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 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 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. R'' and R', and include quinoxalinyl, benzothiazolyl, benzoxazolyl, quino R'' and R' when they form a 4- to 7-membered saturated linyl, quinazolinyl, indolyl, 7-azaindolyl, indolizinyl, inda heterocyclic ring. Zolyl, imidazo 1,2-alpyridinyl and 7H-pyrrolo2,3-dipyrim 0026. A "C-C aryl group refers to a group derived idinyl. from an aromatic hydrocarbon containing from six to ten I0031. In an embodiment of the invention, R' represents a carbon atoms. The aryl group may be monocyclic or poly 9- or 10-membered fused bicyclic heteroaromatic group cyclic (e.g. bicyclic) in which the two or more rings are containing one or two ring heteroatoms independently fused, examples of which include phenyl, 1-naphthyl and Selected from nitrogen, oxygen and Sulphur (Such as qui 2-naphthyl. Also included within the scope of the term noxalinyl, benzothiazolyl, benzoxazolyl, quinolinyl and qui “aryl', as it is used herein, is a group in which an aromatic nazolinyl), the heteroaromatic group being optionally Sub ring is fused to one or more non-aromatic rings as exem stituted by at least one Substituent, e.g. one, two, three or plified by indanyl and tetrahydronaphth 1. An aryl group four Substituents, independently selected from halogen (e.g., may be bonded at any suitable ring atom. fluorine, chlorine, bromine or iodine), cyano, hydroxyl, 0027 A“heteroaryl' or "heteroaromatic' group is an aryl C-C cycloalkyl (cyclopropyl, cyclobutyl, cyclpentyl or group in which from 1 to 4 ring carbon atoms are replaced cyclohexyl), C. C or C alkyl, C. C or C alkoxy, C, C by heteroatoms independently selected from nitrogen, oxy or C alkoxycarbonyl, C. C or C alkoxycarbonylamino, gen and Sulphur. The heteroaryl or heteroaromatic group can C. C. or Chaloalkoxy, NR'R. C-C cycloalkylamino be bonded at any suitable ring atom (i.e. at any carbon or (cyclopropylamino, cyclobutylamino, cyclopentylamino or heteroatom of the ring system). Examples of 5- to 10-mem cyclohexylamino), C. C or C alkylcarbonyloxy, bered heteroaryl or heteroaromatic groups include the fol 0032. C. C. or C alkylcarbonylamino, sulphonamido, lowing: C. C or C alkylsulphonyl, C. C or C alkylsulpho nylamino and –C(O)NR'R''. I0033. In another embodiment, R' represents a 9- or 10-membered fused bicyclic heteroaromatic group contain ing one or two ring heteroatoms independently selected from C. C C, OOO nitrogen, oxygen and Sulphur (Such as quinoxalinyl, benzo thiazolyl, benzoxazolyl, quinolinyl and quinazolinyl), the heteroaromatic group being optionally Substituted by one, two, three or four substituents independently selected from OOCCOO) halogen (e.g. fluorine, chlorine, bromine or iodine), cyano, hydroxyl, Cs-C cycloalkyl, C. C or C alkyl, C. C or C. alkoxy, C. C or C alkoxycarbonyl, C. C or C alkoxy carbonylamino, C, C, or Cs haloalkoxy, NR'R''. Cs-C COOOCO cycloalkylamino, C. C or C alkylcarbonyloxy, C. C or G = O, S or NH C. alkylcarbonylamino, Sulphonamido, C. C or C alkyl Sulphonyl, C. C or C alkylsulphonylamino and —C(O) NROR7. 