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(12) Patent Application Publication (10) Pub. No.: US 2017/0073340 A1 Fieldhouse Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2017/0073340 A1 Fieldhouse Et Al US 2017.0073340A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2017/0073340 A1 Fieldhouse et al. (43) Pub. Date: Mar. 16, 2017 (54) SUBSTITUTED CYCLOPENTANES, A63L/4545 (2006.01) TETRAHYDROFURANES AND C07D 40/12 (2006.01) PYRROLIDINES AS OREXN RECEPTOR A63/498 (2006.01) ANTAGONSTS C07D 417/12 (2006.01) (71) Applicant: TAKEDA PHARMACEUTICAL C07D 413/12 (2006.01) COMPANY LIMITED, Osaka-Shi (JP) (52) U.S. Cl. (72) Inventors: Charlotte Fieldhouse, Cambridgeshire CPC ......... C07D 417/14 (2013.01); C07D 417/12 (GB); Angela Glen, Cambridgeshire (2013.01); A61 K3I/4439 (2013.01); C07D (GB); Tatsuhiko Fujimoto, Kanagawa 413/12 (2013.01); A61K 31/4545 (2013.01); (JP); John Stephen Robinson, C07D 401/12 (2013.01); A61 K3I/498 Cambridgeshire (GB) (2013.01); A61 K3I/4709 (2013.01) (73) Assignee: Takeda Pharmaceutical Company Limited, Osaka-shi (JP) (57) ABSTRACT (21) Appl. No.: 15/120,002 The present invention provides compounds of formula (I) (22) PCT Filed: Feb. 19, 2015 and pharmaceutically acceptable salts thereof. Formula (I) wherein L, X, R. R. R. R. and R are as defined in the (86). PCT No.: PCT/GB2O1S/OSO482 specification, processes for their preparation, pharmaceuti S 371 (c)(1), cal compositions containing them and their use in therapy. (2) Date: Aug. 18, 2016 (30) Foreign Application Priority Data (I) Feb. 20, 2014 (EP) .................................. 14156O10.2 Publication Classification (51) Int. Cl. CO7D 417/4 (2006.01) A6 IK 3/4439 (2006.01) A 6LX 3L/24709 (2006.01) US 2017/0073340 A1 Mar. 16, 2017 SUBSTITUTED CYCLOPENTANES, (0013 R represents a 5- or 6-membered monocyclic TETRAHYDROFURANES AND heteroaromatic group optionally Substituted by at least one PYRROLIDINES AS OREXIN RECEPTOR Substituent independently selected from halogen, hydroxyl, ANTAGONSTS cyano, C-C alkyl, C-C haloalkyl, C-C hydroxyalkyl, C-C alkoxy, C-C haloalkoxy, C-C alkenyl, C-C alky 0001. The present invention relates to amide derivatives, lcarbonyloxy, C-C alkoxycarbonyl, NR'R'', —C(O) processes for their preparation, pharmaceutical composi NR'R'', C-C cycloalkyl, C-C cycloalkyloxy, C-C, tions containing them and their use in therapy, particularly cycloalkylmethyl or a 5- or 6-membered heteroaryl group, in the treatment or prevention of conditions having an the heteroaryl group being optionally Substituted by at least association with the orexin sub-type 1 receptor. one Substituent independently selected from C-C alkyl, 0002 The orexin peptides (orexin A and orexin B, OXA C-C alkoxy and C-C haloalkoxy; and OXB), also known as hypocretins, were discovered in I0014 Rand Reach independently representahydrogen 1998 by two groups (Sakurai et al., Cell, 1998, 92, 573 and atom or a C-C alkyl or C-C cycloalkyl group, or R and De Lecea et al., Proc. Nat. Acad. Sci., 1998, 95, 322). These Ray together with the nitrogen atom to which they are neuropeptides are both derived from the common precursor attached form a 4- to 7-membered saturated heterocyclic pre-pro-orexin and are produced in the lateral hypothalamus. ring optionally Substituted by at least one Substituent inde OXA is a 33 amino acid residue which has similar potency pendently selected from halogen, hydroxyl and C-C, at both the Ox1R (orexin 1 receptors) and OX2R (orexin 2 alkoxy; receptors) whereas OxB is made up of 28 amino acids and I0015I Rand Reach independently representahydrogen binds selectively to the Ox2R. atom or a C-C alkyl or C-C cycloalkyl group, or R and 0003 Orexin receptors are believed to be implicated in R" may together with the nitrogen atom to which they are both feeding behaviour (Sakurai et al., Cell, 1998, 92,573) attached form a 4- to 7-membered saturated heterocyclic and also in regulating sleep architecture (Chemelli el al., ring optionally Substituted by at least one Substituent inde Cell, 1999, 98,437). More recently, it has been shown that pendently selected from halogen and hydroxyl, orexin receptors are implicated in arousal, reward, learning I0016 R represents a hydrogen or halogen atom or a and memory (Harris et al., Trends Neurosci., 2006, 29. 571). hydroxyl group; 0004 WO 2003/099276 describes a broad class of com I0017 R represents a C-C alkyl, C-C alkoxy, benzy pounds, including certain amides, which are useful as factor loxy, Co-Co aryl, or heteroaryl group; Xa inhibitors for treating thromboembolic disorders. 