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    US9428498B2

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    2) United States Patent Espensen et al. oy SUBSTITUTED IMIDAZO[4.5-C)PYRIDINE COMPOUNDS AND COMPOSITIONS ‘THEREOF (71) Applicant: Proximagen Limited, London (GB) (72) Inventors: Max Espensen, London (GB): Lee Patient, London (GIB), David Evans, London (GB); Edward Savory, London (GB: Tain Simpson, London (GB) (73) Assignee: Proximagen Limited, London (GB) (4) Notice: Subjoct to any disclaimer the term of this patent is extended or adjusted under 35 USC. 154(6) by 190 days (21) Appl. Now 147208056 (22) Filed: Mar. 13, 2014 ws) Prior Publication Data 201410275050. A1 Sep. 18, 2014 G0) Foreign Application Priority Data Mat. 13,2013 (GB) 1304526.5 (1) Incl Coz 47102 corp s1s02 AGIK 31/84 corp #7108 (2006.01) (2006.01) (2005.01) (2005.01) (2) Us.cL coc C07 47174 (2013.01) (58) Fleld of Classitication Search cre CO7D 471/04; AIK 31/40 spc 546/112, 118, application file For comple 373: 514926, 927 search history Se (56) References Cited USS. PATENT DOCUMENTS. 71405300 B2* 72008 Jiang ea swa7 20080084631 AL 3/2008 Tang tal. PORFIGN PATENT DOCUMENTS wo oDseiss AL 52002 wo ekiooson3 AL 13008 'US009428498B2 US 9,428,498 B2 Aug. 30, 2016 (10) Patent No.: (4s) Date of Patent: wo 200s18530 a2 22005 Wo 3007120828 42102007 wo aoionsiond AL 62010, wo 2OISOSAI AL 32013 wo Soramsiso AL 32013 WO 21440592 AL 92014 (OTHER PUBLICATIONS Search Report from Great Brittn Patent Application 1304526.5 fot Mar 13,2013 Intemational ‘Search Report, mailed on May 8, 2014, for PCT GB201409076 filed on Mar. 3, 2014 Database Regist [online], Chena Abstracts Service, Columbus, Ohio, US. Jan 19, 2011. X002725294, database accession No Melioayan, Ferdimad S, el “One-pot synthesis of substi Inoles va taniuntv) alkoxide mediated imine Formation cop peratalyved N-zylation” RSC Advance, vo. 3 No. 22, Mar 21 BOIS, p. S388, XPUSSIE ‘Wilson, Rober J. etal. "Copper and Palladium: Catalyzed Amide tion Resetons for the Sjmtesis of Substituted. lmida7o[4.s lyrines" The Journal of Organic Chemisty ol. 79. No, Fb, ‘2014, pp 2200-2913, XPOSSII3S08 Dunks, Peta etal “Semivaracie-sensitive amine oxidsevas: salar adhesion protin-' a patent survey” Exper Opin Tae Patent 2109) MS61471 C2011). * cited by examiner Primary Esaminer — Andrew D Kosar Assistant Examiner — Rayimond Covington (74) Atwornes, Agent, or Firm — Sean Upsher-Smith Laboratories, Ine. B, Mahoney ABs RACT The present invention relates 10. compounds which sre inhibitors of SSAO activity: The invention also relates 10 ‘phamiaceuteal compositions comprising these compounds fd to the use of these compounds in the twatmeat or prevention of medical conditions wherein inhibition of SSAO activity is beneficial, such as inflammatory diseases, ‘immune disorders and the iibition of tumor growth 16 Claims, No Drawings US 9,428,498 B2 1 SUBSTITUTED IMIDAZO|4.5-C/PYRIDINE, COMPOUNDS AND COMPOSITIONS. THEREOF ‘This application claims priority under 35 USCC, 119 10 Great Britin Patent Application No. 1304526., filed Mar 13, 2013, which is incorporated herein by reference in its entirety FIELD OF THE INVENTION The present invention relates to compounds which are inhibitors of SSAO activity. The invention also relates 10 pharmaceutical compenitions comprising these compounds find to the use of these compounds in the treatment oF prevention of modical conditions wherein inhibition of AO activity is beneficial, such as inflammatory diseases, Jmmine disorders and the inhibition of tumour grovth, BACKGROUND ART Semicarbazide-senstive amine oxidase (SSAO) activity js an enzyme activity expressed by Vascular Adhesior Protein-l (VAP-1) or Amine Oxidase, Copper Containing 3 (ACS), belongs to the eopper-contaning amine oxidase Jaily of enzymes (EC.14.3.6) Therefore inhibitors of the SSAO enzyme nay also modulate the biological funetons ‘of the VAP-I protein. Members ofthis enzyme family are sensitive to inhibition by semicarbazide and utilize cupric jon and proteinlerived topa quinone (TPQ) cofactor in the ‘oxidative deamination of primary amines to aldehydes, hydrogen peroxide, and ammonia according tothe fllowing reaction: ‘Known substrates for human SSAO include endogenous methylamine and aminoacetone as well as some xenobiotic amines such as benzylamine [Lyles, In, J. Biochem. Cell Biol, 1996, 28, 259-274; Klinman, Biochim, Biophys. Acta 2003, 1647(1-2), 131-137; Matus eta, Curr. Med. Chem. 1(10), 1285-1298; O'Sullivan etal, Neworoxicology 2008, 25(1-2), 303-315}. In analogy with other copper containing amine oxidases, DNA-sequeace analysis and structure determination sugges hat the tssue-bound human SSAO is a homodimeric glycoprotein consisting of Wo 90-100 kDa subunits anchored tothe plasma membrane hy ‘single N-terminal membrane spanning domain [Morris et al, J. Biol. Chem. 1997, 272, 9388-9392; Smith et a. J Exp. Med. 1998, 188, 17-27; Airenne et a, Protein Science 2005, 14, 1964-1974; Jakobsson etal, Acta Crystallogr D Biol. Crstallog. 