0028. When any chemical moiety or group in formula (I) I0034. In a further embodiment, R' represents a 9- or is described as being optionally substituted, it will be 10-membered fused bicyclic heteroaromatic group contain appreciated that the moiety or group may be either unsub ing one or two ring heteroatoms independently selected from stituted or substituted by one or more of the specified nitrogen, oxygen and Sulphur (Such as quinoxalinyl, benzo substituents. It will be appreciated that the number and thiazolyl, benzoxazolyl, quinolinyl and quinazolinyl), the US 2017/0073340 A1 Mar. 16, 2017 heteroaromatic group being optionally Substituted by one or heteroatoms independently selected from nitrogen, oxygen more (e.g. one or two) halogen, particularly fluorine or and Sulphur. Examples of Such 5- or 6-membered monocy chlorine, atoms. clic heteroaromatic groups include pyrrolyl, imidazolyl, 0035) In a still further embodiment, R' represents any one pyrazolyl, triazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyrim of the following moieties or is selected from a group idinyl, pyridazinyl, triazinyl, thienyl, furyl, furazanyl. containing two or more of such moieties in any combination: oxazolyl, thiazolyl, oxadiazolyl, isothiazolyl, isoxazolyl, 0036 (i) quinoxalin-2-yl, thiadiazolyl and tetrazinyl. 0037 (ii) 6-fluoro-1,3-benzothiazol-2-yl, I0061. The R heteroaromatic group may optionally be 0038 (iii) 5-fluoro-1,3-benzothiazol-2-yl, substituted with at least one 5- or 6-membered heteroaryl 0039 (iv) 1,3-benzothiazol-2-yl, group. The term "heteroaryl group, as used in this context, 0040 (v) 5-chloro-1,3-benzothiazol-2-yl, refers to a monocyclic heteroaromatic group having a total 0041 (vi) 1,3-benzoxazol-2-yl, of 5 or 6 ring atoms, of which one, two, three or four ring 0042 (vii) 6-chloro-1,3-benzothiazol-2-yl, atoms are heteroatoms independently selected from nitro 0043 (viii) 6-chloro-1,3-benzoxazol-2-yl, gen, oxygen and Sulphur atoms. Examples of such heteroaryl 0044 (ix) quinolin-2-yl, groups include pyrrolyl, imidazolyl pyrazolyl, triazolyl, 0045 (x) quinazolin-2-yl, tetrazolyl pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, 0046 (xi) 6-fluoro-1,3-benzoxazol-2-yl, and triazinyl, thienyl, furyl, furazanyl, oxazolyl, thiazolyl, 0047 (xii) 5-fluoro-1,3-benzoxazol-2-yl. oxadiazolyl, isothiazolyl, isoxazolyl, thiadiazolyl and tet 0048. In an embodiment of the invention, L represents razinyl. CH, or NH. 0049. In a further embodiment, L represents NH. 10062) In an embodiment of the invention, R represents a I0050 R and Reach independently represent a hydrogen 5- or 6-membered monocyclic heteroaromatic group con atom or a C. C or C alkyl or C. C or Chaloalkyl group. taining one or two ring heteroatoms independently selected I0051. In one embodiment, R and R” each represent a from trogen, oxygen and Sulphur (Such as pyridinyl, pyrim hydrogen atom. idinyl and pyrazinyl), the heteroaromatic group being I0052. In another embodiment, one of R and R repre optionally Substituted by at least one Substituent, e.g. one, sents a hydrogen atom and the other of R and R' represents three or four substituents, independently selected from fluo a C alkyl (i.e. methyl) or haloalkyl (e.g. trifluoromethyl) rine, chlorine, bromine, hydroxyl, cyano, C. C or C alkyl, C. C or Chaloalkyl, C. C or C. hydroxyalkyl, C. C or group. Calkoxy, C. C or Chaloalkoxy, C. C or Calkenyl, C. 0053. In an embodiment of the invention, X represents C or C alkylcarbonyloxy, C. C or C alkoxycarbonyl CHR. NR'R'', C(O)NR'R'', C-C cycloalkyl, C-C, I0054 R represents a hydrogen or halogen (e.g. fluorine, cycloalkyloxy, C-C cycloalkylmethyl or a 5- or 6-mem chlorine, bromine or iodine) atom or a hydroxyl group. bered heteroaryl group (such as triazolyl, pyrazolyl, oxadi 0055. In one embodiment, R represents a hydrogen or azolyl pyrimidinyl and imidazolyl), the heteroaryl group fluorine atom or a hydroxyl group. 