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  • A61K31/5375—1,4-Oxazines, e.g. morpholine
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  • A61K31/5375—1,4-Oxazines, e.g. morpholine
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Definitions

• LPA is highly implicated in the pathogenesis of a number of physio-pathological diseases, including cancer (Liu et al., 2009; Mills & Moolenaar, 2003), neuropathic pain (Inoue et al., 2004) and fibrosis (Tager et al., 2008).
• cancer Liu et al., 2009; Mills & Moolenaar, 2003
• neuropathic pain Inoue et al., 2004
• fibrosis Tager et al., 2008
• the lipid binds to specific G protein-coupled receptors of which there are seven known isoforms (Noguchi et al., 2009). Binding of LPA activates multiple signalling pathways (Mills & Moolenaar, 2003) including cell migration (van Dijk et al., 1998), proliferation and survival (Brindley, 2004).
• Other cellular responses include smooth muscle contraction, apoptosis and platelet aggregat
• ATX was characterised as a secreted lysophospholipase (lysoPLD) (Tokumura et al., 2002; Gesta et al., 2002). Since then ATX gene knockout mice have shown that the ATX-LPA signalling axis plays a vital role during embryonic development of the cardiovascular and neural system (Tanaka et al., 2006; van Meeteren et al., 2006), resulting in early embryonic lethality (Bachner et al., 1999).
• lysophospholipase lysophospholipase
• ATX belongs to a family of proteins called nucleotide pyrophosphatase/phosphodiesterase (NPP), encoded for by the gene ENPP.
• the family consists of seven structurally related enzymes (ENPP 1-7) conserved within vertebrates which are numbered according to their discovery. They were originally defined by their ability to hydrolyse pyrophosphate or phosphodiester bonds of various nucleotides and nucleotides derivatives in vitro (Stefan et al., 1999; Goding et al., 1998; Gijsbers et al., 2001), though ENPP2 and choline phosphate esters (ENPP6 & 7) have specific activity for other extracellular non-nucleotide molecules.
• ENPP2 (ATX) is unique within the family as it is the only secreted protein, whereas other ENPP members are transmembrane proteins (Stefan et al., 2005).
• WO02/100352 (Merck) and WO 02/080928 (Merck) relate to N-substituted nonaryl-heterocyclo amidyl NMDA/NR2B receptor antagonists for the treatment or prevention of migraines.
• WO2010/115491 (Merck) and WO 2009/046841 (Merck) relate to piperidine and piperazine derivatives as ATX inhibitors.
• WO2010/112116 (Merck) and WO 2010/112124 (Merck) relate to heterocyclic compounds as ATX inhibitors and WO 2011/044978 (Merck) relates to sulfoxide derivatives for treating tumours.
• A-Y 1 —X— is
• W is CH or N
• Z is selected from CH 2 , O and NR 5c ;
• Y 3 is selected from —O—(CR 6a R 6b )—, —(CR 6c R 6d )—O—, —CH ⁇ CH—, —CR 6e R 6f —CR 6g R 6h —, and —O—(CR 6i R 6j —CR 6k R 6l )—;
• R 1a , R 1b , R 1c , R 1d and R 1e are defined according to any one of (a) R 1b is halogen;
• R 1d is halogen, CN, C 1-4 alkyl, C 1-4 haloalkyl or C 1-4 haloalkoxy; and
• R 1a , R 1c and R 1e are H;
• R 1b is halogen;
• R 1d is halogen, CN, C 1-4 alkyl, C 1-4 haloalkyl or C 1-4 haloalkoxy;
• the invention relates to pharmaceutical compositions and combinations comprising compounds of the first aspect, and to the use of such compounds of the first aspect in the treatment of an ATX-dependent or ATX-mediated disease or condition.
• A-Y 1 —X— is
• W is CH or N
• Z is selected from CH 2 , O and NR 6c ;
• Y 3 is selected from —O—(CR 6a R 6b )—, —(CR 6c R 6d )—O—, —CH ⁇ CH—, —CR 6e R 6f —CR 6g R 6h —, and —O—(CR 6i R 6j —CR 6k R 6l )—;
• R 1a , R 1b , R 1c , R 1d and R 1e are defined according to any one of (a) R 1b is halogen;
• R 1d is halogen, CN, C 1-4 alkyl, C 1-4 haloalkyl or C 1-4 haloalkoxy; and
• R 1a , R 1c and R 1e are H;
• R 1b is halogen;
• R 1d is halogen, CN, C 1-4 alkyl, C 1-4 haloalkyl or C 1-4 haloalkoxy;
• A′ is selected from O, S and NR 2a ;
• A′′ is selected from O and S;
• Y 1 is —(CR 2b R 2c ) m — or —CH ⁇ CH—;
• X is selected from —C( ⁇ O)—, —N(R 3 )—C( ⁇ O)— and —C( ⁇ O)—N(R 3 )—;
• Y 2 is —(CR 4a R 4b ) n —;
• m is selected from 0, 1, 2, 3, 4 and 5;
• n is selected from 0, 1, 2, 3, 4 and 5; wherein when Y 1 is —(CR 2b R c ) m — and A is not HO—C( ⁇ O)—, the sum of m and n is not less than 2 and no more than 5; and wherein when Y 1 is —(CR 2b R c ) m — and A is HO—C( ⁇ O)—, the sum of m and n
• A-Y 1 —X— is
• W is CH or N
• Z is selected from CH 2 , O and NR 5c ;
• Y 3 is selected from —O—(CR 6a R 6b )—, —(CR 6c R 6d )—O—, —CH ⁇ CH—, —CR 6e R 6f —CR 6g R 6h —, and —O—(CR 6i R 6j —CR 6k R 6I )—;
• R 1a , R 1b , R 1c , R 1d and R 1e are defined according to any one of (a) R 1b is halogen;
• R 1d is halogen, CN, C 1-4 alkyl, C 1-4 haloalkyl or C 1-4 haloalkoxy; and
• R 1a , R 1c and R 1e are H;
• R 1b is halogen;
• R 1d is halogen, CN, C 1-4 alkyl, C 1-4 haloalkyl or C 1-4 haloalkoxy;
• A′ is selected from O, S and NR 2a ;
• A′′ is selected from O and S;
• Y 1 is —(CR 2b R 2c ) m — or —CH ⁇ CH—;
• X is selected from —C( ⁇ O)—, —N(R 3 )—C( ⁇ O)— and —C( ⁇ O)—N(R 3 )—;
• Y 2 is —(CR 4a R 4b ) n —;
• m is selected from 0, 1, 2, 3, 4 and 5;
• n is selected from 0, 1, 2, 3, 4 and 5; wherein when Y 1 is —(CR 2b R 2c ) m — the sum of m and n is not less than 2 and no more than 5; or
• A-Y 1 —X— is
• W is CH or N
• Z is selected from CH 2 , O and NR 5c ;
• Y 3 is selected from —O—(CR 6a R 6b )—, —(CR 6c CR 6d )—O—, —CH ⁇ CH— and —CR 6e R 6f —CR 6g R 6h —;
• R 1a , R 1b , R 1c , R 1d and R 1e are defined according to any one of (a) R 1b and R 1d is halogen, and R 1a , R 1c and R 1e is H; (b) R 1a and R 1c is halogen, and R 1b , R 1d and R 1e is H; (c) R 1c is C 1-4 haloalkyl, in particular CF 3 , or C 1-4 haloalkoxy, and R 1a , R 1b and R 1e are H, and R 1d is halogen, C 1-4 alkyl, particularly methyl, or H; (d) R 1b
• A′ is selected from O, S and NR 2a ;
• A′′ is selected from O and S;
• Y 1 is —(CR 2b R 2c ) m — or —CH ⁇ CH—;
• X is selected from —C( ⁇ O)—, —N(R 3 )—C( ⁇ O)— and —C( ⁇ O)—N(R 3 )—;
• Y 2 is —(CR 4a R 4b ) n —;
• m is selected from 0, 1, 2, 3, 4 and 5;
• n is selected from 0, 1, 2, 3, 4 and 5; wherein when Y 1 is —(CR 2b R 2c ) m — the sum of m and n is not less than 2 and no more than 5; or
• A-Y 1 —X— is
• W is CH or N
• Z is selected from CH 2 , O and NR 5c ;
• Y 3 is selected from —O—(CR 6a R 6b )—, —(CR 6c CR 6d )—O—, —CH ⁇ CH— and —CR 6e R 6f —CR 6g R 6h —;
• R 1a , R 1b , R 1c , R 1d and R 1e are defined according to any one of (a) R 1b and R 1d is halogen, and R 1a , R 1c and R 1e is H;
• R 1c is C 1-4 haloalkyl, in particular CF 3 , and R 1a , R 1b , R 1d and R 1e are H;
• R 1b is C 1-4 alkyl, R 1d is halogen, and R 1a , R 1c and R 1e is H;
• R 1b is CN, R 1d is halogen, and R 1a , R 1c and R 1e
• Halo or “halogen”, as used herein, may be fluoro, chloro, bromo or iodo.
• C 1-4 alkyl denotes straight chain or branched alkyl having 1-4 carbon atoms. If a different number of carbon atoms is specified, such as C 6 or C 3 , then the definition is to be amended accordingly, such as “C 1 -C 4 alkyl” will represent methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl.
• C 1-4 haloalkyl denotes straight chain or branched alkyl having 1-4 carbon atoms with at least one hydrogen substituted with a halogen. If a different number of carbon atoms is specified, such as C 6 or C 3 , then the definition is to be amended accordingly, such as “C 1 -C 4 -Haloalkyl” will represent methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl that have at least one hydrogen substituted with halogen, such as where the halogen is fluorine: CF 3 CF 2 —, (CF 3 ) 2 CH—, CH 3 —CF 2 —, CF 3 CF 2 —, CF 3 , CF 2 H—, CF 3 CF 2 CHCF 3 or CF 3 CF 2 CF 2 CF 2 —.
• C 1-4 haloalkoxy refers to an —O—C 1-4 alkyl group wherein C 1-4 alkyl is as defined herein and substituted with one or more halogen groups, e.g. —O—CF 3 .
• the term “subject” refers to an animal. Typically the animal is a mammal. A subject also refers to for example, primates (e.g., humans, male or female), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds and the like. In certain embodiments, the subject is a primate. In yet other embodiments, the subject is a human.
• primates e.g., humans, male or female
• the subject is a primate.
• the subject is a human.
• the term “inhibit”, “inhibition” or “inhibiting” refers to the reduction or suppression of a given condition, symptom, or disorder, or disease, or a significant decrease in the baseline activity of a biological activity or process.
• the term “treat”, “treating” or “treatment” of any disease or disorder refers in one embodiment, to ameliorating the disease or disorder (i.e., slowing or arresting or reducing the development of the disease or at least one of the clinical symptoms thereof).
• “treat”, “treating” or “treatment” refers to alleviating or ameliorating at least one physical parameter including those which may not be discernible by the patient.
• “treat”, “treating” or “treatment” refers to modulating the disease or disorder, either physically, (e.g., stabilization of a discernible symptom), physiologically, (e.g., stabilization of a physical parameter), or both.
• “treat”, “treating” or “treatment” refers to preventing or delaying the onset or development or progression of the disease or disorder.
• a subject is “in need of” a treatment if such subject would benefit biologically, medically or in quality of life from such treatment.
• any one of embodiments 1 to 5 refers not only to embodiments indicated by the integers such as 1 and 2 but also to embodiments indicated by numbers with a decimal component such as 1.1, 1.2 or 2.1, 2.2, 2.3.
• “according to any one of embodiments 1 to 3” means according to any one of embodiments 1, 1.1, 2, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7.