2005, 61(Pt 1), 1550-1562] SAO activity has been found in 2 variety of tissues including vascular and non-vaseular smooth muscle tissue, ‘endothelium, and adipose tissue Lewinsohn, Braz. J. Med. Biol. Res. 1984, 17, 223-256; Nakos & Gosseau, Folia Histochem. Cytobiol. 1994, 32, 3-10; Yu et al, Biochem. Pharmacol. 1994, 47, 1058-1059; Casilo et al, Newro- ‘chem. Int. 1998, 33, 415-423; Lyles & Pino, J Neural, Transm. Suppl. 1998, 52, 289-250; Jaakkola et al rm J Pathol. 1999, 155, 1953-1965; Morin etal, J. Pharmacol Exp. Ther, 2001, 297, 563-572; Salmi & Talkanen, Trends Immunol. 2001, 22, 211-216]. In addition, SSAO protein is ‘ound in blood pasa and this soluble form appears to have similar properties as the tissue-bound form [Ye et al Biochem. Pharmacol. 1994, 47, 1085-1089; Kurkijirvi et lJ. Immunol. 998, 161, 1549-1857]. It has recently been shown that eieulating human and rodent SSO originates NilsO,-2R-CHOL OWN, 0 o 2 {rom the tisue-bound form [Gikirk et al, Am. J. Pathol 2003, 163(5), 1921-1928; Abella et al. Diabetologia 2004 47(3), 429-438; Stolen etl, Cire, Res, 2004, 95(1), 50-57], ‘whereas in other mammals the plasmalserum SSAO is also encovled by a separate gene called AOC [Sehwelberger, J Neural. Transm. 2001, 114(6), 757-162}. The precise physiological role of this abundant enzyme daa yet to be filly determined, but it appears that SSAO and its reaction products may have several functions in cell signalling and regulation. For example, recent findings sug- ast that SSAO plays a role in both GLUTS-mediated tlucose uplake [Enrigue-Tarancoa et al, J. Biol. Che 1998, 273, 8025-8032; Morin et al, J. Pharmacol. Exp. Ther’ 2001, 297, 563-572] and adipocyte differentiation [Fontana etal, Biochem, J 2001, 356, 769-777; Mercice ot Al, Biochem. J 2001, 358, 95-342). In addition, SSAO has ’been shown to be involved in inflammatory processes where it acts as an adhesion protein for leukeytes [Salmi & Jlkanen, Trends Immunol. 2001, 22, 211-216; Salmi & Talkanen, in “udhesion Molecules: Functions and Inhibit tion” K. Ley (Pa), 2007, pp. 237-281), and might also play ‘role in connective tise matrix developmeat and mainte- nance [Langfond et al., Cardiovase. Taxicol. 2002, 202), 141-150; GoktORK et al, dm J. Pathol. 2003, 163(5), 1921-1928]. Moreover, # link between SSAO and angio- szeness bs recently been discovered [Noda eal, FASEB. 2008, 22(8), 2928-2935], and based on this Tink it is ‘expected that inhibitors of SSAO have aa. anti-angiogenic fect. Several studies in hnmans have demonstrated that SSAO_ activity in blood plasma is elevated in conditions sich as ‘congestive heart filure, diabetes mellitus, Alzheimer’s di case, and inflammation (Lewinsohn, Braz. J. Med. Bio. Res. 1984, 17, 228-256, Boomsma etal, Cardiovase. Res. 1997, 33, 387-301; Fkblom, Pharmacol, Res. 1998, 37, 87-02: Kurkijirvi et al, "Immunol, 1998, 161,” 1549-1557; Boomsms et al, Diabetologia 1999, 42, 233-287: Meszaros etal, Fur J. Drug Metab. Pharmacokinet. 1999, 24, 299- 302; Yu et al, Biochim. Biophys. Acta 2003, 1641-2) 193-199 Matyus et al, Cur Med. Chem, 2004, 11(10), 1288-1208; O'Sullivan etal, Newotoxicology 2004, 25( 2), 303315; del Mar Hemandez ata, Newrose. Let 2005, 384(1-2), 183-187]. The mechanisms underiying these alterations of enzyme activity are not clear It has been suggested thut reactive aldehydes and hydrogen peroxide produced by endogenous amine oxidases coatebute to the Progression of eardiovascular diseases, diabetic eomplica- tions and Alzheimer's disease [Callingham et al, Prog. Brain Res. 1995, 106, 308-321; Ekblom, Pharmacol. Res. 1998, 37, 87-92: Yu et al, Biochim. Biophys. Acta 2008, 1647(1-2}, 193-199, Jiang at al, Newopathol App! Nero- biol. 2008, 34(2), 194-208]. Furthermore, the enzymatic ‘activity of SSAO is volved in the leukocyte extravasation process at sites of inflammation where SSAO has been shown tobe strongly expressed on the vascular endothelinm [Salmi et al, Immunity 2001, 14(3), 268-276; Salmi & Talkanen, in “sdkesion Molecules: Functions and Inhibi tion” K. Ley (Ed.), 2007, pp. 237-251]. Accordingly, inhi- bition of SSAO has been suggested to have a therapeutic value in the prevention of diabetic complications and in inflammatory diseases [Ekblom, Pharmacol. Res. 1998, 37, £87.92; Salmi otal, Jnmunity 2001, 14(3), 265-276; Sater Cid etal, J Pharmacol. Exp. Ther 2008, 315(2), 953-562] 'SSAO kknockout animals are phenotypically overtly nor- smal but exhibit a marked deerease in the inflammatory responses evoked in response to various inflammatory stimuli [Stolen et al, munity 2005, 22(1), 105-115}. US 9,428,498 B2 3 ‘addition, antagonism of ts Fonction in wildtype animals i ‘multiple imal models of human disease (eg. carrageenan- Induced paw inflammation, oxazolone-induced colitis, Fipopolysaecharide-induced lung inflammation, collagen-in- ‘duced arthritis, endotoxin-induced uveitis) by the use of fntibodies andar small molecules has been shown to be protective in dereasing the leukoey'e inflation, reducing the severity ofthe disease phenotype and redoing levels of inflammatory eytoknes and chemokines [Kirton etal, Bur J. Immurol. 