C18H17F3N3O3 380.1 ; Found 380.
Intermediate 228: (S)-6-((1 -(5-cyano-2-methoxyphenyl)ethyl)amino)-5- (trifluoromethyl)nicotinic acid
Figure imgf000116_0002
To a solution of (S)-methyl 6-((1 -(5-cyano-2-methoxyphenyl)ethyl)amino)-5- (trifluoromethyl)nicotinate (4.5 g, 1 1 .86 mmol) in tetrahydrofuran (90 mL) and water (9 mL) at rt was added lithium hydroxide hydrate (0.996 g, 23.73 mmol). The reaction mixture was stirred at rt for 24 h. The reaction mixture was then concentrated directly in vacuo and water (20 mL) was added. The pH of the resulting aqueous mixture was adjusted to 1 with 1 N aqueous HCI. The acidified mixture was then extracted with with EtOAc (1 x 30 mL, 1 x 10 mL). The combined organic phases were dried over sodium sulphate, filtered, and evaporated in vacuo to provide the product (S)-6-((1 -(5-cyano-2-methoxyphenyl)ethyl)amino)-5- (trifluoromethyl)nicotinic acid (4 g, 10.40 mmol, 88% yield) that was used without further purification, m/z: [M + H]+ Calcd for C17H15F3N3O3 366.1 ; Found 366. Intermediate 229: 6-(((S)-1 -(5-cyano-2-methoxyphenyl)ethyl)amino)-W-(2,3- dihydroxypropyl)-5-(trifluoromethyl)nicotinamide
Figure imgf000117_0001
To a solution of (S)-6-((1 -(5-cyano-2-methoxyphenyl)ethyl)amino)-5-(t fluoromethyl)nicotinic acid (200 mg, 0.547 mmol) in A/,A/-Dimethylformamide (3 mL) at rt was added HATU (271 mg, 0.712 mmol), 3-aminopropane-1 ,2-diol (64.8 mg, 0.712 mmol), and DIPEA (1 mL, 5.73 mmol). The reaction mixture was stirred at rt overnight. Water was then added to the reaction and the resulting aqueous mixture was extracted with EtOAc (1 x 30 mL, 1 x 10 mL). The combined organic phases were dried over sodium sulphate, filtered, and evaporated in vacuo to provide the crude product that was purified by flash chromatography on silica gel (DCM/MeOH = 10/1 ) to provide the desired product 6-(((S)-1 -(5-cyano-2- methoxyphenyl)ethyl)amino)-A/-(2,3-dihydroxypropyl)-5-(trifluoromethyl)nicotinamide (240 mg, 0.493 mmol, 90% yield), m/z: [M + H]+ Calcd for C2oH22F3N404 439.2; Found 439.
Intermediate 230: Methyl 5-((6-(((S)-1 -(5-cyano-2-methoxyphenyl)ethyl)
(trifluoromethyl)nicotinamido)methyl)-1 ,4-dioxane-2-carboxylate
Figure imgf000117_0002
To a solution of 6-(((S)-1 -(5-cyano-2-methoxyphenyl)ethyl)amino)-A/-(2,3-dihydroxypropyl)-5- (trifluoromethyl)nicotinamide (240 mg, 0.547 mmol) in N,N-Dimethylformamide (5 mL) at 60 °C was added methyl 2,3-dibromopropanoate (135 mg, 0.547 mmol) and CS2CO3 (713 mg, 2.190 mmol). The reaction mixture was stirred at 60 °C for 16 h. The reaction was then allowed to cool to rt and water (30 mL) was added. The pH of the resulting aqueous mixture was adjusted to 1 with 1 N aqueous HCI. The acidified mixture was then extracted with with EtOAc (1 x 30 mL, 1 x 10 mL). The combined organic phases were dried over sodium sulphate, filtered, and evaporated in vacuo to provide the crude product that was purified by flash chromatography on silica gel (100% EtOAc) to provide the desired product methyl 5- ((6-(((S)-1 -(5-cyano-2-methoxyphenyl)ethyl)amino)-5- (trifluoromethyl)nicotinamido)methyl)- 1 ,4-dioxane-2-carboxylate (130 mg, 0.1 12 mmol, 20.5% yield), m/z: [M + H]+ Calcd for C24H26F3N406 523.2; Found 523.
Compound 89: 5-((6-(((S)-1 -(5-cyano-2-methoxyphenyl)ethyl)amino)-5- (trifluoromethyl)nicotinamido)methyl)-1 ,4-dioxane-2-carboxylic acid
Figure imgf000118_0001
To a solution of methyl 5-((6-(((S)-1 -(5-cyano-2-methoxyphenyl)ethyl)amino)-5- (trifluoromethyl)nicotinamido)methyl)-1 ,4-dioxane-2-carboxylate (130 mg, 0.1 12 mmol) in Tetrahydrofuran (3 mL) and Water (0.6 mL) at rt was added lithium hydroxide hydrate (14.10 mg, 0.336 mmol). The reaction mixture was stirred at 40 °C for 16 h. The reaction mixture was then concentrated directly in vacuo and water (5 mL) was added. The pH of the resulting aqueous mixture was adjusted to 1 with 1 N aqueous HCI. The acidified mixture was then extracted with with EtOAc (1 x 20 mL, 1 x 5 mL). The combined organic phases were dried over sodium sulphate, filtered, and evaporated in vacuo to provide the crude product that was purified by preperative HPLC (MeCN with 0.1 % TFA) to provide the desired product 5-((6- (((S)-1 -(5-cyano-2-methoxyphenyl)ethyl)amino)-5-(trifluoromethyl)nicotinamido)methyl)-1 ,4- dioxane-2-carboxylic acid (1 1 mg, 0.021 mmol, 18.6% yield), m/z: [M + H]+ Calcd for C23H24F3N406 509.2; Found 509. 1H NMR (400 MHz, DMSO) δ 12.96 (s, 1 H), 8.67 (s, 1 H), 8.54 (d, J = 10.4 Hz, 1 H), 8.24 (s, 1 H), 7.72 (dd, J = 13.9, 5.4 Hz, 2H), 7.20 (d, J = 8.6 Hz, 1 H), 7.00 (d, J = 7.7 Hz, 1 H), 5.78 - 5.72 (m, 1 H), 4.26 - 4.16 (m, 1 H), 4.09 (d, J = 10.4 Hz, 1 H), 3.95 (s, 4H), 3.87 (t, J = 10.3 Hz, 1 H), 3.76 (d, J = 10.1 Hz, 2H), 3.65 (d, J = 1 1 .0 Hz, 1 H), 3.33 - 3.25 (m, 3H), 1 .48 (d, J = 6.9 Hz, 3H).
Example 3: Preparation of compound 90
Figure imgf000119_0001
Figure imgf000119_0002
Intermediate 231 : (/?)-3-chloro-4-((1 -(5-chloro-2-methoxyphenyl)-2- methoxyethyl)amino)benzonitrile
Figure imgf000119_0003
To a solution of (R)-1-(5-chloro-2-methoxyphenyl)-2-methoxyethanamine (6g, 23.7 mmol) and 3-chloro-4-fluorobenzonitrile (4.78 g, 30.7 mmol) in dimethyl sulfoxide (30 mL) stirred under N2 at rt was added DIPEA (12.39 mL, 70.9 mmol). The reaction mixture was stirred at 120 °C for 16 h. The reaction mixture was then allowed to cool and then diluted with EtOAc. The EtOAc layer was then washed with 1 M aq. HCI and then brine. The washed organic layer was then dried over sodium sulfate, filtered and concentrated to dryness. The crude residue was purified by flash chromatography on silica gel (PE/EtOAc = 20/1 ) to provide the desired product (/?)-3-chloro-4-((1-(5-chloro-2-methoxyphenyl)-2-methoxyethyl)amino)benzonitrile (5.3 g, 13.58 mmol, 57.4% yield) as an orange solid, m/z: [M + Na]+ Calcd for Ci7Hi6Cl2N2Na02 373.1 ; Found 373. Intermediate 232: (/?)-3-chloro-4-((1 -(5-chloro-2-methoxyphenyl)-2- methoxyethyl)amino)benzoic acid
Figure imgf000119_0004
To a solution of sodium hydroxide (15.37 g, 384 mmol) in water (40.0 mL) was added (/?)- 3-chloro-4-((1 -(5-chloro-2-methoxyphenyl)-2-methoxyethyl)amino)benzonitrile (5 g, 12.81 mmol) as a solution in methanol (40 mL). The reaction mixture was stirred at 70 °C for 16 h. Following completion, the reaction mixture was quenched with water (50 mL) and acidified to pH 1 with 1 M aqueous HCI. The aqueous layer was then extracted with EtOAc (250 mL). The organic phase was then removed and evaporated in vacuo to provide (f?)-3-chloro-4-((1 -(5- chloro-2-methoxyphenyl)-2-methoxyethyl)amino)benzoic acid (4.3 g, 9.87 mmol, 77% yield) as an oil that solidified to a white solid on standing. The product was used without further purification, m/z: [M + H]+ Calcd for Ci7Hi8CI2N04 370.1 ; Found 370. Intermediate 233: trans-methyl 4-((3-chloro-4-(((/?)-1 -(5-chloro-2-methoxyphenyl)-2- methoxyethyl)amino)benzamido)methyl)cyclohexanecarboxylate
Figure imgf000120_0001
To a solution of (R)-3-chloro-4-((1 -(5-chloro-2-methoxyphenyl)-2- methoxyethyl)amino)benzoic acid (4.2 g, 10.78 mmol), trans-methyl 4- (aminomethyl)cyclohexanecarboxylate hydrochloride (2.83 g, 12.93 mmol), and DIPEA (6.96 g, 53.9 mmol) in A/,A/-Dimethylformamide (20 mL) at rt was added solid HATU (4.10 g, 10.78 mmol) in one charge. The reaction mixture was stirred at 25 °C for 16 h. The reaction mixture was quenched with water, and ethyl acetate (50 mL) was added. The aqueous solution was then extracted with EA (3 x 10 mL). The combined organic phases were then collected and evaporated in vacuo to give the crude product as a orange solid. The crude residue was purified by flash chromatography on silica gel (PE/EtOAc = 20/1 ) to provide the desired product trans-methyl 4-((3-chloro-4-(((f?)-1 -(5-chloro-2-methoxyphenyl)-2- methoxyethyl)amino)benzamido)methyl)cyclohexanecarboxylate (4 g, 7.26 mmol, 67.4% yield) as a white solid, m/z: [M + H]+ Calcd for C26H33CI2N2O5 523.2; Found 523.
Compound 90: trans-4-((3-chloro-4-(((/?)-1 -(5-chloro-2-methoxyphenyl)
methoxyethyl)amino)benzamido)methyl)cyclohexanecarboxylic acid
Figure imgf000121_0001
To a solution of trans-methyl 4-((3-chloro-4-(((f?)-1 -(5-chloro-2-methoxyphenyl)-2- methoxyethyl)amino)benzamido)methyl)cyclohexanecarboxylate (3.9 g, 7.08 mmol) in Methanol (21 mL) and Water (7 mL) at room temp was added lithium hydroxide (0.848 g, 35.4 mmol) in one charge. The reaction mixture was stirred at 25 °C for 24 h. Following completion of the reaction, the mixture was evaporated in vacuo to give a solid. The solid obtained was suspended in water (30 mL) and15% aqueous HCI was slowly added to make the pH of the solution 4-5. The solid particles that formed were filtered from the solution. The crude solid obtained was then purified by flash chromatography on silica gel (DCM/MeOH = 10/1 ) to provide the desired product trans-4-((3-chloro-4-(((f?)-1 -(5-chloro-2-methoxyphenyl)-2- methoxyethyl)amino)benzamido)methyl)cyclohexanecarboxylic acid (3.62g, 6.89 mmol, 97 % yield) as a white solid, m/z: [M + H]+ Calcd for C25H31CI2N2O5 509.2; Found 509. 1 H NMR (400 MHz, DMSO) 5 12.00 (s, 1 H), 8.16 (t, J = 5.6 Hz, 1 H), 7.82 (d, J = 1 .9 Hz, 1 H), 7.56 (dd, J = 8.6, 1 .7 Hz, 1 H), 7.30 (dd, J = 6.8, 2.5 Hz, 2H), 7.13 - 7.06 (m, 1 H), 6.40 (d, J = 8.8 Hz, 1 H), 5.99 (d, J = 7.4 Hz, 1 H), 5.02 (dd, J = 1 1 .8, 7.4 Hz, 1 H), 3.92 (s, 3H), 3.74 (dd, J = 9.9, 7.6 Hz, 1 H), 3.57 (dd, J = 9.9, 4.3 Hz, 1 H), 3.30 (s, 3H), 3.04 (t, J = 6.2 Hz, 2H), 2.1 1 (t, J = 12.0 Hz, 1 H), 1 .88 (d, J = 10.5 Hz, 2H), 1 .73 (d, J = 10.7 Hz, 2H), 1 .44 (s, 1 H), 1 .24 (dd, J = 22.9, 13.3 Hz, 2H), 0.92 (dd, J = 23.8, 1 1.1 Hz, 2H).
The following compounds were synthesized using a similar procedure to that described in Example 3 for Compound 90.
Figure imgf000121_0002
1H), 5.90-5.96 (m,
1H), 5.53(d, J = 5.6Hz,
1H), 5.01-5.03 (m, 1H), 3.77 (s, 3H), 3.75
(dd, J = 4.0, 9.6Hz, 1H), 3.58(dd, J = 6.8Hz, 1H), 3.41 (s,
3H), 2.89-2.91 (m, 2H), 2.21-3.26(m,1H), 1.99(d, 2H), 1.85-1.88
(m, 2H), 1.04-1.43 (m), 1.24-1.44(m, 2H),
0.92-1.308(m, 2H) ppm 1H), 1.005-1.013 (m, 1H), 0.94-1.05 (M,
2H)
3-chloro-4- 1-(5-fluoro-2- trans-methyl 4- 49 1H NMR(400 MHz, fluorobenzonitril methoxyphenyl) (aminomethyl)c 3 MeOD) δ 7.72 (d, J = e -2- yclohexanecarb 2 Hz, 1H), 7.38 (dd, methoxyethana oxylate J=2Hz, 1H), 6.87-6.99 mine (m, 2H), 6.83-6.87 (m,
1H),6.28 (d, J=8.4Hz,
1H), 5.90-5.96 (m, 1H), 5.53(d, J = 5.6Hz,
1H), 5.01-5.03 (m, 1H), 3.77 (s, 3H), 3.75 (dd, J = 4.0, 9.6Hz, 1H), 3.58(dd, J = 6.8Hz, 1H), 3.41 (s, 3H), 2.89-2.91 (m, 2H), 2.21-3.26(m,1H), 1.99(d, 2H), 1.85-1.88 (m, 2H), 1.04-1.43
(m), 1.24-1.44(m, 2H),
0.92-1.308(m, 2H) ppm 1H), 1.005-1.013
(m, 1H), 0.94-1.05 (M,
2H)
93 3-chloro-4- (S)-1-(5-chloro- ethyl 2-(3- 46 1H NMR(400 MHz, fluorobenzonitril 2- (aminomethyl)o 7 CDCI3) δ 7.78 - 7.63 e methoxyphenyl) xetan-3- (m, 1H), 7.38 (d, J = ethanamine yl)acetate 7.5 Hz, 1H), 7.22-
7.08 (m, 2H), 6.84 (dd,
J = 22.5, 13.7 Hz, 2H),
6.32 (dd, J = 18.4, 8.7
Hz, 1H), 5.08 (s, 1H),
4.85 (d, J = 6.8 Hz,
1H), 4.51 (d, J = 12.9
Hz, 2H), 4.47 (d, J =
6.4 Hz, 2H), 3.89 (d, J
= 9.0 Hz, 3H), 3.74 (s,
2H), 2.69 (s, 2H), 1.59
-1.43 (m, 3H).
94 3-chloro-4- (S)-1-(5- ethyl 2-(4- 54
fluorobenzonitril methoxy-2- (aminomethyl)- 3.1
e (trifluoromethyl) 1- pyridin-4- methylpiperidin- yl)ethanamine 4-yl)acetate
95 3-chloro-4- (S)-1-(5- ethyl 2-(4- 52
fluorobenzonitril methoxy-2- (aminomethyl)t 9.9
e (trifluoromethyl) etrahydro-2H- pyridin-4- pyran-4- yl)ethanamine yl)acetate 96 3-chloro-4- (S)-1-(5- ethyl 2-(3- 50 1H NMR(400 MHz, fluorobenzonitril methoxy-2- (aminomethyl)o 2.1 DMSO-d6) δ 8.56 (s, e (trifluoromethyl) xetan-3- 1H), 8.30-8.32(m, 3H), pyridin-4- yl)acetate 7.83 (s,1H), 7.80 (s, yl)ethanamine 1H), 7.54 (d, J = 8Hz,
1H), 6.39 (d, J = 8Hz, 1H), 6.30 (d, J = 8Hz,1H), 4.99 (t, J = 8Hz, 1H), 4.14 (d, J = 8Hz, 1H), 4.12 (s, 3H), 4.07 (d, J = 8Hz, 1H), 3.34-3.36 (m, 4H), 2.33-2.51 (m, 2H), 1.54 (d, J = 8Hz, 3H)ppm
97 3-chloro-4- (S)-1-(6-ethyl- ethyl 2-(3- 46 1H NMR(400 MHz, fluorobenzonitril 3- (aminomethyl)o 2.1 MeOD) δ 7.95 (d, J = e methoxypyridin- xetan-3- 8Hz, 1H), 7.84 (s, 1H),
2- yl)acetate 7.84 (d, J = 4Hz, 7.59 yl)ethanamine (dd, J = 4, 12Hz, 2H),
6.60 (d, J=8Hz, 1H),
5.25 (dd, J = 8, 12Hz,
1H), 4.26 (dd, J 8,
12Hz, 2H), 4.10 (s,
3H), 3.30-3.34 (m,
4H), 2.92 (q,J = 8Hz,
2H), 2.53 (dd, J = 16,
24Hz, 2H), 1.67 (d,
3H), 1.31 (t, J=8Hz,
3H) ppm 98 3-chloro-4- (S)-1-(3- trans-methyl 4- 50 1H NMR(400 MHz, fluorobenzonitril methoxy-6- (aminomethyl)c 2 DMSO) δ 8.37 (t, J = e (trifluoromethyl) yclohexanecarb 6.1 Hz, 1H), 7.84 (dd, pyridin-2- oxylate J = 9.6, 5.2 Hz, 2H), yl)ethanamine 7.72-7.63 (m, 2H),
6.82 (t, J = 6.6 Hz, 1H), 6.21 (d, J = 8.2 Hz, 1H), 5.19-5.09 (m, 1H), 4.17 (d, J = 9.1 Hz, 1H), 4.08 (d, J = 9.0 Hz, 1H), 4.01 (s, 3H), 3.37-3.36 (m, 4H), 2.48-2.35 (m, 2H), 1.46 (d, J = 6.5 Hz, 3H)
99 3-chloro-4- 2-ethoxy-1-(5- trans-methyl 4- 50 1H NMR(400 MHz, fluorobenzonitril fluoro-2- aminomethyl- 7 CDCI3) δ 7.71 (d, J = e methoxyphenyl) cyclohexanecar 2.0 Hz, 1H), 7.44- ethanamine boxylate 7.34 (m, 1H), 7.05-
6.79 (m, 3H), 6.27 (d,
J = 8.6 Hz, 1H), 5.93
(s, 1H), 5.57 (d, J =
4.8 Hz, 1H), 5.39-
5.33 (m, 1H), 4.99 (s,
1H), 3.90 (s, 3H), 3.80
(dd, J = 9.9, 3.8 Hz,
1H), 3.64-3.44 (m,
3H), 3.26 (t, J = 5.7
Hz, 2H), 2.35-2.20
(m, 2H), 2.11 - 1.96
(m, 3H), 1.87 (d, J =
13.3 Hz, 2H), 1.43 (d, J = 12.7 Hz, 2H), 1.23
(dd, J = 15.6, 8.6 Hz, 10H), 1.07-0.96 (m, 2H), 0.88 (t, J = 6.8 Hz, 1H).
100 3-chloro-4- (S)-1-(2-ethyl- trans-methyl 4- 45 1H NMR(500 MHz, fluorobenzonitril 5- aminomethyl- 9 CDCI3) δ 7.89 (d, J = e methoxypyridin- cyclohexanecar 2.1 Hz, 1H), 7.76 (d, J
4- boxylate = 2.1 Hz, 1H), 7.51 (d, yl)ethanamine J = 2.1 Hz, 1H), 7.47
(dd, J = 8.6, 2.1 Hz, 1H), 6.76 (d, J = 8.7 Hz, 1H), 5.87 (s, 1H), 5.68 (q, J = 6.3 Hz, 1H), 4.26-4.08 (m, 1H), 4.00 (s, 3H), 3.39 (qt, J = 13.4, 6.5 Hz, 2H), 2.61 -2.48 (m, 2H), 2.47-2.36 (m, 2H), 2.32 (dt, J = 11.8, 6.1 Hz, 1H), 2.09 (ddd, J = 19.7, 11.5, 3.4 Hz, 2H), 1.96- 1.82 (m, 2H), 1.80- 1.70 (m, 2H), 1.64 (d, J = 6.3 Hz, 3H), 1.15 (t, J = 7.6 Hz, 3H).
101 3-chloro-4- (S)-1-(6-ethyl- trans-methyl 4- 47 1H NMR(400 MHz, fluorobenzonitril 3- aminomethyl- 4.2 MeOD) δ 7.81 (s, 1H), e methoxypyridin- cyclohexanecar 7.60-7.63 (m, 2H), boxylate 7.32 (d, J=8Hz, 1H), 2- 5.16 (q, J=8Hz, 1H), yl)ethanamine 4.00 (s, 3H), 3.19 (d, J
= 8Hz, 2H), 2.82 (q, J = 8Hz, 2H), 2.20-2.24 (m, 1H), 2.01 (d, J=12Hz, 2H), 1.86 (d, J = 12Hz, 2H), 1.57- 1.59 (m, 4H), 1.40 (q, J = 4Hz, 2H), 1.30 (t, J= 8Hz, 3H), 1.06 (q, J=4Hz, 2H) ppm
3-chloro-4- (S)-1-(3- trans-methyl 4- 51 1H NMR(500 MHz, fluorobenzonitril methoxy-6- aminomethyl- 4.2 DMSO) δ 8.56 (s, 1H), e (trifluoromethyl) cyclohexanecar 8.16 (s, 1H), 7.90- pyridin-2- boxylate 7.75 (m, 2H), 7.54 (d, yl)ethanamine J = 8.6 Hz, 1H), 6.37
(d, J = 8.8 Hz, 1H), 6.24 (d, J = 8.0 Hz, 1H), 5.01 -4.92 (m, 1H), 4.09 (d, J = 30.9 Hz, 3H), 3.03 (t, J = 6.2 Hz, 2H), 2.08 (s, 1H), 1.87 (d, J = 11.2 Hz, 2H), 1.72 (d, J = 11.4 Hz, 2H), 1.54 (d, J = 6.7 Hz, 3H), 1.43 (s, 1H), 1.27-1.18 (m, 2H), 0.95-0.85 (m, 2H). 103 3-chloro-4- (S)-1-(3- trans-methyl 4- 51 1H NMR (400 MHz,, fluorobenzonitril methoxy-6- aminomethyl- 4 DMSO)511.99 (s, e (trifluoromethyl) cyclohexanecar 1H), 8.22-8.19 (m, pyridin-2- boxylate 1H), 7.86-7.84 (m, yl)ethanamine 2H), 7.68-7.65 (m,
2H), 6.80 (d, J = 8.7 Hz, 1H), 6.14 (d, J = 8.3 Hz, 1H), 5.17- 5.10 (m, 1H), 4.00 (s, 3H), 3.05 (t, J = 6.3 Hz, 2H), 2.23-2.04 (m, 1H), 1.89 (d, J = 10.8 Hz, 2H), 1.74 (d, J = 10.7 Hz, 2H), 1.50 -1.46 (m, 4H), 1.24 (dt, J = 12.4, 10.0 Hz, 2H), 0.93 (dd, J = 23.8, 11.3 Hz, 2H)
104 3-chloro-4- (S)-1-(5-chloro- trans-methyl 4- 47 HNMR : 1H NMR (500 fluorobenzonitril 2- aminomethyl- 9 MHz, MeOD) 5=8.23 e methoxyphenyl) cyclohexanecar (t, J = 2Hz, 1H), 7.78 ethanamine boxylate (d, J = 3Hz, 1H), 7.48
(dd, J = 2, 10.5 Hz,
1H), 7.21-7.18 (m,
2H), 6.99 (d, J = 10.5
Hz, 1H), 6.40 (d, J =
11 Hz, 1H), 4.97-4.95
(m, 1H), 3.93 (s, 3H),
3.19-3.15 (m, 2H),
2.25-2.18 (m, 1H),
2.04-1.99 (m, 2H),
1.87-1.84 (m, 2H), 1.60-1.53 (m, 4H),
1.45-1.34 (m, 2H), 1.07-0.97 (m, 2H).
105 3-chloro-4- (S)-1-(5-fluoro- trans-methyl 4- 46 HNMR : 1H N MR (500 fluorobenzonitril 2- aminomethyl- 3.1 MHz, MeOD) 5=7.78 e methoxyphenyl) cyclohexanecar (d, J = 2.5Hz, 1H), ethanamine boxylate 7.48 (dd, J = 2 ,10.5
Hz, 1H), 7.00-6.91 (m, 3H), 6.41 (d, J = 10.5 Hz, 1H), 4.95 (m, 1H), 3.92 (s, 3H), 3.16 (d, J = 9 Hz, 2H), 2.22 (m, 1H), 2.01-1.98 (m, 2H), 1.87-1.83 (m, 2H), 1.55-1.53 (m, 4H), 1.41-1.37 (m, 2H), 1.04-0.99 (m, 2H).
106 3-chloro-4- (S)-1-(5- trans-methyl 4- 46 1H NMR(500 MHz, fluorobenzonitril methoxy-2- aminomethyl- 1 MeOD) δ= 8.38 (s, e methylpyrirnidin cyclohexanecar 1H), 7.81 (d, J = 2.0
-4- boxylate Hz, 1H), 7.63 (d, J = yl)ethanamine 8.7 Hz, 1H), 6.75 (d, J
= 8.7 Hz, 1H), 5.15 (t, J = 6.6 Hz, 1H), 4.04 (s, 3H), 3.21 (t, J = 6.1 Hz, 2H), 2.64 (s, 3H), 2.24 (s, 1H), 2.02 (d, J = 11.1 Hz, 2H), 1.88 (d, J = 12.9 Hz, 2H), 1.61 (s, 1H), 1.53 (d, J = 6.6 Hz, 3H), 1.47-
1.36 (m, 2H), 1.12-
0.99 (m, 2H).
107 4-fluoro-3- 1-(2-chloro-5- trans-methyl 4- 51
(trifluoromethyl) methoxy-4- aminomethyl- 3
benzonitrile methylphenyl)et cyclohexanecar
hanamine boxylate
108 4-fluoro-3- 1-(2-chloro-5- trans-methyl 4- 51 1H NMR(400 MHz,
(trifluoromethyl) methoxyphenyl) aminomethyl- 3 CDCI3) δ 7.84 (d, J = benzonitrile ethanamine cyclohexanecar 1.5 Hz, 1H), 7.52 (d, J boxylate = 8.7 Hz, 1H), 7.21 (d,
J = 9.6 Hz, 2H), 6.77
(d, J = 3.0 Hz, 1H),
6.65 (dd, J = 8.8, 3.0
Hz, 1H), 6.28 (d, J =
8.8 Hz, 1H), 5.93 (s,
1H), 5.04-4.83 (m,
2H), 3.61 (s, 3H), 3.26
-3.13 (m, 2H), 2.19 (t,
J = 12.2 Hz, 1H), 1.96
(d, J = 11.1 Hz, 2H),
1.78 (d, J = 11.9 Hz,
2H), 1.49 (d, J = 6.4
Hz, 4H), 1.38-1.14
(m, 3H), 0.94 (dd, J =
24.2, 11.8 Hz, 2H).
109 4-fluoro-3- 1-(5-chloro-2- trans-methyl 4- 54 1H NMR(500 MHz,
(t fluoromethyl) methoxyphenyl) aminomethyl- 3.2 DMSO), 8.279-8.290 benzonitrile -2- cyclohexanecar (t, 1H), 7.990 (s, 1H), methoxyethana boxylate 7.818-7.835 (d, 1 H, J mine = 8.5 Hz), 7.271-7.324 (dd, 1H), 7.266-7.270
(d, 1H), 7.096-7.113 (d, 1H, J = 8.5 Hz), 6.530-6.548 (d, 1 H, J = 8.5 Hz), 5.859-5.872 (d, 1H, J = 6.5 Hz), 5.068-5.078 (m, 1H), 3.913 (s, 3H), 3.703- 3.737 (m, 2H), 3.598- 3.627 (m, 2H), 3.301 (s, 1H), 3.039-3.065 (t, 1H, J = 6.5 Hz), 2.059 (m, 1H), 1.852-1.875 (m, 2H), 1.713-1.736 (m, 2H), 1.440 (m, 1H), 1.166-1.255 (m, 2H), 0.870-0.943 (m, 2H). methyl 4- 1-(5-fluoro-2- trans-methyl 4- 54 1H NMR(400 MHz, chloro-3- methoxyphenyl) aminomethyl- 1 CDCI3) δ 7.78 (s, 1H), (trifluoromethyl) -3- cyclohexanecar 7.51 (d, J = 8.6 Hz, benzoate methoxypropan boxylate 1H), 6.90-6.73 (m,
-1-amine 3H), 6.57 (d, J = 5.9
Hz, 1H), 6.25 (d, J = 8.8 Hz, 1H), 5.90 (s, 1H), 4.96 (d, J = 4.8 Hz, 1H), 3.81 (s, 3H), 3.44-3.21 (m, 5H), 3.20 (t, J = 5.7 Hz, 2H), 2.33-2.11 (m, 2H), 1.95 (t, J = 12.3 Hz, 3H), 1.79 (d, J = 11.9 Hz, 2H), 1.35 (dd,
J = 23.8, 11.9 Hz, 2H), 1.18 (s, 1H), 1.00- 0.81 (m, 2H).
111 4-chloro-3- (S)-1-(5-fluoro- methyl 3- 46 HNMR : 1H NMR (500
(trifluoromethyl) 2- (aminomethyl)c 9.2 MHz, MeOD) 5=7.90- benzonitrile methoxyphenyl) yclobutanecarb 7.89 (m, 1H), 7.65- ethanamine oxylate 7.62 (m, 1H), 6.94- 6.82 (m, 3H), 6.44 (d, J = 11.5 Hz, 1H), 6.27- 6.06 (m, 1H), 5.11 (m, 1H), 4.93-4.90 (m, 1H), 3.90 (s, 3H), 3.50 (t, J = 7.5 Hz, 1H), 3.40 (t, J = 7.5 Hz, 1H), 3.14-2.91 (m, 2H), 2.43-2.34 (m, 2H), 2.06-2.01 (m, 2H), 1.54 (d, J = 8.5 Hz, 3H).
112 4-chloro-3- (S)-1-(5-fluoro- trans-methyl 4- 49 HNMR : 1H NMR (500 (trifluoromethyl) 2- aminomethyl- 7 MHz, MeOD) 5=7.99 benzonitrile methoxyphenyl) cyclohexanecar (d, J = 2Hz, 1H), 7.43 ethanamine boxylate (dd, J = 3, 11 Hz, 1H),
7.02-6.93 (m, 3H), 6.58 (d, J = 10.5 Hz, 1H), 5.00 (m, 1H), 3.92 (s, 3H), 3.17 (d, J = 8.5 Hz, 2H), 2.18 (m, 1H), 2.00-1.97 (m, 2H), 1.86-1.83 (m, 2H), 1.53 (m, 4H),
1.42-1.38 (m, 2H), 1.04-0.99 (m, 2H).
113 3-chloro-4- 1-(5-chloro-2- trans-methyl 4- 47 1H NMR(400 MHz, fluorobenzonitril ethylphenyl)eth aminomethyl- 7 CDCI3) δ 7.73 (d, J = e anamine cyclohexanecar I.9 Hz, 1H), 7.38 (dd, boxylate J = 8.5, 1.9 Hz, 1H),
7.29 (s, 1H), 7.20- 7.15 (m, 2H), 6.24 (d, J = 8.6 Hz, 1H), 5.98 (s, 1H), 4.93 (s, 1H), 4.80-4.67 (m, 1H), 3.25 (t, J = 6.0 Hz, 2H), 2.85-2.61 (m, 2H), 2.26 (t, J = 12.1 Hz, 1H), 2.03 (d, J =
II.5 Hz, 2H), 1.86 (d, J = 11.8 Hz, 2H), 1.56 (d, J = 6.6 Hz, 4H),
I.41 (dd, J = 24.2,
II.9 Hz, 2H), 1.35- 1.25 (m, 3H), 1.01 (dd, J = 23.9, 11.4 Hz, 2H).
114 3-chloro-4- 1-(5-chloro-2- trans-methyl 4- 50 1H NMR(400 MHz, fluorobenzonitril methoxyphenyl) aminomethyl- 7 DMSO) 58.11 (t, J = e -2- cyclohexanecar 5.7 Hz, 1H), 7.77 (d, J methylpropan- boxylate = 1.9 Hz, 1H), 7.56 1 -amine (dd, J = 8.6, 1.7 Hz,
1H), 7.49 (d, J = 2.6 Hz, 1H), 7.24 (dd, J = 8.8, 2.7 Hz, 1H), 7.01 (dd, J = 20.3, 8.9 Hz,
1H), 6.57 (d, J = 8.8 Hz, 1H), 5.96 (d, J = 8.9 Hz, 1H), 4.45 (t, J = 9.0 Hz, 1H), 3.89 (s, 3H), 3.03 (t, J = 6.2 Hz, 2H), 2.22 (dt, J = 13.2, 6.6 Hz, 1H), 2.09 (dd, J = 16.4, 7.6 Hz, 1H), 1.87 (d, J = 10.7 Hz, 2H), 1.72 (d, J = 11.0 Hz, 2H), 1.48- 1.36 (m, 1H), 1.30- 1.15 (m, 2H), 1.07 (t, J = 10.4 Hz, 3H), 0.90 (dd, J = 23.7, 11.3 Hz, 2H), 0.73 (d, J = 6.7 Hz, 3H).
3-chloro-4- 1-(3-chloro-6- trans-methyl 4- 49 1H NMR(400 MHz, fluorobenzonitril methoxy-2- aminomethyl- 3 MeOD) δ 7.74 (d, J = e methylphenyl)et cyclohexanecar 2.0 Hz, 1H), 7.55 (d, J hanamine boxylate = 8.6 Hz, 1H), 7.23 (d,
J = 8.9 Hz, 1H), 6.85 (d, J = 8.9 Hz, 1H), 6.63 (d, J = 8.6 Hz, 1H), 5.20 (d, J = 6.6 Hz, 1H), 3.88 (s, 3H), 3.15 (d, J = 6.9 Hz, 2H), 2.52 (s, 3H), 2.06 (d, J = 13.9 Hz, 1H), 1.95 (d, J = 11.2 Hz, 2H), 1.82 (d, J = 11.6 Hz, 2H), 1.60 (d, J =
6.9 Hz, 4H), 1.50- 1.32 (m, 2H), 0.99 (dd, J = 23.4, 10.9 Hz, 2H).
3-chloro-4- (5-chloro-2- trans-methyl 4- 50 1H NMR(400 MHz, fluorobenzonitril methoxyphenyl) aminomethyl- 5 CDCI3) δ 7.63 (d, J = e (cyclopropyl)me cyclohexanecar 1.7 Hz, 1H), 7.35- thanamine boxylate 7.25 (m, 1H), 7.14 (d,
J = 2.5 Hz, 1H), 7.09 (dd, J = 8.7, 2.6 Hz, 1H), 6.76 (d, J = 8.7 Hz, 1H), 6.19 (d, J = 8.7 Hz, 1H), 5.92 (s, 1H), 5.23 (s, 1H), 4.21 (d, J = 7.2 Hz, 1H), 3.82 (d, J = 15.6 Hz, 3H), 3.17 (t, J = 6.0 Hz, 3H), 2.18 (t, J = 12.0 Hz, 1H), 1.95 (d, J = 12.1 Hz, 2H), 1.77 (d, J = 11.4 Hz, 2H), 1.46 (s, 1H), 1.33 (dd, J = 23.3, 12.0 Hz, 2H), 1.19 (dt, J = 16.0, 6.4 Hz, 1H), 0.93 (dd, J = 23.1, 11.1 Hz, 2H), 0.62-0.51 (m, 1H), 0.43 (td, J = 13.2, 5.2 Hz, 2H), 0.30-0.22 (m, 1H). 117 3-chloro-4- 1-(5-fluoro-2- trans-methyl 4- 50 1H NMR(400 MHz, fluorobenzonitril methoxyphenyl) aminomethyl- 7 MeOD) δ 7.77 (d, J = e -3- cyclohexanecar 2.1 Hz, 1H), 7.47 (dd, methoxypropan boxylate J = 8.6, 2.1 Hz, 1H), -1-amine 7.08-6.82 (m, 3H),
6.36 (d, J = 8.7 Hz, 1H), 5.01 (dt, J = 16.9, 8.5 Hz, 1H), 3.92 (s, 3H), 3.55-3.43 (m, 2H), 3.37 (s, 3H), 3.17 (t, J = 9.7 Hz, 2H), 2.22 (dt, J = 10.8, 6.0 Hz, 1H), 2.15-2.02 (m, 2H), 1.95 (d, J = 10.5 Hz, 2H), 1.82 (d, J = 10.6 Hz, 2H), 1.63 - 1.49 (m, 1H), 1.41 (dt, J = 13.1, 10.1 Hz, 2H), 1.04-0.92 (m, 2H).
118 3-chloro-4- 3-amino-3-(5- - trans-methyl 49 1H NMR(400 MHz, fluorobenzonitril fluoro-2- 4-aminomethyl- 3 CDCI3) δ 7.70 (d, J = e methoxyphenyl) cyclohexanecar 1.8 Hz, 1H), 7.38 (d, J propan-1-ol boxylate = 8.6 Hz, 1H), 7.04-
6.69 (m, 3H), 6.34 (d,
J = 8.6 Hz, 1H), 6.02-
5.73 (m, 2H), 5.01 (d,
J = 5.8 Hz, 1H), 3.75
(td, J = 11.2, 5.7 Hz,
2H), 3.26 (t, J = 6.2
Hz, 2H), 2.27 (t, J =
12.2 Hz, 1H), 2.12 (dd, J = 11.6, 5.6 Hz, 2H),
2.04 (d, J = 11.4 Hz, 2H), 1.86 (d, J = 11.5 Hz, 2H), 1.54 (s, 1H), 1.48- 1.30 (m, 2H), 1.01 (dd, J = 23.4, 11.0 Hz, 2H).
119 3-chloro-4- (S)-3-amino-3- trans-methyl 4- 50 1H NMR(400 MHz, fluorobenzonitril (5-chloro-2- aminomethyl- 8.8 MeOD)58.12(t,
e methoxyphenyl) cyclohexanecar J=8Hz, 1H), 7.79 (s, propan-1-ol boxylate 1H), 7.51 (d, J = 8Hz,
1H), 7.26 (dd, J=4Hz, 8Hz, 1H), 7.24-7.28 (m, 2H), 7.06 (d, J=8Hz, 1H), 6.50 (d, J=8Hz, 1H), 6.35 (d, J = 8Hz, 1H), 4.96 (dd, J=8, 12Hz, 1H), 3.89 (s, 3H), 3.35-3.57 (m, 2H), 3.01 (t, J = 8Hz, 2H), 2.06-2.09 (m, 1H), 1.94-1.97 (m, 2H), 1.86 (d, J= 12Hz, 2H), 1.71 (d, J = 12Hz, 2H), 1.45-1.50 (m, 1H), 1.18-1.21 (m, 2H), 0.8-0.95 (m, 2H) ppm
120 3-chloro-4- 2-methoxy-1- trans-methyl 4- 54 1H NMR(500 MHz, fluorobenzonitril (3-methoxy-6- aminomethyl- 4.2 MeOD)5=8.16(s, e (trifluoromethyl) 1H), 7.68 (d, J = 1.8 pyridin-2- cyclohexanecar Hz, 1H), 7.61 (d, J = yl)ethanamine boxylate 8.6 Hz, 1H), 7.49 (dd,
J = 12.8, 9.6 Hz, 2H), 6.76 (d, J = 8.6 Hz, 1H), 5.24 (t, J = 5.4 Hz, 1H), 3.92 (s, 3H), 3.74-3.61 (m, 2H), 3.23 (S, 3H), 3.11 - 3.02 (m, 2H), 2.12 (s, 1H), 1.90 (d, J = 11.3 Hz, 2H), 1.76 (d, J = 12.8 Hz, 2H), 1.28 (m,
2H), 0.93 (dd, J = 27.8, 8.4 Hz, 2H), 0.80 (s, 1H).
3-chloro-4- 2-methoxy-1- trans-methyl 4- 54 1H NMR(500 MHz, fluorobenzonitril (3-methoxy-6- aminomethyl- 4 MeOD)5=8.16(s, e (trifluoromethyl) cyclohexanecar 1H), 7.68 (d, J = 1.8 pyridin-2- boxylate Hz, 1H), 7.61 (d, J = yl)ethanamine 8.6 Hz, 1H), 7.49 (dd,
J = 12.8, 9.6 Hz, 2H), 6.76 (d, J = 8.6 Hz, 1H), 5.24 (t, J = 5.4
Hz, 1H), 3.92 (s, 3H), 3.74-3.61 (m, 2H), 3.23 (S, 3H), 3.11 -
3.02 (m, 2H), 2.12 (s, 1H), 1.90 (d, J = 11.3 Hz, 2H), 1.76 (d, J =
12.8 Hz, 2H), 1.28 (m, 2H), 0.93 (dd, J =
27.8, 8.4 Hz, 2H), 0.80 (s, 1H).
122 3-chloro-4- 2-methoxy-1 - trans-methyl 4- 54 1H NMR(500 MHz, fluorobenzonitril (5-methoxy-2- aminomethyl- 4 MeOD) δ 8.37 (s, 1H), e (trifluoromethyl) cyclohexanecar 7.71 (d, J = 1.7 Hz, pyridin-4- boxylate 1H), 7.50 (s, 1H), 7.40 yl)ethanamine (dd, J = 8.5, 1.7 Hz,
1H), 6.27 (d, J = 8.6 Hz, 1H), 5.06 (s, 1H), 4.05 (s, 3H), 3.71 (d, J = 4.0 Hz, 1H), 3.63 (d, J = 5.9 Hz, 1H), 3.29
(s,3H), 3.06 (d, J = 6.9 Hz, 2H), 2.14-2.03
(m, 1H), 1.88 (d, J = 13.2 Hz, 2H), 1.74 (d, J = 11.6 Hz, 2H), 1.47
(d, J = 3.4 Hz, 1H),
1.33-1.26 (m, 2H), 0.90 (d, J = 12.5 Hz, 2H).
123 3-chloro-4- 2-methoxy-1- trans-methyl 4- 54 1H NMR(500 MHz, fluorobenzonitril (5-methoxy-2- aminomethyl- 4 MeOD) δ 8.37 (s, 1H), e (trifluoromethyl) cyclohexanecar 7.71 (d, J = 1.7 Hz, pyridin-4- boxylate 1H), 7.50 (s, 1H), 7.40 yl)ethanamine (dd, J = 8.5, 1.7 Hz,
1H), 6.27 (d, J = 8.6 Hz, 1H), 5.06 (s, 1H), 4.05 (s, 3H), 3.71 (d, J = 4.0 Hz, 1H), 3.63 (d,
J = 5.9 Hz, 1H), 3.29
(s,3H), 3.06 (d, J =
6.9 Hz, 2H), 2.14-2.03
(m, 1H), 1.88 (d, J =
13.2 Hz, 2H), 1.74 (d,
J = 11.6 Hz, 2H), 1.47
(d, J = 3.4 Hz, 1H),
1.33-1.26 (m, 2H),
0.90 (d, J = 12.5 Hz,
2H).
124 3-chloro-4- 1-(4-ethyl-6- trans-methyl 4- 47
fluorobenzonitril methoxypyridin- aminomethyl- 4
e 2- cyclohexanecar
yl)ethanamine boxylate
125 3-chloro-4- 1-(4-ethyl-6- trans-methyl 4- 47
fluorobenzonitril methoxypyridin- aminomethyl- 4.2
e 2- cyclohexanecar
yl)ethanamine boxylate
126 4-fluoro-3- (S)-1-(5-chloro- methyl 3- 48 1H NMR(500 MHz,
(trifluoromethyl) 2- (aminomethyl)c 5.1 MeOD) 5=7.90 (d, J = benzonitrile methoxyphenyl) yclobutanecarb 2 Hz, 1H), 7.65 (d, J = ethanamine oxylate 10.5 Hz, 1H), 7.20- 7.18 (m, 2H), 6.84 (d, J = 10.5 Hz, 1H), 6.46 (d, J = 11 Hz, 1H), 6.17 (m, 1H), 5.14 (m, 1H), 4.90 (t, J = 8 Hz, 1H), 3.91 (s, 3H), 3.45 (t, J = 7.5 Hz, 2H), 3.08 (m, 1H), 2.60 (m, 1H), 2.42-2.35 (m,
2H), 2.12-2.04 (m,
2H), 1.53 (d, J = 8.5
Hz, 3H).
127 4-fluoro-3- 1 -(3-methoxy- trans-methyl 4- 49 1H NMR(500 MHz, methylbenzonitr 6- aminomethyl- 4.1 CDCI3)58.36 (s, 1H), ile (trifluoromethyl) cyclohexanecar 7.54 (s, 2H), 7.35 (d, J pyridin-2- boxylate = 7.4 Hz, 1H), 6.12 (d, yl)ethanamine J = 8.5 Hz, 1H), 5.98
(s, 1H), 4.92 (d, J = 5.9 Hz, 1H), 4.17 (s, 1H), 4.10 (s, 3H), 3.27 (s, 2H), 2.28 (s, 3H), 2.02 (s, 3H), 1.87 (d, J = 9.0 Hz, 3H), 1.55 (d, J = 6.7 Hz, 3H), 1.42 (d, J = 11.3 Hz, 2H), 1.02 (d, J = 10.9 Hz, 2H).
128 4-fluoro-3- 1 -(3-methoxy- trans-methyl 4- 49 1H NMR(500 MHz, methylbenzonitr 6- aminomethyl- 4 CDCI3) δ 8.36 (s, 1H), ile (trifluoromethyl) cyclohexanecar 7.54 (s, 2H), 7.35 (d, J pyridin-2- boxylate = 7.4 Hz, 1H), 6.12 (d, yl)ethanamine J = 8.5 Hz, 1H), 5.98
(s, 1H), 4.92 (d, J = 5.9 Hz, 1H), 4.17 (s, 1H), 4.10 (s, 3H), 3.27 (s, 2H), 2.28 (s, 3H), 2.02 (s, 3H), 1.87 (d, J = 9.0 Hz, 3H), 1.55 (d, J = 6.7 Hz, 3H), 1.42 (d, J = 11.3 Hz, 2H),
1.02 (d, J = 10.9 Hz, 2H).
129 3-chloro-4- 1-(3-chloro-2- trans-methyl 4- 49 1H NMR(500 MHz, fluorobenzonitril fluoro-6- aminomethyl- 7 CDCI3) δ 7.69 (d, J = e methoxyphenyl) cyclohexanecar 1.8 Hz, 1H), 7.46 (d, J ethanamine boxylate = 8.6 Hz, 1H), 7.19 (t,
J = 8.6 Hz, 1H), 6.63 (dd, J = 24.8, 8.9 Hz, 2H), 5.96 (s, 1H), 5.52 (d, J = 10.1 Hz, 1H), 5.26-5.08 (m, 1H), 3.89 (s, 3H), 3.26 (t, J = 6.5 Hz, 2H), 2.27 (s, 1H), 2.03 (s, 2H), 1.85 (s,2H), 1.64 (d, J = 6.9 Hz, 3H), 1.57- 1.53 (m, 1H), 1.46- 1.39 (m, 2H), 1.02 (d, J = 12.7 Hz, 2H).
130 3-chloro-4- 1-(3-chloro-2- trans-methyl 4- 49 1H NMR(500 MHz, fluorobenzonitril fluoro-6- aminomethyl- 7 CDCI3) δ 7.69 (d, J = e methoxyphenyl) cyclohexanecar 1.8 Hz, 1H), 7.46 (d, J ethanamine boxylate = 8.6 Hz, 1H), 7.19 (t,
J = 8.6 Hz, 1H), 6.63 (dd, J = 24.8, 8.9 Hz, 2H), 5.96 (s, 1H), 5.52 (d, J = 10.1 Hz, 1H), 5.26-5.08 (m, 1H), 3.89 (s, 3H), 3.26 (t, J = 6.5 Hz, 2H), 2.27 (s, 1H), 2.03 (s, 2H), 1.85
(s,2H), 1.64 (d, J = 6.9 Hz, 3H), 1.57- 1.53 (m, 1H), 1.46- 1.39 (m, 2H), 1.02 (d, J = 12.7 Hz, 2H).
131 3-chloro-4- 1-(6-ethyl-3- trans-methyl 4- 50 1H NMR(500 MHz, fluorobenzonitril methoxypyridin- aminomethyl- 4 MeOD)8.27 (s, 1H), e 2-yl)-2- cyclohexanecar 7.79 (s, 1H), 7.61 (d, J methoxyethana boxylate = 7.0 Hz, 1H), 7.37 (d, mineN28113- J = 8.4 Hz, 1H), 7.17 75-A1 (d, J = 8.5 Hz, 1H),
6.86 (d, J = 8.7 Hz, 1H), 5.36 "C 5.20 (m, 1H), 3.94 (s, 3H), 3.75
(ddd, J = 41.2, 22.1, 14.5 Hz, 2H), 3.36 (s,
3H), 3.19 (d, J = 6.4 Hz, 2H), 2.77 (dd, J = 14.6, 7.6 Hz, 2H), 2.24
(s, 1H), 2.02 (d, J = 11.3 Hz, 2H), 1.88 (d, J = 12.1 Hz, 2H), 1.61 (s, 1H), 1.42 (dd, J =
22.2, 13.7 Hz, 2H), 1.29 (dd, J = 15.9, 8.3 Hz, 4H), 1.05 (dd, J =
23.9, 11.4 Hz, 2H).
132 3-chloro-4- 1-(6-ethyl-3- trans-methyl 4- 50 1H NMR(500 MHz, fluorobenzonitril methoxypyridin- aminomethyl- 4 MeOD)8.26 (s, 1H), e 2-yl)-2- 7.79 (d, J = 1.6 Hz, methoxyethana cyclohexanecar 1 H), 7.61 (d, J = 8.5 mine boxylate Hz, 1 H), 7.37 (d, J =
8.4 Hz, 1 H), 7.17 (d, J = 8.4 Hz, 1 H), 6.86 (d, J = 8.7 Hz, 1 H), 5.36 C 5.15 (m, 1 H), 3.94 (s, 3H), 3.82 C 3.60 (m, 2H), 3.36 (s, 3H), 3.19 (d, J = 6.4 Hz, 2H), 2.77 (dd, J = 14.8, 7.6 Hz, 2H), 2.24 (s, 1 H), 2.02 (d, J = 1 1.1 Hz, 2H), 1.88 (d, J = 12.0 Hz, 2H), 1.61 (s, 1 H), 1.42 (dd, J =
22.4, 13.7 Hz, 2H), 1.28 (dd, J = 15.8, 8.3 Hz, 3H), 1.05 (dd, J =
24.5, 1 1.2 Hz, 2H).
3-chloro-4- 1-(2-ethyl-5- trans-methyl 4- 50 1H NMR (500 MHz, fluorobenzonitril methoxypyridin- aminomethyl- 5 MeOD) 5=8.27 (t, J = e 4-yl)-2- cyclohexanecar 5.5 Hz, 1 H), 8.19 (s, methoxyethana boxylate 2H), 7.83 (d, J = 1.9 mine Hz, 2H), 7.51 (dd, J =
8.6, 1.9 Hz, 2H), 7.16
(s, 2H), 6.38 (d, J = 8.7 Hz, 2H), 5.1 1 (dd,
J = 6.2, 4.2 Hz, 2H), 4.06 (s, 5H), 3.80 (dd,
J = 9.9, 4.0 Hz, 2H), 3.71 (dd, J = 9.9, 6.5 Hz, 2H), 3.41 (s, 5H), 3.18 (t, J = 6.0 Hz,
3H), 2.68 (q, J = 7.5 Hz, 3H), 2.22 (s, 2H), 2.01 (d, J = 12.2 Hz, 3H), 1.86 (d, J = 11.9 Hz, 3H), 1.59 (s, 2H),
1.41 (dd, J = 23.6, 11.4 Hz, 3H), 1.17 (t, J = 7.6 Hz, 5H), 1.03 (q,
J = 11.6 Hz, 3H).