• R 1a , R 1b , R 1c , R 1d and R 1e are defined according to any one of (a) R 1b is halogen, R 1d is halogen, CN, C 1-4 alkyl, C 1-4 haloalkyl or C 1-4 haloalkoxy, and R 1a , R 1c and R 1e is H; (b) R 1b is halogen, R 1d is halogen, CN, C 1-4 alkyl, C 1-4 haloalkyl or C 1-4 haloalkoxy, R 1c is halogen, and R 1a and R 1e is H; (c) R 1b C 1-4 alkyl, R 1d is C 1-4 alkyl, C 1-4 haloalkoxy or CN, R 1a , R 1c and R 1e is H; (d) R 1b is CN, R 1d is C 1-4 haloalkyl or C 1-4 haloalkoxy, and R 1a ,
• R 1a , R 1b , R 1c , R 1d and R 1e are defined according to any one of (a) R 1b is halogen, R 1d is halogen, CN, C 1-4 alkyl, C 1-4 haloalkyl or C 1-4 haloalkoxy, and R 1a , R 1c and R 1e is H; (c) R 1b is C 1-4 alkyl, R 1d is C 1-4 alkyl, C 1-4 haloalkoxy or CN, R 1a , R 1c and R 1e is H; (f) R 1a is halogen, R 1c is halogen, CN, C 1-4 alkyl, C 1-4 haloalkyl or C 1-4 haloalkoxy, and R 1b , R 1d and R 1e is H; and (g) R 1c is halogen, CN, C 1-4 haloalkyl or C 1-4 haloalkoxy, and R 1a , R
• R 1a , R 1b , R 1c , R 1d and R 1e are defined according to any one of (a) R 1b is fluoro, chloro or bromo; R 1d is fluoro, chloro, bromo, CN, methyl, trifluoromethyl or trifluoromethoxy; and R 1a , R 1c and R 1e are H; (c) R 1b is methyl; R 1d is methyl, trfluoromethyl, trifluoromethoxy or CN; R 1a , R 1c and R 1e are H; (f) R 1a is fluoro, chloro or bromo; R 1c is fluoro, chloro, bromo, CN, methyl, trifluoromethyl or trifluoromethoxy; and R 1b , R 1d and R 1e are H; and (g) R 1c is fluoro, chloro, bromo, CN, methyl, trifluoromethyl or trifluoromethoxy; and
• R 1b is fluoro, chloro or bromo
• R 1d is fluoro, chloro, bromo, CN, methyl, trifluoromethyl or trifluoromethoxy
• R 1a , R 1c and R 1e are H.
• R 1b is methyl;
• R 1d is methyl, trfluoromethyl, trifluoromethoxy or CN;
• R 1a , R 1c and R 1e are H.
• R 1a is fluoro, chloro or bromo
• R 1c is fluoro, chloro, bromo, CN, methyl, trifluoromethyl or trifluoromethoxy
• R 1b , R 1d and R 1e are H.
• R 1c is fluoro, chloro, bromo, CN, methyl, trifluoromethyl or trifluoromethoxy
• R 1a , R 1b and R 1e are H
• R 1d is fluoro, chloro, bromo, CN, methyl, trifluoromethyl, trifluoromethoxy, or H.
• embodiment 4.1 of the invention there is provided a compound or salt according to any one of embodiments 1 to 3, wherein R b is CN, R d is methyl, and R a , R c and R e are H.
• Y 3 is selected from —O—(CH 2 )—, —(CH 2 )—O—, —CH ⁇ CH—, —CH 2 —CH 2 —, and —O—(CH 2 —CH 2 )—.
• X is selected from —N(R 3 )—C( ⁇ O)— and —C( ⁇ O)—N(R 3 )—, in particular —N(H)—C( ⁇ O)— and —C( ⁇ O)—N(H)—
• Y 1 is —(CR 2b R c ) m — and Y 2 is —(CR 4a R 4b ) n —; m is selected from 0, 1, 2, 3, 4 and 5; n is selected from 0, 1, 2 and 3; and wherein the sum of m and n is not less than 2 and no more than 5.
• n is selected from 0 and 1; or m is selected from 0 and 1, and n is selected from 2 and 3.
• n 0.
• n is 0.
• X is —C( ⁇ O)—N(R 3 )—.
• A is selected from
• A is selected from
• Y 1 is —(CR 2b R 2c ) m — or —CH ⁇ CH—;
• X is selected from —C( ⁇ O)—, —N(R 3 )—C( ⁇ O)— and —C( ⁇ O)—N(R 3 )—;
• Y 2 is —(CR 4a R 4b ) n —;
• m is selected from 0, 1, 2, 3, 4 and 5;
• n is selected from 0, 1, 2, 3, 4 and 5; wherein when Y 1 is —(CR 2b R 2c ) m — the sum of m and n is not less than 2 and no more than 5;
• L is selected from
• W is CH or N
• Z is selected from CH 2 , O and NR 5c ;
• Y 3 is selected from —O—(CR 6a R 6b )—, —(CR 6c R 6d )—O—, —CH ⁇ CH—, —CR 6e R 6f —CR 6g R 6b —, and —O—(CR 6i R 6j —CR 6k R 6l )—;
• R 1a , R 1b , R 1c , R 1d and R 1e are defined according to any one of (a) R 1b is halogen;
• R 1d is halogen, CN, C 1-4 alkyl, C 1-4 haloalkyl or C 1-4 haloalkoxy; and
• R 1a , R 1c and R 1e are H;
• R 1b is halogen;
• R 1d is halogen, CN, C 1-4 alkyl, C 1-4 haloalkyl or C 1-4 haloalkoxy;
• Y 1 is —(CR 2b R 2c ) m —;
• X is selected from —N(R 3 )—C( ⁇ O)— and —C( ⁇ O)—N(R 3 )—;
• Y 2 is —(CR 4a R 4b ) n —;
• m is selected from 0, 1, 2, 3, 4 and 5;
• n is selected from 0, 1, 2, 3, 4 and 5; wherein the sum of m and n is not less than 2 and no more than 5;
• W is CH or N
• Y 3 is selected from —O—(CR 6a R 6b )— and —CH ⁇ CH—
• Y 1 is —(CH 2 ) m —;
• X is —C( ⁇ O)—NH—
• Y 2 is —(CH 2 ) n —; m is selected from 2, 3 and 4, and n is selected from 0 and 1;
• R 1a , R 1b , R 1c , R 1d and R 1e are defined according to (a) R 1b and R 1d is chloro and R 1a , R 1c and R 1e are H; or
• R 1b is CN; R 1d is CF 3 or OCF 3 ; and R 1a , R 1c and R 1e are H.
• Y 1 is —(CH 2 ) m —;
• X is —C( ⁇ O)—NH—
• Y 2 is —(CH 2 ) n —; m is 3 or 4, and n is 0;
• Y 3 is —O—(CH 2 )—
• R 1a , R 1b , R 1c , R 1d and R 1e are defined according to (a) R 1b and R 1d is chloro and R 1a , R 1c and R 1e are H; or
• R 1b is CN; R 1d is CF 3 ; and R 1a , R 1c and R 1e are H.
• Y 2 is —(CR 4a R 4b ) n — and n is 1 or 2, particularly 2.
• R 4c is methyl or ethyl and R 4d is methyl or H.
• a compound according to embodiment 46 in crystalline form characterized by an x-ray powder diffraction pattern comprising four or more 2-theta values selected from the group consisting of 17.3°, 17.9°, 19.5°, 20.0°, 21.6°, 21.8°, 22.7°, 23.1°, 23.5°, 24.0°, 24.7°, 25.9°, 27.2° and 28.2° at a temperature of 21-26° C.
• a compound according to embodiment 46 in crystalline form characterized by an x-ray powder diffraction pattern comprising six or more 2-theta values selected from the group consisting of 17.3°, 17.9°, 19.5°, 20.0°, 21.6°, 21.8°, 22.7°, 23.1°, 23.5°, 24.0°, 24.7°, 25.9°, 27.2° and 28.2° at a temperature of 21-26° C.
• n is not 1.
• n is not 1” is that a compound where L is
• X is —C( ⁇ O)—N(R 3 )— and n is 1 was observed not to be stable.
• the compounds of the present invention may be prepared by the routes described in the following Schemes or the Examples.
• X is —C( ⁇ O)—N(R 3 )—.
• step (a) involves reacting the compounds shown in scheme 1 in a suitable solvent such as DMF in the presence of a suitable amide coupling reagent, for example ®T3P or HATU, and a suitable base such as DIPEA at a suitable temperature such as room temperature.
• a suitable solvent such as DMF
• a suitable amide coupling reagent for example ®T3P or HATU
• a suitable base such as DIPEA
• step (a) involves reacting the compounds shown in scheme 1 in a suitable solvent such as acetonitrile or methanol in the presence of a suitable base such as 2,3,4,6,7,8-hexahydro-1H-pyrimido[1,2-a]pyrimidine or sodium methoxide at a suitable temperature such as room temperature.
• a suitable solvent such as acetonitrile or methanol
• a suitable base such as 2,3,4,6,7,8-hexahydro-1H-pyrimido[1,2-a]pyrimidine or sodium methoxide
• A, L, R 1a , R 1b , R 1c , R 1d , R 1e , R 3 , Y 1 , Y 2 , Y 3 are as defined in embodiment 1,
• X is —C( ⁇ O)—N(R 3 )—
• R 7 is H and
• P represents a suitable protection group, for example a BOC (tert-butoxy carbonyl) group.
• Step (a) involves reaction of a mono protected amine with an acid in a suitable solvent such as DMF with a suitable base such as diisopropylethylamine with a suitable amide coupling reagent such as T3P ⁇ or HATU at a suitable temperature such as room temperature.
• Step (b) involves the removal of a suitable protection group P which is well known in the art.
• P is BOC
• a compound is treated in a suitable solvent, for example DCM, under acidic conditions, for example by the addition of TFA, at a suitable temperature such as room temperature.
• Step (c) involves reaction of an amine with a chloroformate in a suitable solvent such as DCM with a suitable base such as aqueous sodium hydroxide at a suitable temperature such as room temperature; alternatively reaction of an amine with an acid chloride in a suitable solvent such as DCM with a suitable base such as triethylamine at a suitable temperature such as room temperature.
• a suitable solvent such as DCM
• a suitable base such as aqueous sodium hydroxide
• X is —N(R 3 )—C( ⁇ O)—.
• Step (a) involves reaction of a mono protected amine with an acid in a suitable solvent such as DMF with a suitable base such as diisopropylethylamine with a suitable amide coupling reagent such as T3P ⁇ or HATU at a suitable temperature such as room temperature.
• a suitable solvent such as DMF
• a suitable base such as diisopropylethylamine
• a suitable amide coupling reagent such as T3P ⁇ or HATU
• A, L, R 1b , R 1c , R 1d , R 1e , R 3 , Y 1 , Y 2 , Y 3 are as defined in embodiment 1, X is —N(R 3 )— and Z′ is H or OMe.
• Step (a) involves reaction of an aldehyde (i) with an amine (V) in a suitable solvent such as dichloromethane, with a suitable reducing agent such as sodium triacetoxyborohydride at a suitable temperature such as room temperature.
• a suitable solvent such as dichloromethane
• a suitable reducing agent such as sodium triacetoxyborohydride
• Step (b) involves reaction of a protected heterocycle such as triazole in suitable solvents such as water and acetonitrile, with a suitable oxidising agent such as ceric ammonium nitrate at a suitable temperature such as room temperature.
• a protected heterocycle such as triazole
• suitable solvents such as water and acetonitrile
• a suitable oxidising agent such as ceric ammonium nitrate
• A, L, R 1a , R 1b , R 1c , R 1d , R 1e , R 3 , Y 1 , Y 2 , Y 3 are as defined in embodiment 1,
• X is —CH 2 —,
• Z′ is H or OMe, and
• P′ represents a suitable protection group, for example a BOC (tert-butoxy carbonyl) group.
• Step (c) involves removal of a suitable protecting group such as BOC (tert-butoxy carbonyl) with a suitable acid such as trifluoroacetic acid, in a suitable solvent such as dichloromethane, at a suitable temperature such as room temperature.
• a suitable protecting group such as BOC (tert-butoxy carbonyl)
• a suitable acid such as trifluoroacetic acid
• Step (d) involves reaction of an amine (vi) with a chloroformate (XXXIII) in a suitable solvent such as DCM with a suitable base such as aqueous sodium hydroxide at a suitable temperature such as room temperature; alternatively reaction of an amine (vi) with an acid chloride (XXXIII) in a suitable solvent such as DCM with a suitable base such as triethylamine at a suitable temperature such as room temperature.
• a suitable solvent such as DCM
• a suitable base such as aqueous sodium hydroxide
• A, L, R 1a , R 1b , R 1c , R 1d , R 1e , R 3 , R 4c , R 4d , Y 1 , Y 2 , Y 3 are as defined in embodiment 1.