2008, 38(11), 3119-3130, Salter Cid et a J ‘Pharmacol. Exp. Ther 2005, 315(2), 353-562; McDonald et ‘a, Annual Report in Medicinal Chemistry 2007, 42, 229- 243; Salmi & Jalkanen, in “Adhesion Molecules: Functions ‘and Inhibition” K. Ley (Ea, 2007, pp. 237-251; Noda etal FASEB J. 2008 22(4), 1084-1103; Noda at al, FASEB J. 2008, 22(8), 29282935]. This ant-inflammatory protecti ‘scoms to be afforded across a wide range of inflammatory ‘models all with independent causative mechanisms, rather than being restricted to one particular disease or disease ‘model, This would suggest that SSAO may be a key nodal Point forthe regulation ofthe inflammatory response, and it Js therefore likely that SSAO inhibitors will be effective inflammatory drugs in a wide range of human diseases. VAP-1 has also been implicated in the progression and maintenance of fibrotic diseases inclnding those of the liver ‘and lung, Weston and Adams (J Neural Transm. 2011, 118(7), 1055-64) have summarised the experimental data implicating VAP-1 in liver fbgosis, and Weston at al (EASL Poster 2010) reported that blockade of VAP-1 accelerated the resolution of carbon tetrachloride induced fibrosis. Ia adition VAP-1 has been implicated in inflammation of the Jung (e. Singh etal, 2008, Virehows Arch 442:491-495) suggesting that VAP-I blockers woud reduce ung inflam mation and this be of benefit to the treatment of eystic fibrosis by treating both the pro-ibrotic and pro-inflammae tory aspects of the disease ‘SSAO (VAP-1) is up regulated in gastric cancer and has boon identified in the tamour vasculanre of human mela- roma, hepatoma and head and neck tumours (Yoong K F, MeNab G, Hubscher 8 G, Adams D H. (1998), J Imasunol 160, 3978-88; Inala II, Salmi M, Alanen K, Gréaman R, Jalkanen S (2001), Immunol. 166, 8937-6943; Forster-Hor= vath C, Dome B, Paku Set al- 2008), Melanoma Res. 14 135-40. One report (Mtilatehibara F, Castermans K. Auvinen K. Oude Fgbrink M G, Jalkanen 8, Grilfoen AW. Salmi M. 2010), J Tramnool, 184, 3168-3173.) has shown that mice bearing enzymically inetive VAP-1 grow mela- rnomas more slowly, and have reduced tumour blood vessel number and diameter. The reduced growth of these tumours ‘was also reflected i the reduced (by 60-70%) infiltration of miyeloid suppressor cells. Encouragingly VAP-1 deficiency had ne effect on vessel oc Iymph formation in normal tissue ‘Small molecules of different structural classes have pre- viously been disclosed as SSAO inhibitors for example in WO 0238153 (cimbhydroimidaro[4.S-c}pyridine deriva- tives), in WO 037006008 (2-indanylhydrazine derivatives) Jn WO 2005/014530 (allylhydrazine and hydroxylamine {aminooxy) compounds) and in WO 2007/120528 (ally- Jamino compounds). Additional SSAO inhibitors are dis- ‘losed in. PCT/EP2009/062011 and PCT/EP2009°062018. ‘Additional SSAO inhibitors are disclosed in PCT/GB2012) 052265, “The invention described here relates to a new class of SSAO inhibitors with biological, pharmacological, and pharmacokinetic characteristics that make them suitable for tse as prophylactic or therapeutic agents in a wide range of human inflammatory diseases and immune disorders. This 0 o 4 therapeutic capacity is designed to block SSAO_enz action, reducing the levels of pvo-inllammatory enzyme products (aldehydes, hydrogen peroxide and ammonia) ‘whilst also decreasing the adhesive capacity of immune cells ‘and comespondingly their eetivation and final exte-vass- tion, Diseases where sch an activity is expectad w be therapeutically beneficial include all diseases where immune cals play a prominent role in the inition, maintenance or resolttion af the pathology, such as multiple sclerosis, anti and vascuis DETAILED DESCRIPTION OF THE. INVENTION It has surprisingly been found that dhe compounds of {formula (l below are inhibitors of SSAO. They re therefore useful for the tectment or prevention of diseases in whieh inhibition of SSAO etvity is beneficial, such as inflamima- ‘ion, inflammatory diseases, immune or autoimmune disor ers, and inhibition of tumour growth, “According othe invention there is provided a compound of formula (1) oF a pharmaceutically acceptable sat, or Neoxide