3-chloro-4- 1-(2-ethyl-5- trans-methyl 4- 50 1H NMR(500 MHz, fluorobenzonitril methoxypyridin- aminomethyl- 5 MeOD)5= 8.06 (s, 1H), e 4-yl)-2- cyclohexanecar 7.70 (d, J = 2.0 Hz, methoxyethana boxylate 1H), 7.39 (dd, J = 8.6, mine 2.0 Hz, 1H), 7.04 (s,
1H), 6.26 (d, J = 8.7 Hz, 1H), 4.99 (dd, J = 6.2, 4.1 Hz, 1H), 3.94 (s, 3H), 3.68 (dd, J = 9.9, 4.1 Hz, 1H), 3.64
C3.53 (m, 1H), 3.29
(s, 3H), 3.03 (t, J = 10.3 Hz, 2H), 2.56 (q, J = 7.6 Hz, 2H), 1.98
(s, 1H), 1.84 (d, J = 12.3 Hz, 2H), 1.71 (d, J = 12.1 Hz, 2H), 1.46 (s, 1H), 1.35 C 1.24 (m, 2H), 1.08 "C0.98 (m, 3H), 0.88 (dd, J =
23.5, 12.1 Hz, 2H). 135 3-chloro-4- (R)-1-(5-bromo- trans-methyl 4- 55 1H NMR (400 MHz, fluorobenzonitril 2- aminomethyl- 3.1 MeOD) δ 7.82 (d, J = e methoxyphenyl) cyclohexanecar 1.2Hz, 1H), 7.51 (dd,
-2- boxylate J=1.6, 6.8 Hz, 1H), methoxyethana 7.34-7.40 (m, 1H), mine 7.34(s, 1H), 6.99(d,
J=7.2Hz, 1H), 6.38(d,
J = 6.8Hz, 1H), 5.06-
5.08(m, 1H), 3.96(s,
3H), 3.74 (dd, J=3.2,
7.6Hz, 1H), 3.65 (dd, J
= 3.2, J = 8Hz, 1H),
3.41(s, 3H), 3.18(d,
J=5.6Hz, 2H), 2.21-
2.26(m, 1H), 1.98-
2.05(m, 2H), 1.85-
1.88(m, 2H), 1.56-1.62
(m, 1H), 1.37-1.45(m,
2H), 0.98-1.08(m,2H) ppm
Example 4: Preparation of compound 136
Figure imgf000147_0001
Intermediate 234: (S)-methyl 6-((1 -(5-bromo-2-methoxyphenyl)ethyl)
(trifluoromethyl)nicotinate
Figure imgf000147_0002
A mixture of (S)-1 -(5-bromo-2-methoxyphenyl)ethanamine (33 g, 143 mmol) hydrochloride, methyl 6-chloro-5-(trifluoromethyl)nicotinate (37.8 g, 158 mmol) and DIPEA (62.6 mL, 359 mmol) was combined in DMSO (99 mL) and allowed to stir at 80 °C for 16 h. The reaction mixture was then allowed to cool to 20 °C and ethyl acetate (500 mL) was added. The resulting solution was transferred to a seperatory funnel and washed with brine (4 x 100 mL). The organic phase was then dried over Na2S04 and concentrated to dryness. The resulting oil was was purified by flash chromatography on silica gel (PE/EtOAc = 10/1 ) to provide the desired product (S)-methyl 6-((1-(5-bromo-2-methoxyphenyl)ethyl)amino)-5- (trifluoromethyl)nicotinate (47 g, 76% yield) as a yellow oil. m/z: [M + H]+ Calcd for Ci7Hi7BrF3N203 433.0; Found 433. Intermediate 235: (S)-6-((1 -(5-bromo-2-methoxyphenyl)ethyl)amino)-5- (trifluoromethyl)nicotinic acid
Figure imgf000147_0003
A mixture of (S)-methyl 6-((1 -(5-bromo-2-methoxyphenyl)ethyl)amino)-5- (trifluoromethyl)nicotinate (44 g, 102 mmol) and LiOH (12.16 g, 508 mmol) in methanol (1500 mL) and water (500 mL) was stirred for 16 h at 20 °C. The methanol was removed by rotoray evaporation and then water (15 ml) was added. The pH was adjusted to 2.5 with aqueous 1 N HCI. The resulting slurry was then filtered and washed with water (20 ml). The resulting solid was allowed to dry on filter pad to provide (S)-6-((1 -(5-bromo-2-methoxyphenyl)ethyl)amino)- 5-(trifluoromethyl)nicotinic acid (42 g, 100 mmol, 99%) that was used without further purification, m/z: [M + H]+ Calcd for Ci6Hi5BrF3N203 419.0; Found 419.
Intermediate 236: trans-methyl 4-((6-(((S)-1 -(5-bromo-2-methoxyphenyl)ethyl)amino)- 5-(trifluoromethyl)nicotinamido)methyl)cyclohexanecarboxylate
Figure imgf000148_0001
A mixture of (S)-6-((1 -(5-bromo-2-methoxyphenyl)ethyl)amino)-5-(trifluoromethyl)nicotinic acid (35 g, 83 mmol), trans-methyl 4-(aminomethyl)cyclohexanecarboxylate hydrochloride (18.21 g, 88 mmol), HATU (38.1 g, 100 mmol) and DIPEA (36.5 mL, 209 mmol) in DMF (90 mL) was stirred at 20 °C for 16 h. Ethyl acetate (100 mL) was then added and the resulting solution was washed with brine (4 x 30 mL). The washed organic layer was then concentrated and purified by flash chromatography on silica gel (PE/EtOAc = 2/1 ) to provide the desired product trans-methyl 4-((6-(((S)-1 -(5-bromo-2-methoxyphenyl)ethyl)amino)-5
(trifluoromethyl)nicotinamido)methyl) cyclohexanecarboxylate (46 g, 80 mmol, 96%) as yellow oil. m/z: [M + H]+ Calcd for C25H3oBrF3N304 572.1 ; Found 572.
Intermediate 237: trans-methyl 4-((6-(((S)-1 -(5-cyano-2-methoxyphenyl)ethyl)amino)-5- (trifluoromethyl)nicotinamido)methyl)cyclohexanecarboxylate
Figure imgf000148_0002
A mixture of trans-methyl 4-((6-(((S)-1-(5-bromo-2-methoxyphenyl)ethyl)amino)-5- (trifluoromethyl)nicotinamido)methyl)cyclohexanecarboxylate (45 g, 79 mmol), zinc cyanide (27.6 g, 236 mmol), and Pd(Ph3P)4 (18.17 g, 15.72 mmol) in DMF (220 mL) was stirred at 120 °C under N2 for 18 h. The reaction solution was allowed to cool to 20 °C and then ethyl acetate (100 mL) was added. The resulting solution was washed with brine (3 x 30 mL) and then concentrated, and purified by flash chromatography on silica gel (PE/EtOAc = 2/1 ) to provide the desired product trans-methyl 4-((6-(((S)-1 -(5-cyano-2- methoxyphenyl)ethyl)amino)-5-(trifluoromethyl)nicotinamido)methyl)cyclohexanecarboxylate (38 g, 93%) as a white solid. 1 H NMR (400 MHz, CDCI3) δ 8.58 (s, 1 H), 8.16 (s, 1 H), 7.55- 7.58 (m, 2H), 6.98 (d, J = 8.4Hz, 1 H), 6.03-6.05 (m, 2H), 5.58-5.63 (m, 1 H), 3.98 (s, 3H), 3.68 (s, 3H), 3.31 (t, J = 6.4Hz, 2H), 2.26 (t, J = 8.8Hz, 1 H), 2.06 ( d, J = 12Hz, 2H), 1 .87 (d, J = 12Hz, 2H), 1 .51 -1 .52 (m, 4H), 1 .40-1 .44 (m, 2H), 1 .01 -1 .08 (m, 2H).
Compound 136: trans-4-((6-(((S)-1 -(5-cyano-2-methoxyphenyl)ethyl)amino)-5- (trifluoromethyl)nicotinamido)methyl)cyclohexanecarboxylic acid
Figure imgf000149_0001
To a solution of trans-methyl 4-((6-(((S)-1 -(5-cyano-2-methoxyphenyl)ethyl)amino)-5- (trifluoromethyl)nicotinamido)methyl)cyclohexanecarboxylate (38 g, 73.3 mmol) in THF (441 ml.) was added a solution of lithium hydroxide (3.51 g, 147 mmol) in water (147 ml_). The resulting mixture was stirred at 40 °C for 16h. Following completion of the reaction, the THF was removed by rotary evaporation and the aqueous solution of product was further diluted with water (300ml). Aqueous hydrochloric acid (1 N) was then added until a pH of 2.5 was achieved. The resulting slurry was then filtered and the filtered solid washed with water (200 ml_). The isolated solid was then recrystallized from methanol (200 mL) at 40 °C for 3h, then stirred at 20 °C for 16h. The recrystallized solid was then filtered and washed with methanol (50 mL) and allowed to dry on filter pad. The solid was then collected to provide the desired product trans-4-((6-(((S)-1 -(5-cyano-2-methoxyphenyl)ethyl)amino)-5-
(trifluoromethyl)nicotinamido)methyl)cyclohexanecarboxylic acid as a white solid. Melting point: 195 °C -197.4 °C. m/z: [M + H]+ Calcd for C25H28F3N404 505.2; Found 505. 1H NMR (400 MHz, DMSO) δ 1 1 .98 (s, 1 H), 8.67 (s, 1 H), 8.38 (s, 1 H), 8.23 (s, 1 H), 7.72 (d, J = 8.6 Hz, 1 H), 7.68 (s, 1 H), 7.19 (d, J = 8.5 Hz, 1 H), 6.95 (d, J = 7.8 Hz, 1 H), 5.80 - 5.68 (m, 1 H), 3.95 (s, 3H), 3.07 (s, 2H), 2.12 (t, J = 1 1 .8 Hz, 1 H), 1 .88 (d, J = 12.0 Hz, 2H), 1 .74 (d, J = 1 1 .9 Hz, 2H), 1 .47 (d, J = 6.7 Hz, 4H), 1 .24 (dd, J = 24.3, 12.3 Hz, 2H), 0.93 (dd, J = 24.0, 1 1 .8 Hz, 2H).
The following compounds were synthesized using a similar procedure to that described in Example 4 for Compound 136. CN SM 7 SM 8 SM 9 LC NMR
MS
137 methyl 5,6- (S)-1-(5-bromo- trans-methyl 4- 51 1H NMR (400 MHz, dichloronicotinate 2-(2- aminomethyl- 5 DMSO) 58.41 (d, J = methoxyethoxy)p cyclohexanecar 2.0 Hz, 1H), 8.25 (m, J henyl)ethanamin boxylate = 5.6 Hz, 1H), 8.04 (d, e J = 2.0 Hz, 1H), 7.71 -
7.67 (m, 2H), 7.19 (d,
J = 8.3 Hz, 1H), 7.11
(d, J = 8.3 Hz, 1H),
5.64-5.56 (m, 1H),
4.32-4.26 (m, 2H),
3.73 (dd, J = 5.6, 3.2
Hz, 2H), 3.34 (s, 3H),
3.05 (t, J = 6.3 Hz,
2H), 2.15-2.08 (m,
1H), 1.88 (d, J = 10.9
Hz, 2H), 1.74 (d, J =
10.9 Hz, 2H), 1.48 (d,
J = 6.9 Hz, 3H), 1.30-
1.18 (m, 3H), 0.92 (dd,
J = 23.7, 11.2 Hz, 2H)
138 methyl 5,6- (S)-1-(5-bromo- trans-methyl 4- 47 1H NMR (400 MHz, dichloronicotinate 2- aminomethyl- 4 DMSO) δ 8.39 (d, J =
(2H3)methoxyphe cyclohexanecar 1.9 Hz, 1H), 8.24 (m, J nyl)ethanamine boxylate = 5.6 Hz, 1H), 8.04 (d,
J = 2.0 Hz, 1H), 7.73- 7.67 (m, 2H), 7.18 (m, J = 7.5 Hz, 2H), 5.64- 5.55 (m, 1H), 3.95 (s,
OH), 3.05 (t, J = 6.2 Hz, 2H), 2.11 (ddd, J =
11.1, 7.3, 2.9 Hz, 1H), 1.88 (d, J = 10.9 Hz, 2H), 1.74 (d, J = 10.9 Hz, 2H), 1.45 (d, J = 6.9 Hz, 4H), 1.27- 1.20 (m, 2H), 0.99- 0.84 (m, 2H).
139 methyl 5,6- (S)-1-(5-bromo- trans-methyl 4- 48 1H NMR (400 MHz, dichloronicotinate 2- aminomethyl- 5.3 MeOD) δ 8.41 (d, ethoxyphenyl)eth cyclohexanecar J=1.2Hz, 1H), 8.24- anamine boxylate 8.27 (m, 1H), 8.05 (d,
J-1.2HZ, 1H), 7.60- 7.68 (m, 2H), 7.15 (dd, J = 4Hz, 12Hz, 2H), 5.57-5.67 (m, 1H), 4.21 (dd, J = 8, 12Hz, 2H), 3.04 (t, J = 4Hz,
2H), 2.07-2.09 (m, 1H), 1.88 (d, J = 12Hz, 2H), 1.74 (d, J = 12Hz, 2H), 1.48 (d, J =4Hz, 3H), 1.40 (t, J = 4Hz 3H), 1.20-1.29 (m, 3H), 0.86-0.97 (m, 3H),
140 methyl 5,6- (S)-1-(5-bromo- trans-methyl 4- 49 1H NMR (400 MHz, dichloronicotinate 2- aminomethyl- 9.3 DMSO) δ 8.42 (d, J = isopropoxypheny cyclohexanecar 2Hz, 1H), 8.26 (t, J = l)ethanamine boxylate 4Hz), 8.04 (d, J=2Hz,
1H), 7.66(s, 1H), 7.60- 7.65 (m, 1H), 7.20 (d,
J = 8Hz, 1H), 7.08 (d, J = 7.08, 1H), 5.50- 5.61 (m, 1H), 4.84- 4.88 (m, 1H), 3.04 (t, J
= 4Hz, 1H), 2.05- 2.10(m, 1H), 1.89 (d, J=8Hz, 2H), 1.74 (d, J=8Hz, 2H), 1.45 (d, J = 4Hz, 4H), 1.33 (d, J=4Hz, 6H), 1.23 (dd, J = 8, 12Hz, 2H), 0.93 (dd, J = 8, 12Hz, 2H)ppm methyl 5,6- (S)-2-(2-(1- trans-methyl 4- 50 1H NMR (400 MHz, dichloronicotinate aminoethyl)-4- aminomethyl- 1 DMSO) δ 8.40 (d, J = bromophenoxy)e cyclohexanecar 1.9 Hz, 1H), 8.23 (m, J thanol boxylate = 5.7 Hz, 1H), 8.04 (d,
J = 2.0 Hz, 1H), 7.71 - 7.65 (m, 2H), 7.16 (dd, J = 21.0, 8.8 Hz, 2H), 5.65-5.57 (m, 1H), 4.18 (t, J = 4.7 Hz, 2H), 3.82-3.77 (m, 2H), 3.05 (t, J = 6.2 Hz, 2H), 2.12 (dd, J = 13.8, 10.5 Hz, 1H), 1.88 (d, J = 10.9 Hz, 2H), 1.74 (d, J = 10.4 Hz, 2H), 1.48 (t, J = 12.3 Hz, 4H), 1.25 (d, J = 5.3 Hz, 3H), 0.98- 0.88 (m, 2H).
142 methyl 5,6- 3-amino-3-(5- trans-methyl 4- 50 1H NMR (500 MHz, dichloronicotinate bromo-2- aminomethyl- 1 MeOD) δ 8.38 (d, J = methoxyphenyl)p cyclohexanecar 2.0 Hz, 1H), 8.00 (d, J ropan-1-ol boxylate = 2.0 Hz, 1H), 7.67- 7.57 (m, 2H), 7.17 (d, J = 8.6 Hz, 1H), 7.17 (d, J = 8.6 Hz, 1H), 5.69 (dd, J = 7.7, 4.8 Hz, 1H), 4.90 (s, 15H), 4.01 (s, 3H), 3.82- 3.53 (m, 2H), 3.33 (d, J = 1.4 Hz, 19H), 3.19 (d, J = 6.9 Hz, 2H), 2.22-2.09 (m, 2H), 2.09- 1.96 (m, 2H), 1.87 (d, J = 11.6 Hz, 2H), 1.59 (s, 1H), 1.56 - 1.23 (m, 2H), 1.14- 0.73 (m, 2H).
143 methyl 5-bromo-6- (S)-1-(3- ethyl 2-(3- 49 1H NMR (400 MHz, chloronicotinate methoxy-6- (aminomethyl)o 4.1 d6-DMSO) δ 8.69 (d, J
(trifluoromethyl)p xetan-3- = 2.3 Hz, 1H), 8.46 (s, yridin-2- yl)acetate 1H), 8.37 (d, J = 2.3 yl)ethanamine Hz, 1H), 7.85 (d, J =
8.6 Hz, 1H), 7.68 (s, 1H), 7.67 (s, 1H), 5.69 -5.65 (m, 1H), 4.14- 4.08 (m, 2H), 3.98 (s, 3H), 3.39 -3.38 (m,
4H), 2.45-2.30 (m,
2H), 2.08 (s, 1H), 1.47
(d, J = 6.6 Hz, 3H).
144 methyl 5-bromo-6- (S)-1-(5- ethyl 2-(3- 1H NMR(400 MHz, chloronicotinate methoxy-2- (aminomethyl)o d6-DMSO) δ 8.60 (d, J
49
(trifluoromethyl)p xetan-3- = 2.0 Hz, 1H), 8.51 (s,
4
yridin-4- yl)acetate 1H), 8.42-8.41 (m, yl)ethanamine 1H), 8.35 (d, J = 2.2
Hz, 1H), 8.12 (d, J = 7.8 Hz, 1H), 7.87 (s, 1H), 5.68-5.58 (m, 1H), 4.26-3.99 (m, 6H), 3.37 (s, 3H), 2.55 -2.36 (m, 2H), 1.49 (d, J = 7.0 Hz, 3H).
145 methyl 6-chloro-5- 1-(5-bromo-2- trans-methyl 4- 53 1H NMR (500 MHz,
(trifluoromethyl)nic methoxyphenyl)- aminomethyl- 5.3 MeOD) δ 8.65 (s, 1H), otinate 2- cyclohexanecar 8.26 (s, 1H), 7.65 (d, J methoxyethanam boxylate = 7.9 Hz, 1H), 7.50 (s, ine 1H), 7.20 (t, J = 13.5
Hz, 1H), 5.85 (s, 1H), 4.02 (s, 3H), 3.75 (b,
2H), 3.37 (s, 3H), 3.20 (d, J = 6.4 Hz, 2H),
2.21 (s, 1H), 2.01 (d, J = 12.1 Hz, 2H), 1.87 (d, J = 11.6 Hz, 2H), 1.60 (b, 1H), 1.38 (m, 2H), 1.10-0.97 (m, 2H). 146 methyl 5-bromo-6- 1-(5-bromo-2- trans-methyl 4- 53 1H NMR (500 MHz, chloronicotinate methoxyphenyl)- aminomethyl- 5.3 MeOD) δ 8.65 (s, 1H),
2- cyclohexanecar 8.26 (s, 1H), 7.65 (d, J methoxyethanam boxylate = 7.9 Hz, 1H), 7.50 (s, ine 1H), 7.20 (t, J = 13.5
Hz, 1H), 5.85 (s, 1H),
4.02 (s, 3H), 3.75 (b,
2H), 3.37 (s, 3H), 3.20
(d, J = 6.4 Hz, 2H),
2.21 (s, 1H), 2.01 (d, J
= 12.1 Hz, 2H), 1.87
(d, J = 11.6 Hz, 2H),
1.60 (b, 1H), 1.38 (m,
2H), 1.10-0.97 (m,
2H).
Example 5: Preparation of Compounds 147 and 148
Figure imgf000155_0001
Intermediate 238: 4-((1-(5-bromo-2-methoxyphenyl)-2-methoxyethyl)amino)-3- chlorobenzonitrile
Figure imgf000155_0002
In a microwave tube, a solution of 1 -(5-bromo-2-methoxyphenyl)-2-methoxyethanamine (1.2 g, 4.61 mmol), 3-chloro-4-fluorobenzonitrile (0.861 g, 5.54 mmol), and DIPEA (1 .61 1 mL, 9.23 mmol) in DMSO (12 mL) was heated at 140 °C by microwave for 5 h. Following completion of the reaction, the mixture was allowed to cool to rt then diluted with water (40 mL) and extracted with EA (3 x 50 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated. The crude material was purified by flash chromatography on silica gel (PE/EtOAc = 10/1 to 2/1 ) to provide the desired product 4-((1 -(5-bromo-2- methoxyphenyl)-2-methoxyethyl)amino)-3-chlorobenzonitrile (910 mg, 2.300 mmol, 49.9 % yield) as a white solid, m/z: [M + H]+ Calcd for Ci7Hi7BrCIN202 395.0; Found 395.0. Intermediate 239: 4-((1-(5-bromo-2-methoxyphenyl)-2-methoxyethyl)amino)-3- chlorobenzoic acid
Figure imgf000156_0001
A solution of 4-((1 -(5-bromo-2-methoxyphenyl)-2-methoxyethyl)amino)-3-chlorobenzonitrile (1 .53 g, 3.87 mmol) in aqueous NaOH (7M, 10 mL, 70.0 mmol) and EtOH (15 mL) was stirred at 80 °C for 20 h. Following completion of the reaction, the reaction mixture was cooled to rt and quenched with 2M aqueous HCI (31 mL) and the aqueous mixture then extracted wtih EA (3 x 50 mL). The combined organic layers were dried over anhydrous magnesium sulfate, filtered, and evaporated in vacuo to give the title compound 4-((1 -(5-bromo-2- methoxyphenyl)-2-methoxyethyl)amino)-3-chlorobenzoic acid (1 .4g, 3.34 mmol, 86 % yield) that was used without further purification, m/z: [M + H]+ Calcd for Ci7Hi8BrCIN04 414.0; Found 414.0
Intermediate 240: trans-methyl 4-((4-((1 -(5-bromo-2-methoxyphenyl)-2- methoxyethyl)amino)-3-chlorobenzamido)methyl)cyclohexanecarboxylate
Figure imgf000156_0002
A solution of 4-((1 -(5-bromo-2-methoxyphenyl)-2-methoxyethyl)amino)-3-chlorobenzoic acid (1 .4 g, 3.38 mmol), HATU (1 .926 g, 5.06 mmol), DIPEA (1 .179 mL, 6.75 mmol), and trans- methyl 4-(aminomethyl)cyclohexanecarboxylate (0.867 g, 5.06 mmol) in DMF (10 mL) was stirred at 25 °C for 18 h. Following completion of the reaction, the mixture was diluted with water (30 mL) and extracted with EA (3 x 40 mL). The combined organic layers were then dried over sodium sulfate, filtered ,and evaporated to give a crude product. The crude material was purified by flash chromatography on silica gel (PE/EtOAc = 10/1 to 1/6) to provide the desired product trans-methyl 4-((4-((1 -(5-bromo-2-methoxyphenyl)-2-methoxyethyl)amino)- 3-chlorobenzamido)methyl)cyclohexanecarboxylate (1 .7g, 2.93 mmol, 87 % yield) as a white solid, m/z: [M + H]+ Calcd for C26H33BrCIN205 567.1 ; Found 567.2.
Intermediate 241 : trans-methyl 4-((3-cyano-4-((1 -(5-cyano-2-methoxyphenyl)-2- methoxyethyl)amino)benzamido)methyl)cyclohexanecarboxylate
Figure imgf000157_0001
In a microwave tube was combined zinc (0.196 g, 2.99 mmol), PdCl2(dppf)-CH2Cl2 adduct (2.445 g, 2.99 mmol), Trans-methyl 4-((4-((1 -(5-bromo-2-methoxyphenyl)-2- methoxyethyl)amino)-3-chlorobenzamido)methyl)cyclohexanecarboxylate (1 .70 g, 2.99 mmol) and dicyanozinc (0.351 g, 2.99 mmol) in DMF (12 mL) at 25 °C. The reaction mixture was then stirred at 140 °C by microwave for 3 h. The mixture was then filtered and the filtrate concentrated to dryness. The crude material obtained was purified by reverse phase HPLC [MeOH/Water (0.05% NH4HC03) = 70%] to give the title compound trans-methyl 4-((3-cyano- 4-((1 -(5-cyano-2-methoxyphenyl)-2- methoxyethyl)amino)benzamido)methyl)cyclohexanecarboxylate (1 .2g, 1 .961 mmol, 65.5% yield), m/z: [M + H]+ Calcd for C28H33N405 505.2; Found 505.3.
Compounds 147 and 148: trans-4-((3-cyano-4-((1 -(5-cyano-2-methoxyphenyl)-2- methoxyethyl)amino)benzamido)methyl)cyclohexanecarboxylic acid
Figure imgf000157_0002
To a solution of trans-methyl 4-((3-cyano-4-((1 -(5-cyano-2-methoxyphenyl)-2- methoxyethyl)amino)benzamido)methyl)cyclohexanecarboxylate (180 mg, 0.357 mmol) in THF (3 mL) and MeOH (3 mL) was added aqueous LiOH (1 M, 6 mL, 6.0 mmol) at rt. The reaction mixture was stirred at rt for 22 h. Following completion of the reaction, aqueous HCI (1 M, 6.5 mL) was added to the reaction mixture and the resulting mixture extracted with EA (3 x 30 mL). The combined organic layers were then dried over sodium sulfate, filtered and evaporated. The crude residue was purified by reverse phase HPLC [MeOH/Water (0.05%NH4HCO3) = 40%] to give the title compound trans-4-((3-cyano-4-((1 -(5-cyano-2- methoxyphenyl)-2-methoxyethyl)amino)benzamido)methyl)cyclohexanecarboxylic acid (54 mg, 0.106 mmol, 29.6 % yield) as a white solid, m/z: [M + H]+ Calcd for C27H3i N405 491 .2; Found 491 .3. 1 H NMR (500 MHz, MeOD) δ 8.52 (d, J = 1 .8 Hz, 1 H), 8.13 (d, J = 1 .7 Hz, 1 H), 7.67 "C 7.47 (m, 1 H), 7.41 (d, J = 1 .9 Hz, 1 H), 7.07 (d, J = 8.6 Hz, 1 H), 5.72 (t, J = 5.3 Hz, 1 H), 3.89 (d, J = 8.0 Hz, 3H), 3.69 - 3.53 (m, 2H), 3.26 (s, 3H), 3.09 (t, J = 12.8 Hz, 2H), 2.16 - 1 .98 (m, 1 H), 1 .86 (t, J = 10.8 Hz, 2H), 1 .74 (d, J = 10.9 Hz, 2H), 1 .55 - 1 .38 (m, 1 H), 1 .40 - 1 .25 (m, 2H), 0.91 (tt, J = 12.6, 6.3 Hz, 2H).
Chiral Separation
The Trans-4-((3-cyano-4-((1 -(5-cyano-2-methoxyphenyl)-2- methoxyethyl)amino)benzamido)methyl)cyclohexanecarboxylic acid (50 mg, 0.102 mmol) was prepared by chiral-preparative separation:
Instrument: Gilson-281
Column: WHELK 20*250mm, 10um Mobile phase: HEX/Ethanol (0.1 %DEA)=75/25
Flow rate: 50 mL/min
Detection wavelength: 214nm
Cycle time: 1 1 min
Sample solution: 150 mg dissolved in 6ml Methanol Injection volume: 0.5ml
Compound 147: trans-4-((3-cyano-4-((1 -(5-cyano-2-methoxyphenyl)-2- methoxyethyl)amino)benzamido)methyl)cyclohexanecarboxylic acid (Enantiomer 1 ) m/z: [M + H]+ Calcd for C27H3iN405 491 .2; Found 491 .2
1 H NMR (500 MHz, MeOD) δ 7.99 (d, J = 2.0 Hz, 1 H), 7.87-7.53 (m, 3H), 7.24 (d, J = 8.7 Hz, 1 H), 6.52 (d, J = 9.0 Hz, 1 H), 5.19 (s, 1 H), 4.06 (s, 3H), 3.74 (dt, J = 16.7, 7.8 Hz, 2H), 3.48-3.36 (m, 3H), 3.18 (d, J = 7.1 Hz, 2H), 2.20 - 1 .73 (m, 5H), 1 .65 - 1 .36 (m, 3H), 1 .02 (d, J = 15.0 Hz, 2H).
Compound 148: trans-4-((3-cyano-4-((1 -(5-cyano-2-methoxyphenyl)-2- methoxyethyl)amino)benzamido)methyl)cyclohexanecarboxylic acid (Enantiomer 2) m/z: [M + H]+ Calcd for C27H3iN405 491 .2; Found 491 .2
1 H NMR (500 MHz, MeOD) δ 7.99 (d, J = 2.0 Hz, 1 H), 7.87-7.53 (m, 3H), 7.24 (d, J = 8.7 Hz, 1 H), 6.52 (d, J = 9.0 Hz, 1 H), 5.19 (s, 1 H), 4.06 (s, 3H), 3.74 (dt, J = 16.7, 7.8 Hz, 2H), 3.48-3.36 (m, 3H), 3.18 (d, J = 7.1 Hz, 2H), 2.20 - 1 .73 (m, 5H), 1 .65 - 1 .36 (m, 3H), 1 .02 (d, J = 15.0 Hz, 2H).
The following compounds were synthesized using a similar procedure to that described in Example 5 for Compounds 147 and 148.
Figure imgf000159_0001
151 methyl 5,6- 3-(1-amino-2- trans-methyl 4- 48 1H NMR (500 MHz, dichloronicotin hydroxyethyl)-4- aminomethyl- 7.2 MeOD) δ 8.40 (d, J = ate methoxybenzonitri cyclohexanecarbo 2.0 Hz, 1H), 8.04 (d, J le xylate = 2.0 Hz, 1H), 7.68- 7.54 (m, 2H), 7.16 (d, J = 8.5 Hz, 1H), 5.60
(q, J = 7.0 Hz, 1H),
4.01 (s, 3H), 3.84- 3.75 (m, 2H), 3.75- 3.65 (m, 2H), 3.56 (s, 2H), 2.48 (s, 2H), 1.69 - 1.59 (m, 4H), 1.57
(d, J = 7.0 Hz, 3H).
152 methyl 5,6- 3-(1-amino-2- trans-methyl 4- 48 1H NMR (500 MHz, dichloronicotin hydroxyethyl)-4- aminomethyl- 7.2 MeOD) δ 8.40 (d, J = ate methoxybenzonitri cyclohexanecarbo 2.0 Hz, 1H), 8.04 (d, J le xylate = 2.0 Hz, 1H), 7.68-
7.54 (m, 2H), 7.16 (d,
J = 8.5 Hz, 1H), 5.60
(q, J = 7.0 Hz, 1H),
4.01 (s, 3H), 3.84-
3.75 (m, 2H), 3.75-
3.65 (m, 2H), 3.56 (s,
2H), 2.48 (s, 2H), 1.69
- 1.59 (m, 4H), 1.57
(d, J = 7.0 Hz, 3H). 153 methyl 5,6- 1-(4-bromo-2- trans-methyl 4- 50
dichloronicotin methoxyphenyl)-2- aminomethyl- 1.2
ate methoxyethanami cyclohexanecarbo
ne xylate
154 methyl 5,6- 1-(4-bromo-2- trans-methyl 4- 50
dichloronicotin methoxyphenyl)-2- aminomethyl- 1.2
ate methoxyethanami cyclohexanecarbo
ne xylate
155 3-chloro-4- 1-(5-bromo-2- trans-methyl 4- 47 1H NMR (400 MHz, fluorobenzonitri methoxyphenyl)et aminomethyl- 0 DMSO)58.15(t, J = le hanamine cyclohexanecarbo 5.6 Hz, 1H), 7.80 (d, J xylate = 2.0 Hz, 1H), 7.77-
7.67 (m, 2H), 7.53 (dd,
J = 8.6, 1.8 Hz, 1H),
7.33-7.14 (m, 1H),
6.37 (d, J = 8.8 Hz,
1H), 6.07 (d, J = 8.1
Hz, 1H), 4.93 (dd, J =
14.2, 7.0 Hz, 1H), 4.04
-3.93 (m, 3H), 3.03 (t,
J = 6.2 Hz, 2H), 2.10
(t, J = 12.1 Hz, 1H),
1.87 (d, J = 10.9 Hz,
2H), 1.72 (d, J = 10.6
Hz, 2H), 1.48 (t, J =
10.1 Hz, 3H), 1.43 (s,
1H), 1.30-1.15 (m,
3H), 0.90 (dd, J =
24.0, 10.9 Hz, 2H). 156 3-chloro-4- 1-(5-bromo-2- trans-methyl 4- 47 1H NMR (400 MHz, fluorobenzonitri methoxyphenyl)et aminomethyl- 0 DMSO)58.15(t, J = le hanamine cyclohexanecarbo 5.6 Hz, 1H), 7.80 (d, J xylate = 2.0 Hz, 1H), 7.77-
7.67 (m, 2H), 7.53 (dd, J = 8.6, 1.8 Hz, 1H), 7.33-7.14 (m, 1H), 6.37 (d, J = 8.8 Hz, 1H), 6.07 (d, J = 8.1
Hz, 1H), 4.93 (dd, J =
14.2, 7.0 Hz, 1H), 4.04
-3.93 (m, 3H), 3.03 (t, J = 6.2 Hz, 2H), 2.10 (t, J = 12.1 Hz, 1H), 1.87 (d, J = 10.9 Hz,
2H), 1.72 (d, J = 10.6 Hz, 2H), 1.48 (t, J =
10.1 Hz, 3H), 1.43 (s, 1H), 1.30-1.15 (m, 3H), 0.90 (dd, J = 24.0, 10.9 Hz, 2H).
157 methyl 5- (S)-1-(5-chloro-2- trans-methyl 4- 47 1H NMR (500 MHz, bromo-6- methoxyphenyl)et aminomethyl- 1.2 DMSO) |A 8.63 (d, J = chloronicotinat hanamine cyclohexanecarbo 2.3 Hz, 1H), 8.33 (d, J e xylate = 2.3 Hz, 1H), 8.27 (t,
J = 5.7 Hz, 1H), 7.85 (d, J = 8.0 Hz, 1H), 7.37 (d, J = 2.6 Hz, 1H), 7.24 (dd, J = 8.7, 2.7 Hz, 1H), 7.01 (d, J = 8.8 Hz, 1H), 5.65 "C
5.56 (m, 1H), 3.85 (s,
3H), 3.05 (t, J = 6.3 Hz, 2H), 2.10 (s, 1H),
1.87 (d, J = 10.6 Hz, 2H), 1.74 (d, J = 10.5
Hz, 2H), 1.44 (d, J = 6.9 Hz, 4H), 1.23 (dd, J = 12.6, 2.8 Hz, 2H),
0.92 (d, J = 12.5 Hz, 2H).
3-chloro-4- 1-(5-bromo-2- trans-methyl 4- 50 1H NMR (500 MHz, fluorobenzonitri methoxyphenyl)-2- aminomethyl- 0.2 MeOD) δ= 7.82 (s, le methoxyethanami cyclohexanecarbo 1H), 7.67 (d, J = 8.8 ne xylate Hz, 1H), 7.56 (s, 1H),
7.51 (d, J = 8.7 Hz, 1H), 7.23 (d, J = 8.6 Hz, 1H), 6.37 (d, J =
8.6 Hz, 1H), 5.19- 5.09 (m, 1H), 4.06 (s, 3H), 3.83-3.64 (m, 2H), 3.44 (s, 3H), 3.18
(d, J = 6.6 Hz, 2H), 2.25 (d, J = 12.8 Hz, 1H), 2.02 (d, J = 10.6 Hz, 2H), 1.87 (d, J = 10.8 Hz, 2H), 1.59 (m, 1H), 1.41 (dd, J =
24.1, 11.4 Hz, 2H),
1.04 (dd, J = 24.6, 12.7 Hz, 2H). 159 3-chloro-4- 1-(5-bromo-2- trans-methyl 4- 50 1H NMR(500 MHz, fluorobenzonitri methoxyphenyl)-2- aminomethyl- 0.2 MeOD) δ= 7.82 (s, le methoxyethanami cyclohexanecarbo 1H), 7.67 (d, J = 8.8 ne xylate Hz, 1H), 7.56 (s, 1H),
7.51 (d, J = 8.7 Hz,
1H), 7.23 (d, J = 8.6
Hz, 1H), 6.37 (d, J =
8.6 Hz, 1H), 5.19-
5.09 (m, 1H), 4.06 (s,
3H), 3.83-3.64 (m,
2H), 3.44 (s, 3H), 3.18
(d, J = 6.6 Hz, 2H),
2.25 (d, J = 12.8 Hz,
1H), 2.02 (d, J = 10.6
Hz, 2H), 1.87 (d, J =
10.8 Hz, 2H), 1.59 (m,
1H), 1.41 (dd, J =
24.1, 11.4 Hz, 2H),
1.04 (dd, J = 24.6,
12.7 Hz, 2H).
160 methyl 5- (R)-1-(5-chloro-2- trans-methyl 4- 50 1H NMR (500 MHz, bromo-6- methoxyphenyl)-2- aminomethyl- 1.2 MeOD) δ 8.67 (d, J = chloronicotinat methoxyethanami cyclohexanecarbo 1.5Hz, 1H), 8.26 (d, J e ne xylate = 1.5Hz, 1H), 1.24-
1.26 (m, 2H), 7.01 (d,
J = 8.5Hz, 1H), 5.805
(t, J = 6.5Hz, 1H), 3.94
(s, 3H), 3.69-3.76 (m,
2H), 3.40 (s, 3H), 3.20 (d, J = 6.5, 2H), 2.20- 2.26 (m, 1H), 2.21 (d, J=12Hz, 2H), 1.87 (d, J = 12Hz, 2H), 1.52- 1.60 (m, 1H), 1.41 (dd, J = 12.5, 25.5Hz, 2H), 1.04 (dd, J = 12.5, 23.5Hz, 2H) ppm
4-fluoro-3- 1-(5-bromo-2- trans-methyl 4- 53 1H NMR (500 MHz, (trifluoromethyl methoxyphenyl)-2- aminomethyl- 4.2 DMSO),12.001 (s, )benzonitrile methoxyethanami cyclohexanecarbo 1H), 8.279-8.290 (t, ne xylate 1H), 7.990 (s, 1H),
7.818-7.835 (d, 1 H, J = 8.5 Hz), 7.271-7.324 (dd, 1H), 7.266-7.270 (d, 1H), 7.096-7.113 (d, 1H, J = 8.5 Hz), 6.530-6.548 (d, 1 H, J = 8.5 Hz), 5.859-5.872
(d, 1H, J = 6.5 Hz), 5.068-5.078 (m, 1H), 3.913 (s, 3H), 3.703- 3.737 (m, 2H), 3.598- 3.627 (m, 2H), 3.301 (s, 1H), 3.039-3.065 (t, 1H, J = 6.5 Hz), 2.059 (m, 1H), 1.852-1.875 (m, 2H), 1.713-1.736 (m, 2H), 1.440 (m, 1H), 1.166-1.255 (m, 2H), 0.870-0.943 (m,
2H).
162 4-fluoro-3- 1-(5-bromo-2- trans-methyl 4- 53 1H NMR (500 MHz, (trifluoromethyl methoxyphenyl)-2- aminomethyl- 4.2 DMSO),12.001 (s, )benzonitrile methoxyethanami cyclohexanecarbo 1H), 8.279-8.290 (t, ne xylate 1H), 7.990 (s, 1H),
7.818-7.835 (d, 1 H, J = 8.5 Hz), 7.271-7.324 (dd, 1H), 7.266-7.270 (d, 1H), 7.096-7.113 (d, 1H, J = 8.5 Hz), 6.530-6.548 (d, 1 H, J = 8.5 Hz), 5.859-5.872
(d, 1H, J = 6.5 Hz), 5.068-5.078 (m, 1H), 3.913 (s, 3H), 3.703- 3.737 (m, 2H), 3.598- 3.627 (m, 2H), 3.301 (s, 1H), 3.039-3.065 (t, 1H, J = 6.5 Hz), 2.059 (m, 1H), 1.852-1.875 (m, 2H), 1.713-1.736 (m, 2H), 1.440 (m, 1H), 1.166-1.255 (m, 2H), 0.870-0.943 (m, 2H).
Example 6: Preparation of Compound 163
Figure imgf000167_0001
Intermediate 240: trans-methyl 4-((6-(((S)-1 -(5-fluoro-2-methoxyphenyl)ethyl)amino)-5- methylnicotinamido)methyl)cyclohexanecar oxylate
Figure imgf000167_0002
To a solution of trans-methyl 4-((6-chloro-5- methylnicotinamido)methyl)cyclohexanecarboxylate (96 mg, 0.296 mmol), (S)-1 -(5-fluoro-2- methoxyphenyl)ethanamine (50 mg, 0.296 mmol) and CS2CO3 (96 mg, 0.296 mmol) in N,N- Dimethylformamide (2 ml.) was added (9,9-dimethyl-9H-xanthene-4,5- diyl)bis(diphenylphosphine) (171 mg, 0.296 mmol) and Pd2(dba) (271 mg, 0.296 mmol). The resulting mixture was then stirred at 100 °C for 12 h under nitrogen atmosphere. Following completion of the reaction, the mixture was allowed to cool to rt and then diluted with water (20 ml_). The resulting mixture was then extracted with EA (2 x 10 ml_). The combined organics were then concentrated to dryness and the crude material obtained was purified by flash chromatography on silica gel (PE/EtOAc = 1/1 ) to provide the desired product trans- methyl 4-((6-(((S)-1 -(5-fluoro-2-methoxyphenyl)ethyl)amino)-5- methylnicotinamido)methyl)cyclohexanecarboxylate (260 mg, 0.540 mmol, 30.4 % yield) as a white solid, m/z: [M + H]+ Calcd for C25H33FN3C 458.3; Found 458
Compound 163: trans-4-((6-(((S)-1 -(5-fluoro-2-methoxyphenyl)ethyl)amino)-5- methylnicotinamido)methyl)cyclohexanecar oxylic acid
Figure imgf000167_0003
A solution of trans-methyl 4-((6-(((S)-1 -(5-fluoro-2-methoxyphenyl)ethyl)amino)-5- methylnicotinamido)methyl)cyclohexanecarboxylate (220 mg, 0.457 mmol) and lithium hydroxide hydrate (57.5 mg, 1 .370 mmol) in Tetrahydrofuran (2 mL) and Water (2 mL) was stirred at 45 °C for 12h. Following completion of the reaction, the mixture was allowed to cool to rt and aqueous HCI (1 M) was added until a pH of 6 was obtained. The resulting mixture was then extracted with EA (2 x 3 mL). The combined organics were then concentrated to dryness and the crude material purified by preparative HPLC to provide the product trans-4- ((6-(((S)-1 -(5-fluoro-2-methoxyphenyl)ethyl)amino)-5- methylnicotinamido)methyl)cyclohexanecarboxylic acid (120 mg, 0.271 mmol, 59.2 % yield) as a white solid, m/z: [M + H]+ Calcd for C24H3i FN304 444.2; Found 444.
1 H NMR (400 MHz, DMSO) δ 8.27 (s, 1 H), 8.12 (s, 1 H), 7.74 (s, 1 H), 7.08 (d, J = 9.6 Hz, 1 H), 6.98 (d, J = 6.2 Hz, 2H), 5.59 - 5.52 (m, 1 H), 3.85 (s, 3H), 3.05 (s, 2H), 2.23 (s, 3H), 2.10 (d, J = 12.0 Hz, 1 H), 1 .88 (d, J = 1 1 .2 Hz, 2H), 1 .73 (d, J = 1 1 .9 Hz, 2H), 1 .44 (d, J = 6.7 Hz, 4H), 1 .24 (dd, J = 23.6, 10.7 Hz, 2H), 0.97 - 0.85 (m, 2H). The following compounds were synthesized using a similar procedure to that described in Example 6 for Compound 163.
Figure imgf000168_0001
165 trans-methyl 4-((6- (S)-1-(2-methoxy-5- 44 1H NMR (400 MHz, DMSO) δ chloro-5- methylphenyl)ethanamin 0 8.25 (s, 3H), 7.93 (d, J = 31.2 Hz, methylnicotinamido) e 1H), 7.11 (s, 1H), 7.03 (d, J = 7.6 methyl)cyclohexanec Hz, 1H), 6.89 (d, J = 8.2 Hz, 1H), arboxylate 5.48 (s, 1H), 3.79 (s, 3H), 3.07 (t,
J = 6.4 Hz, 2H), 2.20 (t, J = 11.2 Hz, 6H), 2.12 (t, J = 12.2 Hz, 1H), 1.89 (d, J = 10.7 Hz, 2H), 1.74 (d, J = 11.7 Hz, 2H), 1.50 (t, J = 9.0 Hz, 4H), 1.31 - 1.19 (m, 2H), 0.99
-0.86 (m, 2H).
166 trans-methyl 4-((6- (R)-3-(1 -aminopropyl)-4- 46 1H NMR (400 MHz, DMSO) δ chloro-5- methoxybenzonitrile 5 8.25 (d, J = 1.7 Hz, 1H), 8.12 (s, methylnicotinamido) 1H), 7.81 -7.64 (m, 3H), 7.17 (d, methyl)cyclohexanec J = 8.5 Hz, 1H), 6.67 (s, 1H), 5.48 arboxylate - 5.36 (m, 1 H), 3.94 (s, 3H), 3.04
(d, J = 5.1 Hz, 2H), 2.24 (s, 3H), 2.15-2.06 (m, 1H), 1.88 (d, J =
11.1 Hz, 2H), 1.84- 1.69 (m, 4H), 1.44 (s, 1H), 1.24 (dt, J = 22.5,
11.3 Hz, 2H), 0.98 - 0.85 (m, 5H).
167 trans-methyl 4-((6- (S)-3-(1 -aminopropyl)-4- 46 H NMR (400 MHz, DMSO) δ 8.25 chloro-5- methoxybenzonitrile 5 (s, 1H), 8.16 (s, 1H), 7.83-7.66 methylnicotinamido) (m, 3H), 7.18 (d, J = 8.4 Hz, 1H), methyl)cyclohexanec 6.75 (s, 1H), 5.41 (s, 1H), 3.94 (s, arboxylate 3H), 3.05 (s, 2H), 2.25 (s, 3H),
2.16-2.07 (m, 1H), 1.93-1.69 (m, 6H), 1.44 (s, 1H), 1.24 (dd, J = 22.7, 12.3 Hz, 2H), 0.99 - 0.84 (m, 5H). Example 7: Preparation of Compound 168
Figure imgf000170_0001
Intermediate 241 : (S)-4-((1 -(2,5-dichlorophenyl)ethyl)amino)-3-methylbenzoic acid
Figure imgf000170_0002
A mixture of methyl 4-bromo-3-methylbenzoate (200 mg, 0.873 mmol), (S)-1 -(2,5- dichlorophenyl)ethanamine hydrochloride (198 mg, 0.873 mmol), Pd2(dba)3 (80 mg, 0.087 mmol), Xantphos (101 mg, 0.175 mmol) and CS2CO3 (853 mg, 2.62 mmol) in 1 ,4-Dioxane (2 mL) was stirred at 100 °C under N2 in the microwave for 1 hour. Following completion of the reaction the residue was concentrated directly and purified by flash chromatography on silica gel (PE/EtOAc = 4/1 ) to provide the desired product (S)-methyl 4-((1 -(2,5- dichlorophenyl)ethyl)amino)-3-methylbenzoate (200 mg, 0.473 mmol, 54.2% yield) as a yellow solid, m/z: [M + H]+ Calcd for Ci7Hi8CI2N02 338.1 ; Found 338
Intermediate 242
Figure imgf000170_0003
To a mixture of (S)-methyl 4-((1 -(2,5-dichlorophenyl)ethyl)amino)-3-methylbenzoate (80 mg, 0.237 mmol) in THF (2 mL) and Water (2 mL) was added LiOH (50 mg, 2.088 mmol) and the resulting solution was stirred at rt 16 h. Following completion of the reaction, aqueous HCI (2N) was added until a pH <7 was achieved. The resulting solution was then extracted with ethyl acetate (3 x 50 mL). The combined organics were then washed with water and then brine. The washed organic layer was then dried over MgS04, filtered and concentrated to dryness to provide the desired product (S)-4-((1 -(2,5-dichlorophenyl)ethyl)amino)-3- methylbenzoic acid (80 mg, 0.197 mmol, 83 % yield) as a white solid without the need for further purification, m/z: [M + H]+ Calcd for C16H16CI2NO2 324.1 ; Found 324.
Intermediate 243: trans-methyl 4-((4-(((S)-1 -(2,5-dichlorophenyl)ethyl)amino)-3- methylbenzamido)methyl)cyclohexanecarboxylate
Figure imgf000171_0001
To a mixture of trans-methyl 4-(aminomethyl)cyclohexanecarboxylate (42.3 mg, 0.247 mmol) in DMF (2 mL), was added (S)-4-((1 -(2,5-dichlorophenyl)ethyl)amino)-3-methylbenzoic acid (80 mg, 0.247 mmol), HATU (141 mg, 0.370 mmol), and DIPEA (0.086 mL, 0.494 mmol). The reaction solution was stirred at rt 16 h. Water (100 mL) was then added and the resulting aqueous mixture was extracted with ethyl acetate (3 x 50 mL). The combined organics were then washed with saturated aqueous NaHCC , water, and brine. The washed organic layer was then dried over MgS04, filtered and concentrated to dryness to provide the desired product trans-methyl 4-((4-(((S)-1 -(2,5-dichlorophenyl)ethyl)amino)-3- methylbenzamido)methyl)cyclohexanecarboxylate (80 mg, 0.134 mmol, 54.3 % yield) as a yellow oil that was used without further purification, m/z: [M + H]+ Calcd for C25H31CI2N2O3 477.2; Found 477. Compound 168:.trans-4-((4-(((S)-1 -(2,5-dichlorophenyl)ethyl)amino)-3- methylbenzamido)methyl)cyclohexanecarboxylic acid
Figure imgf000171_0002
To a mixture of trans-methyl 4-((4-(((S)-1 -(2,5-dichlorophenyl)ethyl)amino)-3- methylbenzamido)methyl)cyclohexanecarboxylate (80 mg, 0.168 mmol) in THF (2 mL) and Water (2 mL) was added LiOH (40.1 mg, 1 .676 mmol) and the resulting solution was stirred at rt 16 h. Following completion of the reaction, aqueous HCI (2N) was added until a pH <7 was achieved. The resulting solution was then extracted with ethyl acetate (3 x 50 mL). The combined organics were then washed with water and then brine. The washed organic layer was then dried over MgS04, filtered and concentrated to dryness to provide the the crude product that was purified by prep HPLC to provide the desired product trans-4-((4-(((S)-1 - (2,5-dichlorophenyl)ethyl)amino)-3-methylbenzamido)methyl)cyclohexanecarboxylic acid (51 .1 mg, 0.104 mmol, 61 .9 % yield) as a white solid, m/z: [M + H]+ Calcd for C24H29Cl2N203 463.2; Found 463.
1 H NMR (400 MHz, CDCI3) δ 7.55 (s, 1 H), 7.33 (dd, J = 14.5, 8.2 Hz, 3H), 7.15 (d, J = 6.1 Hz, 1 H), 6.13 (d, J = 8.7 Hz, 1 H), 5.99 (s, 1 H), 4.91 (d, J = 5.8 Hz, 1 H), 4.19 (s, 1 H), 3.26 (s, 2H), 2.28 (s, 4H), 2.03 (d, J = 14.6 Hz, 2H), 1 .86 (d, J = 1 1 .5 Hz, 2H), 1 .56 (d, J = 6.5 Hz, 3H), 1 .41 (d, J = 12.8 Hz, 3H), 1 .01 (d, J = 1 1 .9 Hz, 2H).
The following compounds were synthesized using a similar procedure to that described in Example 7 for Compound 168.
Figure imgf000172_0001
170 methyl 4- (1S)-1-(5- trans-Methyl 4- 44 1 H NMR (400 MHz, MeOD) δ bromo-3- fluoro-2- aminomethyl- 3.3 7.92-7.93 (m, 1H), 7.41 (s, methylbenzoat methoxyphen cyclohexanecar 1H), 7.28 (d, J = 8Hz, 1H), e yl)ethan-1- boxylate 6.77-6.86 (m, 3H), 6.14 (d, J = amine 8Hz, 1H), 4.78-7.85 (m, 1H),
3.81 (s, 3H), 3.04-3.21 (m,
2H), 2.10 (t, J = 8Hz, 1H), 2.18
(s, 3H), 1.89 (d, J = 8Hz, 2H),
1.74 (d, J = 8Hz, 2H), 1.20-
1.50 (m, 6H), 0.87-0.94 (m,
2H) ppm
171 methyl 4- (1S)-1-(5- methyl 2-[3- 44 HNMR : 1H NMR (500 MHz, bromo-3- chloro-2- (aminomethyl)c 5.2 MeOD) 5=7.51 (s, 1H), 7.35 (d, methylbenzoat methoxyphen yclobutyl]acetat J = 10 Hz, 1H), 7.17-7.14 (m, e yl)ethan-1- e 2H), 6.82 (d, J = 10.5 Hz, 1H), amine 6.26 (d, J = 10.5Hz, 1H), 6.05-
6.01 (m, 1H), 4.87 (q, J = 8 Hz,
1H), 3.82 (s, 3H), 3.47-3.41
(m, 1H), 3.36-3.33 (m, 1H),
2.72-2.45 (m, 4H), 2.39-2.37
(m, 4H), 1.94-1.80 (m, 2H),
1.52-1.44 (m, 4H).
172 methyl 4- (1S)-1-(5- methyl 2-[cis-4- 47 HNMR : 1H NMR (500 MHz, bromo-3- chloro-2- (aminomethyl)c 3.2 MeOD) 5=7.53 (d, J = 2 Hz, methylbenzoat methoxyphen yclohexyl]aceta mi 1H), 7.38 (dd, J = 2, 10.5 Hz, e yl)ethan-1- te n 1H), 7.19-7.15 (m, 2H), 6.83 amine (d, J = 10.5 Hz, 1H), 6.28 (d, J
= 11 Hz, 1H), 6.00 (m, 1H),
4.88 (q, J = 8.5 Hz, 1H), 3.91
(s, 3H), 3.36 (t, J = 8.5 Hz,
2H), 2.33 (d, J = 9.5 Hz, 2H), 2.26 (s, 3H), 2.07-2.05 (m,
1H), 1.75-1.74 (m, 1H), 1.60- 1.52 (m, 5H), 1.47-1.38 (m, 4H).