• Step (b) involves hydrolysis of the squarate ester in a suitable solvent such as tetrahydrofuran with a suitable acid such as hydrochloric acid at a suitable temperature such as room temperature.
• a suitable solvent such as tetrahydrofuran
• a suitable acid such as hydrochloric acid
• R 7 is an alkyl group, such as methyl or ethyl, and R 2 is as defined in embodiment 1.
• Step (a) involves reacting a compound (XIII) in a suitable solvent such as acetonitrile and methanol in the presence of a suitable base such as sodium methoxide and sodium hydroxide at a suitable temperature such as 80° C. or reflux.
• a suitable solvent such as acetonitrile and methanol
• a suitable base such as sodium methoxide and sodium hydroxide
• Step (a) involves reacting the acetylene (XIV) with a suitable azide (XV) such as benzyl or 4-methoxybenzyl in suitable solvents such as tert-butanol and water in the presence of a suitable catalyst such as that formed in-situ from copper acetate and sodium ascorbate at a suitable temperature such as room temperature.
• a suitable azide such as benzyl or 4-methoxybenzyl
• suitable solvents such as tert-butanol
• a suitable catalyst such as that formed in-situ from copper acetate and sodium ascorbate at a suitable temperature such as room temperature.
• Step (b) involves removal of the benzyl group in a suitable solvent such as acetonitrile with a suitable oxidising agent such as ceric ammonium nitrate at a suitable temperature such as room temperature; or alternatively in a suitable solvent such as ethanol, with a suitable catalyst such as palladium on carbon, at a suitable temperature such as 70° C., and a suitable pressure of hydrogen such as 30 bar.
• a suitable solvent such as acetonitrile
• a suitable oxidising agent such as ceric ammonium nitrate
• a suitable temperature such as room temperature
• a suitable solvent such as ethanol
• a suitable catalyst such as palladium on carbon
• R 1a , R 1b , R 1c , R 1d , R 1e , Y 2 , Y 3 are as defined in embodiment 1.
• Step (a) is carried out in a suitable solvent such as DCM with a suitable base such as aqueous sodium hydroxide at a suitable temperature such as room temperature.
• a suitable solvent such as DCM
• a suitable base such as aqueous sodium hydroxide
• P represents a suitable protection group, for example p-methoxybenzyl (PMB) or pivaloyloxymethyl (POM)
• R 7 is an alkyl group, such as ethyl
• A, Y 1 , R 3 are defined as in embodiment 1.
• Step (a) involves reaction of an acid (IXX) with a suitable chloroformate such as ethyl chloroformate in a suitable solvent such as acetone and water with a suitable base such as triethylamine at a suitable temperature such as 0° C.
• a suitable chloroformate such as ethyl chloroformate
• a suitable solvent such as acetone and water
• a suitable base such as triethylamine
• Step (b) involves reaction with sodium azide in a suitable solvent such as acetone at a suitable temperature such as 0° C.
• Step (c) involves heating of compound (XXI) in a suitable solvent such as toluene at a suitable temperature such as 110° C., followed by acid hydrolysis of the resulting isocyanate in a suitable acid, such as hydrochloric acid, at a suitable temperature such as 100° C.
• a suitable solvent such as toluene
• acid hydrolysis of the resulting isocyanate in a suitable acid such as hydrochloric acid
• Step (d) involves reductive alkylation of the amine (XXII) with a suitable aldehyde such as formaldehyde in a suitable solvent such as DCM with a suitable reducing agent such as sodium triacetoxyborohydride at a suitable temperature such as room temperature.
• a suitable aldehyde such as formaldehyde
• a suitable solvent such as DCM
• a suitable reducing agent such as sodium triacetoxyborohydride
• Step (e) involves the removal of a suitable protection group P which is well known in the art.
• P a suitable protection group
• a compound is treated in a suitable solvent, for example MeOH, under basic conditions, for example by the addition of sodium hydroxide, at a suitable temperature such as room temperature.
• P is PMB
• a compound is treated in a suitable solvent, for example acetonitrile, with a suitable oxidising agent such as ceric ammonium nitrate, at a suitable temperature such as room temperature.
• P represents a suitable protection group, for example tert-butylcarbamate (BOC)
• Z′ is H or OMe
• Y 1 and R 3 are defined as in embodiment 1.
• Step (a) involves protection of an acetylene amine (XXXVI) with a suitable protecting group such as BOC in a suitable solvent such as THF with a suitable base such as triethylamine at a suitable temperature such as RT.
• a suitable protecting group such as BOC
• THF a suitable solvent
• a suitable base such as triethylamine
• Step (b) involves reacting the acetylene (XXXVII) with a suitable azide (XV) such as benzyl or 4-methoxybenzyl in suitable solvents such as tert-butanol and water in the presence of a suitable catalyst such as that formed in-situ from copper acetate and sodium ascorbate at a suitable temperature such as room temperature, with in-situ deprotection of the amine by a suitable method such as an acid wash.
• a suitable azide such as benzyl or 4-methoxybenzyl
• suitable solvents such as tert-butanol
• a suitable catalyst such as that formed in-situ from copper acetate and sodium ascorbate at a suitable temperature such as room temperature
• Step (c) involves reductive alkylation of the amine (XXIIa) with a suitable aldehyde such as formaldehyde in a suitable solvent such as DCM with a suitable reducing agent such as sodium triacetoxyborohydride at a suitable temperature such as room temperature.
• a suitable aldehyde such as formaldehyde
• a suitable solvent such as DCM
• a suitable reducing agent such as sodium triacetoxyborohydride
• Step (d) involves the removal of a benzyl protecting group which is well known in the art.
• a suitable solvent for example acetonitrile
• a suitable oxidising agent such as ceric ammonium nitrate
• Z′ is H
• the compound is treated in a suitable solvent, for example, ethanol, with a suitable catalyst, such as palladium on carbon, under a suitable pressure of hydrogen, such as 30 bar, at a suitable temperature, such as 70° C.
• Z′′ is Cl or O-succinyl
• P represents a suitable protection group, for example a BOC (tert-butoxy carbonyl) group and L, R 1a , R 1b , R 1c , R 1d , R 1e , R 3 , Y 2 , Y 3 are as defined in embodiment 1.
• Step (a) involves reaction of a mono protected diamine (XXIV) with a chloroformate or O-succinyl ester (XVII) in a suitable solvent such as dichloromethane with a suitable base such as aqueous sodium hydroxide at a suitable temperature such as room temperature; alternatively reaction of an amine with an acid chloride in a suitable solvent such as DCM with a suitable base such as triethylamine at a suitable temperature such as room temperature.
• a suitable solvent such as dichloromethane
• a suitable base such as aqueous sodium hydroxide
• a suitable base such as aqueous sodium hydroxide
• Step (b) involves the removal of a suitable protection group P which is well known in the art.
• P is BOC
• a compound is treated in a suitable solvent, for example DCM, under acidic conditions, for example by the addition of TFA, at a suitable temperature such as room temperature.
• Step (c) involves reductive alkylation of an amine (XXVI) with a suitable aldehyde such as formaldehyde in a suitable solvent such as dichloromethane with a suitable reducing agent such as sodium triacetoxyborohydride at a suitable temperature such as room temperature.
• a suitable aldehyde such as formaldehyde
• a suitable solvent such as dichloromethane
• a suitable reducing agent such as sodium triacetoxyborohydride
• Step (d) involves deprotonation of a carbamate with a suitable base such as sodium hydride in a suitable solvent such as N,N′-dimethylformamide at a suitable temperature such as 0° C., followed by alkylation with a suitable alkylating agent such as iodomethane at a suitable temperature such as room temperature.
• a suitable base such as sodium hydride
• a suitable solvent such as N,N′-dimethylformamide
• R 1a , R 1b , R 1c , R 1d , R 1e , R 6a , R 6b are as defined in embodiment 1.
• Step (a) involves reaction of a benzyl alcohol (XXVIII) dissolved in a suitable solvent such as tetrahydrofuran with phosgene in a suitable solvent such as toluene at a suitable temperature such as 10° C.
• a suitable solvent such as tetrahydrofuran
• phosgene in a suitable solvent such as toluene
• R 7 is an alkyl group, such as methyl or ethyl
• P represents a suitable protection group, for example a BOC (tert-butoxy carbonyl) group
• L, R 1a , R 1b , R 1c , R 1d , R 1e , Y 2 are as defined in embodiment 1.
• Step (a) involves reaction of an iodobenzene (XXIX) with an acrylate ester in a suitable solvent such as N,N′-dimethylformamide with a suitable base such as triethylamine and a suitable catalyst such as palladium bis(tritert-butylphosphine) at a suitable temperature such as 80° C.
• a suitable solvent such as N,N′-dimethylformamide
• a suitable base such as triethylamine
• a suitable catalyst such as palladium bis(tritert-butylphosphine
• Step (b) involves hydrolysis of the ester in a suitable solvent such as tetrahydrofuran with a suitable base such as sodium hydroxide at a suitable temperature such as room temperature.
• a suitable solvent such as tetrahydrofuran
• a suitable base such as sodium hydroxide
• Step (c) involves reaction of a monoprotected diamine (XXIV) with an acid (XXXI) in a suitable solvent such as DMF in the presence of a suitable amide coupling reagent, for example ®T3P or HATU, and a suitable base such as DIPEA at a suitable temperature such as room temperature.
• a suitable amide coupling reagent for example ®T3P or HATU
• DIPEA a suitable base such as DIPEA
• Step (d) involves reduction of a cinnamide in a suitable solvent such as ethanol in the presence of a suitable catalyst such as platinum on carbon under a suitable pressure of hydrogen such as at a suitable temperature such as room temperature.
• a suitable solvent such as ethanol
• a suitable catalyst such as platinum on carbon
• a suitable pressure of hydrogen such as at a suitable temperature such as room temperature.
• W is specifically N
• P represents a suitable protection group, for example a BOC (tert-butoxy carbonyl) group
• R 1a , R 1b , R 1c , R 1d , R 1e , Y 2 , Y 3 are as defined in embodiment 1 and L is specifically
• Step (a) involves reaction of an amine (XXXII) with a chloroformate (XXXIII) in a suitable solvent such as DCM with a suitable base such as aqueous sodium hydroxide at a suitable temperature such as room temperature; alternatively reaction of an amine with an acid chloride in a suitable solvent such as DCM with a suitable base such as triethylamine at a suitable temperature such as room temperature.
• a suitable solvent such as DCM
• a suitable base such as aqueous sodium hydroxide
• Step (b) involves the removal of a suitable protection group P which is well known in the art.
• P is BOC
• a compound is treated in a suitable solvent, for example DCM, under acidic conditions, for example by the addition of TFA, at a suitable temperature such as room temperature.
• Step (c) involves reaction of an amine (XXXV) with a suitable aldehyde such as tert-butyl methyl(3-oxopropyl)carbamate in suitable solvent such as dichloromethane in the presence of a suitable reducing agent such as sodium triacetoxyborohydride at a suitable temperature such as room temperature.
• a suitable aldehyde such as tert-butyl methyl(3-oxopropyl)carbamate
• suitable solvent such as dichloromethane
• a suitable reducing agent such as sodium triacetoxyborohydride
• Z′ is H or OMe and Y 1 is defined in embodiment 1.
• Step (a) involves reacting an acetylene (number) with a suitable azide (XV) such as 4-methoxybenzyl azide in suitable solvents such as tert-butanol and water in the presence of a suitable catalyst such as that formed in-situ from copper acetate and sodium ascorbate at a suitable temperature such as room temperature.
• a suitable azide such as 4-methoxybenzyl azide
• suitable solvents such as tert-butanol
• a suitable catalyst such as that formed in-situ from copper acetate and sodium ascorbate at a suitable temperature such as room temperature.
• Step (b) involves reacting alcohol (number) with a suitable oxidising agent such as Dess Martin periodinane in a suitable solvent such as dichloromethane at a suitable temperature such as room temperature.
• a suitable oxidising agent such as Dess Martin periodinane
• a suitable solvent such as dichloromethane
• protecting group a readily removable group that is not a constituent of the particular desired end product of the compounds of the present invention.