therwok Wherein ‘Y is selected from hydrogen, hydroxyl, NE, Cy-galkyl, —NEhalo-C, alkyl, of Cy alkoxy 7Zis selected from hydropen, halogen, hydroxyl, eyano, Cygallyl, halo-C, allyl, Cealkoxy, halo-C; alkoxy, ‘CONH,, —SO.NH,, "NH, NHC, yalkyl, or —Nithale-C, ally: isa phenyl ring, or a5 or :membered heteroary ring, cither ring being optionally substituted with one oF more substiuents selected Irom halogen, cyano, C, alkyl, halo Cy, galls] eyano-C;, alkyl, —OR™, NR“ NRC (OPOR’, “NRECOMRS, —NR'CONR™R*, —C(O) RR, —C(ORS, C(OVOR', and) —NR°S(O).R" wherein RM, RRS and R® are ench independently selected from hydrogen, C, alkyl o halo-C, alkyl oF Rand R together with th nitrogen to which they are attached form a 3-7 membered eye amino group, option- ally substiuted by one or more substituents selected from: halogen, hydroxyl, cyano, C-alkyl, halo-C, alkyl, Cy alkoxy, halo-C;, alkoxy, CONE, —SO;NH, Ni NHC, ealkyl,—-NHbalo-Cy, all, X is selected from —N— of —C(R?)— RR’ is selected from hydrogen, halogen, eyano, C, «alkyl, NEL halo-C, ali, eyano-Cy cally, OR’, NR“R™, NR'GO}OR™, NRC", —NRICONRR™, CONR™ RY, COR’, “_COVOR', —SO.R", SO.NR™R°? and —NR°S(O).R*: ‘Wis. phenyl ring ora 5 or 6-membered heteroaryl ring, cither ring being optionally substituted with one or more substituents selected from halogen, cyano, C,_ralkyl halo Calley, eyano-C;, alkyl, ORS, —NR™*R”®, —-NRIC (POR®,“NRECOIR', “_NRFCONR™R®, —C(O) US 9,428,498 B2 5 NRUR™, COR’, —C(OVOR, SO_NR”R”* and —NR'S(O),R Rand R are independently hydrogen, C, «alkyl or hale, alkyl. NR, SOR, Vig seleciod from a bond, —O. —(C=0)—, —CONR", NR"C(O)—, of —C, aly” lene, wherein the C, alkylene group is optionally subs tuted by halogen, and wherein any one ofthe earbon stoms of the C, alkylene group may be replaced by —O— oF NR) ’ ishydrogen ora 3-7 membered hetereyelic rng oF 3-7 membered cycloalkyl ring. or aS or Gemiembered heteroaryl ring, any one of the rings being optionally substituted with fone or more substituents selected from halogen, oxo, hydroxyl, eyano, C, alkyl, halo-C, alkyl, eyano-Cy 4° alkyl, OR", —NR™R*, —NR°CO}OR™, —NR'CO) RY," NR°C(OINR™R™,” —CONR™ RY, COR’, C(O)OR®, $0.R°, —SO.NR"R™ and “NR'S(O}R” In adition tothe surpising activity ofthe compounds of formula (I) at the SSAO receptor, it has been surprisingly fund that the claimed compounds have surprisingly low activity atthe hERG jon ehannel. The person skilled in dhe art, for example @ medicinal chemist, understands that low ERG oetvity is an important property fora phamaceutcal ‘drug compound. Without wishing to be bound by theory. it is believed that the —WVR® group as defined in claim Tis ‘especially advantageous in relation t reduced hERG aetiv~ iy It is expected that compounds of the invention may be prepared in the form of hydrates, and solvates. Any refer fence herein, including the claims herein, to “compounds ‘with which the invention is concemed” or “compounds of the invention” or “the present compounds", and the like, Includes reference to salts, hydrates, and solvates of such ‘compounds, The term ‘solvate’ is used herein to describe a ‘molecular complex comprising the compound ofthe inven- tion and a stoichiometric amount of one or more pharma ‘cettially acceptable solvent molecules, for example, tht nol. The term “hydrate” is employed winen said solvent is water, ‘Individual compounds of the invention may exis in an ‘amorphous form and/or several polymomphie forms and may be obtained in different crystal habits. Any reference herein, including the claims herein, to “compourids with Which the jnventinn is concerned” or "compounds ofthe invention” oF “the present compounds”, and the like, includes reference t0 the compounds irrespective of amogpbous of polymorphic form, ‘Since compounds of the invention havea nitrogen atom in ‘an aromatic sing they may form N-oxide, and the invention jnchides compounds ofthe invention in their Noid form. DEFINITIONS ‘The following definitions. shall apply throughout the sation and the appended claims, unles otherwise sated or indicated The tern“C,, alkyl” denotes a straight or branched alkyl sroup having from 1 to 4 carbon atoms. For parts of the range C,ralky] all subgroups thereof are contemplated such as Cy alkyl, Cy alkyl, C,.elkyl, Cyavalkyl and Cy-calky. Examples ‘of said’ C,"cafkyl inelade methyl, ‘eth, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl ‘Unless otherwise specified, the term “C-eycloalkyl” refers to a monoeyche saturated or partially unsaturated hydrocarbon rng system having from 3 0 7 carbon atoms 0 o 6 Examples of ssid C,-cycloalkyl include eyelopropyl, cyclobutyl cyclopentyl, cyelohesyl, cyelohexenyl, cyelo- Deptyl, and eyeloneptenyl. For pats of the range “Cs- cyeloaikyl” all subgroups thereof are contemplated such as CC, reyeloatkyl, C; scyeloalkyl, C,.eyetoalkyl, C)ey~ clolkyl, C,-eyeloalkyl, Cy-cyeloaley, C,.