173 methyl 4- (1S)-1-(5- methyl 2-[trans- 47 HNMR : 1H NMR (500 MHz, bromo-3- chloro-2- 4- 3.2 MeOD) 5=7.52 (d, J = 2 Hz, methylbenzoat methoxyphen (aminomethyl)c 1H), 7.36 (dd, J = 2, 10.5 Hz, e yl)ethan-1- yclohexyl]aceta 1H), 7.18-7.14 (m, 2H), 6.82 amine te (d, J = 10.5 Hz, 1H), 6.26 (d, J
= 11 Hz, 1H), 6.04 (t, J = 7.5 Hz, 1H), 4.87 (q, J = 8 Hz, 1H), 3.90 (s, 3H), 3.25 (m, 2H), 2.25 (s, 3H), 2.22 (d, J = 8.5 Hz, 2H), 1.82-1.78 (m, 4H), 1.51 (d, J = 8.5 Hz, 3H), 1.04- 0.97 (m, 4H).
174 methyl 4- 1-[5-methoxy- trans-Methyl 4- 49 1 H NMR (500 MHz, CDCI3) δ bromo-3- 2- aminomethyl- 4. 8.36 (s, 1H), 7.54 (s, 2H), 7.35 methylbenzoat (trifluoromethy cyclohexanecar (d, J = 7.4 Hz, 1H), 6.12 (d, J - e l)pyridin-4- boxylate 8.5 Hz, 1H), 5.98 (s, 1H), 4.92 yl]ethan-1- (d, J = 5.9 Hz, 1H), 4.17 (s, amine 1H), 4.10 (s, 3H), 3.27 (s, 2H),
2.28 (s, 3H), 2.02 (s, 3H), 1.87 (d, J = 9.0 Hz, 3H), 1.55 (d, J = 6.7 Hz, 3H), 1.42 (d, J = 11.3 Hz, 2H), 1.02 (d, J = 10.9 Hz, 2H).
175 methyl 4- (1S)-1-(5- trans-Methyl 4- 45 HNMR : 1H NMR (500 MHz, bromo-3- chloro-2- aminomethyl- 9.1 MeOD) 5=7.53 (d, J = 2Hz, methylbenzoat methoxyphen cyclohexanecar 1H), 7.38 (dd, J = 2 , 10.5 Hz, e boxylate 1H), 7.21 (d, J = 3Hz, 1H), yl)ethan-1- 7.16 (dd, J = 3, 10.5 Hz, 1H), amine 6.97 (d, J = 11 Hz, 1H), 6.23
(d, J = 11 Hz, 1H), 4.95 (m, 1H), 3.93 (s, 3H), 3.15 (m, 2H), 2.29 (s, 3H), 2.25-2.18 (m, 1H), 2.01-1.98 (m, 2H), 1.87- 1.84 (m, 2H), 1.60-1.56, 2H), 1.52-1.51 (d, J = 8.5 Hz, 3H), 1.44-1.34 (m, 2H), 1.07-0.99 (m, 2H).
176 methyl 4- 1-(5-chloro-2- trans-Methyl 4- 48 HNMR : 1H NMR (500 MHz, bromo-3- methoxyphen aminomethyl- 9.2 MeOD) 5=7.56 (d, J = 2 Hz, methylbenzoat yl)-2- cyclohexanecar 1H), 7.41 (dd, J = 3, 10.5 Hz, e methoxyethan boxylate 1H), 7.24-7.21 (m, 2H), 7.04- -1-amine 7.01 (m, 1H), 6.23 (d, J = 10.5
Hz, 1H), 5.0-5.05 (m, 1H), 3.96 (s, 3H), 3.72-3.61 (m, 2H), 3.41 (s, 3H), 3.18(d, J = 8.5 Hz, 2H), 2.31 (s, 3H), 2.24- 2.17 (m, 1H), 2.03-1.99 (m, 2H), 1.89-1.85 (m, 2H), 1.59 (m, 1H), 1.43-1.31 (m, 2H), 1.05-1.01 (m, 2H).
177 methyl 4- 1-(5-chloro-2- trans-Methyl 4- 48 HNMR : 1H NMR (500 MHz, bromo-3- methoxyphen aminomethyl- 9.2 MeOD) 5=7.56 (d, J = 2 Hz, methylbenzoat yl)-2- cyclohexanecar 1H), 7.41 (dd, J = 3, 10.5 Hz, e methoxyethan boxylate 1H), 7.24-7.21 (m, 2H), 7.04- -1-amine 7.01 (m, 1H), 6.23 (d, J = 10.5
Hz, 1H), 5.0-5.05 (m, 1H), 3.96 (s, 3H), 3.72-3.61 (m, 2H), 3.41 (s, 3H), 3.18(d, J = 8.5 Hz, 2H), 2.31 (s, 3H), 2.24- 2.17 (m, 1H), 2.03-1.99 (m, 2H), 1.89-1.85 (m, 2H), 1.59 (m, 1H), 1.43-1.31 (m, 2H), 1.05-1.01 (m, 2H).
178 methyl 4- (1S)-1-(2- trans-Methyl 4- 44 H NMR (400 MHz, CDCI3) δ bromo-3- chloro-5- aminomethyl- 7.2 7.48 (s, 1H), 7.27 (dd, J = 8.7, methylbenzoat fluorophenyl)e cyclohexanecar 4.9 Hz, 2H), 6.97 (dd, J = 9.4, e than-1 -amine boxylate 3.0 Hz, 1H), 6.82 (td, J = 8.3,
3.0 Hz, 1H), 6.05 (d, J = 8.5 Hz, 1H), 5.91 (s, 1H), 4.85 (d,
J = 6.5 Hz, 1H), 4.12 (s, 1H),
3.19 (s, 2H), 2.28-2.09 (m, 4H), 1.96 (d, J = 11.9 Hz, 2H), 1.79 (d, J = 12.6 Hz, 2H), 1.49 (d, J = 6.6 Hz, 3H), 1.34 (dd, J
= 24.2, 11.6 Hz, 2H), 1.18 (s, 1H), 1.06-0.87 (m, 2H).
179 methyl 4- 3-[(1S)-1- trans-Methyl 4- 44 1 H NMR (400 MHz, CDCI3) δ bromobenzoat aminoethyl]-4- aminomethyl- 7 7.48 (s, 1H), 7.27 (dd, J = 8.7, e methoxybenz cyclohexanecar 4.9 Hz, 2H), 6.97 (dd, J = 9.4, onitrile boxylate 3.0 Hz, 1H), 6.82 (td, J = 8.3,
3.0 Hz, 1H), 6.05 (d, J = 8.5 Hz, 1H), 5.91 (s, 1H), 4.85 (d, J = 6.5 Hz, 1H), 4.12 (s, 1H), 3.19 (s, 2H), 2.28-2.09 (m, 4H), 1.96 (d, J = 11.9 Hz, 2H), 1.79 (d, J = 12.6 Hz, 2H), 1.49 (d, J = 6.6 Hz, 3H), 1.34 (dd, J = 24.2, 11.6 Hz, 2H), 1.18 (s, 1H), 1.06-0.87 (m, 2H). 180 methyl 5- 3-[(1S)-1- trans-Methyl 4- 43 1 H NMR (500 MHz, CDCI3) δ bromo-4- aminoethyl]-4- aminomethyl- 6 7.95 (d, J = 8.6 Hz, 1H), 7.64- methylpyridine methoxybenz cyclohexanecar 7.44 (m, 4H), 6.95 (d, J = 8.4 -2-carboxylate onitrile boxylate Hz, 1H), 6.86 (d, J = 8.5 Hz,
1H), 6.41 (d, J = 8.6 Hz, 2H),
5.96 (s, 1H), 4.86 (d, J = 6.7 Hz, 1H), 3.98 (s, 3H), 3.88 (s, 1H), 3.27 (t, J = 6.4 Hz, 2H), 2.28 (t, J = 12.2 Hz, 1H), 2.04 (d, J = 12.3 Hz, 2H), 1.88 (d, J = 12.3 Hz, 2H), 1.48 (d, J = 6.6 Hz, 3H), 1.40 (d, J = 9.3 Hz, 3H), 1.03 (dd, J = 23.9, 11.4 Hz, 2H).
Example 8: Preparation of Compound 181
Figure imgf000177_0001
Intermediate 244: trans-methyl 4-((5-chloro-6-(((S)-1-(5-cyano-2- hydroxyphenyl)ethyl)amino)nicotinamido)methyl)cyclohexanecarboxylate
Figure imgf000178_0001
To a solution of trans-methyl 4-((5-chloro-6-(((S)-1 -(5-cyano-2- methoxyphenyl)ethyl)amino)nicotinamido)methyl)cyclohexanecarboxylate (1 10 mg, 0.227 mmol) in A/,A/-Dimethylformamide (3 mL) was added decane-1 -thiol (47.5 mg, 0.272 mmol) and potassium 2-methylpropan-2-olate (30.5 mg, 0.272 mmol). The resulting solution was then stirred at 100 °C overnight. The reaction mixture was then allowed to cool to rt and diluted with water. The resulting aqueous mixture was then extracted with ethyl acetate. The combined organic layers were then dried over Na2S04, filtered, and concentrated by rotary evaporation. The crude residue was then purified by prep-HPLC to provide trans-methyl 4- ((5-chloro-6-(((S)-1 -(5-cyano-2- hydroxyphenyl)ethyl)amino)nicotinamido)methyl)cyclohexanecarboxylate (70 mg, 0.141 mmol, 62.3 % yield), m/z: [M + H]+ Calcd for C24H28CIN404 471 .2; Found 471 .
Intermediate 245: trans-methyl 4-((5-chloro-6-(((S)-1 -(5-cyano-2- (difluoromethoxy)phenyl)ethyl)amino)nicotinamido)methyl)cyclohexanecarboxylate
Figure imgf000178_0002
To a mixture of trans-methyl 4-((5-chloro-6-(((S)-1 -(5-cyano-2- hydroxyphenyl)ethyl)amino)nicotinamido)methyl)cyclohexanecarboxylate (80 mg, 0.170 mmol) in THF (2 mL) and Water (2 mL), was added diethyl (bromodifluoromethyl)phosphonate (45.4 mg, 0.170 mmol) at -78 °C. The resulting solution was then allowed warm to rt and stirred at rt 16 h. Following completion of the reaction, aqueous 2M hydrochloric acid was added until a pH <7 was obtained. The resulting aqueous mixture was then extracted with EA (3 x 50 mL). The combined organics were then washed with water and brine. The washed organic layer was then dried over MgS04, filtered, and concentrated to provide the desired product trans-methyl 4-((5-chloro-6-(((S)-1 -(5-cyano-2- (difluoromethoxy)phenyl)ethyl)amino)nicotinamido)methyl)cyclohexanecarboxylate (75 mg, 0.144 mmol, 85 % yield) as a white solid that was used without further purification, m/z: [M + H]+ Calcd for C25H28CIF2N404 521 .2; Found 521 .2
Compound 181 : trans-4-((5-chloro-6-(((S)-1 -(5-cyano-2-
(difluoromethoxy)phenyl)ethyl)amino)nicotinamido)methyl)cyclohexanecarboxylic acid
Figure imgf000179_0001
To a mixture of trans-methyl 4-((5-chloro-6-(((S)-1 -(5-cyano-2- (difluoromethoxy)phenyl)ethyl)amino)nicotinamido)methyl)cyclohexanecarboxylate (80 mg, 0.154 mmol) in THF (2 mL) and Water (2m L) was added LiOH (36.8 mg, 1 .536 mmol) and the resulting solution stirred at rt 16 h. Following completion of the reaction, aqueous 2M hydrochloric acid was added until a pH <5 was obtained. The resulting aqueous mixture was then extracted with EA (3 x 50 mL). The combined organics were then washed with water and brine. The washed organic layer was then dried over MgS04, filtered, and concentrated to provide the desired product trans-4-((5-chloro-6-(((S)-1 -(5-cyano-2- (difluoromethoxy)phenyl)ethyl)amino)nicotinamido)methyl)cyclohexanecarboxylic acid (28mg, 0.054 mmol, 35.2 % yield) as a white solid, m/z: [M + H]+ Calcd for C24H26CIF2N404 507.2; Found 507.1 . 1 H NMR (400 MHz, DMSO) δ 8.39 (d, J = 2.0 Hz, 1 H), 8.24 (t, J = 5.7 Hz, 1 H), 8.03 (d, J = 2.0 Hz, 1 H), 7.96 (d, J = 2.1 Hz, 1 H), 7.80 (dd, J = 8.5, 2.1 Hz, 1 H), 7.35 (d, J = 8.6 Hz, 1 H), 7.32 - 7.27 (m, 1 H), 5.63 - 5.54 (m, 1 H), 3.04 (t, J = 6.3 Hz, 2H), 2.10 (s, 1 H), 1 .87 (d, J = 1 1 .7 Hz, 2H), 1 .73 (d, J = 1 1 .4 Hz, 2H), 1 .50 (d, J = 7.1 Hz, 3H), 1 .43 (s, 1 H), 1 .27 - 1 .19 (m, 3H), 0.91 (dd, J = 26.5, 13.6 Hz, 2H).
Example 9: Preparation of Compound 182
Figure imgf000180_0001
Intermediate 246: (S)-methyl 6-((1 -(5-bromo-2-methoxyphenyl)ethyl)amino)-5- chloronicotinate
Figure imgf000180_0002
To a solution of (S)-1 -(5-bromo-2-methoxyphenyl)ethanamine hydrochloride (1 .2g, 4.5 mmol)and DIPEA (1 .572 ml_, 9.0 mmol) in Dimethyl Sulfoxide (10 mL) stirred under nitrogen was added methyl 5,6-dichloronicotinate (1 .020 g, 4.95 mmol) and the resulting mixture stirred at 100°C for 12 h. The mixture was then concentrated under reduced pressure to give the crude product. Water (10 mL) was added, and the resulting aqueous mixture was extracted with EA (2 x 20 mL). The combined organic layers were then washed with water (2 x 10 mL) and brine (2 x 10 mL). The washed organic layer was then dried over anhydrous MgS04, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel (PE/EtOAc = 5/1 ) to provide the desired product (S)- methyl 6-((1 -(5-bromo-2-methoxyphenyl)ethyl)amino)-5-chloronicotinate (1 .2g, 2.85 mmol, 63.4% yield) as a white solid, m/z: [M + H]+ Calcd for Ci6Hi7BrCIN203 399.0; Found 399.
Intermediate 247: (S)-methyl 5-chloro-6-((1 -(2-methoxy-5- vinylphenyl)ethyl)amino)nicotinate
Figure imgf000180_0003
To a solution of (S)-methyl 6-((1 -(5-bromo-2-methoxyphenyl)ethyl)amino)-5-chloronicotinate (100 mg, 0.225 mmol), C2H3BF3K (36.2 mg, 0.270 mmol) and K2CO3 (93 mg, 0.676 mmol) in Dimethyl Sulfoxide (10 mL) stirred under nitrogen was added PdCI2(dppf) (16.48 mg, 0.023 mmol) and the resulting mixture stirred at 100 °C for 12h. Following completion of the reaction, the mixture was allowed to cool to rt and water (20 mL) was added. The resulting aqueous mixture was then extracted with EA (2 x 10 mL) and the combined organics then concentrated to dryness. The crude product obtained was purified by flash chromatography on silica gel (PE/EtOAc = 3/1 ) to provide the desired product (S)-methyl 5-chloro-6-((1 -(2-methoxy-5- vinylphenyl)ethyl)amino)nicotinate (60 mg, 0.156 mmol, 69.1 % yield) as a yellow oil. m/z: [M + H]+ Calcd for C18H20CIN2O3 347.1 ; Found 347
Intermediate 248: (S)-5-chloro-6-((1 -(5-(2-hydroxyethyl)-2- methoxyphenyl)ethyl)amino)nicotinic acid
Figure imgf000181_0001
A solution of (S)-methyl 5-chloro-6-((1 -(2-methoxy-5-vinylphenyl)ethyl)amino)nicotinate (50 mg, 0.137 mmol) and borane dimethyl sulfide complex (0.014 mL, 0.151 mmol) in Tetrahydrofuran (2 mL) was stirred under nitrogen at rt for 1 h. Aqueous hydrogen peroxide (4.62 μΙ, 0.151 mmol) and NaOH (21 .91 mg, 0.548 mmol) were then added and the resulting mixture stirred at 25 °C for 12 h. Following completion of the reaction, water (20 mL) was added and the resulting aqueous mixture extracted with EA (2 x 10 mL). The combined organics were then concentrated to dryness to provide te desired product (S)-5-chloro-6-((1 - (5-(2-hydroxyethyl)-2-methoxyphenyl)ethyl)amino)nicotinic acid (30 mg, 0.086 mmol, 62.4 % yield) as a clear oil that was used without further purification, m/z: [M + H]+ Calcd for C17H20CIN2C 351 .1 ; Found 351
Intermediate 249: trans-methyl 4-((5-chloro-6-(((S)-1 -(5-(2-hydroxyethyl)-2- methoxyphenyl)ethyl)amino)nicotinamido)methyl)cyclohexanecarboxylate
Figure imgf000181_0002
To a solution of (S)-5-chloro-6-((1 -(5-(2-hydroxyethyl)-2-methoxyphenyl)ethyl)amino)nicotinic acid (500 mg, 1 .283 mmol), trans-methyl 4-(aminomethyl)cyclohexanecarboxylate hydrochloride (320 mg, 1 .539 mmol), and DIPEA (0.269 mL, 1 .539 mmol) in N,N- Dimethylformamide (5 mL) stirred under nitrogen was added HATU (585 mg, 1 .539 mmol). The reaction mixture was stirred at 25 °C for 12 h. Following completion, the reaction was quenched with water (20 mL), and the resulting aqueous mixture extracted with EA (2 x 10 mL). The combined organic phases were then collected and evaporated in vacuo to give the crude product that was purified by flash chromatography on silica gel (PE/EtOAc = 3/1 ) to provide the desired product trans-methyl 4-((5-chloro-6-(((S)-1 -(5-(2-hydroxyethyl)-2- methoxyphenyl)ethyl)amino)nicotinamido)methyl)cyclohexanecarboxylate (520 mg, 0.980 mmol, 76 % yield) as a white solid, m/z: [M + H]+ Calcd for C26H35CIN3O5 504.2; Found 504 Intermediate 250: trans-methyl 4-((5-chloro-6-(((S)-1 -(2-methoxy-5-(2- oxoethyl)phenyl)ethyl)amino)nicotinamido)methyl)cyclohexanecarboxylate
Figure imgf000182_0001
A solution of trans-methyl 4-((5-chloro-6-(((S)-1 -(5-(2-hydroxyethyl)-2- methoxyphenyl)ethyl)amino)nicotinamido)methyl)cyclohexanecarboxylate (450 mg, 0.848 mmol) and dess-martin periodinane (720 mg, 1 .696 mmol) in Dichloromethane (5 mL) was stirred under nitrogen at 25 °C for 12h. Water (2 mL) was then added and the resulting solid was removed by filtration. The filtered solid was washed with DCM ( 2 x 10 mL), and the combined filtrate concentrated to dryness. The crude product obtained was purified by flash chromatography on silica gel (PE/EtOAc = 2/1 ) to provide the desired product trans-methyl 4-((5-chloro-6-(((S)-1-(2-methoxy-5-(2- oxoethyl)phenyl)ethyl)amino)nicotinamido)methyl)cyclohexanecarboxylate (330mg, 0.592 mmol, 69.8 % yield) as a white solid, m/z: [M + H]+ Calcd for C26H33CIN3O5 502.2; Found 502.
Intermediate 251 : trans-methyl 4-((5-chloro-6-(((1 S)-1 -(5-(2-hydroxypropyl)-2- methoxyphenyl)ethyl)amino)nicotinamido)methyl)cyclohexanecarboxylate
Figure imgf000183_0001
To a solution of trans-methyl 4-((5-chloro-6-(((S)-1 -(2-methoxy-5-(2- oxoethyl)phenyl)ethyl)amino)nicotinamido)methyl)cyclohexanecarboxylate (100 mg, 0.179 mmol) in Tetrahydrofuran (2 mL) stirred under nitrogen at 0 °C, was added methylmagnesium bromide (0.072 mL, 0.215 mmol), and the resulting mixture then stirred at rt for 0.5 h. Following completion, the reaction was quenched with water (20 mL), and the resulting aqueous mixture extracted with EA (2 x 10 mL). The combined organic phases were then collected and evaporated in vacuo to give the crude product that was purified by flash chromatography on silica gel (PE/EtOAc = 1 /1 ) to provide the desired product trans-methyl 4-((5-chloro-6-(((1 S)-1 -(5-(2-hydroxypropyl)-2- methoxyphenyl)ethyl)amino)nicotinamido)methyl)cyclohexanecarboxylate (50 mg, 0.092 mmol, 51 .1 % yield) as a white solid, m/z: [M + H]+ Calcd for C27H37CIN3O5 518.2; Found 518
Compound 182: trans-4-((5-chloro-6-(((1 S)-1 -(5-(2-hydroxypropyl)-2- methoxyphenyl)ethyl)amino)nicotinamido)methyl)cyclohexanecarboxylic acid
Figure imgf000183_0002
To a solution of trans-methyl 4-((5-chloro-6-(((1 S)-1 -(5-(2-hydroxypropyl)-2- methoxyphenyl)ethyl)amino)nicotinamido)methyl)cyclohexanecarboxylate (50 mg, 0.092 mmol) in Water (3 mL) was added a solution of lithium hydroxide hydrate (1 1 .54 mg, 0.275 mmol) in Water (3 mL), and the mixture stirred under nitrogen at 25 °C for 1 h. Following completion of the reaction, aqueous 1 M hydrochloric acid was added until a pH <5 was obtained. The resulting aqueous mixture was then extracted with EA (2 x 3 mL). The combined organic layers were then concentrated to provide the crude product that was purified by preparative HPLC to provide the product trans-4-((5-chloro-6-(((1 S)-1 -(5-(2- hydroxypropyl)-2-methoxyphenyl)ethyl)amino)nicotinamido)methyl)cyclohexanecarboxylic acid (25mg, 0.049 mmol, 53.2% yield) as a white solid, m/z: [M + H]+ Calcd for C26H35CIN3O5 504.2; Found 504. 1 H NMR (400 MHz, DMSO) δ 8.67 (d, J = 8.8 Hz, 1 H), 8.22 (d, J = 8.2 Hz, 2H), 7.76 - 7.64 (m, 2H), 7.19 (d, J = 8.5 Hz, 1 H), 7.04 - 6.94 (m, 1 H), 5.74 (s, 1 H), 3.95 (s, 3H), 2.63 (s, 1 H), 2.28 - 1 .97 (m, 2H), 1 .76 (s, 1 H), 1 .63 (dd, J = 29.9, 16.5 Hz, 2H), 1 .45 (t, J = 14.6 Hz, 4H), 1 .26 (d, J = 15.9 Hz, 3H), 1 .06 (s, 1 H), 0.62 (dd, J = 12.7, 6.4 Hz, 1 H).
Example 10: Preparation of Compound 183
Figure imgf000184_0001
Intermediate 252: trans-methyl 4-((5-chloro-6-(((S)-1 -(5-(2-hydroxyethyl)-2- methoxyphenyl)ethyl)amino)nicotinamido)methyl)cyclohexanecarboxylate
Figure imgf000184_0002
To a solution of (S)-5-chloro-6-((1 -(5-(2-hydroxyethyl)-2-methoxyphenyl)ethyl)amino)nicotinic acid (500 mg, 1 .283 mmol), trans-methyl 4-(aminomethyl)cyclohexanecarboxylate hydrochloride (320 mg, 1 .539 mmol), and DIPEA (0.269 mL, 1 .539 mmol) in N,N- Dimethylformamide (5 mL) stirred under nitrogen was added solid HATU (585 mg, 1 .539 mmol), and the resulting mixture stirred at 25 °C for 12 h. Following completion, the reaction was quenched with water (20 mL), and the resulting aqueous mixture extracted with EA (2 x 10 mL). The combined organic phases were then collected and evaporated in vacuo to give the crude product that was purified by flash chromatography on silica gel (PE/EtOAc = 3/1 ) to provide the desired product trans-methyl 4-((5-chloro-6-(((S)-1 -(5-(2-hydroxyethyl)-2- methoxyphenyl)ethyl)amino)nicotinamido)methyl)cyclohexanecarboxylate (520 mg, 0.980 mmol, 76 % yield) as a white solid, m/z: [M + H]+ Calcd for C26H35CIN3O5 504.2; Found 504. Compound 183: trans-4-((5-chloro-6-(((S)-1 -(5-(2-hydroxyethyl)-2- methoxyphenyl)ethyl)amino)nicotinamido)methyl)cyclohexanecarboxylic acid
Figure imgf000184_0003
To a solution of trans-methyl 4-((5-chloro-6-(((S)-1 -(5-(2-hydroxyethyl)-2- methoxyphenyl)ethyl)amino)nicotinamido)methyl)cyclohexanecarboxylate (50 mg, 0.094 mmol) in Tetrahydrofuran (1 mL) and Water (1 mL) stirred under nitrogen, was added lithium hydroxide hydrate (1 1 .86 mg, 0.283 mmol), and the resulting mixture stirred at 25 °C for 12h. Following completion of the reaction, aqueous 1 M hydrochloric acid was added until a pH <5 was obtained. The resulting aqueous mixture was then extracted with EA (2 x 3 mL). The combined organic layers were then concentrated to provide the crude product that was purified by preparative HPLC to provide the product trans-4-((5-chloro-6-(((S)-1 -(5-(2- hydroxyethyl)-2-methoxyphenyl)ethyl)amino)nicotinamido)methyl)cyclohexanecarboxylic acid (33 mg, 0.066 mmol, 70.2% yield) as a white solid, m/z: [M + H]+ Calcd for C25H33CIN3O5 490.2; Found 490. 1 H NMR (400 MHz, DMSO) δ 8.43 (d, J = 1 .9 Hz, 1 H), 8.24 (s, 1 H), 8.02 (d, J = 1 .9 Hz, 1 H), 7.13 (d, J = 1 .9 Hz, 1 H), 7.04 (d, J = 8.5 Hz, 1 H), 6.97 (d, J = 8.3 Hz, 1 H), 6.90 (d, J = 8.3 Hz, 1 H), 5.59 - 5.54 (m, 1 H), 3.83 (s, 3H), 3.51 (t, J = 7.4 Hz, 2H), 3.09 - 3.02 (m, 2H), 2.60 (t, J = 7.2 Hz, 2H), 2.12 (s, 1 H), 1 .89 (d, J = 1 1.3 Hz, 2H), 1 .75 (d, J = 1 1 .2 Hz, 2H), 1 .44 (d, J = 6.9 Hz, 4H), 1 .24 (dd, J = 22.6, 12.8 Hz, 2H), 0.98 - 0.87 (m, 2H).
Example 11 : Preparation of Compound 184
Figure imgf000185_0001
Intermediate 253: (S)-4-((1 -(5-bromo-2-methoxyphenyl)ethyl)amino)-3- chlorobenzonitrile
Figure imgf000186_0001
To a solution of (S)-1 -(5-bromo-2-methoxyphenyl)ethanamine hydrochloride (2 g, 6.0 mmol) in Dimethyl Sulfoxide (10 mL) at rt was added 3-chloro-4-fluorobenzonitrile (1 .307 g, 8.40 mmol) and DIPEA (7.5ml_, 42.9 mmol). The reaction mixture was then stirred at 120 °C for 16 h. Following completion of the reaction, the mixture was allowed to cool to rt and water (30 mL) was added. The resulting aqueous mixture was then extracted with EA (1 x 30 mL, 1 x 10 mL). The combined organic layers were then concentrated to dryness and purified by flash chromatography on silica gel (PE/EtOAc = 8/1 ) to provide the desired product (S)-4-((1 - (5-bromo-2-methoxyphenyl)ethyl)amino)-3-chlorobenzonitrile (2.2 g, 5.41 mmol, 90% yield). m/z: [M + Na]+ Calcd for Ci6Hi4BrCINaN20 387.0; Found 387.
Intermediate 254:(S)-3-chloro-4-((1 -(2-methoxy-5-vinylphenyl)ethyl)amino)benzonitrile
Figure imgf000186_0002
To a solution of (S)-4-((1 -(5-bromo-2-methoxyphenyl)ethyl)amino)-3-chlorobenzonitrile (2.2 g, 6.02 mmol) in A/,A/-Dimethylformamide (15 mL) at rt was added K2C03 (2.50 g, 18.05 mmol), potassium trifluoro(vinyl)borate (967 mg, 7.22 mmol), and PdCI2(dppf) (220 mg, 0.301 mmol). The resulting reaction mixture was stirred at 100 °C for 16 h. Following completion of the reaction, the mixture was cooled to rt and EtOAc (50 mL) was added. The resulting solution was washed with water (90 mL) and the aqueous wash back extracted with EtOAc (1 x 20 mL). The combined organic phases were then concentrated to dryness and purified by flash chromatography on silica gel (PE/EtOAc = 8/1 ) to provide the desired product (S)-3- chloro-4-((1 -(2-methoxy-5-vinylphenyl)ethyl)amino)benzonitrile (1 .2 g, 3.45 mmol, 57.4% yield), m/z: [M + Na]+ Calcd for Ci8Hi7CINaN20 335.1 ; Found 335.
Intermediate 255: (S)-3-chloro-4-((1 -(5-(2-hydroxyethyl)-2- methoxyphenyl)ethyl)amino)benzamide
Figure imgf000187_0001
To a solution of (S)-3-chloro-4-((1 -(2-methoxy-5-vinylphenyl)ethyl)amino)benzonit le (1 .06 g, 3.39 mmol) in Tetrahydrofuran (50 mL) at 0°C was added borane dimethyl sulfide complex (2M in THF, 2.20 mL, 4.40 mmol). The reaction mixture was then stirred at 0°C for 0.5 h and then warmed to rt and stirred an additional 0.5 h. The reaction mixture was then charged with aqueous H202 (10.38 mL, 33.9 mmol) and NaOH (1 .36 g, 33.9 mmol), and the resulting mixture stirred 16 h at rt. Following completion of the reaction, water (20 mL) was added and the resulting aqueous mixture extracted with DCM (3 x 30 mL). The combined organic phases were then concentrated to dryness to provide the desired product (S)-3-chloro-4-((1 -(5-(2- hydroxyethyl)-2-methoxyphenyl)ethyl)amino)benzamide that was used directly in the following reaction without further purification, m/z: [M + H]+ Calcd for Ci8H22CIN203 349.1 ; Found 349.
Intermediate 256: (S)-3-chloro-4-((1 -(5-(2-hydroxyethyl)-2- methoxyphenyl)ethyl)amino)benzoic acid
Figure imgf000187_0002
A solution of (S)-3-chloro-4-((1 -(5-(2-hydroxyethyl)-2-methoxyphenyl)ethyl)amino)benzamide (1 .2 g, 2.408 mmol) and aqueous NaOH (10M, 7.22 mL, 72.2 mmol) in Methanol (20 mL) was heated and stirred at 80 °C for 48 h. Following completion of the reaction, the mixture was allowed to cool to rt and then concentrated directly in vacuo. Aqueous HCI (1 M) was then added until the pH reached <3 and the resulting aqueous mixture extracted with EtOAc (1 x 30 mL, 1 x 10 mL). The combined organic phases were then concentrated to dryness to provide the desired product (S)-3-chloro-4-((1 -(5-(2-hydroxyethyl)-2- methoxyphenyl)ethyl)amino)benzoic acid that was used directly in the following reaction without further purification, m/z: [M + H]+ Calcd for Ci8H2iCIN04 350.1 ; Found 350. Intermediate 257: trans-methyl 4-((3-chloro-4-(((S)-1 -(5-(2-hydroxyethyl)-2- methoxyphenyl)ethyl)amino)benzamido)methyl)cyclohexanecarboxylate
Figure imgf000188_0001
To a solution of (S)-3-chloro-4-((1 -(5-(2-hydroxyethyl)-2-methoxyphenyl)ethyl)amino)benzoic acid (1 .1 g, 3.14 mmol) in A/,A/-Dimethylformamide (6 mL) at rt was added HATU (1 .554 g, 4.09 mmol), trans-methyl 4-(aminomethyl)cyclohexanecarboxylate hydrochloride (0.849 g, 4.09 mmol) and TEA (6 mL, 43.0 mmol). The reaction mixture was stirred at rt for 3 h. Following completion of the reaction, water (30 mL) was added and the resulting aqueous mixture extracted with EtOAc (1 x 30 mL, 1 x 10 mL). The combined organic layers were then concentrated to dryness and purified by flash chromatography on silica gel (PE/EtOAc = 1/1 ) to provide the desired product trans-methyl 4-((3-chloro-4-(((S)-1 -(5-(2-hydroxyethyl)-2- methoxyphenyl)ethyl)amino)benzamido)methyl)cyclohexanecarboxylate (1 .1 g, 2.077 mmol, 66.1 % yield), m/z: [M + H]+ Calcd for C27H36CIN2O5 503.2; Found 503.
Intermediate 258: trans-methyl 4-((3-chloro-4-(((S)-1 -(2-methoxy-5-(2- oxoethyl)phenyl)ethyl)amino)benzamido)methyl)cyclohexanecarboxylate
Figure imgf000188_0002
To a solution of trans-methyl 4-((3-chloro-4-(((S)-1 -(5-(2-hydroxyethyl)-2- methoxyphenyl)ethyl)amino)benzamido)methyl)cyclohexanecarboxylate (1 g, 1 .99 mmol) in Dichloromethane (20 mL) at rt was added Dess-Martin periodinane (1 .69 g, 3.98 mmol). The reaction mixture was stirred at rt for 16 h. Following completion of the reaction, water (10 mL) was added and the resulting aqueous mixture extracted with DCM (1 x 20 mL, 1 x 10 mL). The combined organic layers were then concentrated to dryness and purified by flash chromatography on silica gel (PE/EtOAc = 1 /1 ) to provide the desired product trans-methyl 4-((3-chloro-4-(((S)-1-(2-methoxy-5-(2- oxoethyl)phenyl)ethyl)amino)benzamido)methyl)cyclohexanecarboxylate (647 rr mmol, 58.5 % yield), m/z: [M + H]+ Calcd for C27H34CIN205 501 .2; Found 501 .
Intermediate 259: trans-methyl 4-((3-chloro-4-(((1 S)-1 -(5-(2-hydroxypropyl)-2- methoxyphenyl)ethyl)amino)benzamido)methyl)cyclohexanecarboxylate
Figure imgf000189_0001
To a solution of trans-methyl 4-((3-chloro-4-(((S)-1 -(2-methoxy-5-(2- oxoethyl)phenyl)ethyl)amino)benzamido)methyl)cyclohexanecarboxylate (200 mg, 0.399 mmol) in Tetrahydrofuran (3 mL) at rt was added methylmagnesium bromide (0.399 mL, 1 .198 mmol). The reaction mixture was stirred at rt for 16 h. Following completion of the reaction, water (5 mL) was added and the resulting aqueous mixture extracted with EtOAc (1 x 20 mL, 1 x 5 mL). The combined organic layers were then concentrated to dryness and purified by flash chromatography on silica gel (PE/EtOAc = 1/1 ) to provide the desired product trans-methyl 4-((3-chloro-4-(((1 S)-1 -(5-(2-hydroxypropyl)-2- methoxyphenyl)ethyl)amino)benzamido)methyl)cyclohexanecarboxylate (30 mg, 0.052 mmol, 13.08 % yield), m/z: [M + H]+ Calcd for C28H38CIN205 517.2; Found 517.
Compound 184: trans-4-((3-chloro-4-(((1 S)-1 -(5-(2-hydroxypropyl)-2- methoxyphenyl)ethyl)amino)benzamido)methyl)cyclohexanecarboxylic acid
Figure imgf000189_0002
To a solution of trans-methyl 4-((3-chloro-4-(((1 S)-1 -(5-(2-hydroxypropyl)-2- methoxyphenyl)ethyl)amino)benzamido)methyl)cyclohexanecarboxylate (30 mg, 0.058 mmol) in Tetrahydrofuran (3 mL) and Water (0.5 mL) at rt, was added lithium hydroxide hydrate (7.30 mg, 0.174 mmol). The reaction mixture was stirred at 40 °C for 16 h. Following completion of the reaction, the mixture was concentrated directly in vacuo. Water (5 mL) was then added to the residue and 1 M aqueous HCI was added until the pH was <4. The resulting aqueous mixture was then extracted with EtOAc (1 x 20 mL, 1 x 5 mL). The combined organic layers were then combined and concentrated to dryness. The residue obtained was purified by prep HPLC (MeCN containing 0.1 % TFA) to provide the desired product trans-4-((3-chloro- 4-(((1 S)-1 -(5-(2-hydroxypropyl)-2- methoxyphenyl)ethyl)amino)benzamido)methyl)cyclohexanecarboxylic acid (16 mg, 0.032 mmol, 54.8 % yield), m/z: [M + H]+ Calcd for C27H36CIN2O5 503.2; Found 503. 1H NMR (400 MHz, DMSO) δ 8.12 (m, J = 5.6 Hz, 1 H), 7.78 (d, J = 1 .7 Hz, 1 H), 7.53 (d, J = 8.6 Hz, 1 H), 7.08 (d, J = 3.6 Hz, 1 H), 7.01 (d, J = 8.2 Hz, 1 H), 6.91 (d, J = 8.4 Hz, 1 H), 6.46 (dd, J = 8.8, 4.8 Hz, 1 H), 5.87 (d, J = 7.7 Hz, 1 H), 4.92 - 4.84 (m, 1 H), 3.86 (s, 3H), 3.66 (dt, J = 12.8, 6.4 Hz, 2H), 3.03 (t, J = 6.2 Hz, 2H), 2.60 - 2.54 (m, 1 H), 2.37 (dd, J = 13.2, 6.7 Hz, 1 H), 2.13 (d, J = 12.2 Hz, 1 H), 1 .88 (d, J = 10.9 Hz, 2H), 1 .72 (d, J = 1 1 .0 Hz, 2H), 1 .47 (t, J = 10.7 Hz, 4H), 1 .23 (d, J = 9.7 Hz, 2H), 0.96 - 0.89 (m, 3H), 0.86 (d, J = 6.0 Hz, 2H).
Example 12: Preparation of Compound 185
Figure imgf000190_0001
Intermediate 260: trans-methyl 4-((3-chloro-4-(((S)-1 -(5-(2-hydroxyethyl)-2- methoxyphenyl)ethyl)amino)benzamido)methyl)cyclohexanecarboxylate
Figure imgf000190_0002
To a solution of (S)-3-chloro-4-((1 -(5-(2-hydroxyethyl)-2-methoxyphenyl)ethyl)amino)benzoic acid (90 mg, 0.193 mmol) in A/,A/-Dimethylformamide (2 ml.) at rt was added HATU (95 mg, 0.251 mmol), trans-methyl 4-(aminomethyl)cyclohexanecarboxylate hydrochloride (52.1 mg, 0.251 mmol) and TEA (0.5 ml_, 3.59 mmol). The reaction mixture was stirred at RT for 3 h. Following completion of the reaction, water (20 mL) was added and the resulting aqueous mixture extracted with EtOAc (1 x 20 mL, 1 x 10 mL). The combined organic layers were then concentrated to dryness and the residue obtained purified by prep HPLC (MeCN containing 0.1 % TFA) to provide the desired product trans-methyl 4-((3-chloro-4-(((S)-1 -(5-(2- hydroxyethyl)-2-methoxyphenyl)ethyl)amino)benzamido)methyl)cycloh (58 mg, 0.1 10 mmol, 56.8 % yield), m/z: [M + H]+ Calcd for C27H36CIN2O5 503.2; Found 503.
Compound 185: trans-4-((3-chloro-4-(((S)-1 -(5-(2-hydroxyethyl)-2- methoxyphenyl)ethyl)amino)benzamido)methyl)cyclohexanecarboxylic acid
Figure imgf000191_0001
To a solution of trans-methyl 4-((3-chloro-4-(((S)-1 -(5-(2-hydroxyethyl)-2- methoxyphenyl)ethyl)amino)benzamido)methyl)cyclohexanecarboxylate (58 mg, 0.1 15 mmol) in Tetrahydrofuran (3 mL) and Water (0.5 mL) at rt was added lithium hydroxide hydrate (14.52 mg, 0.346 mmol). The reaction mixture was stirred at 40 °C for 16 h. Following completion of the reaction, the mixture was concentrated directly in vacuo. Water (5 mL) was then added to the residue and 1 M aqueous HCI was added until the pH was <4. The resulting aqueous mixture was then extracted with EtOAc (1 x 20 mL, 1 x 5 mL). The combined organic layers were then combined and concentrated to dryness. The residue obtained was purified by prep HPLC (MeCN containing 0.1 % TFA) to provide the desired product trans-4-((3-chloro- 4-(((S)-1 -(5-(2-hydroxyethyl)-2- methoxyphenyl)ethyl)amino)benzamido)methyl)cyclohexanecarboxylic acid (30 mg, 0.061 mmol, 52.6% yield), m/z: [M + H]+ Calcd for C26H34CIN205 489.2; Found 489. 1H NMR (400 MHz, DMSO) δ 8.13 (s, 1 H), 7.79 (s, 1 H), 7.54 (d, J = 8.7 Hz, 1 H), 7.13 (s, 1 H), 7.04 (d, J = 8.4 Hz, 1 H), 6.92 (d, J = 8.3 Hz, 1 H), 6.47 (d, J = 8.7 Hz, 1 H), 5.89 (d, J = 7.4 Hz, 1 H), 4.90 (d, J = 6.2 Hz, 1 H), 3.86 (s, 3H), 3.49 (s, 2H), 3.04 (t, J = 6.0 Hz, 2H), 2.58 (t, J = 7.0 Hz, 2H), 2.10 (d, J = 12.9 Hz, 1 H), 1.88 (d, J = 1 1 .4 Hz, 2H), 1 .73 (d, J = 12.2 Hz, 2H), 1 .48 (d, J = 6.6 Hz, 4H), 1 .23 (d, J = 10.6 Hz, 2H), 0.91 (dd, J = 24.5, 1 1 .7 Hz, 2H).
Example 13: Preparation of Compound 186
Figure imgf000192_0001
Intermediate 261 : 3-bromo-4-((1 -(5-chloro-2-methoxyphenyl)ethyl)amino)benzonitrile
Figure imgf000192_0002
To a solution of 3-bromo-4-fluorobenzonit le (1 g, 5.00 mmol) and 1 -(5-chloro-2- methoxyphenyl)ethanamine (800 mg, 4.31 mmol) in NMP (10 mL) was added potassium carbonate (1 .382 g, 10.00 mmol) and the resulting mixture was stirred under microwave irradiation at 140 °C for 2 h. Following completion of the reaction, the reaction mixture was allowed to cool to rt and water (50 mL) was added. The resulting aqueous mixture was extracted with ethyl acetate (3 x 50 mL). The combined organic layers were then washed with saturated aqueous NaHC03, water, and brine. The washed organic layer was then dried over MgS04, filtered, and concentrated to dryness. The residue obtained was purified by flash chromatography on silica gel (PE/EtOAc = 5/1 ) to provide the desired product 3-bromo-4-((1 - (5-chloro-2-methoxyphenyl)ethyl)amino)benzonitrile (1 g, 2.358 mmol, 47.2% yield) as a yellow solid, m/z: [M + H]+ Calcd for Ci6Hi5BrCIN20 365.0; Found 365. Intermediate 262: 4-((1-(5-chloro-2-methoxyphenyl)ethyl)amino)-3-ethylbenzonitrile
Figure imgf000192_0003
A mixture of 3-bromo-4-((1 -(5-chloro-2-methoxyphenyl)ethyl)amino)benzonitrile (360 mg, 0.985 mmol), ethylboronic acid (109 mg, 1 .477 mmol), PdCI2(dppf) (72.0 mg, 0.098 mmol), and K2CO3 (272 mg, 1 .969 mmol) in THF (4 mL) and water (2 mL) was stirred at 100 °C under microwave irradiation for 1 h. Following completion of the reaction, the reaction mixture was allowed to cool to rt and water (50 mL) was added. The resulting aqueous mixture was extracted with ethyl acetate (3 x 50 mL). The combined organic layers were then washed with saturated aqueous NaHCC , water, and brine. The washed organic layer was then dried over MgS04, filtered, and concentrated to dryness. The residue obtained was purified by flash chromatography on silica gel (PE/EtOAc = 4/1 ) to provide the desired product 4-((1 -(5-chloro- 2-methoxyphenyl)ethyl)amino)-3-ethylbenzonitrile (300 mg, 0.858 mmol, 87% yield) as a yellow solid, m/z: [M + H]+ Calcd for Ci8H2oCIN20 315.1 ; Found 315.
Intermediate 263: 4-((1-(5-chloro-2-methoxyphenyl)ethyl)amino)-3-ethylbenzoic acid
Figure imgf000193_0001
A mixture of 4-((1 -(5-chloro-2-methoxyphenyl)ethyl)amino)-3-ethylbenzonitrile (300 mg, 0.953 mmol) and NaOH (381 mg, 9.53 mmol) in EtOH (2 mL) and water (2 mL) was stirred at 90 °C for 8 h. Following completion of the reaction, the mixture was allowed to cool to rt and the ethanol removed in vacuo. The solution obtained was acidified with 1 M aqueous HCI until the pH was <3. The resulting aqueous mixture was then extracted with EtOAc (3 x 50 mL). The combined organic layers were then dried over MgS04, filtered, and concentrated to dryness to provide the desired product 4-((1 -(5-chloro-2-methoxyphenyl)ethyl)amino)-3- ethylbenzoic acid (300 mg, 0.773 mmol, 81 % yield) as a white solid that was used without further purification, m/z: [M + H]+ Calcd for Ci8H2iCIN03 334.1 ; Found 334.
Intermediate 264: trans-methyl 4-((4-((1 -(5-chloro-2-methoxyphenyl)ethyl)amino)-3- ethylbenzamido)methyl)cyclohexanecarboxylate
Figure imgf000193_0002
To a mixture of trans-methyl 4-(aminomethyl)cyclohexanecarboxylate (77 mg, 0.449 mmol) in DMF (6 mL) was added 4-((1 -(5-chloro-2-methoxyphenyl)ethyl)amino)-3-ethylbenzoic acid (150 mg, 0.449 mmol), HATU (256 mg, 0.674 mmol) and DIPEA (0.157 mL, 0.899 mmol). The resulting solution was stirred at rt for 16 h. Following completion of the reaction, water (50 mL) was added and the resulting aqueous mixture extracted with EtOAc (3 x 50 mL). The combined organic layers were then washed with saturated aqueous NaHC03, water, and brine. The washed organic layer was then dried over MgS04, filtered, and concentrated to provide the desired product trans-methyl 4-((4-((1 -(5-chloro-2-methoxyphenyl)ethyl)amino)- 3-ethylbenzamido)methyl)cyclohexanecarboxylate (200 mg, 0.246 mmol, 54.8% yield) as a yellow solid that was used without further purification, m/z: [M + H]+ Calcd for C27H36CIN2C 487.2; Found 487.
Compound 186: trans-4-((4-((1 -(5-chloro-2-methoxyphenyl)ethyl)amino)-3- ethylbenzamido)methyl)cyclohexanecarboxylic acid
Figure imgf000194_0001
A mixture of trans-methyl 4-((4-((1 -(5-chloro-2-methoxyphenyl)ethyl)amino)-3- ethylbenzamido)methyl)cyclohexanecarboxylate (100 mg, 0.205 mmol) and NaOH (82 mg, 2.053 mmol) in THF (2 mL) and water (2 mL), was stirred at rt for 8 hours. Following completion of the reaction, the mixture was concentrated directly in vacuo. Water (5 mL) was then added to the residue and 1 M aqueous HCI was added until the pH was <4. The resulting aqueous mixture was then extracted with EtOAc (3 x 30 mL). The organic layers were then combined and concentrated to dryness. The residue obtained was purified by prep HPLC (MeCN containing 0.1 % TFA) to provide the desired product trans-4-((4-((1 -(5-chloro-2- methoxyphenyl)ethyl)amino)-3-ethylbenzamido)methyl)cyclohexanecarboxylic acid (56 mg, 0.107 mmol, 51 .9% yield) as a white solid, m/z: [M + H]+ Calcd for C26H34CIN2C 473.2; Found 473. 1 H NMR(400 MHz CDCI3): δ 7.56 (d, J = 2Hz, 1 H), 7.36 (dd, J = 2.0, 8.8 Hz, 1 H), 7.16- 7.19 (m, 2H), 6.83 (d, J = 8 Hz, 1 H), 6.30 (d, J = 8.4Hz, 1 H), 6.01 -6.02 (m, 1 H), 4.88 (q, J = 6.4Hz, 1 H), 3.91 (s, 3H), 3.27-3.29 (m, 2H), 2.6 (q, J = 8Hz, 2H), 2.27-2.28 (m, 2H), 2.06 (d, J = 10 Hz, 2H), 1 .90 (d, J = 10 Hz, 2H), 1 .53 (d, J = 6.4 Hz, 3H), 1 .41 -1 .51 (m, 2H), 1 .36 (t, J = 8Hz, 3H), 1 .02-1 .05 (m, 2H).
Example 14: Preparation of Compound 187
Figure imgf000195_0001
Intermediate 265: (S)-3-chloro-4-((1 -(5-methoxy-2-(trifluoromethyl)pyridin-4- yl)ethyl)amino)benzonitrile
Figure imgf000195_0002
To a solution of (S)-1 -(5-methoxy-2-(t fluoromethyl)py din-4-yl)ethanamine (6.42g, 21 .26 mmol) and 3-chloro-4-fluorobenzonit le (4.67 g, 30.0 mmol) in Dimethyl Sulfoxide (30 mL) stirred in air at room temp was added A/-ethyl-A/-isopropylpropan-2 -amine (16.16 g, 125 mmol) in one charge. The reaction mixture was stirred at 120 °C for 16 h. Following completion of the reaction, the mixture was allowed to cool to rt and water (100 mL) was added. The resulting aqueous mixture was extracted with EA (200 mL) and the layers seperated. The organic layer was then concentrated to dryness and the residue obtained was purified by flash chromatography on silica gel (PE/EtOAc = 3/1 ) to provide the desired product (S)-3-chloro-4-((1 -(5-methoxy-2-(trifluoromethyl)pyridin-4-yl)ethyl)amino)benzonitrile (5.3 g, 14.9 mmol, 70.1 % yield) as a yellow solid, m/z: [M + H]+ Calcd for Ci6Hi4CIF3N30 356.1 ; Found 356.
Intermediate 266: (S)-3-chloro-4-((1 -(5-methoxy-2-(trifluoromethyl)pyridin-4- yl)ethyl)amino)benzoic acid
Figure imgf000195_0003
A solution of (S)-3-chloro-4-((1 -(5-methoxy-2-(trifluoromethyl)pyridin-4- yl)ethyl)amino)benzonitrile (5.15 g, 14.48 mmol) in concentrated aqueous HCI (30 ml, 326 mmol) was stirred at 80 °C for 16 h. Following completion of the reaction, the mixture was allowed to cool to rt and concentrated directly. Water (50 mL) was added and the resulting aqueous mixture was extracted with EA (2 x 100 mL). The combined organic layers were then concentrated to dryness to provide the desired product (S)-3-chloro-4-((1 -(5-methoxy-2- (trifluoromethyl)pyridin-4-yl)ethyl)amino)benzoic acid (5.7 g, 14.45 mmol, 100% yield) as a white solid that was used without further purification, m/z: [M + H]+ Calcd for C16H15CIF3N2O3 375.1 ; Found 375.
Intermediate 267: (S)-ethyl 4-((3-chloro-4-((1 -(5-methoxy-2-(trifluoromethyl)pyridin-4- yl)ethyl)amino)benzamido)methyl)-4-hydroxycyclohexanecarboxylate
Figure imgf000196_0001
To a solution of (S)-3-chloro-4-((1 -(5-methoxy-2-(trifluoromethyl)pyridin-4- yl)ethyl)amino)benzoic acid (170 mg, 0.422 mmol) in A/,A/-Dimethylformamide (4 mL) at rt was added HATU (241 mg, 0.633 mmol) and the reaction was allowed to stir 10 min. Ethyl 4- (aminomethyl)-4-hydroxycyclohexanecarboxylate (138 mg, 0.548 mmol) and triethylamine (427 mg, 4.22 mmol) were then added and the reaction mixture was stirred at 25 °C for 16 h. Following completion of the reaction, water (10 mL) was added and the resulting aqueous mixture was extracted with EA (2 x 10 mL). The combined organics were the dried over sodium sulfate, filtered, and concentrated to dryness. The residue obtained was purified by flash chromatography on silica gel (PE/EtOAc = 1/10) to provide the desired product (S)-ethyl 4-((3-chloro-4-((1 -(5-methoxy-2-(trifluoromethyl)pyridin-4-yl)ethyl)amino)benzamido)methyl)- 4-hydroxycyclohexanecarboxylate (200 mg, 0.358 mmol, 85 % yield), m/z: [M + H]+ Calcd for C26H32CIF3N3O5 558.2; Found 558.