0056. In another embodiment, R represents a hydrogen being optionally Substituted by at least one Substituent, e.g. atOm. one, two, three or four substituents, independently selected I0057 R represents a hydrogen atom or a C-C, or from C-C, or C-C or C-C alkyl, C-C, or C-C or C-C, or C-C, alkyl or C-C cycloalkyl (cyclopropyl. C-C alkoxy and C-C, or C-C, or C-C haloalkoxy. cyclobutyl, cyclopentyl or cyclohexyl) group. I0063. In another embodiment, R represents a 5- or 0058. In one embodiment, R represents a hydrogenatom 6-membered monocyclic heteroaromatic group containing or methyl group. one or two ring heteroatoms independently selected from I0059 R represents a 5- or 6-membered monocyclic nitrogen, oxygen and Sulphur (Such as pyridinyl, pyrimidi heteroaromatic group optionally Substituted by at least one nyl and pyrazinyl), the heteroaromatic group being option Substituent, e.g. one, two, three or four Substituents, inde ally substituted by one, two, three or four substituents pendently selected from halogen (e.g. fluorine, chlorine, independently selected from fluorine, chlorine, bromine, C. bromine or iodine), hydroxyl, cyano, C. C or C alkyl, C. C, or C alkyl, C. C or Chaloalkyl, C. C or C alkoxy, C, or Chaloalkyl, C. C or C. hydroxyalkyl, C. C or C. C. C or Chaloalkoxy, cyclopropyl or a 5- or 6-membered alkoxy, C. C or Chaloalkoxy, C. C or Calkenyl, C, C heteroaryl group (such as triazolyl pyrazolyl, oxadiazolyl, or C alkylcarbonyloxy, C. C or C alkoxycarbonyl, pyrimidinyl and imidazolyl), the heteroaryl group being -NR'R'', C(O)NR'R'', C-C cycloalkyl (cyclopro optionally Substituted by at least one Substituent, e.g., one, pyl, cyclobutyl, cyclopentyl or cyclohexyl), C-C, two, three or four substituents, independently selected from cycloalkyloxy (cyclopropyloxy, cyclobutyloxy, cyclopenty C-C alkyl, C-C alkoxy and C-C haloalkoxy. loxy or cyclohexyloxy), C-C cycloalkylmethyl (cyclopro I0064. In a further embodiment, R represents a 5- or pylmethyl, cyclobutylmethyl, cyclopentylmethyl or cyclo 6-membered monocyclic heteroaromatic group containing hexylmethyl) or a 5- or 6-membered heteroaryl group, the one or two ring heteroatoms independently selected from heteroaryl group being optionally Substituted by at least one nitrogen, oxygen and Sulphur (Such as pyridinyl, pyrimidi Substituent, e.g. one, two, three or four Substituents, inde nyl and pyrazinyl), the heteroaromatic group being option pendently selected from C-C or C-C, or C-C alkyl, ally substituted by one, two or three (particularly one or two) C-C, or C-C, or C-C alkoxy and C-C, or C-C, or substituents independently selected from fluorine, chlorine, C-C haloalkoxy. bromine, C. C or C alkyl, C. C or C alkoxy, C. C or I0060 R represents a 5- or 6-membered monocyclic C. haloalkoxy, cyclopropyl or a 5- or 6-membered het heteroaromatic group. This Rheteroaromatic group com eroaryl group (such as triazolyl pyrazolyl, oxadiazolyl, prises one or more, e.g., one, two, three or four, ring pyrimidinyl and imidazolyl), the heteroaryl group being US 2017/0073340 A1 Mar. 16, 2017 optionally substituted by one or two substituents indepen preferably attached in the ortho- and/or meta-positions rela dently selected from C-C alkyl, C-C alkoxy and C-C, tive to the point of attachment of the amide moiety, NRC haloalkoxy. (O)—. 