-cyclolkl C.reycloalkyl, C,,.-eycloaliy and C,,-eyeloaiky The term "C) alkoxy” refers toa straight oF branched CC, galkyl group which is attached to the remainder of the molecule through an oxygen atom. For parts of the range CC, galkoxy, all subgroups thereof are contemplated such as Choalkoxy, C alkoxy, Cy palkoxy, C, alkoxy” and Cy-calkoxy. Examples of sai C_alkony include methony, ethoxy, n-propoxs. isopropoxy, a-butoxy, isobutoxy, see- bbutoxy and tet-butoxy. The term “haloC, alkoxy” refers 0 a straight or branched C, alkyl group which is attached tothe remain- der ofthe molecule through at oxygen atom and has one oF ‘more hydrogen atoms thereof replaced with halogen such as ‘Myoro or chloro. For parts of the range C, alkoxy, all subgroups thereof are contemplated. Pxamples of said Cy alkoxy include triluoromethoxy. ‘The tenn “hydroxy. alkyl” denotes straight or branched C; alkyl group that has one or more hydrogen atoms theo? replaced with OH. Examples of said hydroxy alkyl include hydroxymethyl, 2-hydroxyethyl and 2, adlydroxy propyl “The teri “halo-C, alkyl denotes a straight or branched Cy cally! group that has one or more hydrogen atoms thereof replaced with halogen. Examples of said halo-Cy_- alky!incide floromethyl,wflvoromethy, rchloromety ‘and 2-Mhoroethyl “The term “eyano-C;,calkyl” denotes a sight or branched C, alkyl grodp that has one or more hydrogen atoms theeol replaced with cyano, Examples of sud eyano- alkyl include eyanomethyl, 2-cyanoedyl and 3-eyano- propyl The term “amino-C, alkyt” denotes a straight or branched C;, alkyl group substituted with an amino group. Examples of sid amino-Cy,-alkyl group inelude aminom- ethyl and 2-aminoeth. The term °C, calkylamino-C,, alkyl” denotes an amino-C, ,alkyl group as defined above, wherein the ano sroup is Substituted with a straight or branched Cy alkyl sroup. Examples of said C, alkylanino-C, alkyl include ‘methylaminoethy] and ethyiaminopropy!. The term “di(C,,,alkyDamino-C, alkyl” denotes an amino-C, alkyl group as defined above, wherein the amino group is disubstituted with straight or branched C,,-alkyl soups, which ean he the same or different. Examples of said iC, ealkylamino-C;, alkyl include N.N-dimethylamin- comet, N-ethy-N-methylaminoethy] and N/N-dietylam- nome. "The terms “heteroaryl” and “heteroaromatic ring” denote 14 monoeyclic heteroaromatic ring comprising 5 to 6 ring ‘toms in which one or more ofthe ring atoms are other than carbon, such a8 nitrogen, sulphur or oxygen. Examples of heteroaryl groups include fury pyzroy, thienyl, exazol, isoxazolsl, imidszolyl, thizolyl, isothiazolyl, pyridyl, Pyrimidinyl, tetrazolyl, pyrazolyl, pyridazinyl, pyrazinyl And thiadiszoy “The terms “heterocyclyl y denote 4 non-aromatie, fully saturated or partially unsaturated, preferably fully saturated, monocyclic ring system having {rom 310 7 ring atoms, especially Sor 6 rng atoms, in Which fone oF more of the ring atoms ae other than carbon, sch as rogen, sulphur of oxygen, Examples of heterocyclic US 9,428,498 B2 1 roups include piperdiny|, morpholinyl, homomorpholiny azepanyl, piperaziny|, oxo-piperazinyl, diazepiny], tetray~ dropyridinyl, wechydropyranyl, pyrolidinyl, tetahydo- uranyl, and ditydropyerolyl, groups. ‘The term “heteroeyclie-C, alkyl” refers to a heterocy- clic ring that is dirctly linked to a straight or branched ‘C, calky] group via a carbon or nitrogen atom of said ring, Examples of said heterocyclic, «alkyl include pipeidin- yimethy! piperidin-I-yimethyl,-morpholin-4-yl-methyl ad piperazin--ylmethyl. The 'C,.alkyl part, which includes methylene, ethylene, propylene or butylene, is ‘optionally substituted by one or more substituents selected from halogen, amino, methoxy, or hydroxyl “The term “C, alkylene” denotes a sinight or branched divalent saturated hydrocarbon chain having from 1 to 4 ‘carbon atoms. The C, «alkylene chain may be attached t0 the rest ofthe molecule and to the radial group through one ‘carbon within the chain or tough any two carbons within the chain, Examples of «alkylene radicals include meth ylene [-CH,—], 1.2etivleve [--CH,—CH,—], L,Leth- ylene [—CH(CH,}—],L2-propylene [—CH,—CH (CH) and 13-propylene | |—CH,—CH, CH, Whea refering t9 a °C, alkylene” radical, all subgroups thereof are contemplated, such as, -akylene, C.alky- lene, of C, alkylene. “Halogen” refers to fuorine, chlorine, bromine or iodine, preferably fluorine and chlorine, most preferably urine ydroxy" refers to the —OH radical “Cano” refers to the — CN radial. “Ox0" roles to the earbonyl group —O. “Optional” or “optionally” means that the subsequestly ‘described event or circumstance may but need not occur, and thatthe description includes