• the protection of functional groups by such protecting groups, the protecting groups themselves, and their cleavage reactions are described for example in standard reference works, such as J. F. W. McOmie, “Protective Groups in Organic Chemistry”, Plenum Press, London and New York 1973, in T. W. Greene and P. G. M. Wuts, “Protective Groups in Organic Synthesis”, Third edition, Wiley, New York 1999, in “The Peptides”; Volume 3 (editors: E. Gross and J.
• Salts of compounds of the present invention having at least one salt-forming group may be prepared in a manner known to those skilled in the art.
• salts of compounds of the present invention having acid groups may be formed, for example, by treating the compounds with metal compounds, such as alkali metal salts of suitable organic carboxylic acids, e.g. the sodium salt of 2-ethylhexanoic acid, with organic alkali metal or alkaline earth metal compounds, such as the corresponding hydroxides, carbonates or hydrogen carbonates, such as sodium or potassium hydroxide, carbonate or hydrogen carbonate, with corresponding calcium compounds or with ammonia or a suitable organic amine, stoichiometric amounts or only a small excess of the salt-forming agent preferably being used.
• metal compounds such as alkali metal salts of suitable organic carboxylic acids, e.g. the sodium salt of 2-ethylhexanoic acid
• organic alkali metal or alkaline earth metal compounds such as the corresponding hydroxides, carbonates or hydrogen carbonates
• Acid addition salts of compounds of the present invention are obtained in customary manner, e.g. by treating the compounds with an acid or a suitable anion exchange reagent.
• Internal salts of compounds of the present invention containing acid and basic salt-forming groups, e.g. a free carboxy group and a free amino group, may be formed, e.g. by the neutralisation of salts, such as acid addition salts, to the isoelectric point, e.g. with weak bases, or by treatment with ion exchangers.
• Salts can be converted into the free compounds in accordance with methods known to those skilled in the art.
• Metal and ammonium salts can be converted, for example, by treatment with suitable acids, and acid addition salts, for example, by treatment with a suitable basic agent.
• diastereoisomers can be separated, for example, by partitioning between polyphasic solvent mixtures, recrystallisation and/or chromatographic separation, for example over silica gel or by e.g. medium pressure liquid chromatography over a reversed phase column, and racemates can be separated, for example, by the formation of salts with optically pure salt-forming reagents and separation of the mixture of diastereoisomers so obtainable, for example by means of fractional crystallisation, or by chromatography over optically active column materials.
• Intermediates and final products can be worked up and/or purified according to standard methods, e.g. using chromatographic methods, distribution methods, (re-) crystallization, and the like.
• 190° C. including, for example, from approximately ⁇ 80° C. to approximately 150° C., for example at from ⁇ 80 to ⁇ 60° C., at room temperature, at from ⁇ 20 to 40° C. or at reflux temperature, under atmospheric pressure or in a closed vessel, where appropriate under pressure, and/or in an inert atmosphere, for example under an argon or nitrogen atmosphere.
• mixtures of isomers that are formed can be separated into the individual isomers, for example diastereoisomers or enantiomers, or into any desired mixtures of isomers, for example racemates or mixtures of diastereoisomers, for example analogously to the methods described under “Additional process steps”.
• solvents from which those solvents that are suitable for any particular reaction may be selected include those mentioned specifically or, for example, water, esters, such as lower alkyl-lower alkanoates, for example ethyl acetate, ethers, such as aliphatic ethers, for example diethyl ether, or cyclic ethers, for example tetrahydrofuran or dioxane, liquid aromatic hydrocarbons, such as benzene or toluene, alcohols, such as methanol, ethanol or 1- or 2-propanol, nitriles, such as acetonitrile, halogenated hydrocarbons, such as methylene chloride or chloroform, acid amides, such as dimethylformamide or dimethyl acetamide, bases, such as heterocyclic nitrogen bases, for example pyridine or N-methylpyrrolidin-2-one, carboxylic acid anhydrides, such as lower alkanoic acid anhydrides, for example acetic anhydride,
• the compounds of the present invention may also be obtained in the form of hydrates, or their crystals may, for example, include the solvent used for crystallization. Different crystalline forms may be present.
• the invention relates also to those forms of the process in which a compound obtainable as an intermediate at any stage of the process is used as starting material and the remaining process steps are carried out, or in which a starting material is formed under the reaction conditions or is used in the form of a derivative, for example in a protected form or in the form of a salt, or a compound obtainable by the process according to the invention is produced under the process conditions and processed further in situ.
• an optical isomer or “a stereoisomer” refers to any of the various stereo isomeric configurations which may exist for a given compound of the present invention and includes geometric isomers. It is understood that a substituent may be attached at a chiral center of a carbon atom.
• the term “chiral” refers to molecules which have the property of non-superimposability on their mirror image partner, while the term “achiral” refers to molecules which are superimposable on their mirror image partner. Therefore, the invention includes enantiomers, diastereomers or racemates of the compounds of the present invention. “Enantiomers” are a pair of stereoisomers that are non-superimposable mirror images of each other.
• a 1:1 mixture of a pair of enantiomers is a “racemic” mixture.
• the term is used to designate a racemic mixture where appropriate.
• “Diastereoisomers” are stereoisomers that have at least two asymmetric atoms, but which are not mirror-images of each other.
• the absolute stereochemistry is specified according to the Cahn-Ingold- Prelog R-S system. When a compound is a pure enantiomer the stereochemistry at each chiral carbon may be specified by either R or S.
• Resolved compounds whose absolute configuration is unknown can be designated (+) or ( ⁇ ) depending on the direction (dextro- or levorotatory) which they rotate plane polarized light at the wavelength of the sodium D line.
• Certain compounds of the present invention described herein may contain one or more asymmetric centers or axes and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R)- or (S)-.
• the compounds of the present invention may be present in the form of one of the possible isomers or as mixtures thereof, for example as pure optical isomers, or as isomer mixtures, such as racemates and diastereoisomer mixtures, depending on the number of asymmetric carbon atoms.
• the present invention is meant to include all such possible isomers, including racemic mixtures, diasteriomeric mixtures and optically pure forms.
• Optically active (R)- and (S)-isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound of the present invention contains a double bond, the substituent may be E or Z configuration.
• the compound of the present invention contains a disubstituted cycloalkyl
• the cycloalkyl substituent may have a cis- or trans-configuration. All tautomeric forms, for example for group A in embodiment 1, are also intended to be included.
• salt refers to an acid addition or base addition salt of a compound of the present invention.
• Salts include in particular “pharmaceutical acceptable salts”.
• pharmaceutically acceptable salts refers to salts that retain the biological effectiveness and properties of the compounds of the present invention and, which typically are not biologically or otherwise undesirable. In many cases, the compounds of the present invention are capable of forming acid and/or base salts by virtue of the presence of amino and/or carboxyl groups or groups similar thereto.
• Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids, e.g., acetate, aspartate, benzoate, besylate, bromide/hydrobromide, bicarbonate/carbonate, bisulfate/sulfate, camphorsulfonate, chloride/hydrochloride, chlortheophyllonate, citrate, ethandisulfonate, fumarate, gluceptate, gluconate, glucuronate, hippurate, hydroiodide/iodide, isethionate, lactate, lactobionate, laurylsulfate, malate, maleate, malonate, mandelate, mesylate, methylsulphate, naphthoate, napsylate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen
• Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.
• Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, sulfosalicylic acid, and the like.
• Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.
• Inorganic bases from which salts can be derived include, for example, ammonium salts and metals from columns I to XII of the periodic table.
• the salts are derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper; particularly suitable salts include ammonium, potassium, sodium, calcium and magnesium salts.
• Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like.
• Certain organic amines include isopropylamine, benzathine, cholinate, diethanolamine, diethylamine, lysine, meglumine, piperazine and tromethamine.
• the pharmaceutically acceptable salts of the compounds of the present invention can be synthesized from a basic or acidic moiety, by conventional chemical methods.
• such salts can be prepared by reacting free acid forms of the compounds of the present invention with a stoichiometric amount of the appropriate base (such as Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate or the like), or by reacting free base forms of the compounds of the present invention with a stoichiometric amount of the appropriate acid.
• a stoichiometric amount of the appropriate base such as Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate or the like
• Such reactions are typically carried out in water or in an organic solvent, or in a mixture of the two.
• non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile is desirable, where practicable.
• Lists of additional suitable salts can be found, e.g., in “Remington's Pharmaceutical Sciences”, 20th ed., Mack Publishing Company, Easton, Pa., (1985); and in “Handbook of Pharmaceutical Salts: Properties, Selection, and Use” by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).
• any formula given herein is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds of the present invention.
• Isotopically labeled compounds of the present invention have structures depicted by the formulas given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number.
• isotopes that can be incorporated into compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, and chlorine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 18 F 31 P, 32 P, 35 S, 36 Cl, 125 I respectively.
• the invention includes various isotopically labeled compounds of the present invention, for example those into which radioactive isotopes, such as 3 H and 14 C, or those into which non-radioactive isotopes, such as 2 H and 13 C are present.
• isotopically labelled compounds of the present invention are useful in metabolic studies (with 14 C), reaction kinetic studies (with, for example 2 H or 3 H), detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays, or in radioactive treatment of patients.
• PET positron emission tomography
• SPECT single-photon emission computed tomography
• an 18 F or labeled compound of the present invention may be particularly desirable for PET or SPECT studies.
• Isotopically-labeled compounds of the present invention can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Generic Schemes, Examples and Preparations using an appropriate isotopically-labeled reagent in place of the non-labeled reagent previously employed.
• isotopic enrichment factor means the ratio between the isotopic abundance and the natural abundance of a specified isotope.
• a substituent in a compound of the present invention is denoted deuterium, such compound has an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation).
• solvates in accordance with the invention include those wherein the solvent of crystallization may be isotopically substituted, e.g. D 2 O, d 6 -acetone, d 6 -DMSO.
• Compounds of the invention i.e. compounds of the present invention that contain groups capable of acting as donors and/or acceptors for hydrogen bonds may be capable of forming co-crystals with suitable co-crystal formers.
• These co-crystals may be prepared from compounds of the present invention by known co-crystal forming procedures. Such procedures include grinding, heating, co-subliming, co-melting, or contacting in solution compounds of the present invention with the co-crystal former under crystallization conditions and isolating co-crystals thereby formed.
• Suitable co-crystal formers include those described in WO 2004/078163. Hence the invention further provides co-crystals comprising a compound of the present invention.
• any asymmetric atom (e.g., carbon or the like) of the compound(s) of the present invention can be present in racemic or enantiomerically enriched, for example the (R)-, (S)- or (R,S)-configuration.
• each asymmetric atom has at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess in the (R)- or (S)-configuration.
• Substituents at atoms with unsaturated double bonds may, if possible, be present in cis-(Z)- or trans-(E)- form.
• a compound of the present invention can be in the form of one of the possible isomers, rotamers, atropisomers, tautomers or mixtures thereof, for example, as substantially pure geometric (cis or trans) isomers, diastereomers, optical isomers (antipodes), racemates or mixtures thereof.
• Any resulting mixtures of isomers can be separated on the basis of the physicochemical differences of the constituents, into the pure or substantially pure geometric or optical isomers, diastereomers, racemates, for example, by chromatography and/or fractional crystallization.
• any resulting racemates of final products or intermediates can be resolved into the optical antipodes by known methods, e.g., by separation of the diastereomeric salts thereof, obtained with an optically active acid or base, and liberating the optically active acidic or basic compound.
• a basic moiety may thus be employed to resolve the compounds of the present invention into their optical antipodes, e.g., by fractional crystallization of a salt formed with an optically active acid, e.g., tartaric acid, dibenzoyl tartaric acid, diacetyl tartaric acid, di-O,O′-p-toluoyl tartaric acid, mandelic acid, malic acid or camphor-10-sulfonic acid.
• Racemic products can also be resolved by chiral chromatography, e.g., high pressure liquid chromatography (HPLC) using a chiral adsorbent.
• HPLC high pressure liquid chromatography
• the compounds of the present invention can also be obtained in the form of their hydrates, or include other solvents used for their crystallization.
• the compounds of the present invention may inherently or by design form solvates with pharmaceutically acceptable solvents (including water); therefore, it is intended that the invention embrace both solvated and unsolvated forms.
• solvate refers to a molecular complex of a compound of the present invention (including pharmaceutically acceptable salts thereof) with one or more solvent molecules.
• solvent molecules are those commonly used in the pharmaceutical art, which are known to be innocuous to the recipient, e.g., water, ethanol, and the like.