0065. In yet another embodiment, R represents a I0109 Rand Reach independently representahydrogen 6-membered monocyclic heteroaromatic group containing atom or a C. C or C alkyl or C-C cycloalkyl (cyclopro one or two ring nitrogen atoms, the heteroaromatic group pyl, cyclobutyl, cyclopentyl or cyclohexyl) group, or R and being optionally substituted by one, two, three or four Rmay together with the nitrogen atom to which they are substituents independently selected from fluorine, chlorine, attached form a 4-, 5-, 6- or 7-membered saturated hetero bromine, C. C or C alkyl, C. C or Chaloalkyl, C, C cyclic ring optionally Substituted by at least one Substituent, or C, alkoxy, C, C, or Cs haloalkoxy, NR'R' or a 5- to e.g. one or two Substituents, independently selected from 6-membered heteroaryl group which is unsubstituted. halogen (e.g. fluorine, chlorine, bromine or iodine), I0066. In a still further embodiment, R represents any one hydroxyl and C. C or C alkoxy. of the following moieties or is selected from a group 0110. In one aspect, the saturated heterocyclic ring may containing two or more of such moieties in any combination: contain a single ring heteroatom (being the nitrogen atom to 0067 (i) 3-chloropyridin-2-yl, which R and Rare attached). 0068 (ii) 3-bromopyridin-2-yl, 0111. In an alternative aspect, the saturated heterocyclic 0069 (iii) 3-methoxypyridin-2-yl, ring may contain a second ring heteroatom selected from a 0070 (iv) 3-(propan-2-yloxy)pyridin-2-yl, nitrogen or oxygen atom. 0071 (v) 6-bromo-3-methoxypyridin-2-yl, I0112. In one embodiment, R and Reach independently 0072 (vi) 3-(1H-pyrazol-1-yl)pyridin-2-yl, represent a hydrogen atom or a C. C or C alkyl or C-C, 0073 (vii) 3-fluoropyridin-2-yl, or C-C or C-C cycloalkyl, particularly cyclopropyl. 0074 (viii) 3-(piperidin-1-yl)pyridin-2-yl, group, or R and R may together with the nitrogen atom to 0075 (ix) 3-(azetidin-1-yl)pyridin-2-yl, which they are attached form a 4- or 5-membered saturated 0076 (x) 3-(pyrrolidin-1-yl)pyridin-2-yl, heterocyclic ring optionally substituted by one or two sub 0077 (xi) 3-(3-methoxyazetidin-1-yl)pyridin-2-yl, stituents independently selected from fluorine, chlorine, 0078 (xii) 3-methoxy-6-(trifluoromethyl)pyridin-2-yl, bromine, hydroxyl and methoxy. 0079 (xiii) 3-ethoxypyridin-2-yl, I0113. In a second embodiment, Rand Reach represent 0080 (xiv) 3-(trifluoromethoxy)pyridin-2-yl, a hydrogen atom. I0081 (XV) 3-(difluoromethoxy)pyridin-2-yl, I0114. In a third embodiment, R and Reach represent a 0082 (xvi) 3-(1H-1,2,3-triazol-1-yl)pyridin-2-yl, C-C- alkyl group. 0083 (xvii) 3-ethoxy-6-methylpyridin-2-yl, (0.115. In a fourth embodiment, one of R and R repre 0084 (xviii) 3-methoxy-6-methylpyridin-2-yl, and sents a hydrogenatom and the other of R and R represents 0085 (xix) 3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl. a C-C alkyl group. I0086) In a still further embodiment, when R represents a 10116. In a fifth embodiment, one of R and R represents substituted 5- or 6-membered monocyclic heteroaromatic a cyclopropyl group and the other of R and R represents a group, the Substituent(s) is/are independently any one of the C-C alkyl group. following moieties or is/are independently selected from a 0117. In a sixth embodiment, Rand R together with the group containing two or more of Such moieties in any nitrogen atom to which they are attached form an azetidinyl combination: or pyrrolidinyl ring, each optionally Substituted by one or I0087 (i) methyl, two substituents independently selected from fluorine, I0088 (ii) trifluoromethyl, hydroxyl and methoxy. I0089 (iii) methoxy, 10118. In a seventh embodiment, RandR together with 0090 (iv) ethoxy, the nitrogen atom to which they are attached form an 0091 (v) isopropyloxy, aZetidinyl, pyrrolidinyl or piperidinyl ring, each optionally 0092 (vi) difluoromethoxy, Substituted by a methoxy group. 