Compound 187: (S)-4-((3-chloro-4-((1 -(5-methoxy-2-(trifluoromethyl)pyridin-4- yl)ethyl)amino)benzamido)methyl)-4-hydroxycyclohexanecarboxylic acid
Figure imgf000196_0002
solution of (S)-ethyl 4-((3-chloro-4-((1 -(5-methoxy-2-(trifluoromethyl)pyridin-4- yl)ethyl)amino)benzamido)methyl)-4-hydroxycyclohexanecarboxylate (80 mg, 0.143 mmol) in ethanol (1 mL) and water (1 mL) at rt was added lithium hydroxide hydrate (12.03 mg, 0.287 mmol) and the reaction stirred at 45 °C for 16 h. Following completion of the reaction, the mixture was concentrated directly in vacuo. Water (5 mL) was then added to the residue and 1 M aqueous HCI was added until the pH was <4. The resulting aqueous mixture was then extracted with EtOAc (2 x 10 mL). The organic layers were then combined, dried over sodium sulfate, filtered, and concentrated to dryness. The residue obtained was purified by prep HPLC (MeCN containing 0.1 % TFA) to provide the desired product (S)-4-((3-chloro-4-((1 -(5- methoxy-2-(trifluoromethyl)pyridin-4-yl)ethyl)amino)benzamido)methyl)-4- hydroxycyclohexanecarboxylic acid (31 mg, 0.058 mmol, 40.8 % yield), m/z: [M + H]+ Calcd for C24H28CIF3N305 530.2; Found 530.1 . 1 H NMR (400 MHz, de-DMSO) δ 8.56 (s, 1 H), 7.90- 8.00 (m,1 H), 7.82-7.85 (m, 2H), 7.57 (d, J = 8Hz, 1 H), 6.37 (d, J =12Hz, 1 H), 6.26 (d, J = 8Hz, 1 H), 4.97-5.00 (m, 1 H), 1.05 (bs, 1 H), 4.12 (s, 3H), 3.17 (d, J = 8Hz, 2H), 2.07 (bs, 1 H), 1 .24- 1 .67 (m,1 1 H). Example 15: Preparation of Compounds 188 and 189
Figure imgf000197_0001
Intermediate 268 / Intermediate 269
268: ethyl 4-((3-chloro-4-(((S)-1 -(5-methoxy-2-(trif luoromethyl)pyridin-4- yl)ethyl)amino)benzamido)methyl)cyclohex-3-enecarboxylate
Figure imgf000197_0002
269: (S)-ethyl 4-((3-chloro-4-((1 -(5-methoxy-2-(trif luoromethyl)pyridin-4- yl)ethyl)amino)benzamido)methyl)-4-fluorocyclohexanecarboxylate
Figure imgf000198_0001
To a solution of (S)-ethyl 4-((3-chloro-4-((1 -(5-methoxy-2-(t fluoromethyl)pyridin-4- yl)ethyl)amino)benzamido)methyl)-4-hydroxycyclohexanecarboxylate (80 mg, 0.143 mmol) in Dichloromethane (6 mL) at -78 °C was added DAST (0.1 mL, 0.757 mmol) and the reaction allowed to stir at -78 °C for 20 min. Saturated aqueous NaHC03 was added and the mixture allowed to warm to rt. The aqueous mixture was extracted with DCM (2 x 10 mL) and the combined organic layers dried over sodium sulfate. The organic layer was then filtered and concentrated to dryness. The residue obtained was purified by prep HPLC (MeCN containing 0.1 % TFA) to provide a mixture of the desired products ethyl 4-((3-chloro-4-(((S)-1 -(5- methoxy-2-(trifluoromethyl)pyridin-4-yl)ethyl)amino)benzamido)methyl)cyclohex-3- enecarboxylate (17 mg, 0.031 mmol, 21 .96 % yield) and (S)-ethyl 4-((3-chloro-4-((1 -(5- methoxy-2-(trifluoromethyl)pyridin-4-yl)ethyl)amino)benzamido)methyl)-4- fluorocyclohexanecarboxylate (35 mg, 0.063 mmol, 43.6 % yield). Intermediate 268: m/z: [M + H]+ Calcd for C26H3oCIF4N304 540.2; Found 540. Intermediate 269: m/z: [M + H]+ Calcd for C26H3iCIF4N304 560.2; Found 560.
Compounds 188 and 189
188: 4-((3-chloro-4-(((S)-1 -(5-methoxy-2-(trifluoromethyl)pyridin-4- yl)ethyl)amino)benzamido)methyl)cyclohex-3-enecarboxylic acid
Figure imgf000198_0002
189: (S)-4-((3-chloro-4-((1 -(5-methoxy-2-(trifluoromethyl)pyridin-4- yl)ethyl)amino)benzamido)methyl)-4-fluorocyclohexanecarboxylic acid
Figure imgf000198_0003
solution of (S)-ethyl 4-((3-chloro-4-((1 -(5-methoxy-2-(trifluoromethyl)pyridin-4- yl)ethyl)amino)benzamido)methyl)-4-fluorocyclohexanecarboxylate (35 mg, 0.063 mmol) in Ethanol (3 mL) and Water (0.6 mL) at rt was added lithium hydroxide hydrate (5.25 mg, 0.125 mmol) and the reaction stirred at 40 °C for 16 h. Following completion of the reaction, the mixture was concentrated directly in vacuo. Water (5 mL) was then added to the residue and 1 M aqueous HCI was added until the pH was <4. The resulting aqueous mixture was then extracted with EtOAc (2 x 10 mL). The organic layers were then combined, dried over sodium sulfate, filtered, and concentrated to dryness. The residue obtained was purified by prep HPLC (MeCN containing 0.1 % TFA) to provide the desired products 4-((3-chloro-4-(((S)-1 - (5-methoxy-2-(trifluoromethyl)pyridin-4-yl)ethyl)amino)benzamido)methyl)cyclohex-3- enecarboxylic acid (20 mg, 0.039 mmol, 62.5 % yield) and (S)-4-((3-chloro-4-((1 -(5-methoxy- 2-(trifluoromethyl)pyridin-4-yl)ethyl)amino)benzamido)methyl)-4- fluorocyclohexanecarboxylic acid (10 mg, 0.019 mmol, 30.1 % yield). Example 187: m/z: [M + H]+ Calcd for C24H26CIF3N3O4 512.1 ; Found 512. 1H NM (400 MHz, MeOD) δ 8.46 (s, 1 H), 7.83 (s, 1 H), 7.69 (1 H), 7.52 (d, J = 8Hz, 1 H), 6.37 (d, J = 12Hz, 1 H), 5.60 (bs, 1 H), 5.06-5.09 (m, 1 H), 4.16 (s, 3H), 3.85 (s, 2H), 2.49-2.52 (m, 1 H), 2.20-2.28 (m, 2H), 2.00-2.12 (m, 3H), 1 .65-1 .75 (m, 1 H), 1 .61 (d, J = 8Hz, 3H). Example 188: m/z: [M + H]+ Calcd for C24H27CIF4N3O4 532.2; Found 532. 1 H NMR (400 MHz, MeOD) δ 8.46 (s, 1 H), 7.83 (s, 1 H), 7.69 (s, 1 H), 7.52 (dd, J = 4, 8Hz, 1 H), 6.38 (d, J = 8Hz, 1 H), 5.05-5.09 (m, 1 H), 4.17 (s, 3H), 3.3 (d, J = 20 Hz, 2H), 2.51 -2.55 (m, 1 H), 1.70-1 .90 (m, 8H), 1 .61 (d, J = 8Hz, 3H). Example 16: Preparation of Compound 190
Figure imgf000199_0001
Intermediate 270:(S)-tert-butyl 4-((3-chloro-4-((1 -(5-methoxy-2- (trifluoromethyl)pyridin-4-yl)ethyl)amino)benzamido)methyl)-4-(2-ethoxy-2- oxoethyl)piperidine-1 -carboxylate
Figure imgf000200_0001
To a solution of (S)-3-chloro-4-((1 -(5-methoxy-2-(t fluoromethyl)pyridin-4- yl)ethyl)amino)benzoic acid (330 mg, 0.837 mmol) in A/,A/-Dimethylformamide (10 mL) stirred in air at rt was added HATU (414 mg, 1 .088 mmol), tert-butyl 4-(aminomethyl)-4-(2-ethoxy-2- oxoethyl)piperidine-1 -carboxylate trifluoroacetic acid salt (429 mg, 1 mmol), and triethylamine (847 mg, 8.37 mmol). The reaction mixture was stirred at 25 °C for 16 h. Following completion of the reaction, the mixture was concentrated directly and the residue obtained was purified by flash chromatography on silica gel (PE/EtOAc = 1/1 ) to provide the desired product (S)-tert-butyl 4-((3-chloro-4-((1 -(5-methoxy-2-(trifluoromethyl)pyridin-4- yl)ethyl)amino)benzamido)methyl)-4-(2-ethoxy-2-oxoethyl)piperidine-1 -carboxylate (200 mg, 0.304 mmol, 36.4% yield) as a white solid, m/z: [M + H]+ Calcd for C3iH4iCIF3N406 657.3; Found 657.
Intermediate 271 : (S)-ethyl 2-(4-((3-chloro-4-((1 -(5-methoxy-2-(trifluoromethyl)pyridin- 4-yl)ethyl)amino)benzamido)methyl)piperidin-4-yl)acetate
Figure imgf000200_0002
To a solution of (S)-tert-butyl 4-((3-chloro-4-((1 -(5-methoxy-2-(trifluoromethyl)pyridin-4- yl)ethyl)amino)benzamido)methyl)-4-(2-ethoxy-2-oxoethyl)piperidine-1 -carboxylate (150 mg, 0.228 mmol) in DCM (25 mL) stirred in air at rt was added 2,2,2-trifluoroacetic acid (500 mg, 4.39 mmol). The reaction mixture was stirred at 25 °C for 16 h. Following completion of the reaction, the mixture was concentrated directly and the residue obtained was purified by prep HPLC (MeCN containing 0.1 % TFA) to provide the desired product (S)-ethyl 2-(4-((3-chloro- 4-((1 -(5-methoxy-2-(trifluoromethyl)pyridin-4-yl)ethyl)amino)benzamido)methyl)piperidin-4- yl)acetate (120 mg, 0.215 mmol, 94% yield) as a white solid, m/z: [M + H]+ Calcd for C26H33CIF3N404 557.2; Found 557. Compound 190: (S)-2-(4-((3-chloro-4-((1 -(5-methoxy-2-(trifluoromethyl)pyridin-4- yl)ethyl)amino)benzamido)methyl)piperidin-4-yl)acetic acid
Figure imgf000201_0001
To a solution of (S)-ethyl 2-(4-((3-chloro-4-((1 -(5-methoxy-2-(t fluoromethyl)pyridin-4- yl)ethyl)amino)benzamido)methyl)pipe din-4-yl)acetate (70 mg, 0.126 mmol) in MeOH (5 mL) and Water (1 mL) stirred in air at rt was added lithium hydroxide hydrate (10.55 mg, 0.251 mmol). The reaction mixture was stirred at 45 °C for 16 h. Following completion of the reaction, the mixture was concentrated directly in vacuo. Water (5 mL) was then added to the residue and 1 M aqueous HCI was added until the pH was <4. The resulting aqueous mixture was then extracted with EtOAc (2 x 10 mL). The organic layers were then combined, dried over sodium sulfate, filtered, and concentrated to dryness. The residue obtained was purified by prep HPLC (MeCN containing 0.1 % TFA) to provide the desired product (S)-2-(4-((3- chloro-4-((1 -(5-methoxy-2-(trifluoromethyl)pyridin-4- yl)ethyl)amino)benzamido)methyl)piperidin-4-yl)acetic acid (35 mg, 0.066 mmol, 52.7% yield) as white solid, m/z: [M + H]+ Calcd for C24H29CIF3N404 529.2; Found 529.1 . 1H NMR (400 MHz, d6-DMSO) δ 8.56 (s, 1 H), 8.1 1 -8.30 (m, 2H), 7.82 (s, 1 H), 7.81 (s, 1 H), 7.56 (d, J = 8.8Hz, 1 H), 6.37 (d, J = 8.8 Hz, 1 H), 6.3 (d, J =8Hz, 1 H), 4.97-5.00 (m, 1 H), 4.12 (s, 3H), 3.40 (d, J = 6.4Hz, 2H), 3.18 (bs, 2H), 3.05 (bs, 2H), 2.38 (s, 2H), 1 .56-1 .64 (m,4H), 1 .54 (d, J = 8Hz, 3H).
Example 17: Preparation of Compounds 191 and 192
Figure imgf000201_0002
Intermediate 272: 4-chloro-1 -methoxy-2-(prop-1 -en-2-yl)benzene
Figure imgf000202_0001
To a suspension of Methyltriphenylphosphonium bromide (10.06 g, 28.2 mmol) in THF (100 ml.) at 0 °C was added nBuLi (17.60 ml_, 28.2 mmol) and the mixture stirred 10 min. The reddish solution was then cooled to -78 °C and a solution of 1 -(5-chloro-2- methoxyphenyl)ethanone (4 g, 21.67 mmol) in THF (10 mL) was added. The reaction mixture was allowed to warm to rt and stirred 16 h. Saturated aqueous ammonium chloride solution (80 mL) was then added and the resulting aqueous mixture extracted with EA (2 x 200 mL). The combined organic layers were then dried over sodium sulphate, filtered, and concentrated to dryness. The residue obtained was purified by flash chromatography on silica gel (PE/EtOAc = 3/1 ) to provide the desired product 4- chloro-1 -methoxy-2-(prop-1 -en-2- yl)benzene (3 g, 16.43 mmol, 76 % yield), m/z: [M + H]+ Calcd for C10H12CIO 183.0; Found 183.
Intermediate 273: Methyl 5-chloro-6-(2-(5-chloro-2-methoxyphenyl)propyl)nicotinate
Figure imgf000202_0002
To a solution of 4-chloro-1 -methoxy-2-(prop-1 -en-2-yl)benzene (1 .0 g, 5.48 mmol) in Tetrahydrofuran (30 mL) was added 9-BBN (0.663 g, 2.74 mmol). The resulting mixture was stirred at 80 °C for 4 h. The reaction solution was then cooled to rt and transferred to a flask containing a solution of methyl 5,6- dichloronicotinate (0.564 g, 2.74 mmol) and TEA (3.82 mL, 27.4 mmol) in A/,A/-Dimethylformamide (30 mL)/Water (3 mL). Solid PdCI2(dppf) (200 mg, 0.274 mmol) was then added and the mixture stirred and heated at 80 °C under nitrogen for 16 h. Following completion of the reaction, the mixture was allowed to cool to rt and then diluted with ethyl acetate (100 mL). The organic layer was then washed with water and brine. The washed organic layer was then dried over sodium sulphate, filtered, and concentrated to dryness. The residue obtained was purified by flash chromatography on silica gel (PE/EtOAc = 5/1 ) to provide the desired product methyl 5- chloro-6-(2-(5-chloro-2- methoxyphenyl)propyl)nicotinate (0.7 g, 1 .976 mmol, 36.1 % yield), m/z: [M + H]+ Calcd for C17H18CI2NO3 354.1 ; Found 354. Intermediate 274: 5-chloro-6-(2-(5-chloro-2-methoxyphenyl)propyl)nicotinic acid
Figure imgf000203_0001
To a solution of methyl 5-chloro-6-(2-(5-chloro-2-methoxyphenyl)propyl)nicotinate (0.7 g, 1 .976 mmol) in Tetrahydrofuran (10 mL) and Water (10 mL) was added lithium hydroxide hydrate (0.415 g, 9.88 mmol). The resulting mixture was stirred at rt for 16 h. Following completion of the reaction, the mixture was concentrated directly in vacuo. Water (50 mL) was then added to the residue and 1 M aqueous HCI was added until the pH was <4. The resulting aqueous mixture was then extracted with EtOAc (100 mL). The organic layer was then dried over sodium sulfate, filtered, and concentrated to dryness to provide the desired product 5-chloro-6-(2-(5-chloro-2-methoxyphenyl)propyl)nicotinic acid (0.54 g, 1 .587 mmol, 80 % yield) that was used without further purification, m/z: [M + H]+ Calcd for C16H16CI2NO3 340.0; Found 340.
Intermediate 275: trans-methyl 4-((5-chloro-6-(2-(5-chloro-2- methoxyphenyl)propyl)nicotinamido)methyl)cyclohexanecarboxylate
Figure imgf000203_0002
A mixture of HATU (30.7 mg, 0.081 mmol), DIPEA (0.028 mL, 0.162 mmol), 5-chloro-6-(2-(5- chloro-2-methoxyphenyl)propyl)nicotinic acid (1 1 mg, 0.032 mmol), and trans-methyl 4- (aminomethyl)cyclohexanecarboxylate (8.31 mg, 0.049 mmol) in Dichloromethane (10 mL) was stirred for 4 hours at rt. Following completion of the reaction, the mixture was concentrated in vacuo and the residue taken up in EA (20 mL). The organic solution was washed with water (20 mL) and the washed organic layer then dried over sodium sulfate, filtered, and concentrated to dryness to provide the desired product trans-methyl 4-((5-chloro- 6-(2-(5-chloro-2-methoxyphenyl)propyl)nicotinamido)methyl)cyclohexanecarboxylate (20 mg, 0.020 mmol, 61 .4 % yield) as red oil that was used without further purification, m/z: [M + H]+ Calcd for C25H31CI2N2C 493.2; Found 493.1 . Compounds 191 and 192: trans-4-((5-chloro-6-(2-(5-chloro-2- methoxyphenyl)propyl)nicotinamido)methyl)cyclohexanecarboxylic acid
Figure imgf000204_0001
A mixture of trans-methyl 4-((5-chloro-6-(2-(5-chloro-2- methoxyphenyl)propyl)nicotinamido)methyl)cyclohexanecarboxylate (200 mg, 0.405 mmol) and NaOH (162 mg, 4.05 mmol) in Methanol (20 mL) and Water (5 mL) was stirred for 2 h at rt. Following completion of the reaction, the mixture was concentrated directly in vacuo. Water (5 mL) was then added to the residue and 2M aqueous HCI was added until the pH was <4. The resulting aqueous mixture was then extracted with EtOAc (2 x 20 mL). The organic layers were then combined, dried over sodium sulfate, filtered, and concentrated to dryness. The residue obtained was purified by flash chromatography on silica gel (DCM/MeOH = 20/1 ) to provide the desired product as a mixture of enantiomers. The enantiomers were then seperated by chiral-HPLC to afford trans-4-((5-chloro-6-(2-(5-chloro-2- methoxyphenyl)propyl)nicotinamido)methyl)cyclohexanecarboxylic acid (35 mg, 0.073 mmol, 17.99 % yield) as white solid and trans-4-((5-chloro-6-(2-(5-chloro-2- methoxyphenyl)propyl)nicotinamido)methyl)cyclohexanecarboxylic acid (40 mg, 0.083 mmol, 20.56 % yield) as white solid. Example 191 (Enantiomer 1 ) m/z: [M + H]+ Calcd for C24H29CIN204 479.1 ; Found 479.1 . 1 H NMR (400 MHz, MeOD) δ 8.76 (d, J = 2Hz, 1 H), 8.16 (d, J = 2Hz, 1 H), 7.22 (d, J = 2Hz, 1 H), 7.13 (dd, J = 2.0, 8.8Hz, 1 H), 6.8 (d, J = 8.8Hz, 1 H), 3.67-3.86 (m, 1 H), 3.34 (s, 3H), 3.20-3.33 (m, 4H), 2.19-2.25 (m, 1 H), 2.03 (dd, J = 2, 13 Hz, 2H), 1 .88 (dd, J = 2,13 Hz, 2H), 1 .61 -1 .64 (m, 1 H), 1 .47 (q, J = 12 Hz, 2H), 1 .29 (d, J = 8Hz, 3H), 1 .05 (q, J = 12Hz, 2H). Example 192 (Enantiomer 2) m/z: [M + H]+ Calcd for C24H29CIN204 479.1 ; Found 479.1 . 1 H NMR (400 MHz, MeOD) δ 8.76 (d, J = 2Hz, 1 H), 8.16 (d, J = 2Hz, 1 H), 7.22 (d, J = 2Hz, 1 H), 7.13 (dd, J = 2.0, 8.8Hz, 1 H), 6.8 (d, J = 8.8Hz, 1 H), 3.67-3.86 (m, 1 H), 3.34 (s, 3H), 3.20-3.33 (m, 4H), 2.19-2.25 (m, 1 H), 2.03 (dd, J = 2, 13 Hz, 2H), 1 .88 (dd, J = 2,13 Hz, 2H), 1 .61 -1 .64 (m, 1 H), 1 .47 (q, J = 12 Hz, 2H), 1 .29 (d, J = 8Hz, 3H), 1 .05 (q, J = 12Hz, 2H).
Example 18: Preparation of Compounds 193 and 194
Figure imgf000205_0001
Intermediate 276: methyl 3-cyano-4-(1 -(2-ethyl-5-methoxypyridin-4- yl)ethoxy)benzoate
Figure imgf000205_0002
To a solution of 1 -(2-ethyl-5-methoxypy din-4-yl)ethanol (160 mg, 0.883 mmol) in Dimethyl Sulfoxide (3ml_) at rt was added methyl 3-cyano-4-fluorobenzoate (237 mg, 1 .324 mmol) and CS2CO3 (719 mg, 2.207 mmol). The reaction mixture was stirred at 80 °C for 16 h.
The reaction mixture was then allowed to cool to rt and water (30ml_) was added. The resulting aqueous solution was then extracted with EA (2 x 30 ml_). The organic layers were then combined, dried over sodium sulfate, filtered, and concentrated to dryness. The residue obtained was purified by flash chromatography on silica gel (PE/EtOAc = 4/1 ) to provide the desired product methyl 3-cyano-4-(1 -(2-ethyl-5-methoxypyridin-4-yl)ethoxy)benzoate (140 mg, 0.41 1 mmol, 46.6 % yield), m/z: [M + H]+ Calcd for Ci9H2iN204 341 .1 ; Found 341 .
Intermediate 277: (S)-3-cyano-4-(1 -(2-ethyl-5-methoxypyridin-4-yl)ethoxy)benzoic acid
Figure imgf000206_0001
To a solution of methyl 3-cyano-4-(1 -(2-ethyl-5-methoxypyhdin-4-yl)ethoxy)benzoate (140 mg, 0.41 1 mmol) in Methanol (3 mL) and Water (0.6 mL) at rt was added lithium hydroxide hydrate (34.5 mg, 0.823 mmol) and the mixture stirred at rt overnight. Following completion of the reaction, the mixture was concentrated directly in vacuo. Water (5 mL) was then added to the residue and 1 M aqueous HCI was added until the pH was <4. The aqueous solution was then concentrated directly to provide the desired product 3-cyano-4-(1-(2-ethyl-5- methoxypyridin-4-yl)ethoxy)benzoic acid that was used directly in the following reaction, m/z: [M + H]+ Calcd for Ci8Hi9N204 327.1 ; Found 327 Intermediate 278 and Intermediate 279: trans-methyl 4-((3-cyano-4-(1 -(2-ethyl-5- methoxypyridin-4-yl)ethoxy)benzamido)methyl)cyclohexanecarboxylate
Figure imgf000206_0002
To a solution of (S)-3-cyano-4-(1 -(2-ethyl-5-methoxypyridin-4-yl)ethoxy)benzoic acid (140 mg, 0.429 mmol) in A/,A/-Dimethylformamide (3 mL) at rt was added HATU (245 mg, 0.643 mmol), trans-methyl 4-(aminomethyl)cyclohexanecarboxylate hydrochloride (1 16 mg, 0.558 mmol), and triethylamine (1 mL, 7.17 mmol). The reaction mixture was stirred at rt for 16 h. Following completion of the reaction, water (15 mL) was added and the resulting aqueous mixture was extracted with EA (2 x 15 mL). The combined organics were the dried over sodium sulfate, filtered, and concentrated to dryness. The residue obtained was purified by chiral chromatography to provide the desired products trans-methyl4-((3-cyano-4-((S)-1 -(2- ethyl-5-methoxypyridin-4- yl)ethoxy)benzamido)methyl)cyclohexanecarboxylate (40 mg, 0.083 mmol, 19.44 % yield) and trans-methyl 4-((3- cyano-4-((R)-1 -(2-ethyl-5- methoxypyridin-4- yl)ethoxy)benzamido)methyl)cyclohexanecarboxylate (34 mg, 0.071 mmol, 16.53 % yield), m/z: [M + H]+ Calcd for C27H34N305 480.2; Found 480
Compound 193: trans-4-((3-cyano-4-((S)-1 -(2-ethyl-5-methoxypyridin
yl)ethoxy)benzamido)methyl)cyclohexanecarboxylic (Enantiomer 1 )
Figure imgf000207_0001
To a solution of trans-methyl 4-((3-cyano-4-((S)-1 -(2-ethyl-5-methoxypyridin-4- yl)ethoxy)benzamido)methyl)cyclohexanecarboxylate (40 mg, 0.083 mmol) in Methanol (3 mL) and Water (0.6 mL) at rt was added lithium hydroxide hydrate (7.00 mg, 0.167 mmol) and the reaction stirred at 30 °C for 16 h. Following completion of the reaction, the mixture was concentrated directly in vacuo. Water (5 mL) was then added to the residue and 1 M aqueous HCI was added until the pH was <4. The resulting aqueous mixture was then concentrated directly and the residue obtained was purified by prep HPLC (MeCN containing 0.1 % TFA) to provide the desired product trans-4-((3-cyano-4-((S)-1 -(2-ethyl-5- methoxypyridin-4- yl)ethoxy)benzamido)methyl)cyclohexanecarboxylic acid (30 mg, 0.064 mmol, 77% yield), m/z: [M + H]+ Calcd for C26H32N3O5 466.2; Found 466. 1H NMR (400 MHz, de-DMSO) δ 8.54 - 8.44 (m, 2H), 8.25 (d, J = 2.2 Hz, 1 H), 8.04 (dd, J = 8.9, 2.2 Hz, 1 H), 7.58 (s, 1 H), 7.14 (d, J = 9.0 Hz, 1 H), 5.96 (q, J = 6.2 Hz, 1 H), 4.04 (s, 3H), 3.09 (t, J = 6.2 Hz, 2H), 2.82 (q, J = 7.5 Hz, 2H), 2.13 (ddd, J = 12.1 , 8.8, 3.4 Hz, 1 H), 1 .89 (d, J = 10.7 Hz, 2H), 1 .76 (d, J = 10.6 Hz, 2H), 1 .64 (d, J = 6.3 Hz, 3H), 1 .47 (s, 1 H), 1 .27 (dd, J = 12.9, 10.2 Hz, 2H), 1 .20 (t, J = 7.6 Hz, 3H), 0.94 (dd, J = 23.7, 1 1 .1 Hz, 2H).
Compound 194: trans-4-((3-cyano-4-((/?)-1 -(2-ethyl-5-methoxypyridin-4- yl)ethoxy)benzamido)methyl)cyclohexanecarboxylic acid (Enantiomer 2)
Figure imgf000207_0002
To a solution trans-methyl 4-((3- cyano-4-((f?)-1 -(2-ethyl-5-methoxypyridin-4- yl)ethoxy)benzamido)methyl)cyclohexanecarboxylate (34 mg, 0.071 mmol) in Methanol (3 mL) and Water (0.6 mL) at rt was added lithium hydroxide hydrate (5.95 mg, 0.142 mmol) and the reaction stirred at 30 °C for 16 h. Following completion of the reaction, the mixture was concentrated directly in vacuo. Water (5 mL) was then added to the residue and 1 M aqueous HCI was added until the pH was <4. The resulting aqueous mixture was then concentrated directly and the residue obtained was purified by prep HPLC (MeCN containing 0.1 % TFA) to provide the desired product trans-4-((3-cyano-4-((R)-1 -(2-ethyl-5- methoxypyridin-4-yl)ethoxy)benzamido)methyl)cyclohexanecarboxylic acid (27 mg, 0.058 mmol, 82 % yield), m/z: [M + H]+ Calcd for C26H32N3O5 466.2; Found 466. 1H NMR (400 MHz, de-DMSO) δ 8.51 - 8.40 (m, 2H), 8.24 (dd, J = 1 1 .2, 2.2 Hz, 1 H), 8.03 (dd, J = 8.9, 2.1 Hz, 1 H), 7.57 (s, 1 H), 7.14 (d, J = 9.1 Hz, 1 H), 5.96 (q, J = 6.4 Hz, 1 H), 4.03 (s, 3H), 3.09 (t, J = 6.2 Hz, 2H), 2.82 (q, J = 7.6 Hz, 2H), 2.13 (ddd, J = 12.0, 8.7, 3.5 Hz, 1 H), 1 .89 (d, J = 10.7 Hz, 2H), 1 .76 (d, J = 10.6 Hz, 2H), 1 .64 (d, J = 6.3 Hz, 3H), 1 .47 (s, 1 H), 1 .30 - 1 .23 (m, 2H), 1 .20 (t, J = 7.6 Hz, 3H), 0.95 (dd, J = 23.7, 1 1 .2 Hz, 2H).
The following compounds were synthesized using a similar procedure to that described in Example 18 for Compound 194.
Figure imgf000208_0001
6.94 (d, J = 9.0 Hz, 1H), 5.87
(dd, J = 6.8, 2.8 Hz, 1H), 3.94 (s, 3H), 3.71 (qd, J = 11.3, 4.9 Hz, 2H), 3.37 (s, 3H), 3.09 (d, J = 6.9 Hz, 2H), 2.69 -2.49 (m, 2H), 2.10 (d, J = 8.2 Hz, 1H), 1.90 (d, J = 12.2 Hz, 2H), 1.75 (d, J = 11.7 Hz, 2H), 1.48 (s, 1H), 1.36-1.24 (m, 2H), 1.09 (t, J = 7.6 Hz, 3H), 0.93 (dd, J = 23.9, 11.5 Hz, 2H). methyl 3- 1- (6-ethyl-3- trans-methyl 4- 49 1H NMR(500 MHz, MeOD) δ cyano-4- methoxypyridin- (aminomethyl)cy 6.3 8.09 (d, J = 2Hz, 1H), 7.91 fluorobenzoa 2- yl)-2- clohexanecarbox (dd, J = 2, 9Hz, 1H), 7.41 (d, te methoxyethanol ylate J = 8.5Hz, 1H), 7.20 (d, J =
8.5Hz, 1H), 6.00 (dd, J = .03, 8.5Hz, 1H), 4.14 (dd, J = 8.5, 11 Hz, 1H), 3.94 (s, 3H), 3.89 (dd, J = 3.0, 11.5 Hz, 1H), 3.51 (s, 3H),3.33 (s, 3H), 3.2 (d, J = 7Hz, 2H), 2.68-2.72 (m, 2H), 2.20-2.33 (m, 1H), 2.01 (d, J = 11.5, 2H), 1.86 (d, J = 11.5, 2H), 1.50-1.60 (m, 1H), 1.40(q, J = 12Hz, 2H), 1.17 (t, 7.5Hz, 3H), 1.05 (q, J = 12Hz, 2H)ppm methyl 3- 1- (6-ethyl-3- trans-methyl 4- 49 1H NMR(500 MHz, MeOD) δ cyano-4- methoxypyridin- (aminomethyl)cy 6.3 8.09 (d, J = 2Hz, 1H), 7.91 fluorobenzoa 2- yl)-2- clohexanecarbox (dd, J = 2, 9Hz, 1H), 7.41 (d, te methoxyethanol ylate J = 8.5Hz, 1H), 7.20 (d, J = 8.5Hz, 1H), 6.00 (dd, J = .03,
8.5Hz, 1H), 4.14 (dd, J = 8.5, 11 Hz, 1H), 3.94 (s, 3H), 3.89 (dd, J = 3.0, 11.5 Hz, 1H), 3.51 (s, 3H),3.33 (s, 3H), 3.2 (d, J = 7Hz, 2H), 2.68-2.72 (m, 2H), 2.20-2.33 (m, 1H), 2.01 (d, J = 11.5, 2H), 1.86 (d, J = 11.5, 2H), 1.50-1.60 (m, 1H), 1.40(q, J = 12Hz, 2H), 1.17 (t, 7.5Hz, 3H), 1.05 (q, J = 12Hz, 2H)ppm methyl 3- 2-methoxy-1 - trans-methyl 4- 51 1H NMR (500 MHz, MeOD) |A cyano-4- (5-methoxy-2- (aminomethyl)cy 3 8.54 (s, 1H), 8.16 (d, J = 2.1 fluorobenzoa (trifluoromethyl) clohexanecarbox Hz, 1H), 8.00 (dd, J = 8.9, 2.1 te pyridin-4- ylate Hz, 1H), 7.81 (s, 1H), 7.13 (d, yl)ethanol J = 9.0 Hz, 1H), 6.07 (t, J =
4.5 Hz, 1H), 4.18 (s, 3H), 3.88 (d, J = 4.5 Hz, 2H), 3.47 (s, 3H), 3.22 (d, J = 6.9 Hz, 2H), 2.24 (t, J = 12.2 Hz, 1H), 2.02 (d, J = 11.0 Hz, 2H), 1.88 (d, J = 11.4 Hz, 2H), 1.61 (s, 1H), 1.48 C 1.33 (m, 2H), 1.15 "C 0.95 (m, 2H). methyl 3- 2-methoxy-1 - trans-methyl 4- 51 1H NMR (500 MHz, MeOD) |A cyano-4- (5-methoxy-2- (aminomethyl)cy 3 8.42 (s, 1H), 8.04 (d, J = 2.1 fluorobenzoa (trifluoromethyl) clohexanecarbox Hz, 1H), 7.88 (dd, J = 8.9, 2.2 te pyridin-4- ylate Hz, 1H), 7.69 (s, 1H), 7.01 (d, yl)ethanol J = 9.0 Hz, 1H), 5.94 (t, J =
4.6 Hz, 1H), 4.05 (s, 3H), 3.75 (d, J = 4.5 Hz, 2H), 3.35 (s, 3H), 3.09 (t, J = 9.7 Hz,
2H), 2.12 (t, J = 12.3 Hz, 1H), 1.90 (d, J = 11.5 Hz, 2H), 1.76 (d, J = 10.9 Hz, 2H), 1.49 (s, 1H), 1.36 C 1.24 (m, 2H), 1.02 C0.88 (m, 2H)
201 methyl 3- 1-(3-methoxy- trans-methyl 4- 50 1H NMR (400 MHz, MeOD) δ cyano-4- 6- (aminomethyl)cy 6.1 8.44-8.46 (m, 1H), 8.18 (s, fluorobenzoa (trifluoromethyl) clohexanecarbox 1H), 8.01 (d, J = 8Hz, 1H), te pyridin-2- ylate 7.88 (d, J = 8Hz, 1H), 7.72 (d, yl)ethanol J = 8Hz, 1H), 7.13 (d, J =
8Hz,1H), 6.03-6.07 (m, 1H), 3.96 (s, 3H), 3.08 (t, J = 4Hz, 2H), 2.11-2.14 (m, 2H), 1.85 (d, J = 12Hz, 2H), 1.77 (d, J = 12Hz, 2H), 1.68 (d, J = 4Hz, 3H), 1.18-1.21 (m, 1H), 1.23 (q, J = 12Hz, 2H), 0.94 (q, J = 12Hz, 2H) ppm
202 methyl 3- 1-(3-methoxy- trans-methyl 4- 50 1H NMR (400 MHz, dmso-d6) cyano-4- 6- (aminomethyl)cy 6.1 58.45 (t, J = 6Hz, 1H), 8.18 fluorobenzoa (trifluoromethyl) clohexanecarbox (s, 1H), 8.01 (dd, J = 4Hz, te pyridin-2- ylate 8Hz, 1H), 7.87 (d, J = 8Hz, yl)ethanol 1H), 7.71 (d, J = 8Hz, 1H),
7.13 (d, J = 4Hz, 1H), 6.05 (dd, J = 4, 12Hz, 1H), 3.96 (s, 3H), 3.08 (t, J = 6Hz, 1H), 2.09-2.11 (m, 1H), 1.85 (d, J = 12Hz, 2H), 1.77 (d, J = 12Hz, 2H), 1.68 (d, J = 6Hz, 3H), 1.46-1.50 (m, 1H), 1.23 (q, J = 12Hz, 2H), 0.94 (q, J =
12Hz, 2H) ppm
203 methyl 3- 2-methoxy-1 - trans-methyl 4- 53 1H NMR (500 MHz, MeOD) |A cyano-4- (3-methoxy-6- (aminomethyl)cy 5.8 8.52 (s, 1 H), 8.10 (d, J = 2.2 fluorobenzoa (trifluoromethyl) clohexanecarbox Hz, 1 H), 7.96 (dd, J = 8.9, 2.3 te pyridin-2- ylate Hz, 1 H), 7.76 (d, J = 8.6 Hz, yl)ethanol 1 H), 7.64 (d, J = 8.7 Hz, 1 H),
7.16 (d, J = 9.0 Hz, 1 H), 6.08 (dd, J = 7.7, 3.5 Hz, 1 H), 4.16
(dd, J = 1 1.1 , 7.7 Hz, 1 H), 4.05 "0 3.93 (m, 4H), 3.51 (s, 3H), 3.37 (s, 2H), 3.22 (d, J = 6.7 Hz, 2H), 2.25 (s, 1 H), 2.03 (d, J = 10.2 Hz, 2H), 1.88 (d, J = 10.8 Hz, 2H), 1.61 (s, 1 H), 1.42 (d, J = 16.2 Hz, 2H), 1.06 (d, J = 15.3 Hz,
2H).
204 methyl 3- 1- (6-ethyl-3- trans-methyl 4- 46 1H NMR (400 MHz, dmso-d6) cyano-4- methoxypyridin- (aminomethyl)cy 6.1 5 8.42 (t, J = 6Hz, 1 H), 8.18 fluorobenzoa 2- yl)ethanol clohexanecarbox (s, 1 H), 7.96 (dd, J = 2Hz, te ylate 8Hz, 1 H), 7.43 (d, J = 8Hz,
1 H), 7.19 (d, J = 8Hz, 1 H), 7.08 (d, J = 8Hz, 1 H), 5.97 (q, J = 4Hz, 1 H), 3.85 (s, 3H), 3.07 (t, J = 6Hz, 2H), 2.60- 2.64 (m, 2H), 2.09-2.11 (m, 1 H), 1.76 (d, J = 12Hz, 2H), 1.66 (d, J = 6Hz, 3H), 1.46- 1.50 (m, 1 H), 1.23 (q, J = 12Hz, 2H), 1.09 (t, J = 6Hz, 3H), 0.96 (q, J = 12Hz, 2H) ppm
205 methyl 3- 1-(6-ethyl-3- trans-methyl 4- 46 1H NMR (400 MHz, dmso-d6) cyano-4- methoxypyridin- (aminomethyl)cy 6.2 58.42 (t, J = 6Hz, 1H), 8.16 fluorobenzoa 2-yl)ethanol clohexanecarbox (s, 1H), 7.96 (dd, J = 2Hz, te ylate 8Hz, 1H), 7.43 (d, J = 8Hz,
1H), 7.19 (d, J = 8Hz, 1H),
7.08 (d, J = 8Hz, 1H), 5.97 (q,
J = 4Hz, 1H), 3.85 (s, 3H),
3.07 (t, J = 6Hz, 2H), 2.50-
2.64 (m, 2H), 2.09-2.13 (m,
1H), 1.76 (d, J = 12Hz, 2H),
1.66 (d, J = 6Hz, 3H), 1.46-
1.50 (m, 1H), 1.24 (q, J =
12Hz, 2H), 1.09 (t, J = 8Hz,
3H), 0.96 (q, J = 8Hz, 2H) ppm
206 methyl 3- 1-(5-methoxy- trans-methyl 4- 50 1H NMR (400 MHz, DMSO) cyano-4- 2- (aminomethyl)cy 6.1 |A 8.63 (s, 1H), 8.48 (s, 1H), fluorobenzoa (trifluoromethyl) clohexanecarbox 8.24 (s, 1H), 8.04 (d, J = 8.0 te pyridin-4- ylate Hz, 1H), 7.80 (s, 1H), 7.21 (d, yl)ethanol J = 8.2 Hz, 1H), 5.98 (d, J =
4.4 Hz, 1H), 4.10 (s, 3H),
3.08 (s, 2H), 2.12 (s, 1H),
1.89 (d, J = 11.5 Hz, 2H),
1.76 (d, J = 11.2 Hz, 2H),
1.63 (d, J = 3.3 Hz, 3H), 1.47
(s, 1H), 1.25 (d, J = 11.2 Hz,
2H), 0.99 "C 0.90 (m, 2H).
207 methyl 3- 1-(5-methoxy- trans-methyl 4- 50 1H NMR (400 MHz, DMSO) cyano-4- 2- (aminomethyl)cy 6.1 |A 8.63 (s, 1H), 8.47 (s, 1H), fluorobenzoa (trifluoromethyl) clohexanecarbox 8.24 (s, 1H), 8.05 (d, J = 7.9 te pyridin-4- ylate Hz, 1H), 7.80 (s, 1H), 7.21 (d, yl)ethanol J = 8.5 Hz, 1H), 5.99 (d, J =
5.1 Hz, 1H), 4.10 (s, 3H), 3.08 (s, 2H), 2.10 (s, 2H), 1.89 (d, J = 10.9 Hz, 2H), 1.76 (d, J = 11.0 Hz, 2H), 1.63 (d, J = 3.8 Hz, 3H), 1.47 (s, 2H), 1.25 (d, J = 8.7 Hz, 3H), 0.94 (d, J = 11.7 Hz, 2H).
Figure imgf000214_0001
Intermediate 280: 3-(1-chloroethyl)-4-methoxybenzonitrile
Figure imgf000214_0002
To a solution of 3-(1-hydroxyethyl)-4-methoxybenzonitrile (200 mg, 1.129 mmol) in Dichloromethane (5 mL) at 0 °C was added methanesulfonyl chloride (0.159 ml_, 2.257 mmol) and DMAP (6.89 mg, 0.056 mmol). The resulting mixture was stirred at 35 °C for 12 h. Following completion of the reaction the solvent was evaporated directly to provide the crude product 3-(1 -chloroethyl)-4-methoxybenzonitrile (210 mg, 0.751 mmol, 66.6 % yield) as a yellow oil that was used without further purification, m/z: [M + H]+ Calcd for CioHnCINO 196.0; Found 196.0. Intermediate 281 : methyl 3-chloro-4-(1 -(5-cyano-2-methoxyphenyl)ethoxy)benzoate
Figure imgf000215_0001
To a solution of 3-(1 -chloroethyl)-4-methoxybenzonitrile (210 mg, 1 .073 mmol) and methyl 3- chloro-4-hydroxybenzoate (210 mg, 1 .127 mmol) in acetonitrile (5 mL) was added K2CO3 (297 mg, 2.147 mmol) and the mixture was stirred at 70 °C for 12 h. The reaction was then allowed to cool to rt and filtered. The filtrated was then concentrated to dryness and the residue obtained purified by preparative HPLC [water (0.05% TFA)/MeCN gradient] to provide the desired product methyl 3-chloro-4-(1 -(5-cyano-2-methoxyphenyl)ethoxy)benzoate (263 mg, 0.327 mmol, 30.5 % yield) as a white solid, m/z: [M + Na]+ Calcd for Ci8Hi7CIN04 368.1 ; Found 368.0. Intermediate 282: 3-chloro-4-(1-(5-cyano-2-methoxyphenyl)ethoxy)benzoic acid
Figure imgf000215_0002
A solution of methyl 3-chloro-4-(1 -(5-cyano-2-methoxyphenyl)ethoxy)benzoate (263 mg, 0.761 mmol) and LiOH (91 mg, 3.80 mmol) in Tetrahydrofuran (2 mL) and Water (1 mL) was stirred at 45 °C for 5 h. Following completion of the reaction the solvent was evaporated. Water (2 mL) was then added and the resulting aqueous mixture washed with ethyl acetate (2 2 mL). The organic layer was discarded and the aqueous layer acidified to pH <4 with 1 M aqueous HCI. The acidic aqueous layer was then extracted with ethyl acetate (2 x 5 mL) and the combined organic layers then concentrated to dryness to provide the desired product 3- chloro-4-(1 -(5-cyano-2-methoxyphenyl)ethoxy)benzoic acid (240 mg, 0.572 mmol, 75 % yield) as a white solid that was used without further purification, m/z: [M + Na]+ Calcd for Ci7Hi4CINaN04 354.1 ; Found 354.0. Intermediate 283: trans-methyl 4-((3-chloro-4-(1 -(5-cyano-2- methoxyphenyl)ethoxy)benzamido)methyl)cyclohexanecarboxylate
Figure imgf000216_0001
To a solution of 3-chloro-4-(1 -(5-cyano-2-methoxyphenyl)ethoxy)benzoic acid (240 mg, 0.723 mmol) in A/,A/-Dimethylformamide (2 mL) was added trans-methyl 4- (aminomethyl)cyclohexanecarboxylate (124 mg, 0.723 mmol), HATU (330 mg, 0.868 mmol), and DIPEA (0.253 mL, 1 .447 mmol). The reaction was allowed to stir 2 h at rt. Following completion of the reaction, water (5 mL) was added and the resulting aqueous mixture extracted with EA (3 x 5 mL). The combined organic layers were then concentrated to dryness and the residue obtained purified by prep-HPLC [water(0.05% TFA)/CH30H gradient] to afford the product trans-methyl 4-((3-chloro-4-(1 -(5-cyano-2- methoxyphenyl)ethoxy)benzamido)methyl)cyclohexanecarboxylate (250 mg, 0.222 mmol, 30.6 % yield) as a yellow solid, m/z: [M + H]+ Calcd for C26H30CIN2O5 485.2; Found 485.1 .
Intermediate 284 and Intermediate 285: trans-methyl 4-((3-chloro-4-(1 -(5-cyano-2- methoxyphenyl)ethoxy)benzamido)methyl)cyclohexanecarboxylate (Enantiomer 1 )/ (Enantiomer 2)
Figure imgf000216_0002
A solution of trans-methyl 4-((3-chloro-4-(1 -(5-cyano-2- methoxyphenyl)ethoxy)benzamido)methyl)cyclohexanecarboxylate (230 mg, 0.474 mmol) in Methanol (5 mL) was purified by chiral-HPLC to afford the two products trans-methyl 4-((3- chloro-4-(1 -(5-cyano-2-methoxyphenyl)ethoxy)benzamido)methyl)cyclohexanecarboxylate (Enantiomer 1 ) (100 mg, 0.198 mmol, 41 .7% yield) and trans-methyl 4-((3-chloro-4-(1 -(5- cyano-2-methoxyphenyl)ethoxy)benzamido)methyl)cyclohexanecarboxylate (Enantiomer 2) (120 mg, 0.215 mmol, 45.4% yield) as yellow oil. m/z: [M + H]+ Calcd for C26H30CIN2O5 485.2; Found 485.0 m/z: [M + H]+ Calcd for C26H30CIN2O5 485.2; Found 485.1
Compound 208: trans-4-((3-chloro-4-(1 -(5-cyano-2- methoxyphenyl)ethoxy)benzamido)methyl)cyclohexanecarboxylic acid (Enantiomer 1 )
Figure imgf000217_0001
A solution of trans-methyl 4-((3-chloro-4-(1 -(5-cyano-2- methoxyphenyl)ethoxy)benzamido)methyl)cyclohexanecarboxylate (Enantiomer 1 ) (120 mg, 0.247 mmol) and LiOH (29.6 mg, 1 .237 mmol) in Tetrahydrofuran (2 mL) and Water (1 mL) was stirred at 40 °C for 2 h. Following completion of the reaction, the mixture was concentrated directly in vacuo. Water (2 mL) was then added to the residue and 1 M aqueous HCI was added until the pH was <4. The resulting aqueous mixture was then extracted with ethyl acetate (3 x 5 mL). The combined organic layers were then dried over sodium sulfate, filtered and concentrated. The residue obtained was purified by prep HPLC [water (0.1 % TFA)/MeCN gradient] to provide the desired product trans-4-((3-chloro-4-(1 -(5-cyano-2- methoxyphenyl)ethoxy)benzamido)methyl)cyclohexanecarboxylic acid (Enantiomer 1 ) (31 mg, 0.066 mmol, 26.6 % yield).
Enantiomer 1 . m/z: [M + H]+ Calcd for C25H28CIN2O5 471 .2; Found 471 .0.
1 H NMR (400 MHz, CDCI3) δ 7.90 (d, J = 2Hz, 1 H),7.62-7.69 (m, 3H), 7.22 (d, J = 6.8Hz, 1 H), 6.90 (d, J = 6.8Hz, 1 H), 5.92 (q, J = 4.8Hz, 1 H), 4.03 (s, 3H), 3.20 (d, J = 5.6Hz, 2H), 2.22- 2.28 (m, 1 H), 2.02 (d, J = 12Hz, 2H), 1 .87 (d, J = 12 Hz, 2H), 1 .65 (d, J = 8Hz, 3H), 1 .55-1 .58 (m, 1 H), 1.35-1 .46 (m, 2H), 0.99-1 .09 (m, 2H).
Compound 209: trans-4-((3-chloro-4-(1 -(5-cyano-2- methoxyphenyl)ethoxy)benzamido)methyl)cyclohexanecarboxylic acid (Enantiomer 2)
Figure imgf000218_0001
Synthesized by essentially the same procedure as for Compound 208.
Enantiomer 2. m/z: [M + H]+ Calcd for C25H28CIN2O5 471 .2; Found 471 .0. 1H NMR (400 MHz, CDC ) δ 7.90 (d, J = 2Hz, 1 H),7.62-7.69 (m, 3H), 7.22 (d, J = 6.8Hz, 1 H), 6.90 (d, J = 6.8Hz, 1 H), 5.92 (q, J = 4.8Hz, 1 H), 4.03 (s, 3H), 3.20 (d, J = 5.6Hz, 2H), 2.22-2.28 (m, 1 H), 2.02 (d, J = 12Hz, 2H), 1 .87 (d, J = 12 Hz, 2H), 1 .65 (d, J = 8Hz, 3H), 1 .55-1 .58 (m, 1 H), 1 .35-1 .46 (m, 2H), 0.99-1 .09 (m, 2H).
The following compounds were synthesized using a similar procedure to that described in for Compounds 208 and 209.
Figure imgf000218_0002
1H), 3.95 (s, 3H), 3.28 (t, J =
6.2 Hz, 2H), 2.27 (d, J = 11.6
Hz, 1H), 2.05 (d, J = 13.0 Hz,
2H), 1.87 (d, J = 11.0 Hz, 3H),
1.64 (d, J = 6.3 Hz, 3H), 1.56
(b, 1H), 1.49- 1.36 (m, 3H),
1.12-0.96 (m, 2H).
212 methyl 3- 2-(1- trans-methyl 4- 49 1H NMR (500 MHz, CDCI3) δ= chloro-4- chloroethyl)-4- (aminomethyl)cy 7.8 7.93 (d, J = 1.7 Hz, 1H), 7.78 hydroxybenz fluoro-1- clohexanecarbox (dd, J = 8.7, 2.0 Hz, 1H), 7.04 oate methoxybenzen ylate (dd, J = 9.0, 3.1 Hz, 1H), 6.96 e -6.87 (m, 1H), 6.85-6.75 (m,
2H), 6.11 (s, 1H), 5.81 (q, J = 6.3 Hz, 1H), 3.90 (s, 3H), 3.28 (t, J = 6.3 Hz, 2H), 2.27 (t, J = 12.1 Hz, 1H), 2.04 (d, J = 11.8 Hz, 2H), 1.87 (d, J = 11.4 Hz, 2H), 1.61 (d, J = 6.3 Hz, 3H), 1.57 (b, 1H), 1.48-1.31 (m, 2H), 1.03 (m, 2H).
213 methyl 3- 2-(1- trans-methyl 4- 49 1H NMR (500 MHz, CDCI3) δ= chloro-4- chloroethyl)-4- (aminomethyl)cy 7.8 7.93 (d, J = 1.7 Hz, 1H), 7.78 hydroxybenz fluoro-1- clohexanecarbox (dd, J = 8.7, 2.0 Hz, 1H), 7.04 oate methoxybenzen ylate (dd, J = 9.0, 3.1 Hz, 1H), 6.96 e -6.87 (m, 1H), 6.85-6.75 (m,
2H), 6.11 (s, 1H), 5.81 (q, J = 6.3 Hz, 1H), 3.90 (s, 3H), 3.28 (t, J = 6.3 Hz, 2H), 2.27 (t, J = 12.1 Hz, 1H), 2.04 (d, J = 11.8 Hz, 2H), 1.87 (d, J = 11.4 Hz, 2H), 1.61 (d, J = 6.3 Hz, 3H), 1.57 (b, 1H), 1.48-1.31 (m,
2H), 1.03 (m, 2H).
214 methyl 3- 3-(1-hydroxy-2- trans-methyl 4- 50 1H NMR (500 MHz, MeOD) δ= chloro-4- methoxyethyl)- (aminomethyl)cy 1.1 7.78 (d, J = 2.2 Hz, 1H), 7.58 hydroxybenz 4- clohexanecarbox (dd, J = 8.6, 2.1 Hz, 1H), 7.53 oate methoxybenzon ylate (d, J = 2.1 Hz, 1H), 7.50 (dd, J itrile = 8.7, 2.2 Hz, 1H), 7.11 (d, J =
8.7 Hz, 1H), 6.78 (d, J = 8.8 Hz, 1H), 5.83 (dd, J = 6.8, 2.8 Hz, 1H), 3.93 (s, 3H), 3.67 (m, 2H), 3.37 (s, 3H), 3.07 (d, J =
6.9 Hz, 2H), 2.12-2.01 (m, 1H), 1.88 (d, J = 11.5 Hz, 2H), 1.74 (d, J = 12.4 Hz, 2H), 1.48
(d, J = 3.7 Hz, 1H), 1.29 (m, 2H), 0.91 (q, J = 11.8 Hz, 2H).
215 methyl 3- 3-(1-hydroxy-2- trans-methyl 4- 50 1H NMR (500 MHz, MeOD) δ= chloro-4- methoxyethyl)- (aminomethyl)cy 1.1 7.78 (d, J = 2.2 Hz, 1H), 7.58 hydroxybenz 4- clohexanecarbox (dd, J = 8.6, 2.1 Hz, 1H), 7.53 oate methoxybenzon ylate (d, J = 2.1 Hz, 1H), 7.50 (dd, J itrile = 8.7, 2.2 Hz, 1H), 7.11 (d, J =
8.7 Hz, 1H), 6.78 (d, J = 8.8 Hz, 1H), 5.83 (dd, J = 6.8, 2.8 Hz, 1H), 3.93 (s, 3H), 3.67 (m, 2H), 3.37 (s, 3H), 3.07 (d, J =
6.9 Hz, 2H), 2.12-2.01 (m, 1H), 1.88 (d, J = 11.5 Hz, 2H), 1.74 (d, J = 12.4 Hz, 2H), 1.48
(d, J = 3.7 Hz, 1H), 1.29 (m, 2H), 0.91 (q, J = 11.8 Hz, 2H).