• hydrate refers to the complex where the solvent molecule is water.
• the compounds of the present invention including salts, hydrates and solvates thereof, may inherently or by design form polymorphs.
• the compounds of the present invention in free form or in salt form, exhibit valuable pharmacological properties, e.g. as indicated in in vitro tests as provided herein, and are therefore indicated for therapy or for use as research chemicals, e.g. as tool compounds.
• embodiment 107 there is provided a compound according to any one of embodiments 1 to 106 for use in medicine.
• the compounds according to any one of embodiments 1 to 106 are potent inhibitors of ATX (see IC 50 data disclosed herein).
• the compound of the present invention are hence useful in the treatment of an ATX-dependent or ATX-mediated disease or condition.
• the compounds according to any one of embodiments 1 to 106 have favourable pharmacokinetic properties, particularly following oral administration, more particularly at higher doses.
• the compounds according to any one of embodiments 1 to 106 have particularly favourable solubility and absorption profiles.
• a compound according to any one of embodiments 1 to 106 for use in the treatment of an ATX-dependent or ATX-mediated disease or condition.
• a compound according to any one of embodiments 1 to 106 in the treatment of an ATX-dependent or ATX-mediated disease or condition.
• a compound according to any one of embodiments 1 to 106 in the manufacture of a medicament for the treatment of an ATX-dependent or ATX-mediated disease or condition.
• a method of treating an ATX-dependent or ATX-mediated disease or condition comprising administering to the subject a therapeutically effective amount of a compound according to any one of embodiments 1 to 106.
• the compounds of the invention are useful for the treatment of a disease or condition according to embodiments 108, 109, 110 and 111, wherein the disease or condition is selected from fibrosis, pruritus, cirrhosis, cancer, diabetes, kidney diseases, asthma, COPD and pain.
• the compounds of the invention are useful for the treatment of a disease or condition according to embodiment 112, wherein the disease or condition is selected from pulmonary fibrosis, idiopathic pulmonary fibrosis, a diffuse parenchymal interstitial lung disease including iatrogenic drug-induced fibrosis, occupational and/or environmental induced fibrosis (Farmer lung), radiation induced fibrosis, bleomycin induced pulmonary fibrosis, asbestos induced pulmonary fibrosis, acute respiratory distress syndrome (ARDS), kidney fibrosis, tubulointerstitium fibrosis, gut fibrosis, liver fibrosis, alcohol induced liver fibrosis, toxic/drug induced liver fibrosis, infection induced liver fibrosis, viral induced liver fibrosis, cutaneous fibrosis, spinal cord injury/fibrosis, myelofibrosis, renal fibrosis, skin fibrosis, ocular fibrosis, post-transplant fibros
• the compounds of the invention are useful for the treatment of a disease or condition according to embodiment 113, wherein the disease or condition is selected from idiopathic pulmonary fibrosis, breast cancer, pancreatic cancer, prostate cancer, cholestatic pruritus, primary biliary cirrhosis and polycystic kidney disease, particularly idiopathic pulmonary fibrosis.
• the compounds of the invention will be typically formulated as pharmaceutical compositions.
• the present invention provides a pharmaceutical composition
• a pharmaceutical composition comprising a compound according to any one of embodiments 1 to 106, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
• the pharmaceutical composition can be formulated for particular routes of administration such as oral administration, parenteral administration, and rectal administration, etc.
• the pharmaceutical compositions of the present invention can be made up in a solid form (including without limitation capsules, tablets, pills, granules, powders or suppositories), or in a liquid form (including without limitation solutions, suspensions or emulsions).
• the pharmaceutical compositions can be subjected to conventional pharmaceutical operations such as sterilization and/or can contain conventional inert diluents, lubricating agents, or buffering agents, as well as adjuvants, such as preservatives, stabilizers, wetting agents, emulsifers and buffers, etc.
• the pharmaceutical compositions are tablets or gelatin capsules comprising the active ingredient together with
• diluents e.g., lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine
• lubricants e.g., silica, talcum, stearic acid, its magnesium or calcium salt and/or polyethyleneglycol
• binders e.g., magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone
• disintegrants e.g., starches, agar, alginic acid or its sodium salt, or effervescent mixtures
• absorbents colorants, flavors and sweeteners.
• Tablets may be either film coated or enteric coated according to methods known in the art.
• compositions for oral administration include an effective amount of a compound of the present invention in the form of tablets, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsion, hard or soft capsules, or syrups or elixirs.
• Compositions intended for oral use are prepared according to any method known in the art for the manufacture of pharmaceutical compositions and such compositions can contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets may contain the active ingredient in admixture with nontoxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets.
• excipients are, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example, starch, gelatin or acacia; and lubricating agents, for example magnesium stearate, stearic acid or talc.
• the tablets are uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
• a time delay material such as glyceryl monostearate or glyceryl distearate can be employed.
• Formulations for oral use can be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example, peanut oil, liquid paraffin or olive oil.
• an inert solid diluent for example, calcium carbonate, calcium phosphate or kaolin
• water or an oil medium for example, peanut oil, liquid paraffin or olive oil.
• compositions are aqueous isotonic solutions or suspensions, and suppositories are advantageously prepared from fatty emulsions or suspensions.
• Said compositions may be sterilized and/or contain adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure and/or buffers. In addition, they may also contain other therapeutically valuable substances.
• Said compositions are prepared according to conventional mixing, granulating or coating methods, respectively, and contain about 0.1-75%, or contain about 1-50%, of the active ingredient.
• compositions for transdermal application include an effective amount of a compound of the invention with a suitable carrier.
• Carriers suitable for transdermal delivery include absorbable pharmacologically acceptable solvents to assist passage through the skin of the host.
• transdermal devices are in the form of a bandage comprising a backing member, a reservoir containing the compound optionally with carriers, optionally a rate controlling barrier to deliver the compound of the skin of the host at a controlled and predetermined rate over a prolonged period of time, and means to secure the device to the skin.
• compositions for topical application include aqueous solutions, suspensions, ointments, creams, gels or sprayable formulations, e.g., for delivery by aerosol or the like.
• topical delivery systems will in particular be appropriate for dermal application, e.g., for the treatment of skin cancer, e.g., for prophylactic use in sun creams, lotions, sprays and the like. They are thus particularly suited for use in topical, including cosmetic, formulations well-known in the art.
• Such may contain solubilizers, stabilizers, tonicity enhancing agents, buffers and preservatives.
• a topical application may also pertain to an inhalation or to an intranasal application. They may be conveniently delivered in the form of a dry powder (either alone, as a mixture, for example a dry blend with lactose, or a mixed component particle, for example with phospholipids) from a dry powder inhaler or an aerosol spray presentation from a pressurised container, pump, spray, atomizer or nebuliser, with or without the use of a suitable propellant.
• a dry powder either alone, as a mixture, for example a dry blend with lactose, or a mixed component particle, for example with phospholipids
• the inhalation device may be an aerosol vial provided with a valve adapted to deliver a metered dose, such as 10 to 100 ⁇ l, e.g. 25 to 50 ⁇ l, of the composition, i.e. a device known as a metered dose inhaler.
• a metered dose such as 10 to 100 ⁇ l, e.g. 25 to 50 ⁇ l
• Suitable such aerosol vials and procedures for containing within them aerosol compositions under pressure are well known to those skilled in the art of inhalation therapy.
• an aerosol composition may be administered from a coated can, for example as described in EP-A-0642992.
• the inhalation device may be a known nebulizer, for example a conventional pneumatic nebulizer such as an airjet nebulizer, or an ultrasonic nebulizer, which may contain, for example, from 1 to 50 ml, commonly 1 to 10 ml, of the dispersion; or a hand-held nebulizer, sometimes referred to as a soft mist or soft spray inhaler, for example an electronically controlled device such as an AERx (Aradigm, US) or Aerodose (Aerogen), or a mechanical device such as a RESPIMAT (Boehringer Ingelheim) nebulizer which allows much smaller nebulized volumes, e.g.
• a conventional pneumatic nebulizer such as an airjet nebulizer, or an ultrasonic nebulizer, which may contain, for example, from 1 to 50 ml, commonly 1 to 10 ml, of the dispersion
• a hand-held nebulizer sometimes
• the inhalation device may be, for example, a dry powder inhalation device adapted to deliver dry powder from a capsule or blister containing a dry powder comprising a dosage unit of (A) and/or (B) or a multidose dry powder inhalation (MDPI) device adapted to deliver, for example, 3-25 mg of dry powder comprising a dosage unit of (A) and/or (B) per actuation.
• the dry powder composition preferably contains a diluent or carrier, such as lactose, and a compound that helps to protect against product performance deterioration due to moisture e.g. magnesium stearate.
• Anhydrous pharmaceutical compositions and dosage forms of the invention can be prepared using anhydrous or low moisture containing ingredients and low moisture or low humidity conditions.
• An anhydrous pharmaceutical composition may be prepared and stored such that its anhydrous nature is maintained. Accordingly, anhydrous compositions are packaged using materials known to prevent exposure to water such that they can be included in suitable formulary kits. Examples of suitable packaging include, but are not limited to, hermetically sealed foils, plastics, unit dose containers (e.g., vials), blister packs, and strip packs.
• compositions and dosage forms that comprise one or more agents that reduce the rate by which the compound of the present invention as an active ingredient will decompose.
• agents which are referred to herein as “stabilizers,” include, but are not limited to, antioxidants such as ascorbic acid, pH buffers, or salt buffers, etc.
• the compound of the present invention may be administered either simultaneously with, or before or after, one or more other therapeutic agent.
• the compound of the present invention may be administered separately, by the same or different route of administration, or together in the same pharmaceutical composition as the other agents.
• the invention provides a product comprising a compound of the present invention and at least one other therapeutic agent as a combined preparation for simultaneous, separate or sequential use in therapy.
• the therapy is the treatment of a disease or condition mediated by blockade of the epithelial sodium channel.
• Products provided as a combined preparation include a composition comprising the compound of the present invention and the other therapeutic agent(s) together in the same pharmaceutical composition, or the compound of the present invention and the other therapeutic agent(s) in separate form, e.g. in the form of a kit.
• the invention provides a pharmaceutical composition
• a pharmaceutical composition comprising a compound according to any one of embodiments 1 to 106 and one or more therapeutically active co-agent.
• the pharmaceutical composition may comprise a pharmaceutically acceptable excipient, as described above.
• the invention provides a kit comprising two or more separate pharmaceutical compositions, at least one of which contains a compound of the present invention.
• the kit comprises means for separately retaining said compositions, such as a container, divided bottle, or divided foil packet.
• a container, divided bottle, or divided foil packet An example of such a kit is a blister pack, as typically used for the packaging of tablets, capsules and the like.
• the kit of the invention may be used for administering different dosage forms, for example, oral and parenteral, for administering the separate compositions at different dosage intervals, or for titrating the separate compositions against one another.
• the kit of the invention typically comprises directions for administration.
• a pharmaceutical combination comprising:
• a pharmaceutical combination according to embodiment 116, wherein the therapeutically active co-agent is selected from immunosuppresants, analgesics, anti-cancer agent, anti-inflammatories, chemokine receptor antagonists, bronchodilators, leukotriene receptor antagonists, leukotriene formation inhibitors, monoacylglycerol kinase inhibitors, phospholipase A1 inhibitors, phospholipase A2 inhibitors, lysophospholipase D (lysoPLD) inhibitors, decongestants, antihistamines, mucolytics, anticholinergics, antitussives, expectorants, and ⁇ -2 agonists.
• the therapeutically active co-agent is selected from immunosuppresants, analgesics, anti-cancer agent, anti-inflammatories, chemokine receptor antagonists, bronchodilators, leukotriene receptor antagonists, leukotriene formation inhibitors, monoacylg
• Suitable anti-inflammatory drugs include steroids, for example corticosteroids.
• Suitable steroids include budesonide, beclamethasone (e.g. dipropionate), butixocort (e.g. propionate), ciclesonide, ciclesonide, dexamethasone, flunisolide, fluticasone (e.g. propionate or furoate), methyl prednisolone, mometasone (e.g. furoate), prednisolone, rofleponide, and triamcinolone (e.g. acetonide).
• the steroid is long-acting corticosteroids such as budesonide, ciclesonide, fluticasone propionate, fluticasone furoate or mometasone furoate.