10018) R' and R' each independently represent a hydro 0005 We have now discovered a class of compounds that gen atom or a C-C alkyl or C-C cycloalkyl group, or R' are orexin receptor antagonists. Furthermore, certain com and R' may together with the nitrogen atom to which they pounds of the invention show selectivity for the orexin 1 are attached form a 4- to 7-membered saturated heterocyclic receptor over the orexin 2 receptor. ring optionally Substituted by at least one Substituent inde 0006. In accordance with the present invention, there is pendently selected from halogen, hydroxyl and C-C, therefore provided a compound of formula alkoxy; and (0019 R'' and Reach independently represent a hydro (I) gen atom or a C-C alkyl or C-C cycloalkyl group, or R' X and R' may together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic Ra Rb P ring optionally Substituted by at least one Substituent inde pendently selected from halogen and hydroxyl, stf R3 0020 or a pharmaceutically acceptable salt thereof. R2 0021. In the context of the present specification, unless otherwise stated, an “alkyl substituent group or an alkyl moiety in a Substituent group may be linear or branched. wherein Examples of C-C alkyl groups/moieties include methyl, 0007) R' represents an 8- to 10-membered fused bicyclic ethyl, propyl, 2-methyl-1-propyl, 2-methyl-2-propyl. heteroaromatic group optionally Substituted by at least one 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2.2- Substituent independently selected from halogen, cyano, dimethyl-1-propyl, 2-methyl-1-pentyl, 3-meth-1-pentyl, hydroxyl, C-C cycloalkyl, C-C alkyl, C-C alkoxy, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, C-C alkoxycarbonyl, C-C alkoxycarbonylamino, C-C, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3.3-dimethyl-1- haloalkoxy, NR'R. C-C cycloalkylamino, C-C alky butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, tert-butyl, n-pentyl, lcarbonyloxy, C-C alkylcarbonylam,ino, Sulphonamido isopentyl, neopentyl, n-hexyl, n-heptyl and n-octyl. (—SONH2), C-C alkylsulphonyl, C-C alkylsulpho 0022. An “alkenyl substituent group or an alkenyl moi nylamino and –C(O)NR'R'': ety in a Substituent group refers to an unsaturated alkyl 0008 L represents a bond, CH, O, NH or N(CH): group having one or more double bonds. Examples of C-C, 0009 R represents a hydrogen atom or a C-C alkyl or alkenyl groups/moieties include ethenyl, propenyl, 1-bute C-C haloalkyl group; nyl, 2-butenyl, 1-pentenyl, 1-hexenyl, 1,3-butadienyl, 1,3- I0010) R' represents a hydrogen atom or a C-C alkyl or pentadienyl, 1.4-pentadienyl and 1.4-hexadienyl. C-C haloalkyl group; 0023. A “cycloalkyl substituent group/moiety is a satu 0011 X represents CF, CHR, O or NC(O)R’: rated hydrocarbyl ring containing, for example, from 3 to 8 0012 R represents a hydrogen atom or a C-C alkyl or carbon atoms, examples of which include cyclopropyl. C-C cycloalkyl group; cyclobutyl, cyclopenty1 and cyclohexyl. US 2017/0073340 A1 Mar. 16, 2017 0024. A "haloalkyl or “haloalkoxy” substituent group/ nature of substituents will be selected so as to avoid steri moiety comprises at least one halogen atom, e.g. one, two, cally undesirable combinations. three, four or five halogen atoms. Examples of C-C, (0029) R' represents an 8-, 9- or 10-membered fused haloalkyl and C-C haloalkoxy groups/moieties include bicyclic heteroaromatic group optionally Substituted by at fluoromethyl, difluoromethyl, trifluoro ethyl, 2.2.2-trifluo least one Substituent, e.g. one, two, three or four Substitu roethyl, pentafluoroethyl, fluoromethoxy, difluoromethoxy ents, independently selected from halogen (e.g. fluorine, and trifluoromethoxy. chlorine, bromine or iodine), cyano, hydroxyl, C-C, 0025. It will be understood that if R and R together with cycloalkyl (cyclopropyl, cyclobutyl, cyclopentyl or cyclo the nitrogen atom to which they are attached form a 4- to hexyl), C. C or C alkyl, C. C or C alkoxy, C. C or C. 7-membered saturated heterocyclic ring, the heterocyclic alkoxycarbonyl, C. C or C alkoxycarbonylamino, C, C ring may contain one or more (e.g. one or two) further ring or Chaloalkoxy, NR'R''. C-C cycloalkylamino (cyclo heteroatoms (e.g. nitrogen, oxygen or Sulphur atoms) in propylamino, cyclobutylamino, cyclopentylamino or cyclo addition to the nitrogen atom to which R and R are hexylamino), C. C or C alkylcarbonyloxy, C. C or C. attached. However, will be appreciated that the invention alkylcarbonylamino, Sulphonamido, C. C or C alkylsul does not encompass any unstable ring structures or any phonyl, C. C or C alkylsulphonylamino and —C(O) O—O, O—S or S-S bonds. If a substituent is present on the NRR7. ring, it may be attached to any suitable ring atom. Examples 10030) The fused bicyclic heteroaromatic group in R' of Such heterocyclic rings include aZetidinyl, pyrrolidinyl, comprises one or more, e.g. one, two, three or four, ring piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, 1,4- heteroatoms independently selected from nitrogen, oxygen azathianyl, azepanyl and 1,4-oxaazepanyl moieties. Similar and Sulphur. Examples of Such heteroaromatic groups comments apply with respect to Rand R.
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