Example 20: Preparation of Compound 216
Figure imgf000221_0001
Intermediate 286: methyl 3-chloro-4-(1 -(2-methoxyphenyl)ethoxy)benzoate
Figure imgf000221_0002
To a solution of methyl 3-chloro-4-hydroxybenzoate (2.4 g, 12.86 mmol) and 1 -(2- methoxyphenyl)ethanol (2.349 g, 15.43 mmol) in Tetrahydrofuran (120 mL) was added PP i3 (6.07 g, 23.15 mmol). The mixture was then cooled to 0 °C and DIAD (5.00 mL, 25.7 mmol) was added dropwise. The reaction was allowed to stir at 0 °C for 0.5 h then warmed to rt and stirred 16 h. Following completion of the reaction, the mixture was concentrated directly in vacuo and the residue obtained was purified by flash chromatography on silica gel (PE/EtOAc = 10/1 ) to provide the desired product methyl 3-chloro-4-(1 -(2- methoxyphenyl)ethoxy)benzoate (1 .7 g, 4.05 mmol, 31 .5% yield) as yellow solid, m/z: [M + Na]+ Calcd for C26H33CINaN206 343.1 ; Found 343.0.
Intermediate 287: 3-chloro-4-(1-(2-methoxyphenyl)ethoxy)benzoic acid
Figure imgf000221_0003
To a mixture of methyl 3-chloro-4-(1 -(2-methoxyphenyl)ethoxy)benzoate (1 .7 g, 5.30 mmol) in Tetrahydrofuran (10 mL) and Water (5 mL) was added lithium hydroxide hydrate (2.224 g, 53.0 mmol). The resulting mixture was allowed to stir 16 h at rt. Following completion of the reaction, the mixture was concentrated directly in vacuo. Water (5 mL) was then added to the residue and 1 M aqueous HCI was added until the pH was <4 at which point solid had precipitated from solution. The resulting slurry was then filtered to provide 3-chloro-4-(1 -(2- methoxyphenyl)ethoxy)benzoic acid (1 .5 g, 4.00 mmol, 75 % yield) as yellow solid that was used without further purification, m/z: [M - H]" Calcd for Ci6Hi4CI04 305.1 ; Found 305.
Intermediate 288: benzyl 3-((3-chloro-4-(1 -(2- methoxyphenyl)ethoxy)benzamido)methyl)cyclobutanecarboxylate
Figure imgf000222_0001
A solution of triethylamine (0.491 mL, 3.52 mmol), HATU (669 mg, 1 .76 mmol), benzyl 3- (aminomethyl)cyclobutanecarboxylate hydrochloride (300 mg, 1 .17 mmol), and 3-chloro-4- (1 -(2-methoxyphenyl)ethoxy)benzoic acid (360 mg, 1 .17 mmol) in DMF (2 mL) was stirred 16 h at rt. Following completion of the reaction, the solution was directly purified by prep HPLC [water (0.1 % TFA)/MeCN gradient] to provide the desired product benzyl 3-((3-chloro-4-(1 - (2-methoxyphenyl)ethoxy)benzamido)methyl)cyclobutanecarboxylate (250 mg, 0.443 mmol, 37.8% yield) as light yellow solid, m/z: [M + H]+ Calcd for C29H31CINO5 508.2; Found 508.1 .
Compound 216: 3-((3-chloro-4-(1 -(2- methoxyphenyl)ethoxy)benzamido)methyl)cyclobutanecarboxylic acid
Figure imgf000222_0002
To a solution of benzyl 3-((3-chloro-4-(1 -(2- methoxyphenyl)ethoxy)benzamido)methyl)cyclobutanecarboxylate (300 mg, 0.591 mmol) in Methanol (4mL) was added LiOH (42.4 mg, 1 .772 mmol) and the resulting mixture was stirred for 2 h at 25 °C. Following completion of the reaction, the mixture was concentrated directly in vacuo. The residue obtained was washed with diethyl ether. Water (5 mL) was then added to the residue and 1 M aqueous HCI was added until the pH was <4. The resulting aqueous mixture was then extracted with ethyl acetate (30 mL) and the organic phase washed with brine. The washed organic layer was then dried over sodium sulfate, filtered, and concentrated to dryness to provide the desired product 3-((3-chloro-4-(1 -(2- methoxyphenyl)ethoxy)benzamido)methyl)cyclobutanecarboxylic acid (150 mg, 0.355 mmol, 60.2 % yield) as white solid without the need for further purification, m/z: [M + H]+ Calcd for C22H25CINO5 418.1 ; Found 418. 1H NMR (400 MHz, CDC ) δ 7.75 (dd, J = 4.0, 2.1 Hz, 1 H), 7.45 (dd, J = 5.2, 2.3 Hz, 1 H), 7.34 (d,J = 7.5 Hz, 1 H), 7.21 (t, J = 7.7 Hz, 1 H), 6.88 (dd, J = 13.0, 7.8 Hz, 2H), 6.72 (d, J = 8.7 Hz, 1 H),6.45 (d, J = 52.4 Hz, 1 H), 5.80 (d, J = 6.3 Hz, 1 H), 3.88 (s, 3H), 3.38 (d, J = 28.9 Hz, 2H), 3.01 (d, J= 50.2 Hz, 1 H), 2.50 (d, J = 32.5 Hz, 1 H), 2.28 (s, 2H), 1 .97 (s, 2H), 1 .63 (d, J = 6.1 Hz, 3H).
The following compounds were synthesized using a similar procedure to that described in Example 20 for Compound 216.
Figure imgf000223_0001
2.25-2.18 (m, 1H), 2.04-2.03 (m,
2H), 1.89-1.86 (m, 2H), 1.61 (m,
4H), 1.47-1.37 (m, 2H), 1.10-
1.00 (m, 2H).
220 methyl 5- 1-(5-fluoro-2- trans-methyl 4- 46 HNMR : 1H NMR (500 MHz, chloro-6- methoxyphe (aminomethyl)cyclo 6.1 MeOD) 5=8.46 (d, J = 3Hz, 1 H), hydroxynicotin nyl)ethanol hexanecarboxylate 8.19 (d, J = 3Hz, 1H), 7.11 (dd, ate J = 3 , 11.5 Hz, 1H), 6.98-6.94
(m, 2H), 6.59 (q, J = 8Hz, 1H), 3.88 (s, 3H), 3.21 (d, J = 8.5 Hz,
2H), 2.23-2.17 (m, 1H), 2.02- 1.98 (m, 2H), 1.88-1.84 (m, 2H), 1.59 (d, J = 8Hz, 4H), 1.46-1.36 (m, 2H), 1.09-1.02 (m, 2H).
221 methyl 5- 3-(1- trans-methyl 4- 47
chloro-6- hydroxyethyl (aminomethyl)cyclo 2.0
hydroxynicotin )-4- hexanecarboxylate
ate methoxyben
zonitrile
222 methyl 5- 3-(1- trans-methyl 4- 47
chloro-6- hydroxyethyl (aminomethyl)cyclo 2.0
hydroxynicotin )-4- hexanecarboxylate
ate methoxyben
zonitrile
Example 21 : Preparation of Compounds 223 and 224
Figure imgf000225_0001
Intermediate 289: 3-chloro-4-(1-(6-ethyl-3-methoxypyridin-2-yl)-2- methoxyethoxy)benzonitrile
Figure imgf000225_0002
To a solution of 1 -(6-ethyl-3-methoxypy din-2-yl)-2-methoxyethanol (150 mg, 0.710 mmol) and 3-chloro-4-fluorobenzonit le (1 10 mg, 0.710 mmol) in A/,A/-Dimethylformamide (8 mL) at 0 °C was added sodium hydride (29.8 mg, 0.746 mmol) and the reaction allowed to stir 5 h at 0 °C. Following completion of the reaction, the solvent was removed in vacuo and the residue obtained was purified by flash chromatography on silica gel (PE/EtOAc = 10/1 ) to provide the desired product 3-chloro-4-(1-(6-ethyl-3-methoxypyridin-2-yl)-2- methoxyethoxy)benzonitrile (200 mg, 0.461 mmol, 65.0% yield) as white solid, m/z: [M + H]+ Calcd for C18H20CIN2O3 347.1 ; Found 347.
Intermediate 290: 3-chloro-4-(1-(6-ethyl-3-methoxypyridin-2-yl)-2- methoxyethoxy)benzoic acid
Figure imgf000225_0003
To a solution of 3-chloro-4-(1 -(6-ethyl-3-methoxypyridin-2-yl)-2-methoxyethoxy)benzonitrile (300 mg, 0.865 mmol) in EtOH (10 mL) was added sodium hydroxide (346 mg, 8.65 mmol) and the reaction allowed to stir 12 h at 95 °C. Following completion of the reaction, the mixture was cooled to rt and concentrated in vacuo. Water (5 mL) was then added to the residue and 1 M aqueous HCI was added until the pH was <4. The resulting mixture was then concentrated directly to provide the desired product 3-chloro-4-(1-(6-ethyl-3-methoxypyridin-2-yl)-2- methoxyethoxy)benzoic acid (300 mg, 0.697 mmol, 81 % yield) as a yellow oil that was used without further purification, m/z: [M + H]+ Calcd for Ci8H2iCIN05 366.1 ; Found 366.
Intermediate 291 : trans-methyl 4-((3-chloro-4-(1 -(6-ethyl-3-methoxypyridin-2-yl)-2- methoxyethoxy)benzamido)methyl)cyclohexanecarboxylate
Figure imgf000226_0001
To a solution of 3-chloro-4-(1 -(6-ethyl-3-methoxypyridin-2-yl)-2-methoxyethoxy)benzoic acid (300 mg, 0.820 mmol) in DMF (2 mL) was added trans-methyl 4- (aminomethyl)cyclohexanecarboxylate (140 mg, 0.820 mmol), HATU (468 mg, 1 .230 mmol) and DIPEA (159 mg, 1 .230 mmol). The resulting mixture was stirred 16 h at rt. Following completion of the reaction, water was added and the resulting aqueous mixture extracted with EA (3 x 50 mL). The combined organic layers were then washed with saturated aqueous sodium bicarbonate, water, and brine. The washed organic layer was then dried over MgS04, filtered, and concentrated to dryness to provide the desired product trans-methyl 4-((3-chloro- 4-(1 -(6-ethyl-3-methoxypyridin-2-yl)-2- methoxyethoxy)benzamido)methyl)cyclohexanecarboxylate (350 mg, 0.539 mmol, 65.8% yield) as a white solid that was used without further purification. m/z: [M + H]+ Calcd for C27H36CIN2O6 519.2; Found 519.
Intermediate 292: trans-4-((3-chloro-4-(1 -(6-ethyl-3-methoxypyridin
methoxyethoxy)benzamido)methyl)cyclohexanecarboxylic acid
Figure imgf000226_0002
To a solution of trans-methyl 4-((3-chloro-4-(1-(6-ethyl-3-methoxypyridin-2-yl)-2- methoxyethoxy)benzamido)methyl)cyclohexanecarboxylate (350 mg, 0.674 mmol) in MeOH (10 mL) at rt was added sodium hydroxide (270 mg, 6.74 mmol). The resulting mixture was stirred for 1 hr at rt. Following completion of the reaction, the mixture was concentrated directly and the residue obtained was purified by prep HPLC [water (0.1 % TFA)/MeCN gradient] to provide the desired product trans-4-((3-chloro-4-(1 -(6-ethyl-3-methoxypyridin-2- yl)-2-methoxyethoxy)benzamido)methyl)cyclohexanecarboxylic acid (100 mg, 0.188 mmol, 27.9% yield) as a white solid. m/z: [M + H]+ Calcd for C26H34CIN206 505.2; Found 505. 1H NMR (500 MHz, MeOD) 7.85 (d, J = 2.2 Hz, 1 H), 7.58 (dd, J = 8.7, 2.2 Hz, 1 H), 7.41 (d, J = 8.5 Hz, 1 H), 7.20 (d, J = 8.5 Hz, 1 H), 6.95 (d, J = 8.8 Hz, 1 H), 5.93 (dd, J = 7.8, 3.8 Hz, 1 H), 4.20 - 4.05 (m, 1 H), 3.92 (s, 3H), 3.87 (dd, J = 1 1 .0, 3.7 Hz, 1 H), 3.49 (s, 3H), 3.19 (d, J = 6.9 Hz, 2H), 2.72 (q, J = 7.5 Hz, 2H), 2.17 (s, 1 H), 1 .99 (d, J = 1 1 .5 Hz, 2H), 1 .85 (d, J = 1 1 .2 Hz, 2H), 1 .60 (s, 1 H), 1 .42 (dd, J = 23.2, 12.7 Hz, 2H), 1 .18 (t, J = 7.6 Hz, 3H), 1 .03 (dd, J = 23.9, 1 1 .1 Hz, 2H). Separation
trans-4-((3-chloro-4-(1 -(6-ethyl-3-methoxypyridin-2-yl)-2- methoxyethoxy)benzamido)methyl)cyclohexanecarboxylic acid (150 mg, 0.297 mmol) was performed by using a AD-H column (5 μιη, 4.6x250 mm), at a column temperature of 35°C. Instrument: SFC-80 (Thar, Waters)
Column: AD 4.6*250mm, 5um (Decial)
Column temperature: 35 °C
Mobile phase: C02/ MeOH (0.2%Methanol Ammonia)= 80/20
Flow rate: 80 g/min
Back pressure: 100 bar
Detection wavelength: 214 nm
Cycle time: 6.5 min
Sample solution: 100mg dissolved in 20ml Methanol
Injection volume: 1 .0 ml Compound 223: trans-4-((3-chloro-4-(1 -(6-ethyl-3-methoxypyridin-2-yl)-2- methoxyethoxy)benzamido)methyl)cyclohexanecarboxylic acid (Enantiomer 1 )
Figure imgf000228_0001
m/z: [M + H]+ Calcd for C26H34CIN206 505.2; Found 505.
1 H NMR (500 MHz, MeOD) 7.73 (d, J = 2.2 Hz, 1 H), 7.46 (dd, J = 8.7, 2.2 Hz, 1 H), 7.28 (d, J = 8.5 Hz, 1 H), 7.08 (d, J = 8.5 Hz, 1 H), 6.83 (d, J = 8.7 Hz, 1 H), 5.80 (dd, J = 7.8, 3.7 Hz, 1 H), 4.09 "C 3.93 (m, 1 H), 3.80 (s, 3H), 3.75 (dd, J = 1 1 .0, 3.7 Hz, 1 H), 3.37 (s, 3H), 3.07 (d, J = 6.9 Hz, 2H), 2.60 (q, J = 7.6 Hz, 2H), 2.09 (s, 1 H), 1 .89 (d, J = 1 1 .6 Hz, 2H), 1 .74 (d, J = 1 1 .0 Hz, 2H), 1 .47 (s, 1 H), 1 .37- 1 .22 (m, 2H), 1 .06 (t, J = 7.6 Hz, 3H), 0.91 (dd, J = 23.9, 1 1 .3 Hz, 2H).
Compound 224: trans-4-((3-chloro-4-(1 -(6-ethyl-3-methoxypyridin-2-yl)-2- methoxyethoxy)benzamido)methyl)cyclohexanecarboxylic acid (Enantiomer 2)
Figure imgf000228_0002
m/z: [M + H]+ Calcd for C26H34CIN2O6 505.2; Found 505.
1 H NMR (500 MHz, MeOD) 7.85 (d, J = 2.2 Hz, 1 H), 7.58 (dd, J = 8.7, 2.2 Hz, 1 H), 7.41 (d, J = 8.5 Hz, 1 H), 7.20 (d, J = 8.5 Hz, 1 H), 6.95 (d, J = 8.7 Hz, 1 H), 5.92 (dd, J = 7.8, 3.7 Hz, 1 H), 4.1 1 (dt, J = 28.1 , 14.1 Hz, 1 H), 3.92 (s, 3H), 3.87 (dd, J = 1 1 .0, 3.7 Hz, 1 H), 3.49 (s, 3H), 3.19 (d, J = 6.9 Hz, 2H), 2.72 (q, J = 7.6 Hz, 2H), 2.24 (s, 1 H), 2.02 (d, J = 1 1 .0 Hz, 2H), 1 .87 (d, J = 1 1 .2 Hz, 2H), 1 .60 (bs, 1 H), 1 .49-1 .34 (m, 2H), 1 .19 (t, J = 7.6 Hz, 3H), 1 .04 (dd, J = 25.2, 10.4 Hz, 2H).
The following compounds were synthesized using a similar procedure to that described in Example 21 for Compound 224.
Figure imgf000228_0003
225 4-fluoro-3- (S)-1-(5-fluoro-2- trans-methyl 498 1H NMR(400 MHz,
(trifluoromethyl) methoxyphenyl)e 4- .1 MeOD) δ 8.09 (d, J-1.6 benzonitrile thanol (aminomethyl) Hz, 1H), 7.89 (dd, J = cyclohexanec 2.0 Hz, 8.8Hz, 1H), arboxylate 6.93-7.04 (m, 4H), 5.93
(dd, J = 2Hz, 8.6Hz, 1H), 3.94 (s, 3H), 3.2 (d, J = 7.2 Hz, 2H), 2.16-2.18 (m, 1H), 1.99 (d, J = 11 Hz, 2H), 1.85 (d, 11 Hz, 2H), 1.61 (d, 6.4Hz, 4H), 1.3-1.5 (m, 2H), 0.98-1.1 (m, 2H).
226 3-chloro-4- 1-(2-ethyl-5- trans-methyl 475 1H NMR(500 MHz, fluorobenzonitril methoxypyridin- 4- .1 MeOD) δ 7.77 (dd, J = e 4-yl)ethanol (aminomethyl) 6.8, 2.2 Hz, 1H), 7.54- cyclohexanec 7.41 (m, 1H), 6.79 (d, J arboxylate = 8.7 Hz, 1H), 5.68 (q,
J = 6.3 Hz, 1H), 3.90 (s, 2H), 3.08 (d, J = 6.9 Hz, 1H), 2.52-2.34 (m, 1H), 2.10 (d, J = 11.6 Hz, 1H), 1.90 (d, J = 14.0 Hz, 1H), 1.75 (d, J = 11.2 Hz, 1H), 1.52 (t, J = 15.5 Hz, 2H), 1.30 (q, J = 12.7 Hz, 1H), 1.03 (t, J = 7.6 Hz, 2H), 0.92 (dd, J = 23.8, 11.5 Hz, 1H). 227 3-chloro-4- 1-(2-ethyl-5- trans-methyl 475 1H NMR(500 MHz, fluorobenzonitril methoxypyridin- 4- .2 MeOD) δ 7.77 (dd, J = e 4-yl)ethanol (aminomethyl) 6.8, 2.2 Hz, 1H), 7.54- cyclohexanec 7.41 (m, 1H), 6.79 (d, J arboxylate = 8.7 Hz, 1H), 5.68 (q,
J = 6.3 Hz, 1H), 3.90 (s, 2H), 3.08 (d, J = 6.9 Hz, 1H), 2.52-2.34 (m, 1H), 2.10 (d, J = 11.6 Hz, 1H), 1.90 (d, J = 14.0 Hz, 1H), 1.75 (d, J = 11.2 Hz, 1H), 1.52 (t, J = 15.5 Hz, 2H), 1.30 (q, J = 12.7 Hz, 1H), 1.03 (t, J = 7.6 Hz, 2H), 0.92 (dd, J = 23.8, 11.5 Hz, 1H).
228 3-chloro-4- 1-(2- trans-methyl 497 1H NMR(500 MHz, fluorobenzonitril (difluoromethyl)- 4- MeOD) δ 8.28 (s, 1H), e 5- (aminomethyl) 7.90 (d, J = 2.2 Hz, methoxypyridin- cyclohexanec 2H), 7.65 (dd, J = 8.6, 4-yl)ethanol arboxylate 2.2 Hz, 1H), 6.95 (d, J
= 8.7 Hz, 1H), 6.78 (s, 1H), 5.84 (dd, J = 12.5,
6.2 Hz, 1H), 4.10 (s, 3H), 3.20 (d, J = 6.9 Hz, 2H), 2.21 (s, 1H), 2.01 (d, J = 11.9 Hz, 2H), 1.87 (d, J = 11.4 Hz, 2H), 1.68 (d, J =
6.3 Hz, 3H), 1.61 (s, 1H), 1.46- 1.37 (m, 2H), 1.04 (dd, J = 23.8,
11.4 Hz, 2H).
229 3-chloro-4- 1-(2- trans-methyl 1H NMR(500 MHz, fluorobenzonitril (difluoromethyl)- 4- MeOD) δ 8.28 (s, 1H), e 5- (aminomethyl) 7.90 (d, J = 2.2 Hz, methoxypyridin- cyclohexanec 2H), 7.65 (dd, J = 8.6, 4-yl)ethanol arboxylate 2.2 Hz, 1H), 6.95 (d, J
= 8.7 Hz, 1H), 6.78 (s, 1H), 5.84 (dd, J = 12.5,
6.2 Hz, 1H), 4.10 (s, 3H), 3.20 (d, J = 6.9 Hz, 2H), 2.21 (s, 1H), 2.01 (d, J = 11.9 Hz, 2H), 1.87 (d, J = 11.4 Hz, 2H), 1.68 (d, J =
6.3 Hz, 3H), 1.61 (s, 1H), 1.46- 1.37 (m, 2H), 1.04 (dd, J = 23.8, 11.4 Hz, 2H).
230 3-chloro-4- 1-(5-chloro-2- trans-methyl 510 1H NMR(500 MHz, fluorobenzonitril methoxyphenyl)- 4- .0 MeOD) δ= 7.95-7.84 e 2- (aminomethyl) (m, 2H), 7.41 (dd, J = methoxyethanol cyclohexanec 7.0, 1.7 Hz, 1H), 6.43- arboxylate 6.33 (m, 2H), 6.03 (s,
1H), 3.70 (d, J = 17.6 Hz, 3H), 3.13-3.05 (m, 1H), 2.92 (s, 4H), 2.27 (s, 3H), 1.28- 1.12 (m, 2H). 231 3-chloro-4- 1-(5-chloro-2- trans-methyl 510 1H NMR(500 MHz, fluorobenzonitril methoxyphenyl)- 4- .0 MeOD) δ= 7.95-7.84 e 2- (aminomethyl) (m, 2H), 7.41 (dd, J = methoxyethanol cyclohexanec 7.0, 1.7 Hz, 1H), 6.43- arboxylate 6.33 (m, 2H), 6.03 (s,
1H), 3.70 (d, J = 17.6 Hz, 3H), 3.13-3.05 (m, 1H), 2.92 (s, 4H), 2.27 (s, 3H), 1.28- 1.12 (m, 2H).
232 3-chloro-4- 1-(2-ethyl-5- trans-methyl 505 1H NMR(500 MHz, fluorobenzonitril methoxypyridin- 4- MeOD)5=8.08 (s, 1H), e 4-yl)-2- (aminomethyl) 7.79 (d, J = 2.2 Hz, methoxyethanol cyclohexanec 1H), 7.51 (dd, J = 8.7, arboxylate 2.2 Hz, 1H), 7.15 (s,
1H), 6.78 (d, J = 8.8 Hz, 1H), 5.81 (dd, J = 6.6, 2.9 Hz, 1H), 3.93 (s, 3H), 3.70 (qd, J = 11.3, 4.8 Hz, 2H), 3.37 (s,3H), 3.06 (d, J = 6.9 Hz, 2H), 2.67 "C2.51 (m, 2H), 2.01-1.89 (m, 1H), 1.82 (t, J = 15.0 Hz, 2H), 1.72 (d, J = 11.1 Hz, 2H), 1.54-1.41 (m, 1H), 1.36-1.21 (m, 2H), 1.12-0.99 (m, 3H), 0.89 (dt, J = 12.7, 10.1 Hz, 2H). 233 3-chloro-4- 1-(2-ethyl-5- trans-methyl 505 1H NMR(500 MHz, fluorobenzonitril methoxypyridin- 4- MeOD)5= 8.08 (s, 1H), e 4-yl)-2- (aminomethyl) 7.79 (d, J = 2.2 Hz, methoxyethanol cyclohexanec 1H), 7.51 (dd, J = 8.7, arboxylate 2.2 Hz, 1H), 7.15 (s,
1H), 6.78 (d, J = 8.8 Hz, 1H), 5.81 (dd, J = 6.6, 2.9 Hz, 1H), 3.93 (s, 3H), 3.70 (qd, J = 11.3, 4.8 Hz, 2H), 3.37 (s,3H), 3.06 (d, J = 6.9 Hz, 2H), 2.63-2.41 (m, 2H), 1.96 (dd, J = 13.8, 10.5 Hz, 1H), 1.83 (t, J = 14.2 Hz, 2H), 1.72 (d, J = 10.7 Hz, 2H), 1.55- 1.42 (m, 1H), 1.31 (td, J = 13.1, 10.1 Hz, 2H), 1.12-1.01 (m, 4H), 0.89 (dt, J = 12.6, 9.9 Hz, 2H).
234 3-chloro-4- 2-methoxy-1 -(5- trans-methyl 544 1H NMR(500 MHz, fluorobenzonitril methoxy-2- 4- MeOD)8.52 (s, 1H), e (trifluoromethyl)p (aminomethyl) 8.46 (s, 1H), 7.92 (d, J y rid in -4- cyclohexanec = 2.1 Hz, 1H), 7.77 (s, yl)ethanol arboxylate 1H), 7.69 "C 7.62 (m,
1H), 6.99 (d, J = 8.7 Hz, 1H), 5.99 (t, J = 4.4 Hz, 1H), 5.99 (t, J = 4.4 Hz, 1H), 4.17 (s, 3H), 3.86 (d, J = 4.4 Hz, 2H), 3.48 (s, 3H), 3.20
(d, J = 6.4 Hz, 2H), 2.25 (t, J = 12.0 Hz, 1H), 2.07 "C 1.94 (m, 2H), 1.88 (d, J = 11.2 Hz, 2H), 1.61 (s, 1H), 1.47 "C 1.36 (m, 2H), 1.12 C 0.98 (m, 2H).
235 3-chloro-4- 2-methoxy-1 -(3- trans-methyl 545 1H NMR(500 MHz, fluorobenzonitril methoxy-6- 4- MeOD) δ 7.86 (d, J = e (trifluoromethyl)p (aminomethyl) 2.1 Hz, 1H), 7.75 (d, J y rid in -2- cyclohexanec = 8.6 Hz, 1H), 7.61 (t, J yl)ethanol arboxylate = 8.2 Hz, 2H), 7.07 (d,
J = 8.7 Hz, 1H), 5.99 (dd, J = 7.4, 4.0 Hz, 1H), 4.14 (dd, J = 10.8, 7.4 Hz, 1H), 4.02-3.94 (m, 4H), 3.49 (s, 3H), 3.20 (d, J = 6.9 Hz, 2H), 2.25 (t, J = 12.2 Hz, 1H), 2.02 (d, J = 10.7 Hz, 2H), 1.88 (d, J = 11.8 Hz, 2H), 1.61 (s, 1H), 1.42 (dd, J = 24.4, 11.7 Hz, 2H), 1.12- 0.98 (m, 2H).
Example 22: Synthesis of Intermediate compounds
Figure imgf000235_0001
Intermediate 1 : 3-methylenecyclobutanecarboxylic acid
Figure imgf000235_0002
To a solution of 3-methylenecyclobutanecarbonitrile (5.0 g, 53.7 mmol) in Ethanol (20 mL) was added aqueous KOH (35%) (34.4 g, 215 mmol) and the resulting mixture was refluxed overnight.The ethanol was removed under reduced pressure. The solution was then cooled below 10 °C and acidified with concentrated HCI to pH = 5. The mixture was extracted with EtOAc (2x50 mL), the combined organic extracts were dried over anhydrous sodium sulfate and concentrated under vacuum to afford the title compound 3- methylenecyclobutanecarboxylic acid (6 g, 50.8 mmol, 95 % yield) as yellow oil. m/z: [M - H]" Calcd for C6H702 1 1 1 .1 ; Found 1 1 1 .
Intermediate 2: 3-methylenecyclobutanecarboxylic acid
Figure imgf000235_0003
The mixture of 3-methylenecyclobutanecarboxylic acid (6.0g, 53.5 mmol), K2CO3 (14.79 g, 107 mmol) and Me2S04 (7.67 mL, 80 mmol) in Acetone (100 mL) was heated to reflux for 2h. The reaction mixture was cooled to room temperature and filtered. The solvent was removed under reduced pressure. The residue was purified with silica gel chromatography (hexane/EtOAc = 20/1 ) to afford the desired product methyl 3- methylenecyclobutanecarboxylate (6.8 g, 48.5 mmol, 91 % yield) as colorless oil. m/z: [M + H]+ Calcd for C6H802 1 13.1 ; Found 1 13.2.
Intermediate 3: 3-(hydroxymethyl)cyclobutanecarboxylic acid
Figure imgf000236_0001
A dry three-neck flask was charged with methyl 3-methylenecyclobutanecarboxylate (6 g, 47.6 mmol) and dry THF (20 ml) and cooled to -10 °C. BH3.THF (12.26 g, 143 mmol) was then added via a syringe dropwise. The resulting mixture was stirred for 4h at rt and was cooled to -20 °C - 10°C. Methanol was then added and the mixture was stirred for 15min. Sodium hydroxide (3M; 30 ml) and H2O2 (7.29 ml_, 238 mmol) were added in sequence. The mixture was stirred for 2h and a saturated sodium sulfite solution (100 ml) was added. The reaction mixture was diluted with water, then extracted with ethyl acetate, washed with water and brine, dried over sodium sulfate, filtered, and the residue was purified by flash chromatography eluting with (petroleum ether/EtOAc = 3/1 ) to afford methyl 3- (hydroxymethyl)cyclobutanecarboxylate (250 mg, 1 .387 mmol, 2.92 % yield) as a yellow oil.
Intermediate 4: (methyl 3-(((methylsulfonyl)oxy)methyl)cyclobutanecarboxylate)
Figure imgf000236_0002
To a mixture of methyl 3-(hydroxymethyl)cyclobutanecarboxylate (250 mg, 1 .734 mmol), triethylamine (0.363 mL, 2.60 mmol) in THF (20 mL) was added MsCI (0.176 mL, 2.254 mmol) dropwise at 0 °C over 2h. The solvent was removed under reduced pressure to afford the desired product methyl 3-(((methylsulfonyl)oxy)methyl)cyclobutanecarboxylate (300 mg, 1 .080 mmol, 62.3 % yield) as a colorless oil. m/z: [M + H]+ Calcd for C8Hi505S 223.3; Found 223.
Intermediate 5: (methyl 3-(azidomethyl)cyclobutanecarboxylate)
Figure imgf000236_0003
A mixture of methyl 3-(((methylsulfonyl)oxy)methyl)cyclobutanecarboxylate (300 mg, 1 .350 mmol), sodium azide (263 mg, 4.05 mmol) in DMSO (10 mL) was heated to 80 °C and stirred overnight. The reaction mixture was cooled to room temperature and filtered. Water was then added and the mixture was extracted with ethyl acetate (3x50 mL). The filtrate was washed with saturated aqueous NaHCC , water, and brine, then dried over MgS04 and filtered to afford the desired product methyl 3-(azidomethyl)cyclobutanecarboxylate (250 mg, 1 .182 mmol, 88 % yield) as a colorless oil.
Intermediate 6: (methyl 3-(aminomethyl)cyclobutanecarboxylate)
Figure imgf000237_0001
A mixture of methyl 3-(azidomethyl)cyclobutanecarboxylate (250 mg, 1 .478 mmol), Pd/C (15.73 mg, 0.148 mmol) in EtOAc (20 mL) was stirred under a H2 atmosphere overnight. The mixture was filtered and the solvent was removed under reduced pressure to afford the desired product methyl 3-(aminomethyl)cyclobutanecarboxylate (200 mg, 1 .257 mmol, 85 % yield) as a colorless oil. m/z: [M + H]+ Calcd for C7Hi4N02 144.2; Found 144.
Figure imgf000237_0002
Intermediate 7: ethyl 2-(3-cyanocyclobutylidene)acetate
Figure imgf000237_0003
To a suspension of sodium hydride (80 mg, 1 .998 mmol) in dry Tetrahydrofuran (10 mL) cooled to 0 °C with an ice bath was added dropwise a solution of ethyl 2- (diethoxyphosphoryl)acetate (448 mg, 1 .998 mmol) in Tetrahydrofuran (10 mL). The bath was removed and the mixture was stirred for 1 h at rt. The mxiture was then re-cooled to 0 °C with an ice bath and a solution of 3-oxocyclobutanecarbonitrile (190 mg, 1 .998 mmol) in Tetrahydrofuran (2 mL) was then was added dropwise. The resulted mixture was then stirred overnight at rt. Water (20 ml) and diethyl ether (50 ml) were added, the aqueous phase was extracted with diethyl ether (2x20 ml), the combined extracts were washed with water and brine, dired over anhydrous Na2S04 and concentrated to give the title compound ethyl 2-(3- cyanocyclobutylidene)acetate (200 mg, 1 .21 1 mmol, 60.6 % yield) as a clorless oil. m/z: [M + H]+ Calcd for C9H12NO2 166.2; Found 166.
Intermediate 8: ethyl 2-(3-(aminomethyl)cyclobutyl)acetate
Figure imgf000238_0001
To a solution of ethyl 2-(3-cyanocyclobutylidene)acetate (200 mg, 1 .21 1 mmol) in Methanol (10 ml.) was added raney-nickel (50 mg) under a H2 gas balloon. The mixture was stirred overnight at rt. The reaction was filtered and the filtrate was concentrated in vacuo under low temperature to give the title compound ethyl 2-(3-(aminomethyl)cyclobutyl)acetate (100 mg, 0.584 mmol, 48.2 % yield) as a colorless oil. m/z: [M + H]+ Calcd for C9H12NO2 172.1 ; Found 172.1 .
Figure imgf000238_0002
Intermediate 9: ethyl 2-(3-(nitromethyl)oxetan-3-yl)acetate
Figure imgf000238_0003
To a solution of ethyl 2-(oxetan-3-ylidene)acetate (4.5 g, 31 .7 mmol) in Acetonitrile (10 mL) was added nitromethane (3.86 g, 63.3 mmol) and 2,3,4,6,7,8,9, 10-octahydropyrimido[1 ,2- a]azepine (7.23 g, 47.5 mmol) at rt and the reaction mixture was stirred at rt overnight. 2,3,4,6,7,8,9,10-octahydropyrimido[1 ,2-a]azepine (500 mg) was added again. The mixture was then concentrated and the residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate = 1/1 ) to give ethyl 2-(3-(nitromethyl)oxetan-3-yl)acetate (5.8 g, 28.5 mmol, 90 % yield) as a yellow oil. m/z: 1 H NMR (400 MHz, CDCI3) 5.30 (s, 2H), 4.60 (dd, J = 7.6, 25.6Hz, 4H), , 4.095-4.19 (m, 3H), 2.96 (s, 2h), 1 .24-1 .29 (m, 4H),ppm
Intermediate 10: ethyl 2-(3-(aminomethyl)oxetan-3-yl)acetate
Figure imgf000239_0001
To a solution of ethyl 2-(3-(nitromethyl)oxetan-3-yl)acetate (400 mg, 1 .969 mmol) in Methanol (5 mL) was added Pd/C (10 %) (1 17 mg, 0.984 mmol) at 25 °C under a H2 atmosphere. The reaction mixyure was stirred at 25 °C overnight. The mixture was filtered and concentrated to give ethyl 2-(3-(aminomethyl)oxetan-3-yl)acetate (320 mg, 1 .847 mmol, 94 % yield) as a colorless oil.: 1 H NMR (400 MHz, CDCI3) 4.33 (dd, J = 6.8, 17.6Hz, 4H),4.04 (dd, J = 7.2, 14.0, 2H), 2.82( s, 2H), 2.71 (s, 2H), 1 .17 (t, J = 7.2, 3H)ppm
Figure imgf000239_0002
Intermediate 11 : methyl 6-(aminomethyl)morpholine-3-carboxylate
Figure imgf000239_0003
To a solution of 1 ,3-diaminopropan-2-ol (160 mg, 1 .775 mmol) in N,N-Dimethylformamide (5 mL) stirred opened to air at 25 °C was added K2CO3 (1 124 mg, 8.13 mmol) in one charge. The reaction mixture was stirred at 40 °C for 1 h. Methyl 2,3-dibromopropanoate (400 mg, 1 .627 mmol) was then added, the mixture was heated to 40 °C and stirred for 16h. The reaction was filtered and the filtrate was washed with water (10ml_) followed by extraction of the aqueous phase with EtOAc (20 mL). m/z: [M + H]+ Calcd for C7H15N2O3 175.2; Found 175.
Figure imgf000239_0004
Intermediate 12: methyl 4-hydroxy-4-(1 -nitroethyl)cyclohexanecarboxylate
Figure imgf000239_0005
A solution of NaH (0.615 g, 25.6 mmol) in nitroethane (14.42 g, 192 mmol) was stirred at rt for 30 minutes. Methyl 4-oxocyclohexanecarboxylate (2 g, 12.81 mmol) was then slowly added in one charge. The mixture was continued to stir at 36 °C for 16 h. Water (50 mL) was then added at 0 °C, the solution was extracted with EtOAc (3x100 mL), the combined organic phases was collected and evaporated in vacuo to give the crude product as a colorless oil. The resulting crude product was purified on silica gel column chromatography using (petroleum ether/EtOAc = 9/1 ) to get the product methyl 4-hydroxy-4-(1 - nitroethyl)cyclohexanecarboxylate (400 mg, 1 .712 mmol, 13.37 % yield) as a yellow oil. m/z: [M + H]+ Calcd for Ci0Hi8NO5 232.3; Found 232. Intermediate 13: methyl 4-(1 -nitroethyl)cyclohex-3-enecarboxylate
Figure imgf000240_0001
To the solution of methyl 4-hydroxy-4-(1 -nitroethyl)cyclohexanecarboxylate (400 mg, 1 .712 mmol) in Dichloromethane (20 mL) was added a solution of DAST (0.453 mL, 3.42 mmol) in Dichloromethane (5 mL) dropwise. The mixture was stirred under a N2 atmosphere at rt for 3h. Water (10 mL) was added and the solution was extracted with EtOAc (3x20 mL), the organic phases were combined and evaporated in vacuo to give the crude product as a orange oil. The crude was purified by prepearation-TLC, eluting with (petroleum ether/EtOAc = 5/1 ) to get the desired product methyl 4-(1 -nitroethyl)cyclohex-3-enecarboxylate (260 mg, 1 .207 mmol, 70.5 % yield) as colorless oil. m/z: [M + Na]+ Calcd for Ci0Hi5NNaO4 236.2; Found 236.
Intermediate 14: methyl 4-(1 -aminoethyl)cyclohexanecarboxylate
Figure imgf000240_0002
A solution of methyl 4-(1 -nitroethyl)cyclohex-3-enecarboxylate (260 mg, 1.207 mmol) and Pt- C (128 mg, 0.121 mmol) in isopropylalcohol (15 mL) was purged 3 times with H2 and the mixture was continued to stir at 29 °C for 16 h. The mixture was filtered and the Methanol was evaporated in vacuo to give the crude product as colorless oil. m/z: [M + H]+ Calcd for C10H20NO2 186.2; Found 186.
Figure imgf000241_0001
Intermediate 15: methyl 4-carbamoyl-1 -methylcyclohexanecarboxylate
Figure imgf000241_0002
To a solution of methyl 4-(chlorocarbonyl)-1 -methylcyclohexanecarboxylate (0.5 g, 2.286 mmol) in Dichloromethane (2 mL) was added ammonium hydroxide (2 mL, 2.286 mmol) and the mixture was stirred at 25 °C for 0.5 h. Water (20 mL) was added and the mixture was extracted with DCM (2x15 mL), the organic layers were combined and dried over Na2S04 and the solvents were removed in vacuo to give the product as an off white solid (380 mg, yield 79%). m/z: [M + H]+ Calcd for Ci0Hi8NO3 200.3; Found 200.
Intermediate 16: methyl 4-cyano-1 -methylcyclohexanecarboxylate
Figure imgf000241_0003
Phosphorus oxychloride (2984 mg, 19.07 mmol) was added to a solution of methyl 4- carbamoyl-1 -methylcyclohexanecarboxylate (380 mg, 1 .907 mmol) in 1 ,2-Dichloroethane (3 mL).The reaction was refluxed at 80 °C for 2 h. 5 % aqueous NaOH (50 mL) was added slowly to the ice-cooled reaction. The mixture was then extracted with DCM (2x20 mL), the organic layers were combined and dried over Na2S04 evaporated to afford the product (320 mg, yield 88%) a pale yellow oil. m/z: [M + H]+ Calcd for Ci0Hi6NO2 182.2; Found 182. Intermediate 17: methyl 4-(aminomethyl)-1 -methylcyclohexanecarboxylate
Figure imgf000241_0004
Pd-C (88 mg, 0.083 mmol) and HCI (7.19 μΙ, 0.083 mmol) were added to a solution of methyl 4-cyano-1 -methylcyclohexanecarboxylate (150 mg, 0.828 mmol) in isopropanol (10 mL). The reaction was stirred at 25 °C for 18 h under an H2 atmosphere. The reaction was filtered and the filtrate was evaporated in vacuo to afford the product (150 mg, 93%) as a pale yellow solid, m/z: [M + H]+ Calcd for C10H20NO2 186.3; Found 186.
Figure imgf000242_0001
Intermediate 18: (1 s,4s)-cyclohexane-1 ,4-diyldimethanol
Figure imgf000242_0002
To a mixture of c/s-4-(hydroxymethyl)cyclohexanecarboxylic acid (1 .582 g, 10 mmol) in Tetrahydrofuran (20 mL) was slowly added BH3.THF (0.859 g, 10.00 mmol) at 0 °C. The mixture was then stirred at rt for 4h. The mixture was queched with MeOH and concentrated to give a white solid. The solid was suspended in water (10 mL) and the aqueous phase was extracted with ethyl acetate (2x40 mL). The combined organic extracts were washed with water and brine, dried over sodium sulfate and concentrated under vacuum to give the product c/'s-cyclohexane-1 ,4-diyldimethanol (1 .43 g, 8.92 mmol, 89 % yield) as a colorless oil.
Intermediate 19: ((1 s,4s)-4-(hydroxymethyl)cyclohexyl)methyl methanesulfonate
HO"'¾
To a mixture of c/'s-cyclohexane-1 ,4-diyldimethanol (1 .40 g, 9.71 mmol) and triethylamine (2.030 mL, 14.56 mmol) in Dichloromethane (50 mL) was slowly added MsCI (0.794 mL, 10.19 mmol) in DCM (10mL) at 0 °C over 30min. The mixture was then stirred at rt for 2h. The mixture was diluted with 10 mL of water, the organic phase was dried over Na2S04, filtered and concentrated to give the product (c/s-4-(hydroxymethyl)cyclohexyl)methyl methanesulfonate (2.10 g, 8.50 mmol, 88 % yield) as a brown oil. m/z: [M + NH4]+ Calcd for C9H22NC S 240.3; Found 240.
Intermediate 20: ((1 s,4s)-4-(azidomethyl)cyclohexyl)methanol k_A
A mixture of (c/'s-4-(hydroxymethyl)cyclohexyl)methyl methanesulfonate (2.0 g, 9.00 mmol) and sodium azide (1 .170 g, 17.99 mmol) in Dimethyl Sulfoxide (40 mL) was heated at 80 °C and stirred overnight. The reaction was cooled to room temperature, diluted with water (8 mL), extracted with EtOAc, the organic phase was dried over Na2S04, filtered and concentrated to give the product (c/s-4-(azidomethyl)cyclohexyl)methanol (1 .52 g, 8.08 mmol, 90 % yield) as a colorless oil.
Intermediate 21 : ((1s,4s)-4-(aminomethyl)cyclohexyl)methanol
(c/'s-4-(azidomethyl)cyclohexyl)methanol (1.50 g, 8.86 mmol) was dissolved in Ethyl acetate (16 mL) and Pd/C (0.30 g, 0.282 mmol) was added. The mixture was stirred under a hydrogen atmosphere at 30 °C for 16 h. The reaction mixture was filtered through celite and the filtrate was concentrated under reduced pressure to give the product (c/'s-4- (aminomethyl)cyclohexyl)methanol (1 .25 g, 7.85 mmol, 89 % yield) as a pale yellow oil. m/z: [M + H]+ Calcd for C8Hi8NO 144.2; Found 144. Intermediate 22: tert-butyl (((1 s,4s)-4-(hydroxymethyl)cyclohexyl)methyl)carbamate
Figure imgf000243_0001
To a stirred solution of (c/'s-4-(aminomethyl)cyclohexyl)methanol (1 .25 g, 8.73 mmol) and TEA (1 .825 mL, 13.09 mmol) in Tetrahydrofuran (16 mL) was added Boc20 (2.229 mL, 9.60 mmol) at rt. The reaction mixture was stirred at room temperature for 3h. The reaction mixture was diluted with water (6 mL), was extracted with ethyl acetate (3x15 mL) and washed with brine (8 mL). Evaporation of the solvent under reduced pressure afforded a brown oil which was purified by silica gel flash chromatography (petroleum ether/EtOAc = 3/1 -> 1/1 ) to give the title product terf-butyl ((c/'s-4-(hydroxymethyl)cyclohexyl)methyl)carbamate (910 mg, 3.74 mmol, 42.8 % yield) as a white solid, m/z: [M - tBu]+ Calcd for C9H17NO3 187.1 ; Found 187.2
Intermediate 23: ((1s,4s)-4-(((tert-butoxycarbonyl)amino)methyl)cyclohexyl)methyl methanesulfonate ^^-.„^NHB°C
To a mixture of terf-butyl ((c/'s-4-(hydroxymethyl)cyclohexyl)methyl)carbamate (910 mg, 3.74 mmol) and TEA (0.782 ml_, 5.61 mmol) in Dichloromethane (12 mL) was slowly added MsCI (0.321 mL, 4.1 1 mmol) at 0 °C. The reaction mixture was stirred at rt for 4h and was then diluted with 4 mL of water. The organic phase was separated, was dried over Na2S04, filtered and concentrated to give the product (cis-4-(((tert- butoxycarbonyl)amino)methyl)cyclohexyl)methyl methanesulfonate (1 .20 g, 3.36 mmol, 90 % yield) as a yellow oil. m/z: [M + Na]+ Calcd for Ci4H27NNa05S 344.4; Found 344.
Intermediate 24: tert-butyl (((1s,4s)-4-(cyanomethyl)cyclohexyl)methyl)carbamate
Figure imgf000244_0001
A mixture of (c/s-4-(((tert-butoxycarbonyl)amino)methyl)cyclohexyl)methyl methanesulfonate (1 .20 g, 3.73 mmol) and sodium cyanide (0.549 g, 1 1 .20 mmol) in Dimethyl Sulfoxide (25 mL) was stirred at 90 °C for 4h. After cooling to rt, the mixture was partitioned between ethyl acetate and brine and the aqueous phase was extracted with ethyl acetate (2x). The combined organic extracts were washed with water and brine, dried over sodium sulfate and concentrated under vacuum to give orange oil which was purified by silica gel flash chromatography (petroleum ether/EtOAc = 3/1 ) to give the product te/f-butyl ((c/'s-4- (cyanomethyl)cyclohexyl)methyl)carbamate (910 mg, 3.25 mmol, 87 % yield) as a white solid.
Intermediate 25: 2-((1s,4s)-4-(((tert-butoxycarbonyl)amino)methyl)cyclohexyl)acetic acid
Figure imgf000244_0002
To a solution of terf-butyl ((c/'s-4-(cyanomethyl)cyclohexyl)methyl)carbamate (0.50g, 1 .981 mmol) in Ethanol (16 mL) was added aqueous KOH (35%) (3.18 g, 19.81 mmol) and the resulting mixture was refluxed for 20h. The ethanol was removed under reduced pressure, the solution was cooled to below 10° C and then was acidified with 2M HCI to pH = 5. The mixture was extracted with EtOAc (2x30 mL) and the combined organic extracts were dried over anhydrous sodium sulfate and concentrated under vacuum to afford the product 2-(c/'s- 4-(((te/f-butoxycarbonyl)amino)methyl)cyclohexyl)acetic acid (320 mg, 1 .061 mmol, 53.6 % yield) as a pale orange solid, m/z: [M - H]" Calcd for Ci4H24N04 270.4; Found 270.
Intermediate 26: methyl 2-((1s,4s)-4-(((tert- butoxycarbonyl)amino)methyl)cyclohexyl)acetate
Figure imgf000245_0001
To a solution of 2-(c/s-4-(((fe/ -butoxycarbonyl)amino)methyl)cyclohexyl)acetic acid (320 mg, 1 .179 mmol) in Dichloromethane (8 mL) and Methanol (2 mL) was added TMS-diazomethane (0.649 mL, 1 .297 mmol) at rt and the resulting mixture was stirred for 2h. The mixture was diluted with 4 mL of water, the organic phase was separated and dried over anhydrous sodium sulfate and concentrated under vacuum to afford crude product which was purified by silica gel chromatography (hexane/EtOAc = 6/1 ) to obtain the product methyl 2-(c/'s-4- (((te/f-butoxycarbonyl)amino)methyl)cyclohexyl)acetate (228 mg, 0.759 mmol, 64.4 % yield) as awhite solid. [M - H]- Calcd for C15H27NC 284.2; Found 284.1 . Intermediate 27: methyl 2-((1 s,4s)-4-(aminomethyl)cyclohexyl)acetate
Figure imgf000245_0002
To a mixture of methyl 2-(c/s-4-(((fe/ -butoxycarbonyl)amino)methyl)cyclohexyl)acetate (230 mg, 0.806 mmol) in Tetrahydrofuran (2 mL) was added 4M HCI in dioxane (2.015 mL, 8.06 mmol). The mixture was stirred at rt for 3h. The reaction mixture was then cooled to room temperature and was concentrated to give the product methyl 2-(c/'s-4- (aminomethyl)cyclohexyl)acetate hydrochloride (205 mg, 0.715 mmol, 89 % yield) as a white solid, m/z: [M + H]+ Calcd for C10H20NO2 186.3; Found 186.
Figure imgf000246_0001
Intermediate 28: methyl 4-(1 -aminoethyl)-4-hydroxycyclohexanecarboxylate
Figure imgf000246_0002
To a solution of methyl 4-hydroxy-4-(1 -nitroethyl)cyclohexanecarboxylate (1 10 mg, 0.333 mmol) and HCI (50 μΙ, 0.592 mmol) in Tetrahydrofuran (15 mL) was added Pd-C (100 mg, 0.094 mmol). he reaction was placed under an hydrogen atmosphere and stirred at 25 °C for 20 h. The reaction was filtered and the solvent was evaporated in vacuo to give a yellow oil. The product was purified via preparation-TLC with 10 % MeOH (containing 1 % of aqueous ammonia)/DCM to afford a yellow solid (40 mg, yield 47.7%). m/z: [M + H]+ Calcd for C10H20NO3 202.3; Found 202.
Figure imgf000246_0003
Intermediate 29: ethyl 2-(dihydro-2H-pyran-4(3H)-ylidene)acetate
Figure imgf000246_0004
A mixture of dihydro-2H-pyran-4(3H)-one (5 g, 49.9mmol), ethyl 2- (triphenylphosphoranylidene)acetate (19.14 g, 54.9mmol) in toluene (50 ml) was stirred overnight at reflux. The toluene was removed in vacuo, hexane (200 ml) was added and the mixture was stirred 15 min. The mixture was filtered and the filtrate was concentrated in vacuo to give the product ethyl 2-(dihydro-2H-pyran-4(3H)-ylidene)acetate (6.7 g, 79 % yield). 1 H NMR (400 MHz, CDCI3) δ 5.68(s, 1 H), 4.16 (q, J=6Hz, 2H), 3.72-3.78 (m, 4H), 3.01 (t, J=4.4Hz, 2H), 2.33 (t, J=4.4Hz, 2H), 1.28 (t, J = 6Hz, 3H)ppm
Intermediate 30: ethyl 2-(4-(nitromethyl)tetrahydro-2H-pyran-4-yl)acetate
Figure imgf000246_0005
A mixture of ethyl 2-(dihydro-2H-pyran-4(3H)-ylidene)acetate (2 g, 1 1 .75mmol), nitromethane (1 .44g, 23.5mmol) and DBU (3.58g, 23.5mmol) in MeCN (50 ml) was stirred overnight at 60 °C. Water was added to the mixture which was extracted with EtOAc (3x50 ml). The combined organic layers were dried over Na2S04, filtered and concertrated in vacuo to give the product ethyl 2-(4-(nitromethyl)tetrahydro-2H-pyran-4-yl)acetate (1 .9 g)
Intermediate 31 : ethyl 2-(4-(aminomethyl)tetrahydro-2H-pyran-4-yl)acetate
Figure imgf000247_0001
To a solution of ethyl 2-(4-(nitromethyl)tetrahydro-2H-pyran-4-yl)acetate (1 .9 g, 8.22mmol) in Methanol (50 ml) was added Pd/C (1 .79 g, 5.96mmol), TFA (0.937 g, 8.22mmol) and the mixture was paced under an atmosphere of hydrogen. The mixture was stired overnight at rt. The reaction mixture was fitered and concentrated under reduced pressure. Water was added and the mixture was extracted with DCM (3x50 ml). The combined organic phases were concentrated under redued pressure to give ethyl 2-(4-(aminomethyl)tetrahydro-2H-pyran-4- yl)acetate trifluoroacetate (1 .2 g, 72.6 % yield) as a yellow oil. NMR (400 MHz, CDCI3) δ 4.19 (q, J = 8 Hz, 2H), 3.72-3.74 (m, 4H), 3.16 (s, 2H), 2.68 (s, 2H), 1 .60-1 .63 (m, 4H), 1 .29 (t, J = 8Hz, 3H)ppm
Figure imgf000247_0002
Intermediate 32 Intermediate 33
Intermediate 32: ethyl 4-hydroxy-4-(nitromethyl)cyclohexanecarboxylate
Figure imgf000247_0003
To a suspension of ethyl 4-oxocyclohexanecarboxylate (1 .7 g, 9.99 mmol) in Tetrahydrofuran (20 ml.) stirred at O °C was added nitromethane (1 .219 g, 19.98 mmol) and sodium hydride (0.8 g, 20.00 mmol). The reaction mixture was stirred at rt overnight. The reaction mixture was then stirred at 35 °C for 6h. To the reaction mixture was added a saturated ammonium chloride solution (30 ml) and extracted with EtOAc (3x30 ml). The combined organic phases were dried over sodium sulfate and evaporated in vacuo to give the crude product as a brown oil. The crude product was purified by silica gel column chromatography (petroleum ether/EtOAc = 15/1 ) to give ethyl 4-hydroxy-4-(nitromethyl)cyclohexanecarboxylate (0.9g, 3.89 mmol, 39.0 % yield).