instances where the event oF reumstance occurs ad instances in which it docs not “Pharmaceutically acceptable” means being useful in preparing a pharmaceutical composition that is generally sale, nontoxic and neither biologically nor atherwise unde- sirable and includes being useful for veterinary use as well ‘9s human pharmaceutical use “Treatment” as used herein includes prophylaxis of the named disorder or condition, or amelioration or elimination ‘of the disorder once it has been established, “An ellective amount” refers to a amount ofa compound that confers a therapeutic elfect on the treated subject. The therapeutic effect may be objective (ie, measurable by some fest or marker) or subjective (ie. subject gives an indication of or feels an eff). “Prodirugs” refers to compounds that may be converted under physiological conditions or by solvolysis to a biologi cally detive compound of the invention. A prodrug may be inactive when aministered toa subject in need there, but js converted in viv to an active compound ofthe invention. Prodinigs are typically rapidly transformed in vivo to yield the parent compound of the invention, eg. by hydrolysis in the blood. The prodrug compound usually offers advantages ‘of solubility, tissbe compatibility or delayed release in a ‘mammalian organism (see Silverman, R.B., The Organic Chemistry of Drug Design and Drug Action, 2 Bd. Elsevier Academie Press (2004), pp. 498.543), Prodrugs of 1 compound ofthe invention may be prepared by modifying unedional groups, such as a hydroxy, amino oF mereapto groups, present in a compound of the invention in such 3 Way that the modifications are cleaved, either in routine ‘manipulation or in vivo, to the parent compound of the invention. Examples of prodrugs include, but are not Fimited 0 o 8 to, acetate, formate and secinate derivatives of hydroxy {unctional aoups oF plnyl carbamate derivatives of sian ‘untional groups. ‘Throwghout the speciation and he eppended clsims, 9 aiven chemical formula or name shall also encompas all Salts, hydrates, sokates, Neoxides_ and prodrug. fons thereof. Furer, a given chemical formula or name shall cacompas all utomerc and slerisomerc Torms thereof Tautomers inewe enol and keto forms. Stereoisomers include enantiomers and distersomers, Enntiners can be present in their pure forms, oa racemic equal) oF neue ‘iste of two enalomers Dissereomers canbe preset in thee pre forms, ora mixtures of diastereomers. Diaste- reomers aso inclode geometrical isomers, which ean be present in their pre cis or trans forms oF as mixtures of those The compounds of formals (1) may be used as such oF where appropriate, as pharmacologicallyaceepable sas {eid or bse addition ss) thereof The phamscologelly acceplble addition slls mentioned Below are man to Comprise the therapettially sete non-toxic acid and base futon sft forms thatthe compounds are able to form Compounds tht have sie proper can be converted to their pharmaceutically acceptable acid addition salts by ‘eating the base form with an appropriate sci. Exemplary acids include inowanie acid, such as hydrogen ehlovie, iydeogen bromide, hydrogen iodide, sulphur aid, phos: phorie acid; and organic adds sueh as formic acd, seetic ci. propanoi ai, hydronyacti acid, lacie aid pyruvic aid, plyeole acid, mafee seid, mafonie aed, oxalic ack, benzenesuphonic acid tolvenesulpbonie acid, methonessl ‘honic oid tivorocctic ei, fumari id, seciic aid Inalc aid, tararie acd citi aid, sleylc ei, pamine cvaleyic seid, pamoie acid, benzoic aed scarbie aid and the like, Exemplary base ation salt fore are the si, potassium, caleium sal and sls with paemaccutcally !cceplable amines soc as, for example, ammonia, akslam- ins, benzathine, and amino adds, sch as, eg arginine and lysine. The tem addition sl s sed herein alsa comprises solvates which the compounds and sls thereof are able to form, such a, for example, hydrates, lcobolates and the ike The Group Y nan embodiment Ys from hydrogen, hydroxyl, NH NIC, say] such at —-NIEMaty, — NEL, or Nilisopropyl, —NELholoC sally sch es — NE Jwommetiy, oF —C, alkoxy such as mtboxy. In an embodiment Y is hydrogen, ‘The Group 7 Inn embodiment Zs hydrogen, halogen such as Nor or chlor, hydrox, eyano, C, aks! such as mel or Fsopropsl, halo-C, kyl soch as teiooromethyl, C, atkoxy such ab medloxy, hilo, alkoxy such ab wioo- romethory, -CONHy. —SO,Nify) Nig, —- NHC alkyl suchas —NEEMethyl, —Nietiyl, or —Nit jsopropyl, or —NHhalo-C, «alkyl In an embodiment Z is hydrogen. The Group R In an R! embodiment is a phenyl ring, ora $ or 6em- bered heteroury] ring either ring being optionally substituted ‘with one or more substituents selected from halogen such as fMuoro oF chlor, eyano, C, «alkyl such as methyl oF is0- propyl, halo-C,,-alkyl suet as