• Suitable ⁇ 2 -agonists include arformoterol (e.g. tartrate), abediterol, albuterol/salbutamol (e.g. racemate or single enantiomer such as the R-enantiomer, or salt thereof especially sulfate), bambuterol, bitolterol (e.g. mesylate), carmoterol, clenbuterol, etanterol, fenoterol (e.g. racemate or single enantiomer such as the R-enantiomer, or salt thereof especially hydrobromide), flerbuterol, arformoterol (e.g. tartrate), formoterol (e.g.
• arformoterol e.g. tartrate
• abediterol e.g. racemate or single enantiomer such as the R-enantiomer, or salt thereof especially sulfate
• bambuterol bitolterol (e.g. mesy
• racemate or single diastereomer such as the R,R-diastereomer, or salt thereof especially fumarate or fumarate dihydrate
• indacaterol e.g. racemate or single enantiomer such as the R-enantiomer, or salt thereof especially maleate, acetate or xinafoate
• metaproterenol milveterol (e.g. hydrochloride), naminterol, olodaterol (e.g. racemate or single enantiomer such as the R-enantiomer, or salt thereof especially hydrochloride)
• pirbuterol e.g. acetate
• procaterol reproterol
• salmefamol e.g.
• the ⁇ 2 -agonist is an ultra-long-acting ⁇ 2 -agonist such as indacaterol, or potentially carmoterol, milveterol, olodaterol, or vilanterol.
• one of the second active ingredients is indacaterol (i.e.
• a preferred salt of (R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-one is the maleate salt.
• Another preferred salt is (R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-one acetate.
• Another preferred salt is (R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-one xinafoate.
• Suitable bronchodilatory drugs include anticholinergic or antimuscarinic agents, such as aclidinium (e.g. bromide), BEA-2108 (e.g. bromide), BEA-2180 (e.g. bromide), CHF-5407, darifenacin (e.g. bromide), darotropium (e.g. bromide), glycopyrrolate (e.g. racemate or single enantiomer, or salt thereof especially bromide), dexpirronium (e.g. bromide), ipratropium (e.g. bromide), otilonium (e.g. bromide), oxitropium (e.g.
• aclidinium e.g. bromide
• BEA-2108 e.g. bromide
• BEA-2180 e.g. bromide
• CHF-5407 e.g. bromide
• darifenacin e.g. bromide
• the muscarinic antagonists is long-acting muscarinic antagonist such as darotropium bromide, glycopyrrolate or tiotropium bromide.
• Suitable dual anti-inflammatory and bronchodilatory drugs include dual beta-2 adrenoceptor agonist/muscarinic antagonists such as GSK-961081 (e.g. succinate) and AZD-2115.
• Suitable antihistamine drug substances include cetirizine hydrochloride, acetaminophen, clemastine fumarate, promethazine, loratidine, desloratidine, diphenhydramine and fexofenadine hydrochloride, activastine, astemizole, azelastine, ebastine, epinastine, mizolastine and tefenadine, as well as those disclosed in JP 2004107299, WO 03/099807 and WO 04/026841.
• Mass spectra were acquired on LC-MS, SFC-MS, or GC-MS systems using electrospray, chemical and electron impact ionization methods from a range of instruments of the following configurations: Agilent 1100 HPLC systems with an Agilent 6110 Mass Spectrometer, or Micromass Platform Mass Spectrometer or Thermo LTQ Mass Spectrometer; a Waters Acquity UPLC system with SQD Mass Spectrometer, a Waters FractionLynx HPLC system with 3100 Mass Spectrometer, a Waters UPC2 system with TQD Mass Spectrometer or a Waters Prep100 SFC-MS system with SQD2 Mass Spectrometer. [M+H]+ refers to protonated molecular ion of the chemical species.
• NMR spectra were run on Bruker AVANCE 400 MHz or 500 MHz NMR spectrometers using ICON-NMR, under TopSpin program control. Spectra were measured at 298K, unless indicated otherwise, and were referenced relative to the solvent resonance.
• organic compounds according to the preferred embodiments may exhibit the phenomenon of tautomerism.
• chemical structures within this specification can only represent one of the possible tautomeric forms, it should be understood that the compounds of the Examples encompasses any tautomeric form of the drawn structure.
• step 1 A solution of 3,5-dichlorobenzyl 4-(2-((tert-butoxycarbonyl)amino)ethyl)piperidine-1-carboxylate (step 1) (3.5 g, 8.11 mmol) in DMF (40 ml) was cooled to 0° C. 60% sodium hydride/oil (0.487 g, 12.17 mmol) was added. The solution was stirred at 0° C. for 15 mins and then was warmed to RT. Iodomethane (0.761 ml, 12.17 mmol) was added and the resulting mixture was stirred at room temperature for 5 hours. The reaction was quenched with ammonium chloride (20 ml).
• step 2 To a solution of 3,5-dichlorobenzyl 4-(2-((tert-butoxycarbonyl)(methyl)amino)ethyl)piperidine-1-carboxylate (step 2) (2.73 g, 6.13 mmol) in DCM (20 mL) was added trifluoroacetic acid (19 ml, 247 mmol). The reaction mixture was stirred at room temperature for 1 hour. The mixture was concentrated under pressure and the residue was suspended in sat. sodium bicarbonate solution (100 ml). The resultant mixture was extracted with EtOAc (2 ⁇ 100 ml). The organic portion was dried using MgSO 4 , filtered and concentrated under reduced pressure. The oil was applied to a 40 g silica cartridge in DCM and eluted with 0-20% MeOH/DCM containing 1% aqueous ammonia to afford the title compound;
• Step 4 3,5-Dichlorobenzyl 4-(2-(3-hydroxy-N-methylisoxazole-5-carboxamido) ethyl)piperidine-1-carboxylate
• Example 1, step 1 The title compound was prepared from 3,5-dichlorobenzyl 4-(2-(tert-butoxycarbonylamino) ethyl)piperidine-1-carboxylate (Example 1, step 1) analogously to Example 1, step 3;
• step 1 A mixture comprising (2-methylpiperidin-4-yl)methanamine (step 1) (1.123 g 8.76 mmol), di-t-butyl dicarbonate (2.237 ml, 9.63 mmol) and 4-dimethylaminopyridine (0.535 g, 4.38 mmol) in DCM (29.2 ml) was stirred at room temperature for 18 hours. The resulting mixture was diluted with DCM and washed with a minimal volume of water. The organic portion was dried over MgSO 4 , filtered and concentrated under reduced pressure to afford the title compound;
• step 2 A mixture comprising tert-butyl ((2-methylpiperidin-4-yl)methyl)carbamate (step 2) (1.15 g, 5.04 mmol) and 3,5-dichlorobenzyl carbonochloridate (1.327 g, 5.54 mmol) in DCM (15 ml) was treated with aq. saturated sodium bicarbonate (0.504 ml, 5.04 mmol) and stirred at room temperature for 18 hours. The organic portion was separated and the aqueous phase extracted with DCM (2 ⁇ 10 ml). The combined organic extracts were dried over MgSO 4 , filtered and concentrated under reduced pressure. Further purification by chromatography on silica, eluting in 0-20% 2M ammonia in MeOH in DCM afforded the title compound;
• step 3 A mixture comprising of 3,5-dichlorobenzyl 4-(((tert-butoxycarbonyl)amino)methyl)-2-methylpiperidine-1-carboxylate (step 3) (970 mg, 2.249 mmol) and trifluoroacetic acid (173 ⁇ l, 2.249 mmol) in DCM (7.5 ml) was left stirring at room temperature 18 hours. The resulting mixture was loaded on to a 10 g Isolute° SCX-2 cartridge and washed with MeOH. The product was eluted with 2M ammonia in MeOH and the product fractions were concentrated under reduced pressure to afford the title compound;
• Example 1 The title compound was prepared from 3,5-dichlorobenzyl 4-(2-methylamino)ethyl)piperidine-1-carboxylate (Example 1, step 3) and 5-methyl-2-oxo-2,3-dihydrooxazole-4-carboxylic acid analogously to Example 6;
• step 1 3,5-dichlorobenzyl 4-(tert-butoxycarbonylamino)piperidine-1-carboxylate (step 1)(5.3098 g, 13.17 mmol) in DCM (20 ml) was added 4M HCl in dioxane (33 ml, 132 mmol) and the mixture was stirred at RT for 2 hrs. The reaction mixture was concentrated under reduced pressure to afford the title product as hydrochloride salt;
• step 2 To a solution of urocanic acid (122 mg, 0.883 mmol) and 3,5-dichlorobenzyl 4-amino piperidine-1-carboxylate HCl salt (step 2) (300 mg, 0.883 mmol) in DCM (2 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (169 mg, 0.883 mmol) and N-methylmorpholine (0.291 mL, 2.65 mmol) and the mixture was stirred at RT for 3 h. The resulting mixture was diluted with EtOAc, washed with a saturated solution of sodium bicarbonate and brine.
• Step 2 6-((1-(((3,5-Dichlorobenzyl)oxy)carbonyl)piperidin-4-yl)amino)-6-oxohexanoic acid
• step 1 To a suspension of 3,5-dichlorobenzyl 4-(6-ethoxy-6-oxohexanamido)piperidine-1-carboxylate (step 1) (130 mg, 0.283 mmol) in THF (3 mL)/water (1 mL) was added LiOH.H 2 O (26.1 mg, 0.623 mmol) and the reaction mixture stirred at RT for 3 hrs. The resulting mixture was diluted with water and EtOAc and the aqueous portion acidified with 0.1 M HCl solution (pH 5-6). The resulting precipitate was collected by filtration and washed with water to afford the title product;
• step 1 A mixture comprising of 3,5-dichlorobenzyl 2-(2-((tert-butoxycarbonyl)amino)ethyl) morpholine-4-carboxylate (step 1)(500 mg, 1.154 mmol) and trifluoroacetic acid (3556 ⁇ l, 46.2 mmol) in DCM (3.8 ml) was stirred for 1 hour at room temperature. The resulting mixture was concentrated under reduced pressure and the crude product was diluted with EtOAc. The mixture was washed with sat. NaHCO 3 and the organic portion was separated, dried over MgSO 4 , filtered and concentrated under reduced pressure to afford the title compound;
• step 1 A mixture comprising of 3,5-dichlorobenzyl 2-(2-((tert-butoxycarbonyl)(methyl)amino) ethyl)morpholine-4-carboxylate (step 1) (0.9984 g, 2.232 mmol) and triflouroacetic acid (6.88 ml, 89 mmol) in DCM (7.44 ml) was stirred at room temperature for 1 hour. The reaction mixture was diluted with DCM (7.44 ml) and washed with water followed by sat NaHCO 3 . The organic portion was separated, dried over MgSO 4 , filtered and concentrated under reduced pressure to afford the title compound.
• Step 3 3,5-Dichlorobenzyl 2-(2-(N-methyl-2-oxo-2,3-dihydrooxazole-5-carboxamido)ethyl)morpholine-4-carboxylate
• step 2 A mixture comprising of 3,5-dichlorobenzyl 2-(2-(methylamino)ethyl)morpholine-4-carboxylate (step 2)(169 mg, 0.487 mmol), 2-oxo-2,3-dihydrooxazole-5-carboxylic acid ((Example 21, step 1)) (161 mg, 0.487 mmol), T3P® (50% in DMF) (426 ⁇ l, 0.730 mmol) and Huenig's base (425 ⁇ l, 2.433 mmol) in DMF (1622 ⁇ l) was stirred at room temperature for 20 hours. The resulting mixture was diluted with EtOAc and washed with water.