Intermediate 33: ethyl 4-(aminomethyl)-4-hydroxycyclohexanecarboxylate
Figure imgf000248_0001
To a solution of ethyl 4-hydroxy-4-(nitromethyl)cyclohexanecarboxylate (300 mg, 1 .297 mmol) in Ethanol (10 mL) stirred at rt was added Palladium on activated carbon (10% Pd, 138 mg, 0.130 mmol) The mixture was stirred at rt overnight hydrogen atmosphere. The reaction mixture was filtered and the filtrate evaporated in vacuo to give the crude product. . N MR (400 MHz, CDCI3) 5 4.15 (q, J = 8 Hz, 2H), 2.2-2.3 (m, 1 H), 1.49-1 .89 (m, 8H), 1 .29 (t, J = 8Hz, 3H) ppm
Figure imgf000248_0002
Intermediate 34: ethyl 2-(1 -methylpiperidin-4-ylidene)acetate
Figure imgf000248_0003
To a solution of ethyl 2-(triphenylphosphoranylidene)acetate (16.16 g, 46.4 mmol) in Toluene (50 mL) at rt, 1 -methylpiperidin-4-one (5 g, 44.2 mmol) was added. The reaction mixture was stirred at 100 °C overnight. The mixture was concentrated under reduced pressure at 50°C, petroleum ether (20 ml) was added and the mixture was stirred at rt for 15 min. The solid was removed by filtration and washed with petroleum ether (2x10 ml). The filtrate was concentrated under reduced pressure, further petroleum ether (10ml) was added and the mixture was stirred at rt for 15 min. The solid was removed by filtration and the filtrate was concentrated in vacuo to give ethyl 2-(1 -methylpiperidin-4-ylidene)acetate (7.35 g, 40.1 mmol, 91 % yield), m/z: [M+H]+ Calcd for C10H17NO2 184; Found 184
Intermediate 35: ethyl 2-(1 -methyl-4-(nitromethyl)piperidin-4-yl)acetate
Figure imgf000249_0001
To a solution of ethyl 2-(1 -methylpipehdin-4-ylidene)acetate (2.5 g, 13.64 mmol) in Acetonitrile (30 mL) at rt was added nitromethane (1 .666 g, 27.3 mmol) and 2,3,4,6,7,8,9,10- octahydropyrimido[1 ,2-a]azepine (3.12 g, 20.46 mmol). The reaction mixture was stirred at 50 °C for 2 days. The reaction mixture was evaporated in vacuo to give the crude product as a brown oil. The crude product was purified by silica gel column chromatography (DCM/MeOH = 40/1 ) to give a mixture of starting material and product ethyl 2-(1 - methylpiperidin-4-ylidene)acetate. m/z: [M +H]+ Calcd for ΟιιΗ2οΝ204245; Found 245
Intermediate 36: ethyl 2-(4-(aminomethyl)-1 -methylpiperidin-4-yl)acetate
Figure imgf000249_0002
To a solution of ethyl 2-(1 -methyl-4-(nitromethyl)piperidin-4-yl)acetate (900 mg, 3.68 mmol) in Ethanol (15 mL) stirred at rt was added Palladium on activated carbon (10% Pd, 392 mg, 0.368 mmol) and 2,2,2-trifluoroacetic acid (420 mg, 3.68 mmol). The solution was stirred at rt overnight. The reaction mixture was filtered and the filtrate evaporated in vacuo to give the crude product, m/z: [M +H]+ Calcd for C11 H22N2O2215; Found 215
Figure imgf000249_0003
Intermediate 37: tert-butyl 4-(2-ethoxy-2-oxoethylidene)piperidine-1 -carboxylate
Figure imgf000250_0001
To a solution of te/f-butyl 4-oxopipe dine-1 -carboxylate (5 g, 25.09 mmol) in Toluene (100 mL) stirred in air at rt was added ethyl 2-(triphenylphosphoranylidene)acetate (8.74 g, 25.09 mmol) in one charge. The reaction mixture was stirred at 120 °C for 48h. The reaction mixture was diluted with petroleum ether (100 mL) and filtered. The filtrate was evaporated in vacuo to give the crude product as a yellow oil. The crude product was purified by silica gel column chromatography (petroleum ether/EtOAc = 10/1 ) to give the product as a yellow solid, m/z: [M - Boc +H]+ Calcd for C9Hi6N02 170.2; Found 170.2.
Intermediate 38: tert-butyl 4-(2-ethoxy-2-oxoethyl)-4-(nitromethyl)piperidine-1 - carboxylate
Figure imgf000250_0002
To a solution of tert-butyl 4-(2-ethoxy-2-oxoethylidene)piperidine-1 -carboxylate (4.49 g, 16.67 mmol) and nitromethane (2.035 g, 33.3 mmol) in Acetonitrile (40 mL) stirred in air at 20 °C was added 1 ,8-Diazabicyclo[5.4.0]undec-7-ene (2.51 mL, 16.67 mmol) dropwise over 5 min. The reaction mixture was stirred at 80 °C for 48h. The reaction mixture was evaporated in vacuo to give the crude product as a yellow oil.
The crude product was purified by silica gel column chromatography (petroleum ether/EtOAc = 9/1 ) to give the pure product (0.84 g) as a yellow oil and a mixture of products (3.8 g).
Intermediate 39: tert-butyl 4-(aminomethyl)-4-(2-ethoxy-2-oxoethyl)piperidine-1 - carboxylate
Figure imgf000251_0001
To a solution of terf-butyl 4-(2-ethoxy-2-oxoethyl)-4-(nitromethyl)pipe dine-1 -carboxylate (330 mg, 0.999 mmol) and 2,2,2-trifluoroacetic acid (1 14 mg, 0.999 mmol) in Ethanol (20 mL) stirred in air at room temp was added solid Pd/C (106 mg, 0.999 mmol) in one charge. The reaction mixture was stirred at 20 °C under an hydrogen atmosphere for 1 6h. The reaction mixture was filtered and the filtrate was evaporated in vacuo to give the crude product as a orange oil. [M +H]+ Calcd for Ci5H28N204 301 ; Found 301 .
Figure imgf000251_0002
Intermediate 40: methyl 6-chloro-5-vinylnicotinate
Figure imgf000251_0003
To a solution of methyl 6-chloro-5-iodonicotinate in THF (10 vol) was added vinyl tributyl stannane (1 equiv) fl lowed by Xphos Pd G3 precatalyst (10 mol%). The reaction was allowed to stir 1 6 hr at 20 °C. The reaction mixture was then concentrated and loaded directly on a silica gel column with the desired methyl 6-chloro-5-vinylnicotinate was eluted with a 0-100% ethyl acetate/hexanes gradient, m/z: [M + H]+ Calcd for C9H9CIN02 198.0; Found 197.9.
Intermediate 41 : methyl 6-chloro-5-formylnicotinate
Figure imgf000251_0004
To a 0.1 M solution of the methyl 6-chloro-5-vinylnicotinate in tetrahydrofuran was added potassium osmate (2 mol%), Phl(OAc)2 (2.3 equiv) and 2,6-lutidine (2.5 equiv). The reaction was allowed to stir 16 hr at 20 °C. The reaction mixture was then diluted with ethyl acetate and washed with water and then brine. The organic layer was then dried over sodium sulfate, filtered and then concentrated to dryness. The crude product mixture was then purified by silica gel column chromatography with the desired product eluting with a 0-100% ethyl acetate/hexanes gradient to produce pure methyl 6-chloro-5-formylnicotinate. m/z: [M + H]+ Calcd for C8H7CIN03 200.0; Found 199.9.
Intermediate 42: methyl 6-chloro-5-(difluoromethyl)nicotinate
Figure imgf000252_0001
To a solution of the methyl 6-chloro-5-formylnicotinate in dichloromethane (10 vol) at 0 °C was added deoxo-Fluor (1 .1 equiv) dropwise. The reaction was then allowed to stir 1 h at 0 °C, then 20 °C for an additional 1 h. The reaction mixture was then diluted with ethyl acetate and washed with water and then brine. The organic layer was then dried over sodium sulfate, filtered and then concentrated to dryness. The crude product mixture was then purified by silica gel column chromatography with the desired methyl 6-chloro-5- (difluoromethyl)nicotinate eluting with a 0-100% ethyl acetate/hexanes gradient, m/z: [M + H]+ Calcd for C8H7CIF2NC>2 222.0; Found 221 .9.
Figure imgf000252_0002
Intermediate 43: trans-methyl 4-((6-chloro-5- methylnicotinamido)methyl)cyclohexanecarboxylate
Figure imgf000252_0003
A solution of 6-chloro-5-methylnicotinic acid (5g, 25.00 mmol), trans-methyl 4- (aminomethyl)cyclohexanecarboxylate hydrochloride (5.71 g, 27.5 mmol) and N-ethyl-N- isopropylpropan-2-amine (3.55 g, 27.5 mmol) in Ν,Ν-Dimethylformamide (DMF) (25 mL) were stirred under nitrogen was added HATU (1 -[Bis(dimethylamino)methylene]-1 H-1 ,2,3- triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate) (10.45 g, 27.5 mmol), then stirred at 25 °C for 12h.
Then water was added in to the solution, and extracted twice with ethyl acetate (50ml_), the organic phase was collected and evaporated to dryness to give crude product.
The crude product was purified by silica gel column chromatography (150g) eluted with petroleium ether/ethyl acetate 1 :1 to give product trans-methyl 4-((6-chloro-5- methylnicotinamido)methyl)cyclohexanecarboxylate (6.5g, 19.01 mmol, 76 % yield) as a white solid, m/z: [M + H]+ Calcd for Ci6H2iCIN203325.1 ; Found 325
Figure imgf000253_0001
Intermediate 44: 1 -(2-methoxy-5-methylphenyl)ethanone
Figure imgf000253_0002
A solution of 1 -(2-hydroxy-5-methylphenyl)ethanone (1 g, 6.66 mmol), iodomethane (0.829 mL, 13.32 mmol) and K2C03 (1 .380 g, 9.99 mmol) was stirred in N,N-Dimethylformamide (8 mL) at rt overnight. Cold water (40 mL) was added and the aqueous layer was extracted with DCM (2x50 mL). The combined organic layers were dried over Na2S04, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (petroleum ether/EtOAc = 40/1 ) to give 1 -(2-methoxy-5-methylphenyl)ethanone (1 .18 g, 7.04 mmol, 106 % yield) as a colorless oil. m/z: [M + H]+ Calcd for C10H13O2 165.2; Found 165.1
Figure imgf000254_0001
Intermediate 45: 2-bromo-6-methylpyridin-3-ol
Figure imgf000255_0001
To a solution of 6-methylpy din-3-ol (5, 45.8mmol) in Pyridine (15 ml) was added dropwise bromine (3.66g, 22.9). The mixture was strried overnight at rt under a nitrogen atmosphere. To the reaction mixture was added water (200 ml) and the mixture was extracted with EtOAc (3x50 ml). The combined organic layers were washed with brine (3x50 ml), dried over Na2S04 and concentrated in vacuo. The residue was purified by flash chromatography on silica gel to give 2-bromo-6-methylpyridin-3-ol (4.8g) as a light yellow solids 1 H NMR (400 MHz, CDCI3) δ 7.17 (d, J = 8Hz, 1 H), 7.09 (d, J = 8Hz, 2H), 2.40 (s, 3H)ppm
Intermediate 46 : 2-bromo-3-methoxy-6-methylpyridine
Figure imgf000255_0002
A solution of the 2-bromo-6-methylpyridin-3-ol (4.8g, 25.5mmol), K2CO3 (7.1 g, 51 .4mmol), CH3I (5.5g, 38.7) in Acetone (200 mL) was stirred overnight under reflux. The mixture was filtered, evaporated and purified on silica gel chormatography (hexane/ethyl acetate = 10/1 ) to give the resired product 2-bromo-3-methoxy-6-methylpyridine (4.5g,22.3mmol, 87%) as a light yellow. 1 H NMR (400 MHz, CDCI3) δ 7.06 (s, 2 H) 3.89 (s, 3 H) 2.48 (s, 3 H).
Intermediate 47: 2-(1 -ethoxyvinyl)-3-methoxy-6-methylpyridine
Figure imgf000255_0003
2-bromo-3-methoxy-6-methylpyridine(4.1 g, 20.3mmol), tributyl(1 -ethoxyvinyl)stannane (18.4g 50.9mmol), Pd(PPh3) (1 .2g, 1 .038mmol) in DMF (20 ml) were combined under a nitrogen atmosphere and the mixture was stirred overnight at 80 °C. The reaction mixture was filtered water was added and was extracted with EtOAc (3x50 ml). The combined organic layers were concentrated to give 2-(1 -ethoxyvinyl)-3-methoxy-6-methylpyridine (10g, crude) as a brown oil. m/z: [M + H]+ Calcd for CnHi6N02 194.3; Found 194
Intermediate 48: 1 -(3-methoxy-6-methylpyridin-2-yl)ethanone
Figure imgf000256_0001
To a solution of 2-(1 -ethoxyvinyl)-3-methoxy-6-methylpy dine (1 Og, 51 .7mmol, crude) in THF (200ml) was added dropwise hydrogen chloride (261 mmol, 21 .7ml) and the reaction mixtrue was stirred 3h. Water (200 ml) was added and the mixture was extracted with EtOAc (3x50 ml). The combined organic layers were dried over N2S04 and concentrated in vacuo. The residue was purification by silica gel column chromatography (hexane/EtOAc = 5/1 ) to give 1 -(3-methoxy-6-methylpyridin-2-yl)ethanone (3.2g, 37.4%) as a yellow oil. m/z: [M + H]+ Calcd for C9Hi2N02 166.2; Found 166
Figure imgf000256_0002
Intermediate 49: N,5-dimethoxy-N,2-dimethylpyrimidine-4-carboxamide
Figure imgf000256_0003
To a solution of 5-methoxy-2-methylpyrimidine-4-carboxylic acid (500 mg, 2.97 mmol) in Dichloromethane (20 mL) was added Ν,Ο-dimethylhydroxylamine hydrochloride (348 mg, 3.57 mmol), HATU (1696 mg, 4.46 mmol) and DIEA (1 .039 mL, 5.95 mmol). The resulting mixture was stirred at rt overnight. The mixture was poured into water, washed with brine, dried over Na2S04 and concentrated. The residue was purified by column chromatography (petroleum ether/EtOAc = 1/3) to give N,5-dimethoxy-N,2-dimethylpyrimidine-4-carboxamide (550 mg, 2.60 mmol, 88 % yield) as a yellow oil. m/z: [M + H]+ Calcd for C9Hi4N303 212.2; Found 212 Intermediate 50: 1 -(5-methoxy-2-methylpyrimidin-4-yl)ethanone
Figure imgf000256_0004
To a solution of N,5-dimethoxy-N,2-dimethylpy midine-4-carboxamide (100 mg, 0.473 mmol) in Tetrahydrofuran (5 mL) was added methylmagnesium bromide (169 mg, 1 .420 mmol) at 0 °C. The resulting mixture was stirred at 0 °C for 3 h. The mixture was poured into an aqueous solution of NH4CI, extracted with EtOAc, washed with brine, dried over Na2S04 and concentrated to give 1 -(5-methoxy-2-methylpyrimidin-4-yl)ethanone (70 mg, 0.345 mmol, 73.0 % yield) as a pale yellow solid, m/z: [M + H]+ Calcd for C8HnN202 167.2; Found 167
Figure imgf000257_0001
Intermediate 51 : 3-acetyl-4-methoxybenzonitrile
Figure imgf000257_0002
1 -(5-bromo-2-methoxyphenyl)ethanone (212g, 925mmol), dicyano zinc (130g, 1 .1 mol), zinc (9.08g, 139mmol, 15 mol%) and Pd(dppf)CI2 dichloromethane adduct (37.8g, 46.3mmol, 5 mol%) combined in a round bottomed flask. 1060ml of dimethylacetamide added and kept under nitrogen. A thermocouple was place through the septum directly into the reaction vessel. The round bottomed flask was then placed into a heating mantle connected to a temperature controller. The reaction temperature was carefully monitored. There is an exotherm at ~120°C. The temperature was then carefully maintained at 120°C and then cooled to 20°C and stirred overnight at room temperature. The reaction was slowly (~2 minutes) added to a rapidly stirring 4 L of water during which time a precipitation occurred. The mixture was filtered and washed thoroughly with water. The solid was then taken up in IPA (~2L) and heated to ~70C in a water bath for 30min. The slurry was then allowed to cool to 0°C for 2 hours. The solid was rinsed with hexanes and allowed to dry on filter frit. The desired nitrile successfully prepared and isolated as a purple solid (104g, 64% yield), m/z: [M + H]+ Calcd for CioHioN02 176.1 ; Found 176
Figure imgf000258_0001
Intermediate 52: 5-bromo-6-methoxynicotinonitrile
Figure imgf000258_0002
To 6-methoxynicotinonitrile (1 g, 7.49 mmol) in Acetic Acid (6.4 ml.) was added sodium acetate (0.612g, 7.46 mmol). The mixture was stirred and a solution of Br2 (0.768 ml_, 14.9 mmol) in Acetic Acid (6.4 ml.) was added. The mixture was heated to 80 °C for 48 h. The reaction mixture was poured into water and extracted with diethyl ether. The organic phase was washed with 4M aqueous sodium hydroxide solution, 5 percent sodium thiosulfate solution, dried over anhydrous potassium carbonate and the solvent was evaporated to give 5-bromo-6-methoxy-nicotinonitrile.The sample was loaded using MeOH and purified on CombiFlash reverse phase (C18) 50g using a 20-50% MeOH-Water(0.01 % NH4HC03 ) over 30 mins. The appropriate fractions were combined and evaporated in vacuo to give the product 5-bromo-6-methoxynicotinonitrile (700 mg, 3.12 mmol, 41 .9 % yield) as a white soild. m/z: [M + H]+ Calcd for C7H6BrN20 213; Found 212 Intermediate 53: 5-(1 -ethoxyvinyl)-6-methoxynicotinonitrile
Figure imgf000258_0003
Under the protection of nitrogen 5-bromo-6-methoxynicotinonitrile (700 mg, 3.29 mmol)and tributyl(1 -ethoxyvinyl)stannane (1305 mg, 3.61 mmol) were stirred in toluene (10ml). Bis(triphenylphosphine)palladium(ll) chloride (1 15 mg, 0.164 mmol) was added and the reaction was heated to 100 °C overnight The reaction was cooled an filtered. The toluene was evaporated to produce 5-(1 -ethoxyvinyl)-6-methoxynicotinonitrile (500 mg, 1 .102 mmol, 33.5 % yield) m/z: [M + H]+ Calcd for Cn Hi3N202 205.1 ; Found 205.3
Intermediate 54: 5-acetyl-6-methoxynicotinonitrile
Figure imgf000259_0001
To the solution of 5-(1 -ethoxyvinyl)-6-methoxynicotinonitrile (700 mg, 3.43 mmol) in Toluene (10 mL) then add HCI (0.104 mL, 3.43 mmol) . The reaction mixture was stirred at R.T. for overnight. The reaction was quenched with 20ml_ water and extracted with ethyl acetate(20ml_*3). The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by chromatogarphy on silica gel eluted with 4: 1 ethyl acetate:petroleum ether. 346mg (1 .9mmol, 55%yiled) 5-acetyl-6-methoxynicotinonitrile was isolated after concentration, m/z: [M + H]+ Calcd for C9H9N2O2 177.1 ; Found 176.9
Figure imgf000259_0002
Intermediate 55: 1 -(5-ethyl-2-hydroxyphenyl)ethanone
Figure imgf000259_0003
To aluminium trichloride (5.07 g, 38.0 mmol) was added 4-ethylphenyl acetate (3.28 g, 20 mmol) dropwise. The mixture was heated to 130 °C for 120 minutes then cooled. The yellow oil was slowly poured into water and extracted with EtOAc (2x80 ml). The combined organic layers were washed with brine, then dried over MgS04 and concentrated in vacuo to give a yellow oil. The oil was purified by silica gel chromatography (hexane/EtOAc = 10/1 ) to obtain the title compound 1 -(5-ethyl-2-hydroxyphenyl)ethanone (2.33 g, 13.34 mmol, 66.7 % yield) as a pale yellow oil. m/z: [M + H]+ Calcd for C10H13O2 165.1 ; Found 164
Intermediate 56: 1 -(5-ethyl-2-methoxyphenyl)ethanone
Figure imgf000259_0004
To a solution of 1 -(5-ethyl-2-hydroxyphenyl)ethanone (2.33 g, 14.19 mmol) in N,N- Dimethylformamide (15 mL) was added iodomethane (1 .325 mL, 21 .28 mmol). The reaction mixture was stirred at rt for 18 h. Water (10 mL) was added, and then the mixture was extracted with EtOAc (3x20 mL). The combined organic layers were washed with brine (10 mL). The organic layer was dried over Na2S04, and then concentrated under reduced pressure to give the product 1 -(5-ethyl-2-methoxyphenyl)ethanone (2.50 g, 12.81 mmol, 90 % yield) as a yellow oil. m/z: [M + H]+ Calcd for C11 H15O2 179.1 ; Found 179
Figure imgf000260_0001
Intermediate 57 Intermediate 58 Intermediate 59 Intermediate 60
Figure imgf000260_0002
Intermediate 61 Intermediate 62 Intermediate 63
Intermediate 57: methyl 2-chloro-5-methoxyisonicotinate
Figure imgf000260_0003
To a solution of 2-chloro-5-hydroxyisonicotinic acid (8.01 g, 46.2 mmol) and Potassium carbonate (6.38 g, 46.2 mmol) in N,N-Dimethylformamide (50 mL) was added iodomethane (6.55 g, 46.2 mmol) dropwise under a blanket of nitrogen at room temperature. The resulted mixture was stirred at rt overnight. The reaction was quenched with cooled water (20 mL). The mixture was extracted with DCM (2x80 mL). The combined organic layers were washed with brine (50 mL), dried over Na2S04, filtered, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (petroleum ether/EtOAc = 4/1 -> 1/1 ) to give methyl 2-chloro-5-methoxyisonicotinate (4.2 g, 20.62 mmol, 44.7 % yield) as a white solid. 1 H NMR (400 MHz, CDCI3) δ 8.17 (s, 1 H), 7.59 (s, 1 H), 3.98 (s, 3H), 3.91 (s, 3H)ppm Intermediate 58: methyl 5-methoxy-2-vinylisonicotinate
Figure imgf000261_0001
To a solution of methyl 2-chloro-5-methoxyisonicotinate (3.1 g, 15.38 mmol) and tributyl(vinyl)stannane (5.61 g, 17.68 mmol) in N,N-Dimethylformamide (30 mL) at rt was added Pd(Ph3P)4 (0.888 g, 0.769 mmol) under N2. The resulted mixture was stirred at 90 °C under nitrogen overnight. The reaction was quenched with water (50 mL) and the aqueous layer was extracted with DCM (2x 100 mL). The combined organic layers were washed with brine (50 mL), dried over Na2S04, filtered, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (petroleum ether/EtOAc = 4/1 ) to give methyl 5-methoxy-2-vinylisonicotinate (2.34 g, 1 1 .24 mmol, 73.1 % yield) as a light yellow oil. m/z: [M + H]+ Calcd for CioHi2N03 194.1 ; Found 194.0
Intermediate 59: methyl 2-ethyl-5-methoxyisonicotinate
Figure imgf000261_0002
To a solution of methyl 5-methoxy-2-vinylisonicotinate (2.34 g, 12.1 1 mmol) in Ethyl acetate (30 mL) at rt was added Pd/C (1 .289 g, 12.1 1 mmol) under N2. The resulted mixture was stirred at room temperature under a hydrogen atmosphere overnight. The mixture was filtered through a pad of celite and concentrated in vacuo. The residue was purified by column chromatography on silica gel ( petroleum ether/EtOAc = 4/1 ) to give the desired product methyl 2-ethyl-5-methoxyisonicotinate (2.32 g, 10.95 mmol, 90 % yield) as a light yellow oil. m/z: [M + H]+ Calcd for Ci0Hi4NO3 196.1 ; Found 196.0 Intermediate 60: 2-ethyl-5-methoxyisonicotinic acid
Figure imgf000261_0003
To a mixture of methyl 2-ethyl-5-methoxyisonicotinate (2.32 g, 1 1 .88 mmol) in Tetrahydrofuran (20 mL) and Water (5 mL) was added lithium hydroxide hydrate (4.99 g, 1 19 mmol). The solution was stirred at rt overnight. The tetrahydrofuran was evaported under reduce pressure and the pH of the solution was then adjusted to 4 by HCI solution (1 M) (about 15 mL). The solution was then cooled to room temperture and filtered. The residue was purified by chromatography on silica gel (petroleum ether/EtOAc = 3/1 ) to give 2-ethyl-5- methoxyisonicotinic acid (2.5 g, 1 1 .73 mmol, 99 % yield) as a yellow solid, m/z: [M + H]+ Calcd for C9H12NO3 182.1 ; Found 182.0
Intermediate 61 : 2-ethyl-5-methoxyisonicotinoyl chloride
Figure imgf000262_0001
(COCI)2 (1 .812 mL, 20.70 mmol) was slowly added to a mixture of 2-ethyl-5- methoxyisonicotinic acid (2.5 g, 13.80 mmol) in Dichloromethane (20 mL). Subsequently, DMF (0.2 mL, 2.58 mmol) was added and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure and co- evaporated with toluene 3 times to give 2-ethyl-5-methoxyisonicotinoyl chloride (3 g, 13.87 mmol, 101 % yield) as an orange oil.
Intermediate 62: 2-ethyl-N,5-dimethoxy-N-methylisonicotinamide
Figure imgf000262_0002
2-ethyl-5-methoxyisonicotinoyl chloride (2.53 g, 12.67 mmol) was dissolved in dichloromethane (10 mL). The solution was added dropwise to a mixture of Ν,Ο- dimethylhydroxylamine hydrochloride (1 .731 g, 17.74 mmol) and K2CO3 (7.01 g, 50.7 mmol) in Dichloromethane (30 mL) and Water (30.0 mL). The reaction mixture was stirred at room temperature for 2h. The organic layer was separated. The aqueous layer was extracted with dichloromethane (2x100 mL). The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give the product 2-ethyl-N,5-dimethoxy-N-methylisonicotinamide (2.5 g, 10.53 mmol, 83 % yield) as a brown oil. LCMS: rt= 1 .14 min, MH+ = 225.1 Result: desired product was obtained and will be used in next step, m/z: [M + H]+ Calcd for C11 H17N2O3 225.1 ; Found 225.1
Intermediate 63: 1 -(2-ethyl-5-methoxypyridin-4-yl)ethanone
Figure imgf000263_0001
To a solution of 2-ethyl-N,5-dimethoxy-N-methylisonicotinamide (1 .7 g, 7.58 mmol) in Tetrahydrofuran (20 mL) was added methylmagnesium chloride (4.30 mL, 12.89 mmol) at 0 °C. The mixture was stirred for 1 h at 0 °C. The reaction was quenched with cold saturated NH4CI solution (20 mL). The organic layer was separated and concentrated under reduced pressure. The residue was diluted with ethyl acetate (20 mL). The aqueous layer was diluted with water (20 mL) and was extracted with ethyl acetate (3x20 mL). The organic solution and extracts were combined, washed with brine, dried over MgS04, filtered, and concentrated under reduced pressure to give 1-(2-ethyl-5-methoxypyridin-4-yl)ethanone (1 .1 g, 6.12 mmol, 81 % yield) as a brown oil. m/z: [M + H]+ Calcd for C10H14NO2 180.1 ; Found 180.1
Figure imgf000263_0002
Intermediate 64 Intermediate 65 Intermediate 66
Figure imgf000263_0003
Intermediate 70 Intermediate 71
Intermediate 64: methyl 3-hydroxypicolinate
Figure imgf000264_0001
To a solution of 3-hydroxypicolinic acid (13.5g, 97mmol) in Methanol (250 ml) stirred under nitrogen at rt was added sulfuric acid (15.52, 291 mmol) dropwise over 5min.. The mixture was heated to 70°C and stirred for 72 hours. The mixture was cooled and concentrated under reduced pressure. The mixture was neutralized with saturated sodium bicarbonate solution and extracted with EtOAc (2 x 250ml). The organic phase was washed with brine, dried over Na2S04 and concentrated under reduced pressure to provide the desired product methyl 3- hydroxypicolinate (1 1 .2 g, 73.1 mmol, 75 % yield). 1H NMR (400 MHz, CDCI3) δ 10.61 (s, 1 H), 8.29 (d, J = 8Hz, 2H), 7.38-7.42 (m, 2H), 4.81 (s, 3H)ppm Intermediate 65: methyl 6-bromo-3-hydroxypicolinate
Figure imgf000264_0002
A solution of methyl 3-hydroxypicolinate (21 g, 137 mmol) in Water (500 mL) was stired at rt for 2 h. The precipitate was filtered, washed with water and dried in vacuo to provide the desired product methyl 6-bromo-3-hydroxypicolinate (21 g, 91 mmol, 66.0 % yield), m/z: [M + H]+ Calcd for C7H6BrN03 232.0; Found 232
Intermediate 66: methyl 6-bromo-3-methoxypicolinate
Figure imgf000264_0003
To a solution of methyl 6-bromo-3-hydroxypicolinate (21 g, 91 mmol) in Acetone (400 mL) was added iodomethane (38.5 g, 272 mmol) at rt. The mixture was stired for 2 h at 38 °C. The precipitate was filtered, washed with water and dried in vacuo to provide the desired product methyl 6-bromo-3-methoxypicolinate (18g, 73.2 mmol, 81 % yield), m/z: [M + H]+ Calcd for C8H8BrN03 246.0; Found 246.0
Intermediate 67: methyl 3-methoxy-6-vinylpicolinate
Figure imgf000265_0001
To a solution of methyl 6-bromo-3-methoxypicolinate (6 g, 24.38 mmol), potassium trifluoro(vinyl)borate (6.53 g, 48.8 mmol) and potassium carbonate (8.43 g, 61 .0 mmol) in Dimethyl Sulfoxide (30 mL) stirred under nitrogen at rt was added solid Pd(dppf)CI2 (1 .154 g, 2.438 mmol). The reaction mixture was stirred at 85 °C overnight. The mixture was then concentrated under reduced pressure, diluted with Η20 and extracted with EtOAc (3x). The combined organic phases were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to give methyl 3- methoxy-6-vinylpicolinate (4 g, 20.70 mmol, 85 % yield), m/z: [M + H]+ Calcd for C10H12NO3 194.1 ; Found 194
Intermediate 68: 3-methoxy-6-vinylpicolinic acid
Figure imgf000265_0002
A solution of methyl 3-methoxy-6-vinylpicolinate (4 g, 20.7 mmol) and lithium hydroxide hydrate (1 .303 g, 31 .1 mmol) in Methanol (20 mL) was stirred under air at room temperature for 10h. 1 N HCI aqueous solution was used to adjust the pH to 6. The solvent was evaporated to get crude product 3-methoxy-6-vinylpicolinic acid (8 g, 33.5 mmol, 99 % crude yield), m/z: [M + H]+ Calcd for C9H10NO2 180.1 ; Found 180
Intermediate 69: N,3-dimethoxy-N-methyl-6-vinylpicolinamide
Figure imgf000265_0003
To a solution of 3-methoxy-6-vinylpicolinic acid (8 g, 44.6 mmol), Ν,Ο-dimethylhydroxylamine hydrochloride (5.66 g, 58.0 mmol) and N-ethyl-N-isopropylpropan-2 -amine (17.31 g, 134 mmol) in N,N-Dimethylformamide (8 mL) stirred under nitrogen at rt was added a solution of HATU (25.5 g, 67.0 mmol) in N,N-Dimethylformamide (8 mL) in one charge . The reaction mixture was stirred at 85 °C for 10h. The mixture was evaporated in vacuo, water (10 mL) and ethyl acetate (20 ml_) were added, the layers were partitioned and the organic phase was evaporated in vacuo. The residue was purified by flash chromatography eluting with petroleum ether/ethyl acetate 1 : 1 to get the product N,3-dimethoxy-N-methyl-6- vinylpicolinamide (4 g, 18.00 mmol, 40.3 % yield) as a white solid, m/z: [M + H]+ Calcd for C11 H15N2O3 223.1 ; Found 223.2
Intermediate 70: 1 -(3-methoxy-6-vinylpyridin-2-yl)ethanone
Figure imgf000266_0001
A solution of N,3-dimethoxy-N-methyl-6-vinylpicolinamide (4 g, 18.00 mmol) in tetrahydrofuran (THF) (20 mL) was made and stirred under nitrogen. After cooling to 0°C, a solution of methylmagnesium bromide (6.44 g, 54.0 mmol) in diethyl ether was slowly added. The reaction mixture was stirred at 0 °C for 12h. The reaction was quenched with saturated ammonium chloride and extracted with ethyl acetate (2x). After washing with brine, the organics were dried over anhydrous MgS04 and concentrated in vacuum to give 1 -(3- methoxy-6-vinylpyridin-2-yl)ethanone (2.5 g, 14.1 1 mmol, 78 % yield), m/z (M+H)+ Calcd for C10H11 NO2 178.1 ; Found 178
Intermediate 71 : 1 -(6-ethyl-3-methoxypyridin-2-yl)ethanone
Figure imgf000266_0002
A suspension of 1 -(3-methoxy-6-vinylpyridin-2-yl)ethanone (700 mg, 3.95 mmol) Pd/C (2.389 mg, 1 .185 mmol) in Tetrahydrofuran (20 mL) was stirred at rt under an H2 atmosphere for 8h. Pd/C was removed by filtration and the filtrate was concentrated under reduced pressure to give 1 -(6-ethyl-3-methoxypyridin-2-yl)ethanone (400 mg, 2.232 mmol, 56.5 % yield).1H NMR (400 MHz, CDCI3) δ 7.57 (d, J = 8Hz, 1 H), 7.44 (d, J = 8Hz, 1 H), 3.81 (s, 3H), 2.72, (q, J = 8Hz, 2H), 2.53 (s, 3H), 1 .23 (t, J = 8Hz, 3H) ppm
Figure imgf000267_0001
Intermediate 72 Intermediate 73
Intermediate 72: 4-ethyl-2-methoxypyridine
Figure imgf000267_0002
In a flask, 4-bromo-2-methoxypy dine (5 g, 26.6 mmol) , triethylborane (34.6 mL, 34.6 mmol), K2CO3 (7.35 g, 53.2 mmol) and PdCI2(PPh3)2 (0.933 g, 1 .330 mmol) were dissolved in Dioxane/H2O10:1 (30ml_). The reaction mixture was heated to 100 °C for 18 h. The mixture was concentrated to give a residue. The residue was purified by silica gel chromatography (petroleum ether/EtOAc = 10/0 -> 1/2) to give the title compound 4-ethyl-2-methoxypyridine (3.3g, 23.70 mmol, 89 % yield), m/z: [M + H]+ Calcd for C8Hi2NO 138.1 ; Found 138.1 Intermediate 73: 1 -(4-ethyl-6-methoxypyridin-2-yl)ethanone
Figure imgf000267_0003
In a flask, 4-ethyl-2-methoxypyridine (3.3 g, 24.06 mmol), 2-hydroperoxy-2-methylpropane (4.66 mL, 48.1 mmol), Ferrous sulfate heptahydrate (6.69 g, 24.06 mmol), acetaldehyde (13.59 mL, 241 mmol), 2,2,2-trifluoroacetic acid (1 .972 mL, 26.5 mmol) and Acetonitrile (50 mL) were heated at 80 °C for 18 hours. The mixture was filtered and to the filtrate was added saturated NaHCO3 (30 mL). The mixture was extracted with EtOAc (3x30 mL). The combined organic layers were dried over sodium sulfate, filtered and evaporated to give a crude. The crude was purified by silica gel chromatography (petroleum ether/EtOAc = 10/0 -> 1/3) to give the title compound 1 -(4-ethyl-6-methoxypyridin-2-yl)ethanone (2.2g, 7.49 mmol, 31 .1 % yield), m/z: [M + H]+ Calcd for Ci0Hi3NO2 180.1 ; Found 180.2
Figure imgf000268_0001
Intermediate 74 Intermed
Intermediate 74: 1 -(5-chloro-2-vinylphenyl)ethanone
Figure imgf000268_0002
A mixture of 1 -(2-bromo-5-chlorophenyl)ethanone (10 g, 42.8 mmol), 4,4,5,5-tetramethyl-2- vinyl-1 ,3,2-dioxaborolane (9.89 g, 64.2 mmol), Pd(dppf)CI2 (3.13 g, 4.28 mmol) and potassium carbonate (1 1 .84 g, 86 mmol) in THF (40 mL) and H20 (20 mL) was stirred at 100 °C under N2 in a microwave apparatus for 1 h. Water was added and the mixture was extracted with ethyl acetate (3x50 mL). The combined organic layers were washed with saturated NaHCC , water and brine, then dried over MgS04 and filtered. The resulting residue was purified by silica gel flash chromatography (petroleum ether/EtOAc = 10/1 ) to give 1 -(5- chloro-2-vinylphenyl)ethanone (8 g, 39.9 mmol, 93 % yield) as a yellow solid, m/z: [M + H]+ Calcd for CioHioCIO 181 .0; Found 181 .
Intermediate 75: 1 -(5-chloro-2-ethylphenyl)ethanone
Figure imgf000268_0003
To a solution of 1 -(5-chloro-2-vinylphenyl)ethanone (8 g, 44.3 mmol) in dry EtOAc (100 mL) was added Pd/C (0.471 g, 4.43 mmol). The mixture was stirred under an hydrogen atomospher overnight. The mixture was filtered and the filtrate was concentrated to afforded 1 -(5-chloro-2-ethylphenyl)ethanone (8 g, 39.4 mmol, 89 % yield) as a yellow oil. m/z: [M + H]+ Calcd for CioHi2CIO 183.1 ; Found 183
Figure imgf000269_0001
Intermediate 76
Intermediate 76: 1 -(3-chloro-5-methoxyphenyl)ethanone
Figure imgf000269_0002
To a solution of 1 -bromo-3-chloro-5-methoxybenzene (2 g, 9.03 mmol) in Toluene (40 mL) was added (PPh3)2PdCI2 (0.380 g, 0.542 mmol) and t butyl(1 -ethoxyvinyl)stannane (3.59 g, 9.93 mmol) ). The reaction mixture was degassed twice under N2.The reaction mixture was stirred at 120 °C for 18 hours. The mixture was cooled to room temperature and 3 mL of concentrated HCI were added. The mxiture was stirred at room temperature for 3 h. Water (20 mL) was added to the reaction mixture which was then extracted with EtOAc (3x30 mL). The combined organic layers were dried over sodium sulfate, filtered and evaporated to give a crude product which used next step without further purification, m/z: [M + H]+ Calcd for C9H10CIO2 185.0; Found 185.1
Figure imgf000269_0003
Intermediate 77: 1 -(3,5-difluoro-2-methoxyphenyl)ethanone
Figure imgf000269_0004
To a solution of 1 -(3,5-difluoro-2-hydroxyphenyl)ethanone (100 mg, 0.581 mmol) in N,N- Dimethylformamide (10 mL) was added K2C03 (161 mg, 1 .162 mmol) and iodomethane (0.073 mL, 1 .162 mmol). he resulting mixture was stirred at rt overnight. The mixture was poured into water and extracted with EtOAc,washed with brine, dried over Na2S04 and concentrated to give 1-(3,5-difluoro-2-methoxyphenyl)ethanone (100 mg, 0.403 mmol, 69.3 % yield) as a colorless oil. m/z: [M + H]+ Calcd for C9H9F2O2 187.1 ; Found 187
Figure imgf000270_0001
Intermediate 78 Intermediate 79
Intermediate 78: 2-bromo-1 -(5-fluoro-2-methoxyphenyl)ethanone
Figure imgf000270_0002
Copper(ll) bromide (7.58 g, 33.9 mmol) was suspended in Chloroform (20 mL) and the mixture was heated to reflux. 1 -(5-fluoro-2-methoxyphenyl)ethanone (3.36 g, 19.98 mmol) was dissolved in Chloroform (20 mL) and the solution was added dropwise to the reaction. After 4h, the reaction was filtered, concentrated in vacuo and recrystalled with MeOH to give the product 2-bromo-1 -(5-fluoro-2-methoxyphenyl)ethanone (3.0 g, 9.71 mmol, 48.6 % yield) as a white solid, m/z: [M + H]+ Calcd for C9H9BrF02 247.0; Found 246
Intermediate 79: 1 -(5-fluoro-2-methoxyphenyl)-2-methoxyethanone
Figure imgf000270_0003
To a solution of 2-bromo-1 -(5-fluoro-2-methoxyphenyl)ethanone (6.0 g, 24.29 mmol) in Methanol (30 mL) was added Silver carbonate (13.39 g, 48.6 mmol) and boron trifluoride etherate (9.23 mL, 72.9 mmol). The solution was stirred at room temperature under an argon atmosphere overnight. The mixture was filtered, diluted with dichloromethane (100 mL) and washed with water (50 mL). The organic fraction was dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo. The crude residue was purified by flash column chromatography on silica gel (petroleum ether/EtOAc = 5/1 ) to give1 -(5-fluoro-2- methoxyphenyl)-2-methoxyethanone (4.5 g, 20.43 mmol, 84 % yield) as a yellow solid, m/z: [M + H]+ Calcd for C10H12FO3 199.1 ; Found 199
Figure imgf000271_0001
Intermediate 80 Intermediate 81 Intermediate 82
Intermediate 80: 3-chloro-6-methoxy-2-methylbenzaldehyde
Figure imgf000271_0002
To a mixture of 1 -chloro-4-methoxy-2-methylbenzene (15.6 g, 100 mmol) in Dichloromethane (200 mL) was added dichloro(methoxy)methane (13.74 g, 120 mmol) and titanium(IV) chloride (37.8 g, 199 mmol). The mixture was stirred at 5 °C for 2 h. Water (20 mL) was added and the mixture was extracted with DCM (3x150 mL). The combined organic layers were concentrated and purified by flash chromatography (petroleum ether/DCM = 3/1 ) to give 3- chloro-6-methoxy-2-methylbenzaldehyde (2.1 g, 1 1 .37 mmol, 1 1 .42 % yield), m/z: [M + H]+ Calcd for C9H10CIO2 185.0; Found 185
Intermediate 81 : 1 -(3-chloro-6-methoxy-2-methylphenyl)ethanol
Figure imgf000271_0003
To a solution of 3-chloro-6-methoxy-2-methylbenzaldehyde (1 .8 g, 9.75 mmol) in Tetrahydrofuran (60 mL) stirred under nitrogen at 0 °C was added a solution of methylmagnesium bromide (14.62 mL, 14.62 mmol). The reaction mixture was stirred at 0 °C for 3h. The mixture was diluted with 100 mL of a 1 N HCI solution and the mixture was evaporated evaporated in vacuo. 200 mL of water was added and the mixture was extracted by ethyl acetate (3x200 ml). The combined organic layers were dried over Na2S04 and evaporated to afford 1 -(3-chloro-6-methoxy-2-methylphenyl)ethanol (1 .5 g, 4.86 mmol, 49.8 % yield), m/z: [M - OH]+ Calcd for C10H12CIO 183.1 ; Found 183
Intermediate 82: 1 -(3-chloro-6-methoxy-2-methylphenyl)ethanone
Figure imgf000272_0001
To a solution of 1 -(3-chloro-6-methoxy-2-methylphenyl)ethanol (1 .5 g, 7.48 mmol) in Dichloromethane (50 mL) was added pyridinium chlorochromate (8.06 g, 37.4 mmol). The reaction mixture was stirred at rt overnight. The whole reaction mixture was filtered through a pad of silica gel and the filtrate was concentrated in vacuo to give 1 -(3-chloro-6-methoxy- 2-methylphenyl)ethanone (1 .45 g, 6.79 mmol, 91 % yield) as a yellow solid, m/z: [M + H]+ Calcd for C10H12CIO2 199.1 ; Found 199
Figure imgf000272_0002
Intermediate 83
Intermediate 83: 3-(cyclopropanecarbonyl)-4-methoxybenzonitrile
Figure imgf000272_0003
Isopropylmagnesium chloride (187 mg, 1 .816 mmol) (2 M solution in THF) was added to a solution of 3-bromo-4-methoxybenzonitrile (350 mg, 1 .651 mmol) in anhydrous Tetrahydrofuran (10 mL) at -78 °C. This solution was stirred at -78 °C for 1 h. A solution of N- methoxy-N-methylcyclopropanecarboxamide (320 mg, 2.476 mmol) in anhydrous THF (5 mL) was added slowly to the reaction mixture. The reaction mixture was stirred at -78 °C for 1 hour and then stirred at rt overnight. The solution was quenched by a saturated NH4CI solution and extracted by ethyl acetate (3x20 mL). The combined organic layers were concentrated to give the product 3-(cyclopropanecarbonyl)-4-methoxybenzonitrile (300 mg, 0.596 mmol, 36.1 % yield) as a crude yellow oil. m/z: [M + H]+ Calcd for C12H12NO2 202.1 ; Found 202.1
Figure imgf000273_0001
Intermediate 84 Intermediate 85
Intermediate 84: 1 -(3-chloro-2-fluoro-6-methoxyphenyl)ethanol
Figure imgf000273_0002
To a solution of 2, 2, 6, 6-tetramethylpipe dine (528 mg, 3.74 mmol) in Tetrahydrofuran (10 ml.) was added n-butyllithium in hexane(1 .5ml, 3.74 mmol) at -78 °C. After completion of the addition the reaction mixture was stirred at -78 °C for 1 h. Then, 1 -chloro-2-fluoro-4- methoxybenzene (200 mg, 1 .246 mmol) was added and the mixture was stirred for another 1 h. Acetaldehyde (274 mg, 6.23 mmol) was then added and the mixture was stirred for another 1 h. The reaction was quenched with saturated NH4CI (10ml_) and was extrated with EtOAc (2x10 ml_). T combined organic layers were dried over Na2S04 and concentrated, m/z: [M - OH]+ Calcd for C9H9CIFO 187.0; Found 187
Intermediate 85: 1 -(3-chloro-2-fluoro-6-methoxyphenyl)ethanone
Figure imgf000273_0003
To a solution of 1 -(3-chloro-2-fluoro-6-methoxyphenyl)ethanol (6.6g, 32.3 mmol) in Dichloromethane (200 ml.) was added PCC (13.91 g, 64.5 mmol) at rt and then the reaction mixture was stirred at rt overnight. The mixture was concentrated and purified by flash chromatography (petroleum ether/EtOAc = 9/1 ) to give 1 -(3-chloro-2-fluoro-6- methoxyphenyl)ethanone (6.3g, 31 .1 mmol, 96 % yield) as yellow oil. m/z: [M + H]+ Calcd for C9H9CIFO2 203.0; Found 203
Figure imgf000274_0001
Intermediate 86
Intermediate 86: 4-methoxy-3-(2-methoxyacetyl)benzonitrile
Figure imgf000274_0002
Isopropylmagnesium chloride (2 M solution in THF; 2.36 mL; 4.72 mmol) was added to an ice-cooled solution of 3-bromo-4-methoxybenzonitrile (500 mg, 2.38 mmol) in anhydrous THF (10 mL). This solution was stirred at 0°C for 10 minutes and then was added dropwise to a cooled (-78 °C) solution of A/,2-dimethoxy-A/-methylacetamide (471 mg, 3.54 mmol) in anhydrous THF (5 mL). The reaction mixture was stirred at this temperature for 1 h and then stirred at rt for 1 h. The reaction mixture was then treated with a 10% aqueous potassium hydrogen sulfate solution and was extracted with DCM. The organic phase was passed through an hydrophobic frit and was evaporated under reduced pressure. The residue was purified by flash chromatography (hexane/EtOAc = 3/2) to afford the title compound (200 mg, 33 %) as a colorless oil. m/z: [M + H]+ Calcd for C11 H12NO3 206.1 ; Found 206
Figure imgf000274_0003
Intermediate 87: 1 -(5-bromo-2,4-dimethoxyphenyl)ethanone
Figure imgf000274_0004
A solution of 1 -(2,4-dimethoxyphenyl)ethanone (100 mg, 0.555 mmol) and NBS (99 mg, 0.555 mmol) in A/,A/-Dimethylformamide (3 mL) was stirred under a nitrogen atmosphere at 25 °C for 12 h. Water was added to the solution which was then extracted with EtOAc (2 x 20 mL). The organic phase was collected and evaporated to dryness to give crude product as a yellow solid. The crude product was purified by silica gel chromatography (hexane/EtOAc = 5/1 ) to give product 1 -(5-bromo-2,4-dimethoxyphenyl)ethanone (120 mg, 0.440 mmol, 79 % yield) as a white solid, m/z: [M + H]+ Calcd for Ci0Hi2BrO3 259.0; Found 259
Figure imgf000275_0001
Intermediate 91 Intermediate 92
Intermediate 88: 2-bromo-5-methoxy-4-(trimethylsilyl)pyridine
Figure imgf000275_0002
To a mixture of TEMPO (19.45 g, 124 mmol) in THF (10 mL) was added n-BuLi (6.13 g, 96 mmol) at -76 °C under a nitrogen atmosphere. 2-bromo-5-methoxypyridine (18 g, 96 mmol) and TMSCI (18.35 mL, 144 mmol) were then added in sequence. The solution was stirred at rt 1 h. Water was added and the mixture was extracted with ethyl acetate (3x50 mL). The organic layer was washed with saturated NaHC03, water and brine. The organic layer was then dried over MgS04 and filtered. The residue was purified by flash chromatography eluting with (hexane/EtOAc = 4/1 ) 2-bromo-5-methoxy-4-(trimethylsilyl)pyridine (18 g, 62.3 mmol, 65.0 % yield) as an yellow oil. m/z: [M + H]+ Calcd for C9Hi5BrNOSi 260.0; Found 260.2
Intermediate 89: 1 -(6-bromo-3-methoxy-4-(trimethylsilyl)pyridin-2-yl)-2- methoxyethanone
Figure imgf000276_0001
To a mixture of TEMPO (14.05 g, 90 mmol) in THF (10 mL) was added n-BuLi (4.43 g, 69.2 mmol) at -76 °C under a nitrogen atmosphere. -bromo-5-methoxy-4-(trimethylsilyl)pyridine (18 g, 69.2 mmol) and and methyl 2-methoxyacetate (12.71 mL, 104 mmol) were then added in sequence. The solution was stirred at rt 1 h. Water was added and the mixture was extracted with ethyl acetate (3x50 mL). The organic layer was washed with saturated NaHC03, water and brine. The organic layer was then dried over MgS04 and filtered. The residue was purified by flash chromatography eluting with (hexane/EtOAc = 4/1 ) 1-(6-bromo- 3-methoxy-4-(trimethylsilyl)pyridin-2-yl)-2-methoxyethanone (8 g, 14.45 mmol, 20.88 % yield) as an yellow oil. m/z: [M + H]+ Calcd for Ci2Hi9BrN03Si 332.0; Found 332
Intermediate 90: 1 -(6-bromo-3-methoxypyridin-2-yl)-2-methoxyethanone
Figure imgf000276_0002
To a mixture of potassium fluoride (2.80 g, 48.2 mmol) in THF (10 mL) was added 1 -(6-bromo- 3-methoxy-4-(trimethylsilyl)pyridin-2-yl)-2-methoxyethanone (8 g, 24.08 mmol) at rt. The solution was stirred at rt for 1 h. Water was then added and the mixture was extracted with ethyl acetate (3x50 mL). The filtrate was washed with saturated NaHC03, water, and brine. The organic layer was dried over MgS04 and filtered. The residue was purified by flash chromatography (hexane/EtOAc = 1/1 ) to get 1 -(6-bromo-3-methoxypyridin-2-yl)-2- methoxyethanone (4 g, 13.84 mmol, 57.5 % yield) as a yellow oil. m/z: [M + H]+ Calcd for CgHn BrNOs 260.0; Found 260
Intermediate 91 : 2-methoxy-1 -(3-methoxy-6-vinylpyridin-2-yl)ethanone
Figure imgf000276_0003
To a mixture of 1 -(6-bromo-3-methoxypyridin-2-yl)-2-methoxyethanone (2 g, 7.69 mmol) in dioxane (2 mL) was added K2C03 (1 .594 g, 1 1 .53 mmol) and PdCI2(dppf) (0.056 g, 0.077 mmol) at 100 °C under a nitrogen atmosphere. The solution was then stirred at 100 °C 12h. Water was then added and the mixture was extracted with ethyl acetate (3x50 mL). The filtrate was washed with saturated NaHCC , water, and brine. The organic layer was dried over MgS04 and filtered. The residue was purified by flash chromatography (hexane/EtOAc = 1/1 ) to get 2-methoxy-1 -(3-methoxy-6-vinylpyridin-2-yl)ethanone (600 mg, 2.316 mmol, 30.1 % yield) as a yellow oil. m/z: [M + H]+ Calcd for CnHi4N03 208.1 ; Found 208
Intermediate 92: 1 -(6-ethyl-3-methoxypyridin-2-yl)-2-methoxyethanone
Figure imgf000277_0001
To a mixture of 2-methoxy-1 -(3-methoxy-6-vinylpyridin-2-yl)ethanone (600 mg, 2.90 mmol) in EtOH (10 mL) was added Pd/C (30.8 mg, 0.290 mmol) at rt. The reaction was put under an atmosphere of hydrogen and the solution was stirred at rt 12h. The mixture was filtered to get 1 -(6-ethyl-3-methoxypyridin-2-yl)-2-methoxyethanone (600 mg, 2.58 mmol, 89 % yield) as a yellow oil. m/z: [M + H]+ Calcd for CnHi6N03 210.1 ; Found 210
Figure imgf000277_0002
Intermediate 93
Intermediate 93: 1 -(2-ethyl-5-methoxypyridin-4-yl)-2-methoxyethanone
Figure imgf000277_0003
To a solution of 2, 2, 6, 6-tetramethylpiperidine (2.93 g, 20.78 mmol) in Tetrahydrofuran (10 mL) was added n-butyllithium (1 .331 g, 20.78 mmol) at -78 °C. After completion of the addition, the mixture was stirred at -78 °C for 1 h. 2-ethyl-5-methoxypyridine (1 .9 g, 13.85 mmol) was then added and the mixture was stirred at -78 °C for 1 h. A/,2-dimethoxy-N- methylacetamide (2.213 g, 16.62 mmol) was then added and the reaction mixture was subsequently quenchened with water. The mixture was extracted with EtOAc (2x10 mL) and the combined organix layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (hexane/EtOAc = 10/1 ) to give the 1 -(2-ethyl-5-methoxypyridin-4-yl)-2-methoxyethanone (1 g, 4.30 mmol, 31 .1 % yield), m/z: [M + H]+ Calcd for CnHi6N03 210.1 ; Found 210
Figure imgf000278_0001
Intermediate 94 Intermediate 95 Intermediate 96
Intermediate 94: 2-bromo-4-chlorophenyl acetate
Figure imgf000278_0002
To a solution of 2-bromo-4-chlorophenol (20 g, 96 mmol) in Dichloromethane (200 mL) was added acetyl chloride (1 1 .35 g, 145 mmol) and triethylamine (29.3 g, 289 mmol). The mixture was stirred at 0 °C for 3 h. Water was then added and the mixture was extracted with ethyl acetate. The organic layer was dried over Na2S04, filtered and purified by chromatography on silica gel (hexane/EtOAc = 5/1 ) to give the desire product 2-bromo-4-chlorophenyl acetate (23 g, 92 mmol, 96 % yield) as a yellow solid.