0093 (vii) trifluoromethoxy, I0119 Rand R7 each independently represent a hydrogen atom or a C. C or C alkyl or C-C cycloalkyl (cyclopro 0094 (viii) fluorine, pyl, cyclobutyl, cyclopentyl or cyclohexyl) group, or R and 0095 (ix) chlorine, R" may together with the nitrogen atom to which they are 0096 (x) bromine, attached form a 4-, 5-, 6- or 7-membered saturated hetero 0097 (xi) triazolyl (e.g. 1,2,3-triazol-2-yl, 1,2,3-triazol cyclic ring optionally Substituted by at least one Substituent, 1-yl or 1,2,4-triazol-1-yl), e.g. one or two Substituents, independently selected from 0098 (xii) pyrazolyl (e.g. pyrazol-1-yl), halogen (e.g. fluorine, chlorine, bromine or iodine) and 0099 (xiii) oxadiazolyl, hydroxyl. 0100 (xiv) 3-methyl-1,2,4-oxadiazol-5-yl, I0120 In one aspect, the saturated heterocyclic ring may 010.1 (XV) azetidinyl (e.g. azetidin-1-yl), contain a single ring heteroatom being the nitrogen atom 0102 (xvi) 3-methoxyazetidin-1-yl, which R and Rare attached). 0103 (xvii) pyrrolidinyl (e.g. pyrrolidin-1-yl), I0121. In an alternative aspect, the saturated heterocyclic 0104 (xviii) piperidinyl (e.g. piperidin-1-yl), ring may contain a second ring heteroatom selected from a 0105 (xix) pyrimidinyl (e.g. pyrimidin-2-yl), nitrogen or oxygen atom. 0106 (XX) imidazolyl (e.g. imidazol-1-yl), and I0122) In one embodiment, Rand Reach independently 0107 (xxi) cyclopropyl. represent a hydrogen atom or a C. C or C alkyl or C-C, 0108. When R represents a substituted 6-membered or C-C or Cs-C cycloalkyl, particularly cyclopropyl, and monocyclic heteroaromatic group, the Substituent(s) is/are group, or R and R may together with the nitrogen atom to US 2017/0073340 A1 Mar. 16, 2017

which they are attached form a 4 or 5-membered saturated 0152 Examples of compounds of the invention include: heterocyclic ring optionally substituted by one or two sub (O153 3-Bromo-N-(1S, 2S)-2-(6-fluoro-1,3-benzothi stituents independently selected from fluorine, chlorine, azol-2-yl)aminocyclopentyl-pyridine-2-carboxamide; bromine and hydroxyl. 0154 6-Bromo-N-(1S. 2S)-2-(6-fluoro-1,3-benzothi (0123. In a second embodiment, Rand Reach represent azol-2-yl)aminocyclopentyl-3-methoxypyridine-2-carbox a hydrogen atom. amide; 0124. In a third embodiment, R and R7 each represent a (O155 N-(1S,2S)-2-(6-Fluoro-1,3-benzothiazol-2-yl) C-C alkyl group. aminocyclopentyl-3-methoxypyridine-2-carboxamide; 0125. In a fourth embodiment, one of R and R7 repre 0156 3-Chloro-N-(1S,2S)-2-(6-fluoro-1,3-benzothi sents a hydrogen atom and the other of R and R7 represents aZol-aminocyclopentylpyridine-2-carboxamide; a C-C alkyl group. (O157 N-(1S, 2S)-2-(6-Fluoro-1,3-benzothiazol-2-yl) 0126. In a fifth embodiment, one of R and R7 represents aminocyclopentyl-3-methoxy-N-methylpyridine-2-car a cyclopropyl group and the other of R and R7 represents a boxamide; C-C alkyl group. 