• Step 1 2-Methoxythiazole-5-carboxylic acid To a solution of tert-butyl 2-chlorothiazole-5-carboxylate (100 mg, 0.455 mmol) in MeCN (880 ⁇ l) and MeOH (880 ul) was added 5.4M NaOMe in MeOH (337 ⁇ l, 1.821 mmol) followed by 2M NaOH (881 ⁇ l, 1.762 mmol). The reaction mixture was heated to 80° C. overnight and, after cooling to RT, the mixture was evaporated under reduced pressure. The residue was acidified with a minimal volume of 6M aqueous hydrochloric acid. The resulting precipitate was filtered, washed with water and dried in a high vacuum oven overnight to afford the title compound;
• Step 2 2-Oxo-2,3-dihydrothiazole-5-carboxylic acid 2-Methoxythiazole-5-carboxylic acid (step 1)
• Step 3 3,5-Dichlorobenzyl 4-(2-(N-methyl-2-oxo-2,3-dihydrothiazole-5-carboxamido)ethyl)piperidine-1-carboxylate 2-Oxo-2,3-dihydrothiazole-5-carboxylic acid
• the resultant crude material was solubilised in minimal DCM and loaded on to a 1 g Isolute® SCX/PEAX cartridge pre-wetted with DCM and eluted with MeOH and the product fractions were evaporated under reduced pressure. Further purification was carried out using preparative LC-MS to afford the title compound together with a small amount of TFA. To remove the TFA, the mixture was dissolved in EtOAc and washed with water, dried over MgSO4 (anh), filtered and evaporated to yield an oil. The oil was dried in the high vacuum oven overnight to afford the title compound;
• Step 2 3,5-Dichlorobenzyl 4-aminopiperidine-1-carboxylate 3,5-Dichlorobenzyl 4-((tert-butoxycarbonyl)amino)piperidine-1-carboxylate (step 1)
• Step 3 4-(1-Benzyl-1H-1,2,3-triazol-4-yl)butanoic acid Benzyl azide
• Step 4 4-(1H-1,2,3-Triazol-4-yl)butanoic acid 4-(1-Benzyl-1H-1,2,3-triazol-4-yl)butanoic acid (step 3)
• Step 5 3,5-Dichlorobenzyl 4-(4-(1H-1,2,3-triazol-4-yl)butanamido)piperidine-1-carboxylate 4-(1H-1,2,3-Triazol-4-yl)butanoic acid (step 4)
• a magnetic stir bar and thermometer was put into a 500 mL round-bottomed flask.
• 4-(1H-1,2,3-triazol-4-yl)butanoic acid (10 g, 64.45 mmol) and 200 mL DCM were added and the whole degassed with three times with nitrogen.
• the suspension was stirred and cooled to 0-4° C. with an ice bath.
• Triethylamine 24.26 g, 241.69 mmol
• the solids in the suspension dissolved and a colorless solution was obtained.
• Diphenylphosphinic chloride (15.25 g, 64.45 mmol) in 15 mL DCM was added dropwise within 15 min and the temperature kept below 5° C.
• the water layer was separated off and the organic layer washed twice with 200 mL of saturated NaHCO 3 aqueous and 200 mL of water. The organic layer was then concentrated under vacuum to get a light yellow sticky oil.
• EtOAc 200 mL was added to dissolve the oil. The solution was heated to 60 ⁇ 5° C. and then cooled to 10 ⁇ 5° C. in 3 hours. The whole was filtrated to collect the solid. The solid was washed with 40 mL cooled EtOAc ( ⁇ 10° C.). The wet cake was dried under vacuum at 70 ⁇ 5° C. overnight (—16 hours) to get a white crystal as product (20.5 g).
• Step 1 3,5-Dichlorobenzyl 4-((tert-butoxycarbonyl)(methyl)amino)piperidine-1-carboxylate A solution of tert-butyl methyl(piperidin-4-yl)carbamate
• Step 2 3,5-Dichlorobenzyl 4-(methylamino)piperidine-1-carboxylate 3,5-Dichlorobenzyl 4-((tert-butoxycarbonyl)(methyl)amino)piperidine-1-carboxylate
• Step 3 3,5-Dichlorobenzyl 4-(N-methyl-4-(1H-1,2,3-triazol-4-yl)butanamido)piperidine-1-carboxylate 4-(1H-1,2,3-Triazol-4-yl)butanoic acid (Example 17, step 4)
• Step 2 3,5-dichlorobenzyl 4-(methylamino)piperidine-1-carboxylate (Step 2) (456 mg, 1.289 mmol) were dissolved in DMF (6 ml) and treated with DIPEA (1.126 ml, 6.45 mmol) followed by 50% T3P® in DMF (1.505 ml, 2.58 mmol). After stirring at RT for 9 days, the mixture was evaporated under reduced pressure. The crude product was solubilised in DCM and washed with 10% citric acid. The organic portion was passed through a phase separating cartridge and the filtrate was evaporated under reduced pressure. The crude residue was purified by chromatography on silica eluting with 0-10% MeOH in EtOAc to afford the title compound;
• Step 1 3-(1-Benzyl-1H-1,2,3-triazol-4-yl)propanoic acid Benzyl azide
• Step 2 3-(1H-1,2,3-Triazol-4-yl)propanoic acid 3-(1-Benzyl-1H-1,2,3-triazol-4-yl)propanoic acid (step 1)
• Step 3 3,5-Dichlorobenzyl 4-(3-(1H-1,2,3-triazol-4-yl)propanamido)piperidine-1-carboxylate 3-(1H-1,2,3-Triazol-4-yl)propanoic acid (step 2)
• Step 3 5-(1H-1,2,3-Triazol-4-yl)pentanoic acid 5-(1-(4-Methoxybenzyl)-1H-1,2,3-triazol-4-yl)pentanoic acid
• Step 4 3,5-Dichlorobenzyl 4-(5-(1H-1,2,3-triazol-4-yl)pentanamido)piperidine-1-carboxylate 5-(1H-1,2,3-Triazol-4-yl)pentanoic acid (step 3)
• Step 1 2-Oxo-2,3-dihydrooxazole-5-carboxylic acid Ethyl 2-chlorooxazole-5-carboxylate
• Step 2 tert-Butyl 4-(2-(2-oxo-2,3-dihydrooxazole-5-carboxamido)ethyl)piperidine-1-carboxylate
• Step 3 2-oxo-N-(2-(piperidin-4-yl)ethyl)-2,3-dihydrooxazole-5-carboxamide tert-Butyl 4-(2-(2-oxo-2,3-dihydrooxazole-5-carboxamido)ethyl)piperidine-1-carboxylate (step 2)
• Step 4 3,5-Dichlorobenzyl 4-(2-(2-oxo-2,3-dihydrooxazole-5-carboxamido)ethyl)piperidine-1-carboxylate 2-oxo-N-(2-(piperidin-4-yl)ethyl)-2,3-dihydrooxazole-5-carboxamide (step 3)
• Step 1 tert-Butyl 4-(2-(3-(3-hydroxyisoxazol-5-yl)propanamido)ethyl)piperidine-1-carboxylate
• Step 3 3,5-Dichlorobenzyl 4-(2-(3-(3-hydroxyisoxazol-5-yl)propanamido)ethyl)piperidine-1-carboxylate 3-(3-Hydroxyisoxazol-5-yl)-N-(2-(piperidin-4-yl)ethyl)propanamide (step 2)
• Example 1 The title compound was prepared from commercially available 5-hydroxy-1H-pyrazole-3-carboxylic acid and 3,5-dichlorobenzyl 4-(2-(methylamino)ethyl)piperidine-1-carboxylate (Example 1, step 3) analogously to Example 15 step 3;
• Step 2 3,5-Dichlorobenzyl piperazine-1-carboxylate1-tert-Butyl 4-(3,5-dichlorobenzyl) piperazine-1,4-dicarboxylate (step 1)
• Step 3 tert-Butyl methyl(3-oxopropyl)carbamate
• tert-butyl (3-hydroxypropyl)(methyl)carbamate (1.858 g, 9.82 mmol) was solubilised in DCM (40 ml) and treated with sodium bicarbonate (4.12 g, 49.1 mmol) followed by Dess-Martin reagent (5.21 g, 12.28 mmol). The reaction mixture was stirred at RT for 2 hrs and then partitioned between DCM and sodium bicarbonate solution. Sodium thiosulphate was added and the organic portion was separated. The aqueous layer was extracted with DCM ( ⁇ 2) and the combined organic extracts were dried over MgSO 4 (anh), filtered and evaporated under reduced pressure to afford the title compound without further purification;
• Step 4 3,5-Dichlorobenzyl 4-(3-((tert-butoxycarbonyl)(methyl)amino)propyl)piperazine-1-carboxylate tert-Butyl methyl(3-oxopropyl)carbamate (step 3)
• step 4 The title compound was prepared by acid hydrolysis of 3,5-dichlorobenzyl 4-(3-((tert-butoxycarbonyl)(methyl) amino)propyl)piperazine-1-carboxylate (step 4) analogously to step 2;
• Step 6 3,5-Dichlorobenzyl 4-(3-(N-methyl-2-oxo-2,3-dihydrooxazole-5-carboxamido)propyl)piperazine-1-carboxylate
• Example 21 step 1 The title compound was prepared from 2-oxo-2,3-dihydrooxazole-5-carboxylic acid (Example 21 step 1) and 3,5-dichlorobenzyl 4-(3-(methylamino)propyl)piperazine-1-carboxylate (step 5) analogously to Example 15 step 3;
• Step 1 3,5-Dichlorobenzyl 4-(2-((tert-butoxycarbonyl)amino)ethyl)piperazine-1-carboxylate 3,5-Dichlorobenzyl piperazine-1-carboxylate (Example 26, step 2)
• step 1 The title compound was prepared from 3,5-dichlorobenzyl 4-(2-((tert-butoxycarbonyl)amino) ethyl)piperazine-1-carboxylate (step 1) analogously to 3,5-dichlorobenzyl 4-(3-(methylamino) propyl) piperazine-1-carboxylate (Ex 26 step 5);
• Example 1 The title compound was prepared from commercially available 5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxylic acid and 3,5-dichlorobenzyl 4-(2-(methylamino)ethyl)piperidine-1-carboxylate (Example 1, step 3) analogously to Example 15 step 3;
• Example 1 step 3 The title compound was prepared from potassium 5-carboxytetrazol-1-ide and 3,5-dichlorobenzyl 4-(2-(methylamino)ethyl)piperidine-1-carboxylate (Example 1 step 3) analogously to Example 16;
• Step 3 (E)-tert-Butyl (2-(1-(3-(3,5-dichlorophenyl)acryloyl)piperidin-4-yl)ethyl)carbamate
• step 2 To (E)-3-(3,5-dichlorophenyl)acrylic acid (step 2) (1.365 g, 6.29 mmol) in NMP (12 ml) was added HATU (2.87 g, 7.55 mmol) and the mixture was stirred for 5 minutes at RT.
• HATU (2.87 g, 7.55 mmol)
• tert-Butyl (2-(piperidin-4-yl)ethyl)carbamate 1.36 g, 6.29 mmol
• DIPEA 3.30 ml, 18.87 mmol
• Step 4 (E)-1-(4-(2-Aminoethyl)piperidin-1-yl)-3-(3,5-dichlorophenyl)prop-2-en-1-one
• step 3 To (E)-tert-butyl (2-(1-(3-(3,5-dichlorophenyl)acryloyl)piperidin-4-yl)ethyl)carbamate (step 3) (400 mg, 0.936 mmol) in DCM (5 ml) was added TFA (0.865 ml, 11.23 mmol) and the mixture was stirred at RT for 1 h. The solvent was removed under reduced pressure and the crude material was dissolved in MeOH and loaded on to an Isolute° SCX-2 cartridge (10 g). The cartridge was washed with excess MeOH. The product was eluted using 2.0 M ammonia in MeOH and the solvent removed under reduced pressure to afford the title compound as a white solid;
• Step 5 (E)-3-(3,5-Dichlorophenyl)-1-(4-(2-(methylamino)ethyl)piperidin-1-yl)prop-2-en-1-one (E)-1-(4-(2-Aminoethyl)piperidin-1-yl)-3-(3,5-dichlorophenyl)prop-2-en-1-one (step 4)
• Step 6 2-Oxo-2,3-dihydrooxazole-5-carboxylic acid To a solution of ethyl 2-oxo-2,3-dihydrooxazole-5-carboxylate
• Step 7 (E)-N-(2-(1-(3-(3,5-Dichlorophenyl)acryloyl)piperidin-4-yl)ethyl)-N-methyl-2-oxo-2,3-dihydrooxazole-5-carboxamide
• step 5 To the mixture containing (E)-3-(3,5-dichlorophenyl)-1-(4-(2-(methylamino)ethyl)piperidin-1-yl)prop-2-en-1-one (step 5) (118 mg, 0.346 mmol) and 2-oxo-2,3-dihydrooxazole-5-carboxylic acid (step 7) (2.59 ml, 0.2M solution in DMF, 0.519 mmol) and DIPEA (0.483 ml, 2.77 mmol) in DMF (3.458 ml) was added T3P® (50% solution in EtOAc) (2.421 ml, 4.149 mmol). The reaction mixture was stirred at RT for 1 h.