trifluoromethyl, eyan0-C) alkyl Such as ‘methyleyano, —OR* such as’ methoxy’ ar siloromationy, “NUE such os NI, NIM. ethyl, —NHisopropyl, —NR°C(O)OR", —NRIC(OR SNRSCONRE RE, CONRER", COR sh 8 US 9,428,498 B2 9 ~COCH,, ~C(O)OR', and —NR'S(O).R", Ina embod rent RI fs optionally subsite phen, pyc, pyeol, Tuan, imidazole, or hopheve TR", RR and Rar each independently selected rom hydrogen, C, alkyl such as methyl, el oe isopropyl, oe tales allt soc a eoromety, oF Re sind R™ together withthe nttogen to which they are tached forma a 37 membered cyclic amino group mich as iri, azetiine, oxetne, pyridine, piperidine, pipex “ioc, homopiperidie, homopiperiine, morpholine, of let raydrofuran, opioslly substituted by one oF more sub- stents selec Irom: halogen suchas fluoro oF chlor, hydroxyl, eyane, C, aks! sch a methyl or sopropy, halo, «alkyl such a ihuoomethyl C, alkoxy suchas methoxy, halo calkoxy soch "3s. ‘illuoromethoxy, CON, SONI NI” NTC, alkyl Ntthalo-C, allyl ‘The Group X In an embodiment X_is selected from —1 ry “The Group R? Than embodiment Rs hydrogen, halogen sch a for or chloro, eyano, C, alkyl such ss methyl or ety! or isopropyl, halo-C, ealkyl such as teifuoremethy. In an embodiment Ris hydrogen, The Group W In an embodiment W is phony rng. In an alternative ‘enodiment Wa G-membered heterocyclic ring selected from pyridine, pyridacine, pyrazine. or pyrimidine. In an altemative embodiment W is a Smembored ring selected fiom oxarole thiavole or imidamle. Any ofthe aforemen- tioned rings are optionally substtuted with one oF mere substi as defined in claims I. In an embodiment W is substituted With one or more groups selected from floor, loro, eyano, metlyl or uillsromcy The Group W Tn an embodiment V is sleted from a bond, — 0 N(R’)—stch as NHI oF N(CH), (C=O) —CONR®"such as —CONH— of —CON(CH,)— NR'C(O)_ such as NCO) or — N(CH CO) or —C ealkylene, whercin the C, alkylene arcu is ‘optonaiy subsite by halogen suchas ote oF chlor, aia wherein any oue of the carbon atoms of the Cy alkylene group may be replaced by —O— or N(R’) such as —CH,O- in eilher direction or —CH, NEL CH;—N(CH,)— in either diretion The Group R? In an embodiment R° is hydrogen, nan alternative embodiment Ran opGionaly substitied 3-7 membered heterocyclic ring such as aviridine, azetidine, oxetane, py rode. piper, piperazine, hospiperiine. bomopip- ‘zine, morpholine, or ttrydrofuran, In an embodiment isan opionlly substitute 3-7 membered eyeloal ing suchas eyelopropyl, eyclopenty or eyeotony. nan ater nutive embodiment Ris an optionally subsiued Sor Gmembersd hoteroan ring such as imidazole, phony, pling, thiophene. The optional substivents are define in Formula (In an embodiment any one of the rings is ‘optional substituted with ne ox more subsients selected From halogen such Huo or chlor, oxo, hyeoxy.eyano, calli such as mets, ety propyl butyl OF pro: ye halo Ney, DCM ($0 mL.) and 1M ag citric acid (50 ml.) The organic faction was dried (MpSO,) and concentrated in vacuo 0 a ave the ene title compound (134 g) asa brown solid, ECMS (ES"} 245.1 [MHI 8 Intermediate 19 tert-Butyl 4[4-(methoxyearbony)} piperazine I-carboxylate isola) Intermediate 21 was prepared similarly to Intermediate 19, using methyl 2-chlorthiazole-5-carboxylate instead of | ‘methyl 2-chlorothiazole-4-carboxylateto give the tte com- poutd asa white solid (712 mg, 64.4%). LMS (ES*): 350.2 IMNal*, HPLC: Rt 6.34 mi, 99.0% purity. Intermediates 22:30 Intermediates 22-30 were prepared similarly to Interme= owe 11, by LIOH mediated ester hydrolysis; see Table 2 3.52 mmol) and DIPEA below. sumo), N-oe-piperazine (655 n 25 US 9,428,498 B2 26 TABLE 2 iow (orLinien sat Intermed Form, S(Oxan- hnizopyain- Frm tmnedie 10 trp ed Meow soi TEMS ES 3280 NU Nios iam 646-0 rom tne 12 Satonyctonyinino) White sod Prestoniypyndiae’- Used ee ont LEAS ey sas mr Liu 2 rom ieee 13 [iGlepeyintisnioo) Of wht said Porimiiae’seabomtte Urctende CMS TES) 298 {ysloprnylamioo)prniie- OFF white soit Hue, fe 038 one ¢¢ycoronyeaamey) From Imeameite 17 Poniae eatonge sel Pak sl et $99 ms, 7.19% TCM ES 2074 IN US 9,428,498 B2 Ne sete ter 4 Nae lennon be ‘atone Intermediate 31 6-,6-Dinydro-2H-pyran-4-y1)pyridavin-3-carbox ‘lic Acid Methyl 6-chloropytidazine-S-carboxylate (1.00 g, $79 mol), 4-(44,5.Stetramethy 1 3,2-dioxaborolan-2'y1)3, Gedihydeo-2H pyran (122 g. 5.79 mmol), PACPPh,), (536 img, 0.44 mmol) and CS,CO, (3.40 g, 104 mmol) were fuspended in dioxane (8 ml.) and water (8 mL) and heated ing microwave reactor at 125°C for 30min, IM aq HCI (10 IIL) was added, the precipitate was removed by filtration ‘and the fllrte Was eoncentrated in vacuo, The reside Was passed through silica pad eluting with 30% MeOH ia DCM nd concentrated in vacuo to give the ttle compound as 2 White solid (246 mg, 79.2%). LOMS (FS") 207.1 [Mill HPLC: Rt 3.30 mi, 49.9% purity Suva exo pipratin vistas cei Suoxy exon dit vonage thi pera Limit) Intermed, Form, Fron irene 1 Tense sea (besa HPLC: ana A sng eae fine ine Sin tars y ro Item 2 Yield 712 ne, 96 TMS (eS Son [bows HPLC: Rt Intermediate 32 = N-(3-4(4-Chloropheny)aminolpyridin- yl}pyeidine-3-carboxamide 6 CK 2 xi 0 a Intermediate 7 234 mg, 1.07 mmo), pyridine-4-carbox- yilie eid (393 mg, 3.20 mmol) and DIPEA (741 ul, 4.26 ‘mmol were dissolved in DMF (10 ml.) and EDC (613 mg. 3.20 mmol) was added. The reaction mixture ws ster for 18 h and further pyridine-3-carboxylie acid (393 mg, 3.20 mmol) and EDC (613 mg, 3.20 mmol) were added. The reaction mixture was stimed for 5h, diluted with IM ag Na.CO; (50 mL.) and extracted into DCM @xS0 ml). The combined organic frations were dried (MgS0,) and con- centratad in vacuo, The reside was purified by column chromatography to give the tite compound as a red gum (297 mg, 85.89%). LEMS (ES): 325.1 [MH] HDLC: Rt 4.08 mia, 99.0% purty o US 9,428,498 B2 29 30 Intermediates 33-51 Intermediates 33-51 were prepared similarly to Interme> dite 42, by coupling of Intermediates 7 or ¥ with the appropriate carboxylic acid; see Table 3 below. TABLI Aide cots Inman Fomm, Nave Yi, LEMS, HPLC Noe Frm inmate 7 Gloopnncints lsat ve LCM (ES 3252 IN wo rom Itemeite 7 Cllorpieayninoprdin4y)- Yalow sai Stars sacle Yield me, 1.1% SSthranile CMS ES aa Na xs ee rom Item 7 cy Glowpbenyaninlpyrdin}- Yate sol L Stores spyriarae Yield SI0 ms, 3.29% s Side TEMS ES at. [sp US 9,428,498 B2 31 32 ‘TABLE 3-continued i ssnsae Name Yiel, LEMS, HPLC 6 Cy Ne om temo 7 Cilowpbemsninopidin4y!}- Yel ot ~) Stmempslies pyrene Yield 633 me. 73.5% schon TOMS S110 [sp ” ° ee rom air 7 a1 CGlompteayninlpedi“y Fy k ee on tenets 7 and 22 yy Seer BE 1 , US 9,428,498 B2 33 34 ‘TABLE 3-continued i ssnsae Name Yiel, LEMS, HPLC » NilBoe tout N-(S4(4- Fm men 7 and 25 Slocpisikanopyisa- Of whe sid eutbanoy pve Yiu 984 ms, MP4 LOM Miprenletieaamae CESS. HPLC eS6 mi, 974% panty Wr cx a é “ 24\Cydeponsincianito}- Fr Inemetes # ad Bidar iment Ym LCMS (ES") 379.2 [MH] HPLC: Ret) mio 3% wry oe Aetelanipecs amie Y VY Mimyemaine sewtonamide Ys $99 me, 71.2% A N tse Raat, 00% puny US 9,428,498 B2 35 36 ‘TABLE 3-continved ioe ti IP ae Sl gor x L) ee US 9,428,498 B2 37 38 ‘TABLE 3-continued ity ‘a | t h t — wos ‘nu uows us e 5 exe Tien 6 Coins $a re ee nase or Se me ea I - & : t:360)mbe tems DN onl 3 {sich Sied Oana Se Hue: 2a? mi, 09% . p spout Yn mais 777 BP Ee epemiongenn Sil Feeint ore erage rt am CaS So Eire US 9,428,498 B2 39 ‘TABLE 3-continued 4% STN DR & & c- se 8 gpa ete te Jeane hal bestia gums Jeune bent Mingenaine-earoyie era SH ‘Sorepeay ania) Sewbwnoy- hat Mippensise casei 40 —oy Intemedisee Form, Hues We 6 i, “ rom temeiates 7a 29 Yet 2 mg 1096 LGM eS 359.0 Ne Yo ms 57.9% Hue: Wid, 05 US 9,428,498 B2 vow a Se Intermediate $2 1-{5-13-4-Fhuorophenyl)-3H-imidaz0l4,-clpysi 2-ylipyedin-2-yl} piperazine Tehydeochioride Intermediate 52 was prepared similarly to Example 27 using Intermediate 2 instead of Intermediate 1, to give the 4S tile compound (684 mg, 100%6) ax a white solid. LCMS (B84): 375.1 [MAT Intermediate $3, N-{3-((4-FluorophenyDamino)pyridin-lyl}-6 gy (oxan-d-ybpynidazine-3-carboxamide o xt Tike nay f)- Boge Y Hours) aulpyancie’ eS me, 220%, X [ | sie ee 5 TeMs chs ann se Intermediate 46 (220 mg, 0.56 mmol) was dissolved in MeOH (10 mL), PIC (cat) was addod and the reaction mixture was stirred under hydrogen for 2 h, The reaction mixture was filered throvgh Celite and concentrated in vacuo 10 give the enude tile compound which was used ‘without purification. CMS (PS*): 394.2 [MH Intermediate 54 2-Choro-5-{3-(4-luoropheny))-3H-imidazo(4,5-c} pyridin-2-ylpyridine CL) Intermediate 2 (1.00 g, 4.01 mmol) and 2-chloro-5-pysi- imoboine 45.5.4 Forpeyl 3 Yee st mg 139% tens (es) 30 ty Hee: UAT? a, 9.9% py From mene 2 inicio: We ies Sire, oa Example 33 4-(5:[3-(5-Chlonopyridin-2-y)-S4-imidazo[4.5-c} » debeimmiypmerentss 7 LOO . . \ ; Fxample 38 was prepared similarly to Example 32, using 4s Intermediate 5 instead of Intermediate 4, 10 give the tile compound (29.0 mg, 4.53%) asa white solid. LMS (ES*): 3940 [MEI}*. HPLC: Rt 4.68 min, 97.8% purity US 9,428,498 B2 OL Example 34 4-{54[3.-Pluoropysiin-2-) 311 imider0[4 5c] pyniin-2llpyrimidin-2-1} morpholine CO++-O ¢ Example 34 was prepared similarly to Example 32, wsing Intermediate 6 instead of Intermediate 4, to give the tile ‘compound ($3.2 mg, 7.5%) a5 a white solid. LCMS (FS") 378.1 [MH] HPLC: Rt 4.36 min, 98.4% purity. Example 35 4-{5-13-(4-Chloropheny])-3H-iidazo[4.S-c}pyriin 2-yllpyridn-2-y}piperazine-1-carboxamide Dihy- “drochloride CO >-OX Example 27 tribydrochlorie (94.5 mg, 0.19 mmol) was

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