1 H NMR (400 MHz, CDCI3) δ 7.60 (d, J = 2.5Hz, 1 H), 7.29 (dd, J = 2.5, 8.5Hz, 1 H), 7.05 (d, J = 8.5Hz, 1 H), 2.34 (s, 1 H)ppm
Intermediate 95: 1 -(3-bromo-5-chloro-2-hydroxyphenyl)ethanone
Figure imgf000278_0003
To a solution of 2-bromo-4-chlorophenyl acetate (20 g, 80 mmol) was added 1 -(3-bromo-5- chloro-2-hydroxyphenyl)ethanone (17 g, 61 .3 mmol, 77 % yield). The mixture was stirred at 135 °C overnight. Water was then added and the mixture was extracted with ethyl acetate. The organic layer was dried over Na2S04, filtered and purified by chromatography on silica gel (hexane/EtOAc = 1/1 ) to give the desire product 1 -(3-bromo-5-chloro-2- hydroxyphenyl)ethanone (17 g, 61 .3 mmol, 77 % yield) as a yellow solid, m/z: [M + H]+ Calcd for C8H7BrCI02 248.9; Found 249
Intermediate 96: 1 -(3-bromo-5-chloro-2-methoxyphenyl)ethanone
Figure imgf000279_0001
To a solution of 1 -(3-bromo-5-chloro-2-hydroxyphenyl)ethanone (18.83 g, 75 mmol) in N,N- Dimethylformamide (100 ml.) was added iodomethane (16.07 g, 1 13 mmol) and K2C03 (20.86 g, 151 mmol). After completion of the addition, the reaction mixture was stirred at 80 °C overnight. The reaction mixture was cooled to room temperature and was diluted with ethyl acetate (100 ml_). The organic layer was washed with brine (3x), dried over Na2S04, filtered and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (hexane/EtOAc = 5/1 ) to give 1 -(3-bromo-5-chloro-2-methoxyphenyl)ethanone (15 g, 34.2 mmol, 45.3 % yield), m/z: [M + H]+ Calcd for C9H9BrCI02 263.0; Found 263
Figure imgf000279_0002
Intermediate 97 Intermediate 98 Intermediate 99 Intermediate 97: 4-chloro-1 -(5-chloro-2-hydroxyphenyl)butan-1 -one
Figure imgf000279_0003
To aluminium chloride (2.000 g, 15.00 mmol) in Dichloromethane (16 mL) was added 1 - chloro-4-methoxybenzene (1 .426 g, 10 mmol) and 4-chlorobutanoyl chloride (1 .692 g, 12.00 mmol) a 1 0-5 °C. The mixture was stirred to rt for 18h. The yellow oil was slowly poured into water and extracted with DCM (2x30 ml). The combined organic layers were washed brine, then dried over MgS04 and concentrated in vacuo to give a yellow oil which was used in the next step without further purification, m/z: [M - H]" Calcd for C10H10CI2O2 231 .0.
Intermediate 98: (5-chloro-2-hydroxyphenyl)(cyclopropyl)methanone
Figure imgf000280_0001
To 4-chloro-1 -(5-chloro-2-hydroxyphenyl)butan-1 -one (2.2 g, 9.44 mmol) in Methanol (10 mL) was added KOH (5.30 g, 9.44 mmol). The mixture was stirred at rt for 30 minutes. The mixture was concentrated to give an oil which was poured into water (5 mL) and extracted with EtOAc (2x30 ml). The combined organic layers were washed with brine, then dried over MgS04 and concentrated in vacuo to give a yellow oil. The oil was purified by silica gel chromatography (hexane/EtOAc = 20/1 ) to obtain the title compound 5-chloro-2- hydroxyphenyl)(cyclopropyl)methanone (750 mg, 3.43 mmol, 36.4 % yield) as a white solid, m/z: [M + H]+ Calcd for CioH8CI02 195.0; Found 195
Intermediate 99: (5-chloro-2-methoxyphenyl)(cyclopropyl)methanone
Figure imgf000280_0002
To a solution of (5-chloro-2-hydroxyphenyl)(cyclopropyl)methanone (750 mg, 3.81 mmol) in A/,A/-Dimethylformamide (15 mL) was added iodomethane (0.356 mL, 5.72 mmol). The mixture was stirred at rt for 18 h. Water (10 mL) was added and the mixture was then extracted with EtOAc (3x20 mL). The combined organic layers were washed with brine (10 mL). The organic layer was dried over Na2S04 and then concentrated under reduced pressure to give a brown oil which was purified by silica gel chromatography (hexane/EtOAc = 20/1 ) to obtain the title compound (5-chloro-2-methoxyphenyl)(cyclopropyl)methanone (790 mg, 3.60 mmol, 94 % yield) as a yellow oil. m/z: [M + H]+ Calcd for C11 H12CIO2 21 1 .1 ; Found 21 1
Figure imgf000281_0001
Intermediate 100
Intermediate 100: 2-ethoxy-1 -(5-fluoro-2-methoxyphenyl)ethanone
Figure imgf000281_0002
To a solution of 2-bromo-1 -(5-fluoro-2-methoxyphenyl)ethanone (1 .50 g, 6.07 mmol) in ethanol(18 mL), was added silver carbonate (2.51 g, 9.1 1 mmol)and boron trifluoride diethyl etherate (0.971 mL, 7.89 mmol). The solution was stirred at room temperature under argon for 2 days, filtered and diluted with dichloromethane (100 mL). The organic layer was washed with water (50 mL) and dried over anhydrous magnesium sulfate. After filtering and evaporated in vacuo, the crude product was purified by flash column chromatography on silica gel (200-300 mesh. Petroleum ether/EtOAc 5:1 was used to elute to the product. This provided 2-ethoxy-1 -(5-fluoro-2-methoxyphenyl)ethanone (850 mg, 3.97 mmol, 65.3 % yield)(N33532-96-B1 ) as a yellow solid. m/z: [M + H]+ Calcd for C11 H13FO3 213.1 ; Found 213
Figure imgf000281_0003
Intermediate 101 : 1 -(5-fluoro-2-methoxyphenyl)-3-methoxypropan-1 -one
Figure imgf000281_0004
To a flask with 1 -(5-fluoro-2-methoxyphenyl)ethanone (1 g, 5.95 mmol) and Et3N (1 .003 mL, 7.20 mmol) in Dichloromethane (5ml_) \cooled to 0 °C was added trimethylsilyl thfluoromethanesulfonate (1 .586 g, 7.14 mmol) dropwise. The reaction mixture was stirred at 0 °C for 15 min to give a light yellow solution. Dimethoxymethane (0.633 g, 8.33 mmol) was then added at 0 °C. Additional trimethylsilyl trifluoromethanesulfonate (0.264 g, 1 .189 mmol) was then added dropwise and the reaction mixture was allowed to stirred at rt for 1 h. The mixture was quenched with water (5ml_) and was extracted with DCM (2x1 OmL). The combined organic layers were washed with brine (10 mL) and dried over anhydrous MgS04. The filtrate was concentrated under vacuum to give 1 -(5-fluoro-2-methoxyphenyl)-3- methoxypropan-1 -one (1 g, 4.71 mmol, 79 % yield) as a colourless oil. m/z: [M + H]+ Calcd for C11 H14FO3 213.1 ; Found 213
Figure imgf000282_0001
Intermediate 101 Intermediate 102
Intermediate 102: 1 -(5-chloro-2-hydroxyphenyl)-2-methylpropan-1 -one
Figure imgf000282_0002
To aluminium chloride (4.00 g, 30.0 mmol) in Dichloromethane (60 mL) was added 1 -chloro- 4-methoxybenzene (2.85 g, 20 mmol) and 3-methylbutanoyl chloride (2.65 g, 22.00 mmol) at rt. The mixture was stirred at rt for 18h. The mixture was slowly poured into ice-water and extracted with DCM (2x30 mL). The combined organic layers were washed with brine, dried over anhydrous MgS04 and concentrated in vacuo to give 1 -(5-chloro-2-hydroxyphenyl)-2- methylpropan-1 -one (3.86 g, 15.31 mmol, 77 % yield) as a yellow solid, m/z: [M - H]" Calcd for CioHioCI02 197.0; Found 197
Intermediate 103: 1 -(5-chloro-2-methoxyphenyl)-2-methylpropan-1 -one
Figure imgf000283_0001
To a solution of 1 -(5-chloro-2-hydroxyphenyl)-2-methylpropan-1 -one (3.61 g, 18.17 mmol) in N,N-Dimethylformamide (25 mL) was added iodomethane (1 .697 mL, 27.3 mmol). The mixture was stirred at rt for 18 h. Water (10 mL) was added and the mixture was extracted with EtOAc (3x20 mL). The combined organic layers were washed with brine (10 mL). The organic layer was dried over Na2S04 and was concentrated under reduced pressure to give a crude product that was purified by silica gel chromatography (hexane/EtOAc = 20/1 ) to obtain 1 -(5-chloro-2-methoxyphenyl)-2-methylpropan-1 -one (3.5g, 15. mmol, 83% yield) as a yellow oil. m/z: [M + H]+ Calcd for CnHi4CI02 213.1 ; Found 213.
Figure imgf000283_0002
Intermediate 104 Intermediate 105
Intermediate 104: 2-bromo-1 -(5-chloro-2-methoxyphenyl)ethanone
Figure imgf000283_0003
Copper(ll) bromide (22.38 g, 100 mmol) was suspended in EtOAc (120 mL) and the mixture was heated to reflux. A solution of 1-(5-chloro-2-methoxyphenyl)ethanone (10 g, 54.2 mmol) in Chloroform (80 mL) was added dropwise to the reaction. After 4 h, the reaction was filtered and concentrated in vacuo. The residue was dissolved in EtOAc and the organic mixture was washed with saturated aqueous NaHC03 and water, was dried over Na2S04 and concentrated. The residue was purified with silica gel chromatography (EtOAc/petroleum ether = 1/10) to get 2-bromo-1 -(5-chloro-2-methoxyphenyl)ethanone (9.5 g, 33.9 mmol, 62.6 % yield), m/z: [M + H]+ Calcd for C9H9BrCI02 263.0; Found 263
Intermediate 105: 1 -(5-chloro-2-methoxyphenyl)-2-methoxyethanone
Figure imgf000284_0001
To a solution of 2-bromo-1-(5-chloro-2-methoxyphenyl)ethanone (500 mg, 1.897 mmol) in Methanol (25 mL) was added silver carbonate (785 mg, 2.85 mmol) and BF3.Et20 (0.481 ml_, 3.79 mmol). The resulting mixture was stirred at rt for 2 days. The mixture was filtrated and concentrated. The residue was dissloved in EtOAc and was washed with water, dried over Na2S04 and concentrated to give 1-(5-chloro-2-methoxyphenyl)-2-methoxyethanone (185 mg, 0.664 mmol, 35.0 % yield) as a yellow solid, m/z: [M + H]+ Calcd for CioHi2CI03 215.1 ; Found 215
Figure imgf000284_0002
Intermediate 106
Figure imgf000284_0003
Intermediate 109 Intermediate 106: 4-cyanophenyl-N,N,N',N'-tetramethyldiamidophosphate
Figure imgf000284_0004
A mixture of 4-hydroxybenzonitrile (2 g, 16.79 mmol), DMAP (0.410 g, 3.36 mmol) and pyridine (2.72 mL, 33.6 mmol) in Tetrahydrofuran (80 mL) was cooled to 0 °C. Bis(dimethylamino)phosphorochloridate (3.15 g, 18.47 mmol) was then added dropwise and the reaction mixture was stirred at rt overnight. The reaction mixture was quenched by saturated NH4CI (30ml) and was extracted with EtOAc (2x50 mL). The combined organic layers were washed with brine (2x30 mL), dried over anhydrous MgS04 and concentrated under vacuum to give 4-cyanophenyl-N,N,N',N'-tetramethyldiamido-phosphate (4.5 g, 15.99 mmol, 95 % yield) as a light yellow oil. m/z: [M + H]+ Calcd for C11 H17N3O2P 254.1 ; Found 254
Intermediate 107: 3-pivaloyl-4-cyanophenyl-N,N,N',N'-tetramethyldiamidophosphate
Figure imgf000285_0001
A solution of 4-cyanophenyl-N,N,N',N'-tetramethyldiamido-phosphate (3.5 g, 13.82 mmol) in Tetrahydrofuran (50 mL) was cooled to 0°C. Magnesium 2,2,6,6-tetramethylpiperidin-1 -ide (19.00 mL, 15.20 mmol) was added at 0 °C for and the mixtrure was stirred for 1 h. Zinc chloride (1 M in diethyl ether) (27.6 mL, 27.6 mmol) was added and the reaction mixture was stirred at 0 °C for 30 min. CuCN.2LiCI (1 M in THF, 0.5 eq, 6.91 mL) and pivaloyl chloride (2.500 g, 20.73 mmol) were then added and the reaction mixture was allowed to warm to 25 °C over 12 h. The reaction was quenched by adding water (30 mL) and was extracted with EtOAc (2x100 mL). The combined organic layers were washed with brine (2x50 mL), dried over anhydrous MgS04 and concentrated under vacuum to give the crude product which was purified by flash chromatography on silica gel (EtOAc/hexane = 1/4 -> 1/0) to give 3-pivaloyl- 4-cyanophenyl-N,N,N',N'-tetramethyldiamido-phosphate (4 g, 10.08 mmol, 72.9 % yield) as a white solid, m/z: [M + H]+ Calcd for C16H25N3O3P 338.2; Found 338.
Intermediate 108: 4-hydroxy-3-pivaloylbenzonitrile
Figure imgf000285_0002
A solution of 3-pivaloyl-4-cyanophenyl-N,N,N',N'-tetramethyldiamido-phosphate (1 .5 g, 4.45 mmol) in formic acid (9 mL, 235 mmol), ethanol (9 mL) and water (0.9 mL) was stirred under microwave condition (Power = 100 W, max temperature = 120 °C) for 1 h. The organic solvents were removed under vacuum and the reaction mixture was neutralized with sat. aq. NaHCC and extracted with DCM (3x30 mL), dried over anhydrous MgS04 and concentrated under vacuum to give the crude product. The residue was purified by silica gel column chromatography (hexane/EtOAc = 3/1 ) to give 4-hydroxy-3-pivaloylbenzonitrile (900 mg, 3.99 mmol, 90 % yield) as a white solid, m/z: [M + H]+ Calcd for Ci2Hi4N02 204.1 ; Found 204.
Intermediate 109: 4-methoxy-3-pivaloylbenzonitrile
Figure imgf000286_0001
To a mixture of 4-hydroxy-3-pivaloylbenzonitrile (900 mg, 4.43 mmol) and K2C03 (918 mg, 6.64 mmol) in A/,A/-Dimethylformamide (5 mL) was added iodomethane (691 mg, 4.87 mmol) and the reaction mixture was stirred at rt for 3 h. Water (5mL) was added and the mixture was extracted with EtOAc (2x30 mL). The combined organic layers were washed with 5% aq. LiCI (2x15 mL) and brine (20 mL), dried over anhydrous MgS04 and concentrated under vacuum to give 4-methoxy-3-pivaloylbenzonitrile (920 mg, 3.81 mmol, 86 % yield) as a light yellow solid, m/z: [M + H]+ Calcd for Ci3Hi6N02 218.1 ; Found 218
Figure imgf000286_0002
Intermediate 1 10 Intermediate 1 1 1 Intermediate 1 12
Intermediate 110: 5-methoxy-2-(trifluoromethyl)pyridine
Figure imgf000286_0003
To a solution of 6-(trifluoromethyl)pyridin-3-ol (30 g, 184 mmol) and KOH (31 .0 g, 552 mmol) in Dimethyl Sulfoxide (300 mL) stirred under air at 0 °C was added iodomethane (1 1 .50 mL, 184 mmol) dropwise. The reaction mixture was stirred at 25°C for 16 h. Water (300 mL) was added and the reaction mixture was extacted with MTBE (2x150 mL). The combined organic layers were washed with brine (100 mL) and evaporated in vacuo to give the crude product as a yellow oil. m/z: [M + H]+ Calcd for C7H7F3NO 178.1 ; Found 178 Intermediate 111 : 1 -(5-methoxy-2-(trifluoromethyl)pyridin-4-yl)ethanol
Figure imgf000287_0001
To a solution of 2,2,6, 6-tetramethylpiperidine (33.9 g, 240 mmol) in Tetrahydrofuran (400 mL) stirred under nitrogen at -70 °C was added n-BuLi in hexanes (2.4 M, 93 mL, 224 mmol) dropwise over 15 min. The reaction mixture was warmed to 0 °C and stirred for 5 min. The mixture was cooled to -70 °C and was trated with 5-methoxy-2-(trifluoromethyl)pyridine (28.36 g, 160 mmol) dropwise over 30 min. The reaction mixture was stirred at -70 °C for 30 min. Acetaldehyde (35.3 g, 801 mmol) was added dropwise over 2 min. The reaction mixture was stirred at -70 °C for 20 min. The reaction mixture was quenched with water. Water (100 mL) was added and the mixture was extracted with dichloromethane (2x250 mL). The combined organic layers were evaporated in vacuo to give the crude product as a yellow oil. The crude product was purified via silica gel column chromatography (petroleum ether/ethyl acetate = 8/1 ) to give the product as a yellow oil. m/z: [M + H]+ Calcd for C9H10F3NO2 222.1 ; Found 222
Intermediate 112: 1 -(5-methoxy-2-(trifluoromethyl)pyridin-4-yl)ethanone
Figure imgf000287_0002
To a solution of 1 -(5-methoxy-2-(trifluoromethyl)pyridin-4-yl)ethanol (31 .55 g, 143 mmol) in Dichloromethane (500 mL) stirred under air at rt was added Dess-Martin periodinane (91 g, 214 mmol) in one portion. The reaction mixture was stirred at 25 °C for 16h. The pH of the reaction mixture was adjusted to 8 with saturated aqueous NaHC03. The mixture was filtered and the phases were separated. The organic layer was evaporated in vacuo to give the crude product as a yellow oil. The crude product was purified via silica gel column chromatography (petroleum ether/ethyl acetate = 8/1 ) to give 1 -(5-methoxy-2-(trifluoromethyl)pyridin-4- yl)ethanone (29.93g, 96%yield) as a white solid m/z: [M + H]+ Calcd for C9H8F3NO2 220.1 ; Found 220.
Figure imgf000288_0001
Intermediate 113: 3-methoxy-6-(trifluoromethyl)picolinic acid
Figure imgf000288_0002
To a mixture of 6-bromo-3-methoxypicolinic acid (3.6 g, 15.52 mmol) and K2CO3 (4.29 g, 31 .0 mmol) in A/,A/-Dimethylformamide (20 mL) was added iodomethane (4.40 g, 31 .0 mmol). The reaction mixture was stirred at 60 °C for 4h. The mixture was then poured into water (10 mL) and was extracted with EtOAc (3x30 mL). The combined organic layers were washed by aqueous LiCI (2x30 mL) and brine (50 mL), dried over anhydrous MgS04 and concentrated in vacuum to give crude methyl 6-bromo-3-methoxypicolinate as a clourless gum. Ethyl 2- chloro-2,2-difluoroacetate (7.38 g, 46.5 mmol), potassium fluoride (9.01 g, 155 mmol) and copper(l) iodide (8.86 g, 46.5 mmol) and A/,A/-Dimethylformamide (20.00 mL) were then added and the reaction mixture was stirred at 120 °C for 18h. The mixture was cooled to rt and water (30 mL) was added. The mixture was filtered and extracted with EtOAc (3x30 mL). The combined organic layers were washed by aqueous LiCI (2x30 mL) and brine (50 mL), dried over anhydrous MgS04 and concentrated in vacuum to give methyl 3-methoxy-6- (trifluoromethyl)picolinate as a crude product. The crude product was dissloved in methanol (20 mL) and a solution of LiOH (1 .858 g, 78 mmol) in water (20 mL) was added. The reaction mixture was stirred at 40 °C for 1 h. The pH was then adjusted to 5 with 1 N HCI. The mixture was extracted with EtOAc (3x30 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous MgS04 and concentrated under vacuum to give 3-methoxy-6- (trifluoromethyl)picolinic acid (1 .7 g, 6.92 mmol, 44.6 % yield) as a white solid, m/z: [M + H]+ Calcd for C8H7F3NO3 222.0; Found 222 Intermediate 114: 1 -(3-methoxy-6-(trifluoromethyl)pyridin-2-yl)ethanone
Figure imgf000289_0001
3-methoxy-6-(trifluoromethyl)picolinic acid (1 .5g, 6.78 mmol) was dissloved in N,N- Dimethylformamide (20 mL). HATU (3.87 g, 10.17 mmol) and Λ/,Ο-dimethylhydroxylamine hydrochloride (0.860 g, 8.82 mmol) were then added. The reaction mixture was stirred at rt for 5 min. DIPEA (3.55 mL, 20.35 mmol) was then added and the reaction mixture was stirred at rt for 2h. The mixture was quenched with water (20 mL) and was extracted with EtOAc (2x50 mL). The combined organic layers were washed with 5% aq. LiCI (3x30 mL) and brine (2x50 mL), dried over anhydrous MgS04 and concentrated under vacuum to give Λ/,3- dimethoxy-N-methyl-6-(trifluoromethyl)picolinamide as a light yellow gum. Crude Λ/,3- dimethoxy-N-methyl-6-(trifluoromethyl)picolinamide was dissloved in THF (20 mL) and the mixture was cooled to 0 °C. Methylmagnesium bromide (2.427 g, 20.35 mmol) was added dropwise and the reaction mixture was stirred at rt overnight. The reaction was quenched by saturated NH4CI (50 mL) and was extracted with EtOAc (2x100 mL). The combined organic layers were washed with brine (80 mL), dried over anhydrous MgS04 and concentrated under vacuum to give 1 -(3-methoxy-6-(trifluoromethyl)pyridin-2-yl)ethanone (1.2 g, 4.93 mmol, 72.6 % yield) as a white soild. m/z: [M + H]+ Calcd for C9H9F3NO2 220.1 ; Found 220
Figure imgf000289_0002
Intermediate 115: 2-bromo-1 -(5-bromo-2-methoxyphenyl)ethanone
Figure imgf000289_0003
A mixture of copper(ll) bromide (19.50 g, 87 mmol) in Ethyl acetate (150 mL) was heated to 100 °C and then a solution of 1 -(5-bromo-2-methoxyphenyl)ethanone (10 g, 43.7 mmol) in Chloroform (50 mL) was added dropwise under a nitrogen atmosphere. The mixture was stirred at 100 °C for 5 h. The mixture was filtered through a pad of silica gel (100-200 mesh) and the filtrate was evaporated to afford the crude product. The crude product was triturated in a mixture of EtOAc/petroleum ether = 1/1 (30 mL) to afford pure 2-bromo-1 -(5-bromo-2- methoxyphenyl)ethanone (12 g, 15.59 mmol, 35.7 % yield) as a white solid, m/z: [M + H]+ Calcd for 306.9; Found 307
Intermediate 116: 1 -(5-bromo-2-methoxyphenyl)-2-hydroxyethanone
Figure imgf000290_0001
A mixture of sodium formate (2.65 g, 39.0 mmol) in EtOH (50 mL) was heated to 100 °C and then a solution of 2-bromo-1 -(5-bromo-2-methoxyphenyl)ethanone (12 g, 39.0 mmol) in EtOH (50 mL) was added dropwise under a nitrogen atmosphere. The mixture was stirred at 100 °C for 5 h. The mixture was filtered through a pad of silica gel (100-200 mesh) and the filtrate was evaporated to afford the crude product. The crude product was triturated in a mixture of EtOAc/petroleum ether = 1/1 (30 mL) to afford pure 1 -(5-bromo-2-methoxyphenyl)-2- hydroxyethanone (4 g, 14.69 mmol, 37.7 % yield) as a white solid, m/z: [M + H]+ Calcd for C9HioBr03 245.0; Found 245
Figure imgf000290_0002
Intermediate 117: 4-methoxy-3-(2-methoxyacetyl)benzonitrile
Figure imgf000290_0003
Isopropyl magnesium chloride (2 M solution in THF; 2.36 mL; 4.72 mmol) was added to an ice-cold solution of 3-bromo-4-methoxybenzonitrile (500 mg, 2.38 mmol) in anhydrous THF (10 mL). This solution was stirred for 10 minutes and then was added dropwise at -78 °C a solution of A/,2-dimethoxy-N-methylacetamide (471 mg, 3.54 mmol) in anhydrous THF (5 mL). The reaction mixture was stirred for 1 h at -78 °C and then stirred at rt for 1 h. The reaction mixture was then treated with 10 percent aqueous potassium hydrogen sulfate and was extracted with DCM. The organic phase was passed through a hydrophobic frit and evaporated under reduced pressure. The residue was purified by flash chromatography (hexane/EtOAc = 3/2) to afford the 4-methoxy-3-(2-methoxyacetyl)benzonitrile (200 mg, 33%) as a colorless oil. m/z: [M + H]+ Calcd for C11 H12NO3 206.1 ; Found 206
Figure imgf000291_0001
Intermediate 118: 5-methoxy-2-(trif luoromethyl)-4-(trimethylsilyl)pyridine
Figure imgf000291_0002
To a solution of 2,2,6, 6-tetramethylpiperidine (2.392 g, 16.94 mmol) in Tetrahydrofuran (100 ml.) cooled to -70 °C was added dropwise n-BuLi in hexanes (6.77 ml_, 16.94 mmol). The mixture was stirred for at -70 °C for 30 min. A solution of 5-methoxy-2-(trifluoromethyl)pyridine (2 g, 1 1 .29 mmol) in Tetrahydrofuran (100 mL) was then added dropwise. After the addition was complete, the mixture was allowed to stir at 0 °C for 45 min. The mixture was cooled again to -70 °C. TMSCI (1 .732 mL, 13.55 mmol) was added dropwise and the resulting reaction mixture was stirred for at -70 °C for 1 h. The reaction was quenched with aqueous NH4CI (100 mL) and the mixture was extracted with ethyl acetate (3 x 50mL). The combined organic layers were washed with brine, dried over anhydrous Na2S04 and concentrated to give the title compound 5-methoxy-2-(trifluoromethyl)-4-(trimethylsilyl)pyridine (2 g, 7.22 mmol, 63.9 % yield) as a deep yellow oil. m/z: [M + H]+ Calcd for C10H15F3NOS1 250.1 ; Found 250. Intermediate 119: 2-methoxy-1 -(3-methoxy-6-(trifluoromethyl)-4- (trimethylsilyl)pyridin-2-yl)ethanone
Figure imgf000291_0003
To a solution of 5-methoxy-2-(t fluoromethyl)-4-(t methylsilyl)py dine (5 g, 20.06 mmol) in Tetrahydrofuran (10 mL) cooled to -70 °C was added dropwise ί-BuLi in hexane (23.14 mL, 30.1 mmol) over a period of 30 min. After the addition was complete, the mixture was stirred for 1 h. Methyl 2-methoxyacetate (3.13 g, 30.1 mmol) was then added dropwise and the resulting mixture was stirred for 1 h before being allowed to warm to rt. The reaction was quenched with aqueous NH4CI (100 mL) and the mixture was extracted with ethyl acetate (3 x 50mL). The combined organic layers were washed with brine, dried over anhydrous Na2S04 and concentrated. The residue was purified by flash chromatography on silica gel (petroleum ether/EtOAc = 19/1 ) to give the title compound 2-methoxy-1 -(3-methoxy-6-(trifluoromethyl)- 4-(trimethylsilyl)pyridin-2-yl)ethanone (5 g, 15.56 mmol, 78 % yield) as a yellow oil. m/z: [M + H]+ Calcd for C13H19F3NO3S1 322.1 ; Found 322
Intermediate 120: 2-methoxy-1 -(3-methoxy-6-(trifluoromethyl)pyridin-2-yl)ethanone
Figure imgf000292_0001
To a solution of 2-methoxy-1 -(3-methoxy-6-(trifluoromethyl)-4-(trimethylsilyl)pyridin-2- yl)ethanone (5 g, 15.56 mmol) in Tetrahydrofuran (5 mL) was added TBAF in THF (31 .1 mL, 31 .1 mmol). The mixture was stirred for 4 h at rt. The mxiture was diluted with ethyl acetate (100 mL), was washed with water (10 mL) and brine (20 mL) and was dried over anhydrous Na2S04. The mixture was concentrated in vacuo to give a deep yellow oil which was purified by flash chromatography (100% EtOAc) to give the title compound 2-methoxy-1 -(3-methoxy- 6-(trifluoromethyl)pyridin-2-yl)ethanone (2.5 g, 8.73 mmol, 56.1 % yield) as a yellow solid, m/z: [M + H]+ Calcd for C10H11 F3NO3 250.1 ; Found 250
Figure imgf000292_0002
Intermediate 121 : 5-methoxy-2-(trifluoromethyl)pyridine
Figure imgf000292_0003
lodomethane (1.741 g, 12.26 mmol) was added to a mixture of 6-(trifluoromethyl)pyridin-3-ol (2 g, 12.26 mmol) and K2C03 (1 .695 g, 12.26 mmol) in N,N-Dimethylformamide (50 mL). The reaction mixture was stirred at rt for 3 h. The reaction was quenched with water (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with aq. 5% LiCI (2 x 100 mL) and brine (100 mL), dried over anhydrous MgS04 and concentrated under vacuum to give 5-methoxy-2-(trifluoromethyl)pyridine (200 mg, 1 .073 mmol, 87 % yield) as a yellow oil. m/z: [M + H]+ Calcd for C7H7F3NO 178.1 ; Found 178
Intermediate 122: 2-methoxy-1 -(5-methoxy-2-(trifluoromethyl)pyridin-4-yl)ethanone
Figure imgf000293_0001
To a solution of 2,2,6, 6-tetramethylpiperidine (2.87 g, 20.32 mmol) in THF (30 mL) was added dropwise 2.6M n-BuLi in toluene (6.95 mL, 18.07 mmol) at -78 °C. The reaction mixture was stirred at 0 °C for 20 min. The solution was cooled to -78 °C and was treated dropwise with methyl 2-methoxyacetate (4.70 g, 45.2 mmol). The reaction mixture was stirred at -78 °C for 30 min. 5-methoxy-2-(trifluoromethyl)pyridine (2 g, 1 1 .29 mmol) was then added at -78 °C. The reaction mixture was stirred at this temperature for 2 h. The reaction mixture was quenched with sat. NH4CI and extracted with EtOAc (3 x 40 mL). The combined organic layer was dried over sodium sulfate, filtered and evaporated to give a residue. The residue was purified by flash chromatography on silica gel (petroleum ether/EtOAc = 10/1 -> 2/1 ) to give the title compound 2-methoxy-1 -(5-methoxy-2-(trifluoromethyl)pyridin-4-yl)ethanone (2 g, 8.03 mmol, 71 .1 % yield) as a white solid, m/z: [M + H]+ Calcd for C10H11 F3NO3 250.1 ; Found 250.1
Figure imgf000293_0002
Intermediate 123 Intermediate 124
Intermediate 123: 2-bromo-1 -(5-bromo-2-methoxyphenyl)ethanone
Figure imgf000293_0003
1 -(5-bromo-2-methoxyphenyl)ethanone (15 g, 20.46 mmol, 35.5 % yield) copper(ll) bromide (12.87 g, 57.6 mmol) were suspended in ethyl acetate (40 mL) and Chloroform (80 mL) at 25 °C. The reaction mixture was stirred at 80 °C for 40 h. The mixture was filtered, the filtrate was diluted with water (50 mL) and the mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were dried over sodium sulfate, filtered and evaporated to give a residue. The residue was purified by flash chromatography on silica gel (petroleum ether/EtOAc = 10/1 -> 2/1 ) to give the title compound which used next step without further purification, m/z: [M + H]+ Calcd for C9H9Br202 306.9; Found 306.9
Intermediate 124: 1 -(5-bromo-2-methoxyphenyl)-2-methoxyethanone
Figure imgf000294_0001
To a solution of 2-bromo-1 -(5-bromo-2-methoxyphenyl)ethanone (12.6 g, 17.18 mmol) in Methanol (60 mL) was added silver carbonate (5.69 g, 20.62 mmol) and BF3-OEt2 (2.4 mL, 18.90 mmol). The solution was stirred at room temperature under argon for 100 h. The reaction mixture was filtered through a pad of celite. The cake was washed with DCM (50 mL) and the filtrate was concentrated to give a residue. The residue was diluted with EtOAc (50 mL) and was washed with water (50 mL). The aqueous phase was further extracted with EtOAc (3 x 50 mL). The combined organic layers were dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo. The crude residue was purified by flash chromatography on silica gel (petroleum ether/EtOAc = 1 /1 ) to give 1 -(5-bromo-2- methoxyphenyl)-2-methoxyethanone (4.5 g, 9.21 mmol, 53.6 % yield) as a yellow solid, m/z: [M + H]+ Calcd for Ci0Hi2BrO3 259.0; Found 259.0
Figure imgf000294_0002
Intermediate 125 Intermediate 126
Intermediate 125: 2-bromo-1 -(4-bromo-2-methoxyphenyl)ethanone
Figure imgf000294_0003
Copper(ll) bromide (1463 mg, 6.55 mmol) was added to a solution of 1 -(4-bromo-2- methoxyphenyl)ethanone (500 mg, 2.183 mmol) in Chloroform (20 mL) and the solution was stirred at 80 °C for 12 h under N2.The mixture was then cooled to room temperature and was diluted with water (20 mL). The mixture was extrated with DCM (3 x 50 mL). The combined organic layers were dried over Na2S04, filtered and the filtrate was concentrated to give 2- bromo-1 -(4-bromo-2-methoxyphenyl)ethanone (640 mg, 1 .559 mmol, 71 .4 % yield) as a yellow oil. m/z: [M + H]+ Calcd for C9H9Br202 306.9; Found 306.8
Intermediate 126: 1 -(4-bromo-2-methoxyphenyl)-2-methoxyethanone
Figure imgf000295_0001
To a solution of 2-bromo-1 -(4-bromo-2-methoxyphenyl)ethanone (640 mg, 2.078 mmol) in Methanol (20 mL) was added silver carbonate (719 mg, 2.61 mmol) and boron trifluoride diethyl etherate (0.294 mL, 2.390 mmol). The solution was stirred at room temperature under argon for 12 h. The reaction was filtered, diluted with dichloromethane (50 mL) and washed with water (50 mL). The organic layer was dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo. The crude residue was purified by flash chromatography on silica gel (petroleum ether/EtOAc = 10/1 ) to give 1 -(4-bromo-2-methoxyphenyl)-2- methoxyethanone (240 mg, 0.556 mmol, 26.7 % yield) as a yellow solid, m/z: [M + H]+ Calcd for CioHi2Br03 259.0; Found 258.9
Figure imgf000295_0002
Intermediate 127: ethyl 2-(5-bromo-2-methoxyphenyl)-2-oxoacetate
Figure imgf000295_0003
To a solution of aluminum trichloride (10.7g, 80 mmol) in Tetrahydrofuran (THF) (10 mL) was added ethyl 2-chloro-2-oxoacetate (10.8 g, 80 mmol) at 0 °C, After the completion of addition, the mixture was stirred at 0 °C for 1 h. 1 -bromo-4-methoxybenzene (5.0 g, 26.7 mmol) was then added and stirred at 0 °C for 1 h. The reaction was quenched withwater and extracted twice with 20ml of ethyl acetate. The organics were combined and dried over sodium sulfate. After filtering, the filtrate was concentrated under reduced pressure. The resulting residue was purified by flash chromatography eluting with a 10:1 ratio of petroleum ether/ethyl acetate to give ethyl 2-(5-bromo-2-methoxyphenyl)-2-oxoacetate (7.0g, 24.38 mmol, 91 % yield), m/z: [M + H]+ Calcd for CnHi2Br04 287.0; Found 287.6
Figure imgf000296_0001
Intermediate 128: (S)-2-bromo-1 -(5-chloro-2-methoxyphenyl)ethanol
Figure imgf000296_0002
A solution of 2M borane dimethylsulfide in tetrahydrofuran (65.5ml, 131 mmol) and (3a'S)- 3',3'-diphenylhexahydrospiro[[1 ,3,2]dioxaborolane-2, 1 '-pyrrolo[1 ,2-c][1 ,3,2]oxazaborol]-7'- ium-6-uide (4.29 g, 1 1 .95 mmol) was stirred at room temperature for 30 min under a nitrogen atmosphere. This mixture was then added to a solution of 2-bromo-1 -(5-chloro-2- methoxyphenyl)ethanone (35 g, 120 mmol) in 175ml of tetrhydrofuran over a 5 hour time period. The reaction mixture was then stirred at 25 °C for 16h. The reaction mixture was quenched with water, partitioned between ethyl acetate 300 mL . The organic phase was washed with saturated brine 50 mL, water 50 mL , evaporated in vacuo to give the crude products as a yellow oil. The crude residue was purified by flash chromatography on silica gel (petroleum ether/EtOAc = 20/1 ) to give (S)-2-bromo-1 -(5-chloro-2-methoxyphenyl)ethanol (25 g, 85 mmol, 90 % purity, 70.9 % yield) as an orange solid, m/z: [M - OH]+ Calcd for C9Hn BrCI02 247.0; Found 247 Intermediate 129: (S)-2-(5-chloro-2-methoxyphenyl)oxirane
Figure imgf000297_0001
A solution of (R)-2-bromo-1 -(5-chloro-2-methoxyphenyl)ethanol (35 g, 1 19 mmol) and sodium hydroxide (23.72 g, 593 mmol) in Tetrahydrofuran (150 mL) and Water (150 mL) was stirred in under air at rt for 16h. The solution was extracted with EtOAc (3 x 100 mL) and the combined organic phases were collected and evaporated in vacuo to give the crude product as a orange oil. The crude product 2-(5-chloro-2-methoxyphenyl)oxirane (25 g, 1 15 mmol,85%purity, 97 % yield) is used in the next reaction without further purification, m/z: [M + H]+ Calcd for C9H10CIO2 185.0; Found 185
Intermediate 130: (R)-2-azido-2-(5-chloro-2-methoxyphenyl)ethanol
Figure imgf000297_0002
To a solution of 2-(5-chloro-2-methoxyphenyl)oxirane (25 g, 108 mmol) in Acetonitrile (200 mL) stirred under air at rt was added sodium azide (10.56 g, 162 mmol) in one charge. The reaction mixture was stirred at 80°C for 16h. Brine (100mL) was added and the solution was extracted with EtOAc (3 x 10OmL). The organic phase was collected and evaporated in vacuo to give the crude product as an orange solid. The crude residue was purified by flash chromatography on silica gel (petroleum ether/EtOAc = 20/1 ) to give (f?)-2-azido-2-(5-chloro- 2-methoxyphenyl)ethanol (17 g, 67.2 mmol, 62.0 % yield), m/z: [M + H]+ Calcd for C9H11CIN2O3 228.1 ; Found 228
Intermediate 131 : (R)-2-(1 -azido-2-methoxyethyl)-4-chloro-1 -methoxybenzene
Figure imgf000297_0003
To a solution of (R)-2-azido-2-(5-chloro-2-methoxyphenyl)ethanol (13.7 g, 54.2 mmol) in Tetrahydrofuran (150 mL) stirred under a nitrogen atmosphere at 0°C was added NaH (1.560 g, 65.0 mmol) in one charge. The reaction mixture was stirred at 0 °C for 0.5h. To the reaction mixture was then added iodomethane (9.23 g, 65.0 mmol) in one charge. The reaction mixture was stirred at 25 °C for 5h. Brine (100ml_) was added and the solution was extracted with EtOAc (3 x 100ml_). The organic phase was collected and evaporated in vacuo to give the crude product as an orange oil. m/z: [M - Ν3 Calcd for C10H12CIO2 199.1 ; Found 199
Intermediate 132: (R)-1 -(5-chloro-2-methoxyphenyl)-2-methoxyethanamine
Figure imgf000298_0001
To a solution of (R)-2-(1 -azido-2-methoxyethyl)-4-chloro-1 -methoxybenzene (15.7 g, 65.0 mmol) in Methanol (150 mL) stirred under air at rt was added SnCI2 (37.0 g, 195 mmol) portionwise. The reaction mixture was stirred at 70 °C for 16h. The reaction mixture was quenched with Na2C03 (20 g), filtered and the filter cake was washed with EtOAc (3 x 40mL). The organic phase was collected and evaporated in vacuo to give the crude product as an orange oil. The crude product was used in the next reaction without further purification.
The desired product was isolated as orange solid (R)-1 -(5-chloro-2-methoxyphenyl)-2- methoxyethanamine (1 1 g, 40.8 mmol, 80% purity, 73.9% yield), m/z: [M + H]+ Calcd for C10H15CINO3 216.1 ; Found 216
The following intermedites were synthesized in a similar way to intermediate 132.
Figure imgf000298_0002
Figure imgf000299_0001
Intermediate 135: (Z)-1 -(5-fluoro-2-methoxyphenyl)-2-methoxyethanone oxime
Figure imgf000299_0002
To the solution of 1 -(5-fluoro-2-methoxyphenyl)-2-methoxyethanone (5.0 g, 25.2 mmol) in Methanol (30 mL) was added hydroxylamine hydrochloride (2.63 g, 37.8 mmol) and pyridine (0.188 mL, 2.329 mmol) The mixture was heated to 80 °C and stirred for 3 hours. The wa allowed to cool and thesolvent was removed by rotavap. The residue was taken up in ethyl acetate (20 mL) and washed twice with water(10mL). The organic layer was separated and dried over sodium sulfate anhydrous. The organic solvent was evaporated to give crude product (Z)-1 -(5-fluoro-2-methoxyphenyl)-2-methoxyethanone oxime (7.0 g, 24.62 mmol, 98 % yield) . m/z: [M + H]+ Calcd for Ci0Hi2FNO3214.1 ; Found 214.1
Intermediate 136: 1 -(5-fluoro-2-methoxyphenyl)-2-methoxyethanamine
Figure imgf000299_0003
A solution of of (Z)-1 -(5-fluoro-2-methoxyphenyl)-2-methoxyethanone oxime (5.0 g, 23.45 mmol) in tetrahydrofuran (30ml) was cooled to 0°C under nitrogen atmosphere. LiAIH4 (2.67 g, 70.4 mmol) was slowly added. The mixture was stirred for 0.5 h at 0°C and cautiously warmed to reflux for 1 hr The reaction was cooled in an ice/water bath, then diluted with dry ethyl acetate (20ml). It was quenched by slowly adding water (20ml) and aq. sodium hydroxide solution (15% w/v, 10ml). The mixture was stirred for a while. Then the organic layer was seperated and dried with sodium sulfate anhydrous. After filtration, the filtrate was condensed under vacuum by rotavap to give 1 -(5-fluoro-2-methoxyphenyl)-2- methoxyethanamine (3.6 g, 16.26 mmol, 69.3 % yield), m/z: [M + H]+ Calcd for Ci0Hi4FNO2 200.1 ; Found 200.0
Figure imgf000300_0001
Intermediate 137: (£)-1 -(3-methoxy-6-(trifluoromethyl)pyridin-2-yl)ethanone oxime
Figure imgf000300_0002
To a flask with 1 -(3-methoxy-6-(trifluoromethyl)pyridin-2-yl)ethanone (1 .2g, 5.48 mmol) in Methanol (10 mL) was added pyridine (1 .329 mL, 16.43 mmol) and the reaction mixture was stirred at 80 °C for 2h. The solvent was then removed in vacuum and the resuide was dissloved in EtOAc (150 mL). The solution was washed with brine (2 x 50 mL), dried over anhydrous MgS04 and concentrated in vacuum to give 1 -(3-methoxy-6- (trifluoromethyl)pyridin-2-yl)ethanone oxime as a yellow gum, which was directly used in next step reaction without further purification, m/z: [M + H]+ Calcd for C9H9F3N2O 235.1 ; Found 235.1
Intermediate 138: 1 -(3-methoxy-6-(trifluoromethyl)pyridin-2-yl)ethanamine
Figure imgf000300_0003
To a solution of 1 -(3-methoxy-6-(trifluoromethyl)pyridin-2-yl)ethanone oxime (1 .6g, 6.83 mmol)in ethanol (15ml), was added zinc (2.234 g, 34.2 mmol) and ammonium chloride(3.65 g, 68.3 mmol). The resulting mixture was heated to 80 °C and stirred for 5h. The reaction concentrated to dryness under reduce pressure. This residue was purified by flash chromatography on silica gel (methanol/ethyl acetate, 1 :5) to afford product 1 -(3-methoxy-6- (trifluoromethyl)pyridin-2-yl)ethanamine ( . g, 4.76 mmol, 69.7 % yield) as a yellow solid. m/z: [M + H]+ Calcd for C9H11 F3N2O322I .I ; Found 221 .2
The following intermediates were synthesized in a similar way to intermediate 138.
Figure imgf000300_0004
139 1 -(5-chloro-2- 1 -(5-chloro-2- methoxyphenyl)ethanamine methoxyphenyl)ethanone 186.1
140 1 -(2-chloro-5- 1 -(2-chloro-5- methoxyphenyl)ethanamine methoxyphenyl)ethanone 186.0
141 1 -(5-chloro-2- 1 -(5-chloro-2- ethylphenyl)ethanamine ethylphenyl)ethanone 167.3
142 1 -(3-chloro-5- 1 -(3-chloro-5- methoxyphenyl)ethanamine methoxyphenyl)ethanone 186.1
143 1 -(4-ethyl-6-methoxypyridin-2- 1 -(4-ethyl-6- yl)ethanamine methoxypyridin-2- yl)ethanone 181 .1
144 1 -(5-ethyl-2- 1 -(5-ethyl-2- methoxyphenyl)ethanamine methoxyphenyl)ethanone 180.1
145 1 -(3,5-difluoro-2- 1 -(3,5-difluoro-2- methoxyphenyl)ethanamine methoxyphenyl)ethanone 188.1
146 1 -(3-chloro-6-methoxy-2- 1 -(3-chloro-6-methoxy-2- methylphenyl)ethanamine methylphenyl)ethanone 200.0
147 1 -(3-chloro-2-fluoro-6- 1 -(3-chloro-2-fluoro-6- methoxyphenyl)ethanamine methoxyphenyl)ethanone 204.0
148 3-(1 -amino-2-methoxyethyl)-4- 4-methoxy-3-(2- methoxybenzonitrile methoxyacetyl)benzonitril
e 207.1
149 4-(1 -amino-2-methoxyethyl)-3- 3-methoxy-4-(2- methoxybenzonitrile methoxyacetyl)benzonitril
e 206.1
150 1 -(6-ethyl-3-methoxypyridin-2-yl)-2- 1 -(6-ethyl-3- methoxyethanamine methoxypyridin-2-yl)-2- methoxyethanone 21 1 .1
151 1 -(2-ethyl-5-methoxypyridin-4-yl)-2- 1 -(2-ethyl-5- methoxyethanamine methoxypyridin-4-yl)-2- methoxyethanone 21 1 .2 152 1 -(5-chloro-2-methoxyphenyl)-2- 1 -(5-chloro-2- methylpropan-1 -amine methoxyphenyl)-2- methylpropan-1 -one 214.1
153 1 -(5-chloro-2-methoxyphenyl)-2- 1 -(5-chloro-2- methoxyethanamine methoxyphenyl)-2- methoxyethanone
216.1
154 1 -(5-methoxy-2- 1 -(5-methoxy-2-
(tnfluoromethyl)pyridin-4- (t fluoromethyl)py din-4- yl)ethanamine yl)ethanone 221 .1
155 1 -(3-methoxy-6- 1 -(3-methoxy-6-
(trifluoromethyl)pyridin-2- (t fluoromethyl)py din-2- yl)ethanamine yl)ethanone 221 .2
156 2-methoxy-1 -(5-methoxy-2- 2-methoxy-1 -(5-methoxy-
(trifluoromethyl)pyridin-4- 2-(t fluoromethyl)py din- yl)ethanamine 4-yl)ethanone 251 .1
157 1 -(4-bromo-2-methoxyphenyl)-2- 1 -(4-bromo-2- methoxyethanamine methoxyphenyl)-2- methoxyethanone 260.0
158 1 -(5-chloro-2-methoxyphenyl)-2- 1 -(5-chloro-2- methoxyethanamine methoxyphenyl)-2- methoxyethanone 216.0
159 2-ethoxy-1 -(5-fluoro-2- 2-ethoxy-1 -(5-fluoro-2- methoxyphenyl)ethanamine methoxyphenyl)ethanone 214.1
160 (5-chloro-2- (5-chloro-2- methoxyphenyl)(cyclopropyl)metha methoxyphenyl)(cyclopro namine pyl)methanone 212.0
161 1 -(5-fluoro-2-methoxyphenyl)-3- 1 -(5-fluoro-2- methoxypropan-1 -amine methoxyphenyl)-3- methoxypropan-1 -one 214.2
162 1 -(3-bromo-5-chloro-2- 1 -(3-bromo-5-chloro-2- methoxyphenyl)ethanamine methoxyphenyl)ethanone 263.1
Figure imgf000303_0001
Intermediate 163: (/?,£)-N-(1 -(5-methoxy-2-(trif luoromethyl)pyridin-4-yl)ethylidene)-2- methylpropane-2-sulfinamide
Figure imgf000303_0002
To a solution of 1 -(5-methoxy-2-(t fluoromethyl)py din-4-yl)ethanone (29.93 g, 137 mmol) and (R)-2-methylpropane-2-sulfinamide (24.83 g, 205 mmol) in Tetrahydrofuran (400 mL) stirred under nitrogen at rt was added tetraethoxytitanium (62.3 g, 273 mmol) in one charge. The reaction mixture was stirred at 80 °C for 16h. The reaction mixture was quenched with water, partitioned between EtOAc (250 mL) and water (150 mL), and the aqueous phase was extracted with EtOAc (250 mL). The combined organic phases were evaporated in vacuo to give the crude product as a yellow oil. The crude residue was purified by flash chromatography on silica gel (petroleum ether/EtOAc = 4/1 ) to give the product as a yellow oil. m/z: [M + H]+ Calcd for C13H17F3N2O2S 323.1 ; Found 323 Intermediate 164: (/?)- V-((S)-1 -(5-methoxy-2-(trifluoromethyl)pyridin-4-yl)ethyl)-2- methylpropane-2-sulfinamide
Figure imgf000303_0003
To a solution of (/?,E)-A/-(1 -(5-methoxy-2-(trifluoromethyl)pyridin-4-yl)ethylidene)-2- methylpropane-2-sulfinamide (40.55 g, 126 mmol) in Tetrahydrofuran (400 mL) stirred under nitrogen at -70 °C was added L-selectride (252 mL, 252 mmol) dropwise over 1 h. The reaction mixture was stirred at -70 °C for 1 h. The reaction mixture was quenched with methanol, 1 M HCI aqueous solution was added to adjust the pH to 6. Ethyl acetate (25 mL) and water (10 mL) were then added and the layers were separated. The aqueous phase was further extracted with ethyl acetate (25 mL). The combined the organic layers were evaporated in vacuo to give the crude product as a yellow oil. The crude residue was purified by flash chromatography on silica gel (petroleum ether/EtOAc = 2/1 ). Fractions containing a mixture of the two isomers were concentrated and further purified by preparation-HPLC to get the pure product (21 .6 g) as a white solid, m/z: [M + H]+ Calcd for C13H19F3N2O2S 325.1 ; Found 325
Intermediate 165: (S)-1 -(5-methoxy-2-(trifluoromethyl)pyridin-4-yl)ethanamine hydrochloride
Figure imgf000304_0001
(/?)-A/-((S)-1 -(5-methoxy-2-(trifluoromethyl)pyridin-4-yl)ethyl)-2-methylpropane-2-sulfinamide (7.4 g, 22.81 mmol) was added to a solution of HCI (4M in dioxane) (57.0 mL, 228 mmol) . The reaction mixture was stirred at 20 °C for 16 h. The solution was evaporated in vacuo to give the crude product (6.43 g) as a white solid. m/z: [M + H]+ Calcd for C9H11 F3N2O 221 .1 ; Found 221
The following intermediate compounds were synthesized in a similar way to Intermediate 165.