• Step 1 tert-Butyl 4-((3-(3-hydroxyisoxazol-5-yl)propanamido)methyl)piperidine-1-carboxylate
• Step 2 3-(3-Hydroxyisoxazol-5-yl)-N-(piperidin-4-ylmethyl)propanamide To tert-butyl 4-((3-(3-hydroxyisoxazol-5-yl)propanamido)methyl)piperidine-1-carboxylate (step 1)
• step 2 3-(3-hydroxyisoxazol-5-yl)-N-(piperidin-4-ylmethyl)propanamide (step 2) (200 mg, 0.690 mmol) in DCM (7 ml) was added 2M NaOH solution (6.90 ml, 13.80 mmol) and the mixture stirred vigorously at RT for 16 hrs. The mixture was diluted with EtOAc (50 ml) and acidified with 2M HCl. The organics were dried (MgSO 4 ) and concentrated under reduced pressure. The residue was dissolved in MeOH/EtOAc and dry loaded onto silica (10 g).
• Step 2 3,5-Dichlorobenzyl 4-(3-aminopropyl)piperazine-1-carboxylate To 3,5-dichlorobenzyl 4-(3-(tert-butoxycarbonylamino)propyl)piperazine-1-carboxylate (step 1)
• Step 3 3,5-Dichlorobenzyl 4-(3-(1H-1,2,3-triazole-4-carboxamido)propyl)piperazine-1-carboxylate To 1H-1,2,3-triazole-4-carboxylic acid
• Example 1 The title compound was prepared analogously to Example 34, step 3 from 1H-1,2,3-triazole-4-carboxylic acid and 3,5-dichlorobenzyl 4-(2-(methylamino)ethyl)piperidine-1-carboxylate (Example 1, step 3) (200 mg, 0.579 mmol);
• Step 1 tert-Butyl 4-(2-(methylamino)ethyl)piperidine-1-carboxylate
• Step 2 tert-Butyl 4-(2-aminoethyl)piperidine-1-carboxylate
• Step 2 tert-Butyl 4-(2-(N-methyl-1H-1,2,3-triazole-4-carboxamido)ethyl)piperidine-1-carboxylate To 1H-1,2,3-triazole-4-carboxylic acid
• step 1 (150 mg, 1.327 mmol) and tert-butyl 4-(2-(methylamino)ethyl)piperidine-1-carboxylate (step 1) (322 mg, 1.327 mmol) in DMF (6 ml) was added DIPEA (0.695 ml, 3.98 mmol) and 50% T3P® in DMF (1.549 ml, 2.65 mmol). The resulting orange solution was stirred for 4 hrs. The mixture was diluted with EtOAc (200 ml) and washed with 1M HCl (2 ⁇ 50 ml). The organics were dried (MgSO 4 ) and concentrated under reduced pressure.
• Step 3 N-Methyl-N-(2-(piperidin-4-yl)ethyl)-1H-1,2,3-triazole-4-carboxamide To tert-butyl 4-(2-(N-methyl-1H-1,2,3-triazole-4-carboxamido)ethyl)piperidine-1-carboxylate (step 2)
• Step 4 3-Chloro-5-cyanobenzyl carbonochloridate 3-Chloro-5-(hydroxymethyl) benzonitrile
• Step 5 3-Chloro-5-cyanobenzyl 4-(2-(N-methyl-1H-1,2,3-triazole-4-carboxamido)ethyl) piperidine-1-carboxylate
• step 4 To 3-chloro-5-cyanobenzyl carbonochloridate (step 4) (65.5 mg, 0.285 mmol) and N-methyl-N-(2-(piperidin-4-yl)ethyl)-1H-1,2,3-triazole-4-carboxamide (step 3) (78 mg, 0.285 mmol) in DCM (5 mL) was added saturated aqueous sodium bicarbonate solution (5 mL, 0.285 mmol), and the mixture stirred vigorously for 16 hrs. The resulting mixture was acidified with 10% citric acid solution and the organic portion was separated, dried (MgSO 4 ) and concentrated under reduced pressure.
• Step 1 3-Chloro-5-fluorobenzyl 2,5-dioxopyrrolidin-1-yl carbonate
• Step 3 4-(1-((Pivaloyloxy)methyl)-1H-1,2,3-triazol-4-yl)butanoic acid
• Step 4 tert-Butyl 4-(4-(1-((pivaloyloxy)methyl)-1H-1,2,3-triazol-4-yl)butanamido)piperidine-1-carboxylate
• Step 6 3-Chloro-5-fluorobenzyl 4-(4-(1-((pivaloyloxy)methyl)-1H-1,2,3-triazol-4-yl)butanamido)piperidine-1-carboxylate
• step 5 To a stirred suspension of (4-(4-oxo-4-(piperidin-4-ylamino)butyl)-1H-1,2,3-triazol-1-yl)methyl pivalate (step 5) (150 mg, 0.387 mmol) and 3-chloro-5-fluorobenzyl 2,5-dioxopyrrolidin-1-yl carbonate (117 mg, 0.387 mmol) in DCM (5 mL) was added NaOH (1.547 mL, 1.547 mmol) with stirring at RT and the mixture was stirred at RT for 18 hrs. A further 5 ml DCM was added followed by 1M NaOH (1 ml). The reaction mixture was diluted with DCM (30 ml) and the organic portion was dried over MgSO 4 , filtered and concentrated under reduced pressure to afford the title product;
• Step 7 3-Chloro-5-fluorobenzyl 4-(4-(1H-1,2,3-triazol-4-yl)butanamido)piperidine-1-carboxylate
• Step 1 (E)-(4-(4-((1-(3-(3,5-Dichlorophenyl)acryloyl)piperidin-4-yl)amino)-4-oxobutyl)-1H-1,2,3-triazol-1-yl)methyl pivalate
• Step 2 (E)-N-(1-(3-(3,5-Dichlorophenyl)acryloyl)piperidin-4-yl)-4-(1H-1,2,3-triazol-4-yl)butanamide
• Step 2 (E)-(4-(4-((1-(3-(2,4-Dichlorophenyl)acryloyl)piperidin-4-yl)amino)-4-oxobutyl)-1H-1,2,3-triazol-1-yl)methyl pivalate
• Example 37 The title compound was prepared from (4-(4-oxo-4-(piperidin-4-ylamino)butyl)-1H-1,2,3-triazol-1-yl)methyl pivalate (Example 37, step 5) (200 mg, 0.516 mmol) and (E)-3-(2,4-dichlorophenyl)acrylic acid (step 1) analogously to Example 38 step 1.
• Step 3 (E)-N-(1-(3-(2,4-Dichlorophenyl)acryloyl)piperidin-4-yl)-4-(1H-1,2,3-triazol-4-yl)butanamide
• reaction mixture comprising tert-butyl (piperidin-4-ylmethyl)carbamate (1 g, 4.67 mmol), 3,5-dichlorobenzyl carbonochloridate, (1.117 g, 4.67 mmol) and sodium bicarbonate (15 mL, 4.67 mmol) in DCM (15.55 mL) was stirred at room temperature for 18 hours.
• the reaction mixture was separated and the organic portion was dried over MgSO 4 , filtered and solvent concentrated under reduced pressure to give the title compound as a yellow oil;
• Example 37 The title compound was prepared from (4-(4-oxo-4-(piperidin-4-ylamino)butyl)-1H-1,2,3-triazol-1-yl)methyl pivalate (Example 37, step 5) (200 mg, 0.516 mmol) and commercially available 3-(2,4-dichlorophenyl)propanoic acid (Fisher) (113 mg, 0.516 mmol) analogously to Example 38, steps 1 and 2;
• Step 1 3-Chloro-5-cyanobenzyl carbonochloridate To a stirred yellow solution of 3-chloro-5-(hydroxymethylbenzonitrile
• Step 2 3-Chloro-5-cyanobenzyl 4-(4-(1-((pivaloyloxy)methyl)-1H-1,2,3-triazol-4-yl)butanamido)piperidine-1-carboxylate
• Step 1 tert-Butyl 3-(4-(1H-1,2,3-triazol-4-yl)butanamido)-8-azabicyclo[3.2.1]octane-8-carboxylate
• a reaction mixture comprising of tert-butyl 3-amino-8-azabicyclo[3.2.1]octane-8-carboxylate (commercial supplier Fluorochem, 250 mg, 1.105 mmol), 4-(1H-1,2,3-triazol-4-yl)butanoic acid (Example 17, step 4) (171 mg, 1.105 mmol), T3P® 50% DMF (1.29 ml, 2.209 mmol) and TEA (462 ⁇ l, 3.31 mmol) in DMF (3.6 ml) was stirred for 4 hours. The reaction mixture was concentrated under reduced pressure. The resulting oil was diluted with DCM and washed with water. The organic portion was dried over MgSO 4 , filtered and concentrated under reduced pressure. The material was taken crude to the next step.
• Step 2 N-(8-Azabicyclo[3.2.1]octan-3-yl)-4-(1H-1,2,3-triazol-4-yl)butanamide
• a reaction mixture comprising of tert-butyl 3-(4-(1H-1,2,3-triazol-4-yl)butanamido)-8-azabicyclo[3.2.1]octane-8-carboxylate (401 mg, 1.103 mmol) in dioxane (5 ml) was treated with 4M HCl in dioxane (0.827 ml, 3.31 mmol) and stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure to afford the title compound. The material was taken on to the next step without further purification.
• a reaction mixture comprising of N-(8-azabicyclo[3.2.1]octan-3-yl)-4-(1H-1,2,3-triazol-4-yl)butanamide (294 mg, 1.116 mmol), 3,5-dichlorobenzyl carbonochloridate (267 mg, 1.116 mmol) and sodium hydroxide (5.58 ml, 112 mmol) in DCM (3.7 ml) was stirred at room temperature for 18 hours. The reaction mixture was separated and the organic portion was dried over MgSO 4 , filtered and concentrated under reduced pressure. Further purification was carried out using preparative LC-MS and the resulting product fractions were concentrated under reduced pressure to give aqueous solutions which were extracted with ethyl acetate. The organic extracts were dried over MgSO 4 , filtered and concentrated under reduced pressure to afford the title compound.
• Example 17 The title compound was prepared from 4-(1H-1,2,3-triazol-4-yl)butanoic acid (Example 17, Step 4) and tert-butyl 4-aminoazepane-1-carboxylate analogously to Example 45 step 3;
• Step 1 tert-Butyl 3-((((3,5-dichlorobenzyl)oxy)carbonyl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate
• a reaction mixture comprising of tert-butyl 3-amino-8-azabicyclo[3.2.1]octane-8-carboxylate (210 mg, 0.928 mmol), 3,5-dichlorobenzyl carbonochloridate (222 mg, 0.928 mmol), and sodium hydroxide (4.64 ml, 93 mmol) in DCM (3.1 ml) was stirred at room temperature for 4 hours. The reaction mixture separated and the organic portion dried over MgSO 4 , filtered and concentrated under reduced pressure. No further purification was carried out and the material was taken on crude to the next step.
• a reaction mixture comprising of tert-butyl 3-((((3,5-dichlorobenzyl)oxy)carbonyl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate (388.3 mg, 0.904 mmol) in dioxane (5 mL) was treated with 4M HCl in dioxane (0.678 mL, 2.71 mmol) and stirred at room temperature for 3 hours. The resulting mixture concentrated under reduced pressure. No further purification was carried out and the material was taken on crude to the next step.
• a reaction mixture comprising 3,5-dichlorobenzyl 8-azabicyclo[3.2.1]octan-3-ylcarbamate hydrochloride (118 mg, 0.322 mmol), 4-(1H-1,2,3-triazol-4-yl)butanoic acid (Example 17, step 4) (50 mg, 0.322 mmol), TEA (135 ⁇ l, 0.967 mmol) and T3P® (376 ⁇ l, 0.645 mmol) in DMF (1.0 ml) was stirred at room temperature overnight. The reaction mixture was diluted with water and extracted with DCM. The organic portion was concentrated under reduced pressure.

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