Figure imgf000304_0002
169 (S)-1 -(6-ethyl-3- 1 -(6-ethyl-3-methoxypyridin- 181 .2 methoxypyridin-2- 2-yl)ethanone
yl)ethanamine hydrochloride
170 (S)-1 -(5-chloro-2- 1 -(5-chloro-2- 167.2 ethylphenyl)ethanamine ethylphenyl)ethanone
hydrochloride
Figure imgf000305_0001
Intermediate 171 : (S,£)-W-(1 -(5-bromo-2-methoxyphenyl)ethylidene)-2-methylpropane- 2-sulfinamide
Figure imgf000305_0002
To a solution of 1 -(5-bromo-2-methoxyphenyl)ethanone (50 g, 218 mmol) in Tetrahydrofuran (300 mL) was added (S)-2-methylpropane-2-sulfinamide (39.7 g, 327 mmol) and tetraethoxytitanium (100 g, 437 mmol). The reaction mixture was stirred at 80 °C overnight. The mixture was quenched by adding water (600 mL) and EtOAc (600 mL). The mixture was then filtered and the filtrate partitioned between ethyl acetate and water. The aqueous phase was further extracted with ethyl acetate (200 mL). The combined organic layers were dried over sodium sulphate and evaporated in vacuo to give the crude product as a brown oil. The crude was used as is in the following reaction, m/z: [M + H]+ Calcd for Ci3HigBrN02S 332.0; Found 332 Intermediate 172: (S)-1 -(5-bromo-2-methoxyphenyl)ethanamine
Figure imgf000305_0003
To a solution of (S,E)-W-(1 -(5-bromo-2-methoxyphenyl)ethylidene)-2-methylpropane-2- sulfinamide (63 g, 190 mmol) in Tetrahydrofuran (600 mL) was added NaBH4 (17.93 g, 474 mmol) at 0 °C. The reaction mixture was stirred at rt overnight. The mixture was quenched by adding water (1000 mL) and EtOAc (1000 mL) and the phases were separated. The aqueous phase was further extracted with ethyl acetate (200 mL). The combined organic layers were dried over sodium sulphate and evaporated in vacuo to give the crude product as a brown oil. The crude residue was purified by flash chromatography on silica gel (hexane/EtOAc = 1/1 ) to give the desired product (S)-A/-((S)-1 -(5-bromo-2- methoxyphenyl)ethyl)-2-methylpropane-2-sulfinamide (38 g, 1 14 mmol, 60.0% yield), m/z: [M + H]+ Calcd for C13H21 BrN02S 334.0; Found 334
Intermediate 173: (S)-1 -(5-bromo-2-methoxyphenyl)ethanamine hydrochloride
Figure imgf000306_0001
A solution of (S)-A/-((S)-1 -(5-bromo-2-methoxyphenyl)ethyl)-2-methylpropane-2-sulfinamide (13.8 g, 41 .3 mmol) in 4N HCI in dioxane (51 .5 mL, 206 mmol) at rt was stirred 15hr. The mixture was concentrated and diluted with EtOAc (15ml). A white precipitate was formed and filtered to produce pure (S)-1 -(5-bromo-2-methoxyphenyl)ethanamine (7.8 g, 33.9 mmol, 82% yield) as HCI salt as a white solid, m/z: [M - NH2]+ Calcd for C9Hi3BrNO 212.9; Found 213.
The following intermediates were synthesized in a similar way to intermediate 173.
Figure imgf000306_0002
176 (S)-1 -(2-ethyl-5- 1 -(2-ethyl-5- 181 .2 164.2 methoxypyridin-4- methoxypyridin-4- yl)ethanamine hydrochloride yl)ethanone
177 (S)-1 -(5-chloro-2- 1 -(5-chloro-2- 186.1 169.1 methoxyphenyl)ethanamine methoxyphenyl)ethanone
hydrochloride
178 (S)-3-(1 -amino-2,2- 4-methoxy-3- 219.1 202.1 dimethylpropyl)-4- pivaloylbenzonitrile
methoxybenzonitrile
hydrochloride
179 (S)-1 -(2,3,5- 1 -(2,3,5- 224.1
trichlorophenyl)ethanamine trichlorophenyl)ethanone
hydrochloride
Figure imgf000307_0001
Intermediate 180: 1 -(5-bromo-2-methoxyphenyl)-2-methoxyethanol
Figure imgf000307_0002
To a solution of 1 -(5-bromo-2-methoxyphenyl)-2-methoxyethanone (6.4 g, 24.70 mmol) in methanol (40 mL) was added NaBH4 (1 .402 g, 37.1 mmol). The solution was stirred at rt under N2 for 3 h. Following completion, the reaction mixture was quenched with water and concentrated directly in vacuo. Water (50 mL) was added to the residue and the resulting aqueous mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated to dryness to provide the desired compound that was carried on without further purification, m/z: [M + Na]+ Calcd for CioHi3BrNa03 283.0; Found 283.
Intermediate 181 : 4-bromo-2-(1 -chloro-2-methoxyethyl)-1 -methoxybenzene
Figure imgf000308_0001
To a solution of 1 -(5-bromo-2-methoxyphenyl)-2-methoxyethanol (6.5g, 24.89 mmol) in CHCb (20 mL) was added POCb (10 mL, 107 mmol). The solution was stirred at 80 °C under N2 for 3 h. Following completion, the reaction mixture was concentrated directly in vacuo. Water (50 mL) was added to the residue and the resulting aqueous mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrated to dryness to provide the desired compound that was carried on without further purification, m/z: [M - Cl]+ Calcd for CioHi4Br02 245.0; Found 245.0.
Intermediate 182: 2-(1 -azido-2-methoxyethyl)-4-bromo-1 -methoxybenzene
Figure imgf000308_0002
A slurry of sodium azide (5.09 g, 78 mmol) and 4-bromo-2-(1 -chloro-2-methoxyethyl)-1 - methoxybenzene (7.3 g, 26.1 mmol) in DMF (15 mL) was stirred at 80 °C under N2 for 18 h. Following completion, the reaction mixture was diluted with water (50 mL) and the resulting aqueous mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated to dryness to provide the desired compound that was carried on without further purification, m/z: [M - Ν3 Calcd for CioHi4Br02 245.0; Found 245.0.
Intermediate 183: 1 -(5-bromo-2-methoxyphenyl)-2-methoxyethanamine
Figure imgf000308_0003
A suspension of 2-(1 -azido-2-methoxyethyl)-4-bromo-1 -methoxybenzene (7.3 g, 25.5 mmol) and SnCI2 (4.84 g, 25.5 mmol) in methanol (40 mL) was stirred at 25 °C for 6 h. To the reaction mixture was then added saturated aqueous NaHC03 (15 mL) and the resulting mixture allowed to stir at rt for 30 min. The mixture was then filtered through a pad of Celite and the cake was washed with EtOAc (2 x 30 mL). The filtrate was then concentrated dryness and then slurried in EtOAc (60 mL) and filtered. The filtrate was then concentrated to dryness and the material obtained was purified by reverse phase chromatography [water (0.05%NH4HCO3)/MeOH = 3/1 ) to provide the desired product 1 -(5-bromo-2- methoxyphenyl)-2-methoxyethanamine (4.5 g, 10.38 mmol, 40.7% yield) as a white solid. [M + H]+ Calcd for Ci0Hi4BrNO2 260.0; Found 260.0.
The following intermediate compounds were synthesized in a similar way to Intermediate 183.
Figure imgf000309_0003
Figure imgf000309_0001
Intermediate 187: (S,£)-W-(1 -(5-bromo-2-methoxyphenyl)propylidene)-2- methylpropane-2-sulfinamide
Figure imgf000309_0002
To a suspension of 1 -(5-bromo-2-methoxyphenyl)propan-1 -one (7.68 g, 31 .6 mmol) in Tetrahydrofuran (150 mL) at rt was added (S)-2-methylpropane-2-sulfinamide (5.74 g, 47.4 mmol) and tetraethoxytitanium (18.02 g, 79 mmol). The reaction mixture was stirred at 80 °C for 16 h. The reaction mixture was then cooled to rt and concentrated directly. DCM (200 mL) and water (400 mL) were then added and the resulting mixture was filtered and the residue washed with DCM (3 x 100 mL). The filtrate was then transferred to a seperatory funnel and washed with water (50 mL). The washed organic layer was then concentrated to dryness and the material obtained was purified by flash chromatography on silica gel (PE/EtOAc = 10/1 ) to provide the desired product (R,E)-A/-(1-(5-bromo-2-methoxyphenyl)propylidene)-2- methylpropane-2-sulfinamide (7.4 g, 19.23 mmol, 60.9% yield), m/z: [M + H]+ Calcd for Ci4H2iBrN02S 346.1 ; Found 346.
Intermediate 188: (S)-W-((S)-1 -(5-bromo-2-methoxyphenyl)propyl)-2-methylpropane-2- sulfinamide
Figure imgf000310_0001
To a solution of (/?,E)-A/-(1 -(5-bromo-2-methoxyphenyl)propylidene)-2-methylpropane-2- sulfinamide (7.4 g, 21 .37 mmol) in Tetrahydrofuran (100 mL) at 0° C was added NaBH4 (2.4 g, 64.1 mmol). The reaction mixture was then allowed to warm to rt and stirred for 16 h. Water (100 mL) was added to the reaction and the resulting aqueous mixture was extracted with EtOAc (2 x 200 mL). The combined organic layers were dried over sodium sulphate and evaporated in vacuo to give the crude product. The crude residue was purified by flash chromatography on silica gel (PE/EtOAc = 1 /1 ) to provide the two products (R)-A/-((S)-1 -(5- bromo-2-methoxyphenyl)propyl)-2-methylpropane-2 -sulfinamide (3.5 g, 10.05 mmol, 47.0 % yield), m/z: [M + H]+ Calcd for Ci4H23BrN02S 348.1 ; Found 348. And (R)-A/-((R)-1 -(5-bromo- 2-methoxyphenyl)propyl)-2-methylpropane-2-sulfinamide (1 .5 g, 4.31 mmol, 20.15% yield). m/z: [M + H]+ Calcd for Ci4H23BrN02S 348.1 ; Found 348.
Intermediate 189: (S)-W-((S)-1 -(5-cyano-2-methoxyphenyl)propyl)-2-methylpropane-2- sulfinamide
Figure imgf000310_0002
To a solution of (S)-A/-((S)-1 -(5-bromo-2-methoxyphenyl)propyl)-2-methylpropane-2- sulfinamide (2 g, 5.74 mmol) in N,N-Dimethylformamide (15 mL) at rt was added dicyanozinc (1 .348 g, 1 1 .48 mmol). To the solution was then added Pd(PPh3)4 (0.664 g, 0.574 mmol). The reaction headspace was then purged with nitrogen. The reaction mixture was then stirred and heated at 120 °C for 16 h. The reaction mixture was then allowed to cool to rt. Water (100 mL) was then added to the reaction and the resulting aqueous mixture was extracted with EtOAc (2 x 100 mL). The combined organic layers were dried over sodium sulphate and evaporated in vacuo to provide the crude product. The crude residue was purified by flash chromatography on silica gel (PE/EtOAc = 4/1 ) to provide the product (S)-A/-((S)-1 -(5-cyano- 2-methoxyphenyl)propyl)-2-methylpropane-2-sulfinamide (1 .3 g, 2.65 mmol, 46.1 % yield), m/z: [M + H]+ Calcd for Ci5H23BrN202S 295.2; Found 295.
Intermediate 190: (S)-3-(1 -aminopropyl)-4-methoxybenzonitrile
Figure imgf000311_0001
A solution of (S)-A/-((S)-1 -(5-cyano-2-methoxyphenyl)propyl)-2-methylpropane-2-sulfinamide (1 .3 g, 4.42 mmol) in hydrogen chloride (4M in isopropanol,15 mL, 60.0 mmol) was stirred at rt for 16 h. The mixture was concentrated in vacuo and water (50 mL) was added. The resulting aqueous mixture was extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with water (5 mL) and the organic layers discarded. The combined aqueous phases were then basified with saturated aqueous sodium bicarbonate solution. The basic aqueous layer was then extracted with EtOAc (4 x 15 mL). The combined organic layers were dried over sodium sulphate and concentrated in vacuo to provide the product (S)-3-(1 - aminopropyl)-4-methoxybenzonitrile (620 mg, 3.26 mmol, 73.8% yield) without the need for further purification, m/z: [M + H]+ Calcd for CnHi5N20 191.1 ; Found 191 .
The following intermediate compounds were synthesized in a similar way to intermediate 190.
Figure imgf000311_0002
Figure imgf000312_0001
Intermediate 193: 3-amino-3-(5-fluoro-2-methoxyphenyl)propanoic acid
Figure imgf000312_0002
A solution of 5-fluoro-2-methoxybenzaldehyde (1 g, 6.49 mmol), malonic acid (0.675 g, 6.49 mmol), and ammonium acetate (1 .000 g, 12.98 mmol) in ethanol (20 mL) was stirred at 80 °C for 16 h. The reaction mixture was then cooled to 0 °C and filtered to provide the desired product 3-amino-3-(5-fluoro-2-methoxyphenyl)propanoic acid (400 mg, 1 .876 mmol, 28.9% yield) as a white solid without the need for further purification, m/z: [M + H]+ Calcd for C10H13FNO3 214.1 ; Found 214. Intermediate 194: 3-amino-3-(5-fluoro-2-methoxyphenyl)propan-1 -ol
Figure imgf000312_0003
To a solution of 3-amino-3-(5-fluoro-2-methoxyphenyl)propanoic acid (120 mg, 0.56 mmol) in tetrahydrofuran (2 mL) at 0 °C was added BH3*THF (1 M in THF, 1 .69 mL, 1 .69 mmol). The reaction mixture was stirred at 0 °C for 30 min and then warmed slowly to rt and stirred 16 h. Following 16 h stir, the reaction was quenched with MeOH and then concentrated to dryness. The residue obtained was dissolved in EtOAc (20 ml) and washed with saturated aqueous NaHCC solution (10 mL) and brine (10 mL). The washed organic layer was dried over anhydrous MgS04, filtered, and then concentrated to dryness to provide the desired product 3-amino-3-(5-fluoro-2-methoxyphenyl)propan-1 -ol (100 mg, 0.452 mmol, 80% yield) as a colourless oil without the need for further purification, m/z: [M + H]+ Calcd for C10H15FNO2 200.1 ; Found 200.
Figure imgf000312_0004
Intermediate 195: ethyl 3-amino-3-(5-bromo-2-methoxyphenyl)propanoate
Figure imgf000313_0001
To a solution of 5-bromo-2-methoxybenzaldehyde (90 g, 419 mmol) in ethanol (300 mL) stirred under nitrogen atmosphere at rt was added a solution of ammonia (28.5 g, 1674 mmol) in ethanol (300 mL). The reaction was allowed to stir 30 min at rt. To the reaction was then added 3-ethoxy-3-oxopropanoic acid (83 g, 628 mmol) and the resulting mixture stirred at reflux for 16 h. The product solution was then concentrated directly to dryness and DCM (200 mL) was added. The organic solution was then washed with saturated aqueous sodium bicarbonate solution (50 mL) and water (50 mL). The washed organic layer was dried over sodium sulphate, filtered, and then concentrated to dryness to provide the crude product as a yellow oil. The crude residue was purified by flash chromatography on silica gel (DCM/MeOH = 50:1 to 5:1 ) to provide the desired product ethyl 3-amino-3-(5-bromo-2- methoxyphenyl)propanoate (25 g, 83 mmol, 19.8% yield), m/z: [M + H]+ Calcd for Ci2Hi7BrN03 302.0; Found 302. Intermediate 196: 3-amino-3-(5-bromo-2-methoxyphenyl)propan-1 -ol
Figure imgf000313_0002
To a solution of ethyl 3-amino-3-(5-bromo-2-methoxyphenyl)propanoate (17 g, 56.3 mmol) in tetrahydrofuran (200 mL) at rt was added portion wise sodium borohydride (8.51 g, 225 mmol). The reaction mixture was stirred at 40° C for 16h. The reaction mixture was quenched with water (50 mL) and ethyl acetate (50 mL) was added. The layers were seperated and the organic layer was washed with water (50 mL) and then brine (50 mL). The washed organic layer was then dried over sodium sulphate, filtered, and concentrated to dryness to provide the crude product as a colourless oil. The crude residue was purified by flash chromatography on silica gel (DCM/MeOH = 50:1 to 5: 1 ) to provide the desired product 3-amino-3-(5-bromo- 2-methoxyphenyl)propan-1 -ol (10 g, 36.5 mmol, 64.9% yield) as a yellow oil. m/z: [M + H]+ Calcd for CioHi5BrN02 260.0; Found 260. The following intermediates were synthesissed in a similar way to intermediate 196.
Figure imgf000314_0004
Figure imgf000314_0001
Intermediate 198: methyl 3-amino-3-(5-bromo-2-methoxyphenyl)propanoate
Figure imgf000314_0002
To a solution of 5-bromo-2-methoxybenzaldehyde (5.0g, 23.2 mmol) and malonic acid (2.9 g, 27.9 mmol) in ethanol (50 mL) was added ammonium formate (2.96 g, 34.9 mmol) and the reaction mixture was stirred at reflux for 7 h. Water was then added and the resulting slurry was filtered to provide 3-amino-3-(5-bromo-2-methoxyphenyl)propanoic acid (3 g, 10.94 mmol, 47.1 % yield) as white solid, m/z: [M + H]+ Calcd for Ci0Hi3BrNO3 274.0; Found 274. The isolated carboxylic acid was carried on directly without further purification. To a solution of 3-amino-3-(5-bromo-2-methoxyphenyl)propanoic acid (2.6 g, 9.49 mmol) in methanol (30 mL) was added SOCI2 (1 .385 mL, 18.97 mmol), the resulting mixture was stirred at 65 °C overnight. The mixture was then concentrated directly to provide methyl 3-amino-3- (5-bromo-2-methoxyphenyl)propanoate (2.5 g, 8.24 mmol, 87% yield) as a white solid without the need for further purification, m/z: [M + H]+ Calcd for CnHi5BrN03 288.0; Found 288.1 .
Intermediate 199: 4-amino-4-(5-bromo-2-methoxyphenyl)-2-methylbutan-2-ol
Figure imgf000314_0003
To a solution of methyl 3-amino-3-(5-bromo-2-methoxyphenyl)propanoate (2.8 g, 9.72 mmol) in tetrahydrofuran (40 mL) was added methylmagnesium bromide (4.64 g, 38.9 mmol) at 0 °C. The resulting solution was stirred for 3 h. An aqueous solution of NH4CI was then added to the mixture followed by dilution with EtOAc. The organic layer was washed with brine and dried over Na2S04. The organic solution was then filtered and concentrated to provide 4- amino-4-(5-bromo-2-methoxyphenyl)-2-methylbutan-2-ol (2 g, 4.86 mmol, 50.0 % yield) as a white solid that was used without further purification, m/z: [M + H]+ Calcd for Ci2Hi9BrN02 288.1 ; Found 288.
288 (M+H) Purity 70% (214 nm)
Figure imgf000315_0001
Intermediate 200: (/?,Z)-ethyl 2-(5-bromo-2-methoxyphenyl)-2-((tert- butylsulfinyl)imino)acetate
Figure imgf000315_0002
To a solution of ethyl 2-(5-bromo-2-methoxyphenyl)-2-oxoacetate (8 mg, 27.9 mmol) in tetrahydrofuran (200ml_) was added (R)-2-methylpropane-2-sulfinamide (30.4 mg, 251 mmol). The reaction mixture was then stirred at 70 °C for 6h. The reaction mixture was then cooled to rt and quenched with water (40 mL). The aqueous mixture was then extracted with EtOAc (2 x 20 mL) and the combined organic layers were dried over sodium sulphate and evaporated in vacuo to provide the crude product. The crude residue was purified by flash chromatography on silica gel (PE/EtOAc = 10/1 ) to provide the desired product (R,Z)-ethyl 2-(5-bromo-2-methoxyphenyl)-2-((tert-butylsulfinyl)imino)acetate(3.5g 8.97mmol) 32.2% yield m/z: [M + H]+ Calcd for Ci5H2iBrN04S 390.0; Found 390.
Intermediate 201 : 5-bromo-2-methoxyphenyl)-2-hydroxy-2-methylpropylidene)-2- methylpropane-2-sulfinamide
Figure imgf000316_0001
To a solution of (R,Z)-ethyl 2-(5-bromo-2-methoxyphenyl)-2-((tert-butylsulfinyl)imino)acetate (300 mg, 0.769 mmol) in tetrahydrofuran (15 mL) at 0 °C was added methylmagnesium bromide (192 mg, 1 .614 mmol). The resulting mixture was stirred at 0 °C for 3 h. An aqueous solution of NH4CI was added to the mixture and the resulting aqueous solution was extracted with EtOAc. The organic layers were then washed with brine, dried over sodium sulfate, and concentrated to provide (R,Z)-A/-(1 -(5-bromo-2-methoxyphenyl)-2-hydroxy-2- methylpropylidene)-2-methylpropane-2-sulfinamide (80 mg, 0.123 mmol, 16% yield) as a yellow solid that was used without further purification, m/z: [M + H]+ Calcd for CisF BrNC S 376.1 ; Found 376.
Intermediate 202: (/?)- V-((/?)-1 -(5-bromo-2-hydroxyphenyl)-2-hydroxy-2-methylpropyl)- 2-methylpropane-2-sulfinamide
Figure imgf000316_0002
To a solution of (/?,Z)-A/-(1 -(5-bromo-2-methoxyphenyl)-2-hydroxy-2-methylpropylidene)-2- methylpropane-2-sulfinamide (320 mg, 0.850 mmol) in tetrahydrofuran (20 mL) at 0 °C was added L-selectride (194 mg, 1 .020 mmol). The resulting mixture was stirred at 0 °C for 3 h. Methanol was added to the reaction mixture, followed by an aqueous solution of NH4CI. The resulting mixture was extracted with EtOAc, washed with brine, dried over sodium sulfate, and then concentrated to provide the desired product (R)-A/-((/?)-1 -(5-bromo-2- methoxyphenyl)-2-hydroxy-2-methylpropyl)-2-methylpropane-2-sulfinamide (200 mg, 0.381 mmol, 44.8% yield) as a white solid that was used without further purification, m/z: [M + H]+ Calcd for Ci5H25BrN03S 378.1 ; Found 378.
Intermediate 203: (/?)-1 -amino-1 -(5-bromo-2-methoxyphenyl)-2-methylpropan-2-ol
Figure imgf000317_0001
To a solution of (R)-W-((R)-1 -(5-bromo-2-methoxyphenyl)-2-hydroxy-2-methylpropyl)-2- methylpropane-2-sulfinamide (200 mg, 0.529 mmol) in 1 ,4-Dioxane (8 mL) was added concentrated aqueous HCI (0.080 mL, 2.64 mmol) and the resulting mixture was stirred at rt 16 h. The mixture was then concentrated directly to provide the desired product (R)-1 -amino- 1 -(5-bromo-2-methoxyphenyl)-2-methylpropan-2-ol (120 mg, 0.285 mmol, 53.8% yield) as a yellow oil that was carried on without further purification, m/z: [M + H]+ Calcd for Cn Hi7BrN02 274.0; Found 274.
Figure imgf000317_0002
Intermediate 204: (S)-2-(1 -aminoethyl)-4-bromophenol
Figure imgf000317_0003
To a solution of (S)-1 -(5-bromo-2-methoxyphenyl)ethanamine hydrochloride (1 1 .5 g, 43.1 mmol) in Dichloromethane (100 mL) at rt was added BBr3 (16.31 mL, 173 mmol). The reaction mixture was stirred at rt 16 h. To the reaction mixture was then added water (300 mL) and DCM (200 mL). The mixture was transferred to a seperatory funnel and the layers allowed to separate. The aqueous phase was extracted with DCM (2 x 50 mL). The pH of the aqueous phase was then adjusted to alkaline and further extracted with DCM (2 x 100 mL). The combined organic phases were dried over sodium sulphate, filtered, and evaporated in vacuo to provide the crude product (S)-2-(1 -aminoethyl)-4-bromophenol (2.7g, 12.5mmol) that was used without further purification, m/z: [M + H]+ Calcd for CeHnBrNO 216.0; Found 216.
Figure imgf000318_0001
Intermediate 205: (S)-ferf-butyl (1 -(5-bromo-2-hydroxyphenyl)ethyl)carbamate
Figure imgf000318_0002
To a solution of (S)-2-(1 -aminoethyl)-4-bromophenol (3.2 g, 14.81 mmol) in Dichloromethane (100 mL) stirred at 20 °C was added Boc20 (3.78 mL, 16.29 mmol) and TEA (4.1 mL, 29.4 mmol). The reaction mixture was stirred at 20 °C 16 h. To the reaction mixture was then added water and the mixture was transferred to a seperatory funnel and the layers allowed to separate. The organic layer was then removed, dried over sodium sulphate, filtered, and evaporated in vacuo to provide the crude product. The crude residue was purified by flash chromatography on silica gel (hex EtOAc = 15/1 ) to provide the desired product (S)-tert-butyl (1 -(5-bromo-2-hydroxyphenyl)ethyl)carbamate (2.77 g, 8.76 mmol, 59.2 % yield), m/z: [M + Na]+ Calcd for Ci3Hi8BrNNa03 338.0; Found 338.
Intermediate 206: (S)-ferf-butyl (1 -(5-bromo-2-ethoxyphenyl)ethyl)carbamate
Figure imgf000318_0003
To a solution of P i3P (324 mg, 1 .233 mmol) in Tetrahydrofuran (6 mL) stirred under nitrogen at 0 °C was added DEAD (0.180 mL, 1 .139 mmol) and mixture allowed to stir at 0 °C for 10 minutes. To the reaction was then added EtOH (0.5 mL, 8.56 mmol) and allowed to stir at 0 °C for 30 min. A solution of (S)-tert-butyl (1 -(5-bromo-2-hydroxyphenyl)ethyl)carbamate (300 mg, 0.949 mmol) in Tetrahydrofuran (3 mL) was then added dropwise over 1 min. The reaction mixture was allowed to warm slowly to 20 °C and stirred 16 h. The reaction mixture was then diluted with water (30 mL) and the aqueous layer extracted with EtOAc (2 x 30 mL). The combined organic phases were dried over sodium sulphate, filtered, and evaporated in vacuo to give the crude product. The crude residue was purified by flash chromatography on silica gel (PE/EtOAc = 15/1 ) to provide the desired product (S)-tert- butyl (1 -(5-bromo-2- ethoxyphenyl)ethyl)carbamate (260 mg, 0.755 mmol, 80% yield), m/z: [M + H]+ Calcd for Ci5H23BrN03 344.1 ; Found 344
Intermediate 207: (S)-1 -(5-bromo-2 -ethoxyphenyljethanamine
Figure imgf000319_0001
To a solution of (S)-tert-butyl (1 -(5-bromo-2-ethoxyphenyl)ethyl)carbamate (260 mg, 0.755 mmol) in Dichloromethane (5 mL) was added concentrated aqueous hydrogen chloride (2 mL, 24.00 mmol). The reaction mixture was stirred at 20 °C 16 h. The mixture was then concentrated directly to provide the desired product (S)-1 -(5-bromo-2- ethoxyphenyl)ethanamine (220 mg, 0.676 mmol, 89% yield) that was used without further purification, m/z: [M + H]+ Calcd for Ci0Hi5BrNO 244.0; Found 244.
The following intermediates were synthesized in a similar way to intermediate 207.
Figure imgf000319_0003
Figure imgf000319_0002
Intermediate 211 : (S)-3-(1 -aminoethyl)-4-methoxybenzonitrile
Figure imgf000320_0001
Solid 3-acetyl-4-methoxybenzonitrile (40 g, 228 mmol) was added to a 3L bottle. DMSO (225 mL) was then added and mix allowed to stir until completely dissolved. In a 1 L beaker, triethanolamine (30.3 ml, 228 mmol) was dissolved in water (750 mL) and sec-butylamine (92 ml, 913 mmol) was added. Using a pH meter, this aqueous solution was brought to pH 8 using 12 M aqueous HCI. Ice was added to keep the temperature <40C. This pH 8 solution was slowly added to the DMSO solution in the 3L bottle while stirring. Water (1 L) was added, followed by (4-formyl-5-hydroxy-6-methylpyridin-3-yl)methyl dihydrogen phosphate (1 .129 g, 4.57 mmol). The s-aminotransaminase ATA-237 from Codexis (4g, 10%w/w) was then added as a dry powder and the resulting mixture allowed to stir at rt for 1 1 1 h. After 24 h, an additional amount of enzyme (1 g) was added to the reaction. Following completion of the reaction, the mixture was diluted with 1 :1 MeTHF/TBME. The aqueous layer was then brought to a pH of 2-3 with 12 M aqueous HCI. Celite (40 g) was added directly to the stirring mixture and the resulting slurry then filtered through a pad of of celite (60 g). The filter pad was rinsed with 0.1 N aqueous HCI. The filtered solution was then transferred to a seperatory funnel and the layers allowed to seperate. The aqueous layer was washed twice with TBME (200 mL). The aqueous layer was then brought to pH 1 1-12 by slow addition of solid NaOH with constant stirring. The aqueous layer was then extracted with EtOAc (4 x 200 mL). The EtOAc layer was then washed with brine and dried over sodium sulfate and concentrated to provide high purity product (S)-3-(1 -aminoethyl)-4-methoxybenzonitrile (29.5 g, 167 mmol, 73.3 % yield, >99%ee) that was used without further purification, m/z: [M + H]+ Calcd for CioHi2N20 177.1 ; Found 177.
Figure imgf000320_0002
Intermediate 212: (/?)-3-(1 -hydroxyethyl)-4-methoxybenzonitrile
Figure imgf000321_0001
To a toluene solution of (S)-1 -methyl-3,3-diphenylhexahydropyrrolo[1 ,2-c][1 ,3,2]oxazaborole (1 mL, 1 M, 1 .000 mmol) was added DCM (5ml_) and mixture cooled to -30 °C under nitrogen atmosphere. The solution was then charged with BH3*THF (1 M in THF, 7 mL, 7.00 mmol) dropwise. The mixture was stirred at -35 °C for 0.5 h. To the resulting solution was then added a solution of 3-acetyl-4-methoxybenzonitrile (1 g, 5.71 mmol) in Dichloromethane (25 mL) dropwise over 2 h. The reaction mixture was stirred at -35 °C for 0.5 h, and then allowed to warm slowly to 0°C. Methanol (5 mL), water (20 mL), and Ethyl acetate (20 mL) were then added. The mixture was then transferred to a seperatory funnel and the organic phase removed and evaporated in vacuo to give the crude product as a orange oil. The crude residue was purified by flash chromatography on silica gel (PE/EtOAc = 3/1 ) to provide the desired product as a white solid. The material was further purified by chiral prep-HPLC to provide the desired product (R)-3-(1 -hydroxyethyl)-4-methoxybenzonitrile (450 mg, 2.54 mmol, 44.5% yield) as a white solid. (400 mHz, CDCI3) 7.74 (s, 1 H), 7.59 (1 H, J = 2, 8.4Hz, 1 H), 6.94 (d, J = 8.4Hz,1 H), 5.15 (1 H, J=, 6.4H, 12.8Hz, 1 H), 1 .50 (d, J = 6.4Hz, 3H)
Figure imgf000321_0002
Intermediate 213: 1 -(5-fluoro-2-methoxyphenyl)ethanol
Figure imgf000321_0003
To a solution of NaBH4 (45.0 mg, 1 .189 mmol) in methanol (10 mL), was added 1 -(5-fluoro- 2-methoxyphenyl)ethanone (200 mg, 1 .189 mmol) and the resulting mixture stirred at rt for 2 h. The reaction mixture was then concentrated directly in vacuo. Cold water (10 mL) was added and the resulting aqueous mixture was extracted with DCM (3 >< 15 mL). The combined organic layers were dried over Na2S04, filtered and concentrated to give provide 1 -(5-fluoro- 2-methoxyphenyl)ethanol (194 mg, 1 .140 mmol, 96 % yield) as a colorless oil that was used without further purification, m/z: [M - H20]+ Calcd for C9H10FO 153.1 ; Found 153.2.
The following intermediates were synthesized in a similar way to intermediate 213.
Figure imgf000322_0003
Figure imgf000322_0001
Intermediate 218: (S,£)-W-(1 -(5-bromo-2,4-dimethoxyphenyl)ethylidene)-2- methylpropane-2-sulfinamide
Figure imgf000322_0002
A solution of 1 -(5-bromo-2,4-dimethoxyphenyl)ethanone (30g, 1 10 mmol), (S)-2- methylpropane-2-sulfinamide (26.7 g, 220 mmol) and tetraethoxytitanium (50.2 g, 220 mmol) in Tetrahydrofuran (300 mL) was stirred under nitrogen at 85 °C for 12 h. The reaction mixture was then cooled to rt and diluted with water. This aqueous mixture was then extracted with EtOAc (2 x 200 mL). The combined organics were then concentrated to dryness and the resulting brown oil purified by flash chromatography on silica gel (PE/EtOAc = 3/1 ) to provide the desired product (S,E)-A/-(1 -(5-bromo-2,4-dimethoxyphenyl)ethylidene)-2-methylpropane- 2-sulfinamide (31 g, 81 mmol, 73.9% yield) as a yellow oil. m/z: [M + H]+ Calcd for Ci4H2iBrN03S 362.0; Found 362.
Intermediate 219: (S)-W-((S)-1 -(5-bromo-2,4-dimethoxyphenyl)ethyl)-2-methylpropane- 2-sulfinamide
Figure imgf000323_0001
To a solution of (S,E)-A/-(1 -(5-bromo-2,4-dimethoxyphenyl)ethylidene)-2-methylpropane-2- sulfinamide (30 g, 83 mmol) in Tetrahydrofuran (120 mL) stirred under nitrogen at 0 °C was added NaBH4 (6.27 g, 166 mmol) portionwise over 20 min. The resulting mixture was then allowed to warm to rt and stirred for 30 min. Water was then added to the reaction mixture and the resulting aqueous mixture was extracted with EtOAc (2 x 100 mL). The combined organics were then concentrated to dryness and the resulting brown oil purified by flash chromatography on silica gel (PE/EtOAc = 1/1 ) to provide the desired product (S)-A/-((S)-1 -
(5-bromo-2,4-dimethoxyphenyl)ethyl)-2-methylpropane-2-sulfinamide (8.5g, 22.17 mmol, 26.8% yield) as a white solid, m/z: [M + H]+ Calcd for Ci4H23BrN03S 364.1 ; Found 364.
Intermediate 220: (S)-W-((S)-1 -(5-cyano-2,4-dimethoxyphenyl)ethyl)-2-methylpropane- 2-sulfinamide
Figure imgf000324_0001
To a solution of (S)-A/-((S)-1 -(5-bromo-2,4-dimethoxyphenyl)ethyl)-2-methylpropane-2- sulfinamide (700 mg, 1 .825 mmol) in A/,A/-Dimethylformamide (2 mL) stirred under nitrogen, was added dicyanozinc (429 mg, 3.65 mmol) and Pd(PP i3)4 (422 mg, 0.365 mmol). The reaction was then stirred under N2 at 120 °C for 2 h. Water was then added to the reaction mixture and the resulting aqueous mixture was extracted with EtOAc (2 x 10 mL). The combined organics were then concentrated to dryness and the resulting brown oil purified by flash chromatography on silica gel (PE/EtOAc = 1/1 ) to provide the desired product (S)-/V- ((S)-1 -(5-cyano-2,4-dimethoxyphenyl)ethyl)-2-methylpropane-2-sulfinamide (560 mg, 1 .624 mmol, 89 % yield) as a white solid, m/z: [M + H]+ Calcd for Ci5H23N203S 31 1 .1 ; Found 31 1 . Intermediate 221 : (S)-5-(1 -aminoethyl)-2,4-dimethoxybenzonitrile
Figure imgf000324_0002
To a solution of (S)-A/-((S)-1 -(5-cyano-2,4-dimethoxyphenyl)ethyl)-2-methylpropane-2- sulfinamide (560 mg, 1 .714 mmol) in ethanol (2 mL) at 0 °C was added HCI (2 M in ethanol, 2 mL, 4.00 mmol) dropwise at 0 °C. The reaction mixture was then allowed to warm to rt and stirred for 12h. The reaction mixture was then directly concentrated to dryness. The resulting solid was then suspended in EtOAc and filtered. The isolated solid was then dissolved in 1 M aqueous NaOH and the aqueous solution then extracted with EtOAc (3 x 3 mL). The organic layers were then combined and concentrated to dryness to provide the product (S)-5-(1 - aminoethyl)-2,4-dimethoxybenzonitrile (300 mg, 1 .382 mmol, 81 % yield) as a yellow oil that was used without further purification, m/z: [M + H]+ Calcd for Cn Hi5N202 207.1 ; Found 207. The following intermediate was synthesized in a similar way to intermediate 221 .
Figure imgf000325_0001
Biological data examples
As stated above, the compounds according to Formula I are RORy modulators, and are useful in the treatment of diseases mediated by RORy. The biological activities of the compounds according to Formula I can be determined using any suitable assay for determining the activity of a candidate compound as a RORy modulator, as well as tissue and in vivo models.
Dual Fluorescence Energy Transfer (FRET) Assay
This assay is based on the knowledge that nuclear receptors interact with cofactors (transcription factors) in a ligand dependent manner. RORy is a typical nuclear receptor in that it has an AF2 domain in the ligand binding domain (LBD) which interacts with co- activators. The sites of interaction have been mapped to the LXXLL motifs in the co-activator SRC1 (2) sequences. Short peptide sequences containing the LXXLL motif mimic the behavior of full-length co-activator. The assay assesses ligand-mediated interaction of the co-activator peptide with the purified bacterial-expressed RORy ligand binding domain (RORy-LBD) by measuring TR-FRET signal between Europium-labelled SRC1 (2) and APC-labelled RORy protein. RORy has a basal level of interaction with the co-activator SRC1 (2) in the absence of ligand, thus it is possible to find ligands that inhibit or enhance the RORy/SRC1 (2) interaction. Data were collected and analyzed by Activitybase.
Materials
Generation of RORy-LBD bacterial expression plasmid
Human RORy Ligand Binding Domain (RORy-LBD) was expressed in E.coli strain BL21 (DE3) as an amino-terminal polyhistidine tagged fusion protein. DNA encoding this recombinant protein was sub-cloned into a modified pET21 a expression vector (Novagen). A modified polyhistidine tag (MKKHHHHHHLVPRGS) was fused in frame to residues 263-518 of the human RORy sequence.
Protein Purification
Approximately 50 g E.coli cell pellet was resuspended in 300 mL of lysis buffer (30 mM imidazole pH 7.0 and 150 mM NaCI). Cells were lysed by sonication and cell debris was removed by centrifugation for 30 minutes at 20,000g at 4°C. The cleared supernatant was filtered through a 0.45 uM cellulose acetate membrane filter. The clarified lysate was loaded onto a column (XK-26) packed with ProBond Nickel Chelating resin (Invitrogen), pre- equilibrated with 30 mM imidazole pH 7.0 and 150 mM NaCI. After washing to baseline absorbance with the equilibration buffer, the column was developed with a gradient from 30 to 500 mM imidazole pH 7.0. Column fractions containing the RORy-LBD protein were pooled and concentrated to a volume of 5 mis. The concentrated protein was loaded onto a Superdex 200 column pre-equilibrated with 20 mM Tris-CI pH 7.2 and 200 mM NaCI. The fractions containing the desired RORy-LBD protein were pooled together.
Protein Biotinylation
Purified RORy-LBD was buffer exchanged by exhaustive dialysis [3 changes of at least 20 volumes (>8000x)] against PBS [100mM NaPhosphate, pH 8 and 150mM NaCI]. The concentration of RORy-LBD was approximately 30uM in PBS. Five-fold molar excess of NHS- LC-Biotin (Pierce) was added in a minimal volume of PBS. This solution was incubated with occasional gentle mixing for 60 minutes at ambient RT. The modified RORy-LBD was dialyzed against 2 buffer changes - TBS pH 8.0 containing 5mM DTT, 2mM EDTA and 2% sucrose - each at least 20 times of the volume. The modified protein was distributed into aliquots, frozen on dry ice and stored at -80°C. The biotinylated RORy-LBD was subjected to mass spectrometric analysis to reveal the extent of modification by the biotinylation reagent. In general, approximately 95% of the protein had at least a single site of biotinylation and the overall extent of biotinylation followed a normal distribution of multiple sites ranged from one to five. A biotinylated peptide corresponding to amino acid 676 to 700 (CPSSHSSLTERHKILHRLLQEGSPS) of the co-activator steroid receptor coactivator SRC1 (2) was generated using similar method. Assay
Preparation of Europium labeled SRC1 (2) peptide: biotinylated SRC1 (2) solution was prepared by adding an appropriate amount of biotinylated SRC1 (2) from the 100uM stock solution to a buffer containing 10 mM of freshly added DTT from solid to give a final concentration of 40 nM. An appropriate amount of Europium labeled Streptavidin was then added to the biotinylated SRC1 (2) solution in a tube to give a final concentration of 10 nM. The tube was inverted gently and incubated for 15 minutes at room temperature. Twenty-fold excess biotin from the 10 mM stock solution was added and the tube was inverted gently and incubated for 10 minutes at room temperature.
Preparation of APC labeled RORy-LBD: biotinylated RORy-LBD solution was prepared by adding an appropriate amount of biotinylated RORy-LBD from the stock solution to a buffer containing 10 mM of freshly added DTT from solid to give a final concentration of 40 nM. An appropriate amount of APC labeled Streptavidin was then added to the biotinylated RORy- LBD solution in a tube to give a final concentration of 20 nM. The tube was inverted gently and incubated for 15 minutes at room temperature. Twenty-fold excess biotin from the 10 mM stock solution was then added and the tube was inverted gently and incubated for 10 minutes at room temperature.
Equal volumes of the above-described Europium labeled SRC1 (2) peptide and the APC labeled RORy-LBD were gently mixed together to give 20nM RORy-LBD, 10nM APC- Strepavidin, 20nM SRC1 (2) and 5nM Europium-Streptavidin. The reaction mixtures were incubated for 5 minutes. Using a Thermo Combi Multidrop 384 stacker unit, 25 ul of the reaction mixtures per well was added to the 384-well assay plates containing 10Onl of test compound per well in 100% DMSO. The plates were incubated for 1 hr and then read on ViewLux in Lance mode for EU/APC.
Human PBMC IL17 Secretion Assay
RORy is required for IL-23-enhanced secretion of IL-17 after activation of Th17 cells. This assay is designed to measure levels of IL-17 secreted from frozen and pooled Peripheral Blood Mononucleocyte cells (PBMCs) isolated from blood, then stimulated with soluble anti- CD3 and anti-CD28 antibodies and exogenous IL-23. Inhibition of RORy activity by a compound will result in decreased IL-17 secretion and accumulation in the tissue culture supernatant.
Assay plates were stamped with test compounds and controls in DMSO (0.5ul/well or 0.2ul/well) for a starting concentration of 10uM final assay concentration after dilution with cells and stimulation mix, with a 3-fold 10 point dilution series across the plate. Previously frozen PBMC pools were thawed in their cryovials and allowed to recover in 20ml complete medium (IMDM, 10% fetal bovine serum (FBS), 1 X Penicillyn/Streptomycin, 1 X L-glutamine, 1 X nonessential amino acids, 1 X sodium pyruvate and 0.05 mM 2-mercaptoethanol) in a 37°C water bath for 2-4 hours. Cells were then pelleted by centrifugation, the supernatant discarded, and the cells were resuspended in fresh medium at a concentration of 1 .5x106 cells/ml. 10Oul of cells were dispensed into each well, and the plates were incubated at 37°C for 72 hours. To make the stimulation mix, appropriate amounts of the following stimuli were added to complete medium to make the indicated final assay concentrations: 50ug/ml human recombinant IL-23, 1 ug/ml aCD3 clone UCHT1 and 1 ug/ml aCD28 clone CD28.2. 100ul of stimulation mix was added per well and the plates were incubated at 37°C for 72 hours. At the end of culture, 25ul of supernatant was transferred to MSD plates. The MSD plates were covered and incubated for 1 hour at room temperature on a rotary plate shaker at 300rpm. At the end of the hour, 25ul of 1 X MSD IL-17 detection antibody was added per well and the plates were again shaken at 300 rpm for 1 hour at room temperature. After this incubation, plates were washed three times using a plate washer with 0.5% Tween-20 in PBS (150ul per well per wash). After removing residual wash buffer, 150ul of 2X MSD Read Buffer T was added per well and plates were analyzed with either a MSD sector Imager 6000 or a Quickplex SQ120 plate reader.
Maximum signal in this assay was compared to wells with DMSO added alone (no compound; 0% inhibition), and minimum signal was compared to wells containing fully active concentrations of a reference compound (100% inhibition). Data were analyzed with Activitybase. Assay Data
The data described below represents a mean pICso value of multiple test results if the test was performed more than once. It is understood that the data illustrated below may have reasonable variation depending on the specific conditions and procedures used by the person conducting the testing.
All exemplified compounds were tested in the dual FRET assay described above. All tested compounds were found to have a pICso between 4.4 and 8.2. All exemplified compounds, except compounds 6, 9, 12, 19, 12, 22, 38, 53, 57, 64, 66, 68, 70, 72, 85, 94, 106, 124, 132, 134, 137, 141 , 149, 152, 153, 154, 157, 162, 163, 165, 166, 174, 186, 198, 199, 221 , 222, 224, 233 were found to have a pICso between 5.0 and 8.2, for example, Compounds 1 and 136 each demonstrated a pICso value of 7.3. Compounds 131 , 145, 170, 193, 120, 156, 158, 169, 204, 51 , 161 , 179, 136, 17, 39, 75, 82, 86, 87, 108, 1 15, 1 18, 226, 208, 212, 230, 228, 104, 130, 90, 98, 100, 101 , 135, 173, 79, 81 , 96, 97, 103, 105, 175, 225, 93, 1 12, 1 19, 171 , 206, 44, 59, 102, 172, 202, 213, 214 and 1 were found to have a pICso of 7 or above.
Compounds 1 , 17, 75, 76, 77, 90, 91 , 102, 103, 104, 105, 109, 1 12, 1 19, 120 ,127, 128, 130 ,136, 156, 158, 161 , 175, 176, 208, 212, 214, 230 and 234 were also tested in the Human PBMC IL17 secretion assay described above. All tested compounds were found to have a pICso of 7.0 or above, for example, compounds 1 and 136 demonstrated a pICso of 7.2 and 7.0 respectively.
It will be understood that the present invention has been described above purely by way of example, and modification of detail can be made within the scope of the invention. Each feature disclosed in the description, and where appropriate the claims and drawings may be provided independently or in any appropriate combination.

Claims

1 . A compound of formula I
Figure imgf000330_0001
or a pharmaceutically acceptable salt thereof,
wherein
Figure imgf000330_0002
Cy is C3-6 cycloalkyl, C3-6 cycloalkenyl or C3-6 heterocycloalkyl wherein Cy is optionally substituted with one or more substituents independently selected from the group consisting of halo, hydroxyl and C1-3 alkyl;
n is 0 or 1 ;
R2 is H or C1-3 alkyl;
X1 is CH or N;
X3 is CH or N, with the proviso that when X3 is N, X1 is CH;
X2 is C-R3;
R3 is H, halo, C1-3 alkyl, CN or C1-3 haloalkyl;
Y is NH, CH2 or O;
R4 is H, C3-6 cycloalkyl or C1-5 alkyl, wherein the C1-5 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of O-C1-5 alkyl and hydroxyl;
R5 is phenyl or a six membered heteroaryl, wherein R5 is substituted with one to three substituents independently selected from the group consisting of:
(i) halo,
(ii) C1-5 alkyl optionally substituted with one or more hydroxyl groups,
(iii) O-C1-5 alkyl wherein one or more of the hydrogens on the alkyl is optionally deuterated or wherein the O-C1-5 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of halo, hydroxyl and O-C1-3 alkyl;
(iv) C1-5 haloalkyl; and
(v) CN.
2. The compound or pharmaceutically acceptable salt thereof according to Claim 1 , wherein the compound of formula I is selected from the group consisting of:
Figure imgf000331_0001
Formula IA; and
Figure imgf000331_0002
The compound or pharmaceutically acceptable salt thereof according to Claim 1 or Claim 2, wherein Cy is selected from the group consisting of C3-6 cycloalkyl, cyclohexene, tetrahydropyran, oxetane, morpholine, 1 ,4-dioxan and piperidine.
The compound or pharmaceutically acceptable salt thereof according to Claim 3, wherein Cy is selected from the group consisting of cyclohexyl, cyclobutyl, and oxetane.
The compound or pharmaceutically acceptable salt thereof according to Claim wherein R1 is
Figure imgf000332_0001
The compound or pharmaceutically acceptable salt thereof according to Claim wherein R1 is
Figure imgf000332_0002
7. The compound or pharmaceutically acceptable salt thereof according to any preceding claim, wherein R2 is H.
8. The compound or pharmaceutically acceptable salt thereof according to any preceding claim, wherein R3 is C1-3 haloalkyl or halo.
9. The compound or pharmaceutically acceptable salt thereof according to Claim 8, wherein R3 is CI.
10. The compound or pharmaceutically acceptable salt thereof according to Claim 8, wherein R3 is CF3.
1 1 . The compound or pharmaceutically acceptable salt thereof according to any preceding claim, wherein Y is NH.
12. The compound or pharmaceutically acceptable salt thereof according to any preceding claim, wherein R4 is C1-5 alkyl.
13. The compound or pharmaceutically acceptable salt thereof according to Claim 12, wherein R4 is CH3.
14. The compound or pharmaceutically acceptable salt thereof according to any preceding claim wherein R5 is phenyl substituted with two substituents independently selected from the group consisting of:
(i) Halo;
(ii) C1-5 alkyl optionally substituted with one or more hydroxyl groups;
(iii) O-C1-5 alkyl wherein one or more of the hydrogens on the alkyl is optionally deuterated or wherein the O-C1-5 alkyl is substituted with one or more substituents independently selected from the group consisting of halo, hydroxl and O-C1-3 alkyl;
(iv) C1-5 haloalkyl; and
(v) CN.
15. The compound or pharmaceutically acceptable salt thereof according to Claim 14, wherein R5 is a phenyl substituted with O-C1-5 alkyl and at least one other substituent, independently selected from the group consisting of halo, C1-5 alkyl, C1-5 haloalkyl and CN.
16. The compound or pharmaceutically acceptable salt thereof according to Claim 15, wherein R5 is a phenyl substituted with O-C1-5 alkyl and CN.
17. The compound or pharmaceutically acceptable salt thereof according to Claim 16, wherein R5 is
Figure imgf000333_0001
18. A compound selected from the group consisting of compounds 1 , 87, 90, 102, 136, 158, and 208 or a pharmaceutically acceptable salt thereof.
19. A compound which is Compound 1 or a pharmaceutically acceptable salt thereof.
20. A compound which is Compound 136 or a pharmaceutically acceptable salt thereof.
21 . A compound which is the hydrochloride salt of Compound 1 .
22. A compound which is the hydrochloride salt of Compound 136.
23. A pharmaceutical composition comprising a compound or pharmaceutically acceptable salt thereof as defined in any one of Claims 1 to 22, and a pharmaceutically acceptable excipient.
24. The pharmaceutical composition according to Claim 23, wherein said compound is Compound 1 or a pharmaceutically acceptable salt thereof.
25. The pharmaceutical composition according to Claim 23, wherein said compound is Compound 136 or a pharmaceutically acceptable salt thereof.
26. A method of treatment of an inflammatory, metabolic or autoimmune disease mediated by RORy comprising administering to a subject in need thereof, a therapeutically effective amount of a compound as defined in any of Claims 1 to 22, or a pharmaceutically acceptable salt thereof.
27. A method for the treatment of multiple sclerosis, psoriasis, Sjogren's syndrome, innflamatory bowel disease or ankylosing spondylitis in a human in need thereof comprising administering to said human an effective amount of a compound or pharmaceutically acceptable salt thereof as defined in any one of Claims 1 to 22.
28. A compound or pharmaceutically acceptable salt thereof as defined in any of Claims 1 to 22 for use in therapy.
29. A compound for use according to Claim 28, wherein the compound is Compound 1 , or a pharmaceutically acceptable salt thereof.
30. The compound for use according to Claim 29, wherein the compound is Compound 136 or pharmaceutically acceptable salt thereof.
31 . A compound or pharmaceutically acceptable salt thereof as defined in any of Claims 1 to 22 for use in the treatment of an inflammatory, metabolic or autoimmune disease mediated by RORy.
32. A compound or pharmaceutically acceptable salt thereof according to Claim 31 , wherein the disease is multiple sclerosis, psoriasis, Sjogren's syndrome, innflamatory bowel disease or ankylosing spondylitis.
33. A compound for use according to Claim 32, wherein the compound is Compound 1 or pharmaceutically acceptable salt thereof.
34. A compound for use according to Claim 32, wherein the compound is Compound 136 or pharmaceutically acceptable salt thereof.
35. Use of a compound or pharmaceutically acceptable salt thereof as defined in any one of Claims 1 to 22, in the manufacture of a medicament for use in the treatment of multiple sclerosis, psoriasis, Sjogren's syndrome, innflamatory bowel disease or ankylosing spondylitis.
36. Use of a compound according to Claim 35, wherein the compound is Compound 1 or pharmaceutically acceptable salt thereof.
37. Use of a compound according to Claim 35, wherein the compound is Compound 136 or pharmaceutically acceptable salt thereof.
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