0158 N-(1S,2S)-2-(6-Fluoro-1,3-benzothiazol-2-yl) I0127. In a sixth embodiment, RandR together with the aminocyclopentyl-3-(2H-1,2,3-triazol-2-yl)pyridine-2- nitrogen atom to which they are attached form an azetidinyl carboxamide; or pyrrolidinyl ring optionally substituted by one or two 0159) N-1S,2S)-2-(6-Fluoro-1,3-benzoxazol-2-yl) substituents independently selected from fluorine and aminocyclopentyl-3-methoxypyridine-2-carboxamide; hydroxyl. 0160 N-(1S,2S)-2-(6-Fluoro-1,3-benzothiazol-2-yl) I0128 R represents a C-C, or C-C, or C-C alkyl, aminocyclopentyl-3-(propan-2-yloxy)pyridine-2-carbox C-C, or C-C, or C-C alkoxy, benzyloxy, Co-Co aryl, or amide; heteroaryl group. 0.161 N-(1S,2S)-2-(6-Fluoro-1,3-benzothiazol-2-yl) I0129. In one embodiment, R represents a C-C alkyl, aminocyclopenyl-3-methoxy-6-methylpyridine-2-carbox C-C alkoxy or benzyloxy group. amide; I0130. In another embodiment, R represents a C-C, 0162 N-(1S,2S)-2-(6-fluoro-1,3-benzothiazol-2-yl) alkoxy or benzyloxy group. aminocyclopentyl-3-(1H-pyrazol-1-yl)pyridine-2-carbox 0131) R' and R'' are defined as for R and Rabove. amide; (0132) R'' and R' are defined as for R and R7 above. (0163 3-Fluoro-N-(1S,2S)-2-(6-fluoro-1,3-benzothi 0133. In a preferred embodiment of the invention, azol-2-yl)aminocyclopentylpyridine-2-carboxamide: 0134) R' represents a 9- or 10-membered fused bicyclic 0164 N-(1S,2S)-2-(6-Fluoro-1,3-benzothiazol-2-yl) heteroaromatic group optionally Substituted by at least one aminocyclopentyl-3-(piperidin-1-yl)pyridine-2-carboxam halogen atom; ide; 0135 L represents NH; 0.165 3-(AZetidin-1-yl)-N-(1S,2S)-2-(6-fluoro-1,3- 0.136 R. represents a hydrogen atom; benzothiazol-2-yl)aminocyclopentylpyridine-2-carbox I0137) R' represents a hydrogen atom; amide; 0138 X represents CHR: 0166 N-(1S,2S)-2-(6-Fluoro-1,3-benzothiazol-2-yl) I0139 R represents hydrogen or methyl: aminocyclopentyl-3-(pyrrolidin-1-yl)pyridine-2-carbox 0140 R represents a 5- or 6-membered monocyclic amide; heteroaromatic group optionally Substituted by at least one (0167 N-(1S,2S)-2-(6-Fluoro-1,3-benzothiazol-2-yl) substituent independently selected from fluorine, chlorine, aminocyclopentyl-3-(3-methoxyaZetidin-1-yl)pyridine-2- bromine, C-C alkyl, C-C alkoxy, or a 5- or 6-membered carboxamide; heteroaryl group; and 0.168. 3-Methoxy-N-(1S,2S)-2-(duinoxalin-2-yl)amino 0141 R represents a hydrogen atom. cyclopentylpyridine-2-carboxamide; 0142. In another preferred embodiment, (0169 N-(1S: 2S)-2-(6-Fluoro-1,3-benzothiazol-2-yl) 0143 R represents a 9- or 10-membered fused bicyclic aminocyclopentyl-3-methoxy-6-(trifluoromethyl)pyri heteroaromatic group optionally Substituted by at least one dine-2-carboxamide; halogen atom; (0170 3-Ethoxy-N-(1S,2S)-2-(6-fluoro-1,3-benzothi 014.4 L represents NH; azol-2-yl)aminocyclopentylpyridine-2-carboxamide; 0145 R represents a hydrogen atom; 0171 N-(1S,2S)-2-(6-fluoro-1,3-benzothiazol-2-yl) I0146) R' represents a hydrogen atom; aminocyclopentyl-3-(trifluoromethoxy)pyridine-2-car 0147 X represents CHR: boxamide; I0148 R represents hydrogen or methyl: (0172 3-(Difluoromethoxy)-N-(1S,2S)-2-(6-fluoro-1,3- I0149 R represents a pyridinyl group optionally substi benzothiazol-2-yl)aminocyclopentylpyridine-2-carboxam tuted by at least one Substituent, e.g. one or two Substituents, ide; independently selected from fluorine, chlorine, bromine, (0173 N-(1S,2S)-2-(6-Chloro-1,3-benzothiazol-2-yl) C-C alkyl, C-C haloalkyl, C-C alkoxy, C-C, aminocyclopentyl-3-(2H-1,2,3-triazol-2-yl)pyridine-2- haloalkoxy, NR'R' or a 5- to 6-membered heteroaryl carboxamide; group which is unsubstituted; 0.174 N-(1S,2S)-2-(6-Chloro-1,3-benzothiazol-2-yl) 0150 R represents a hydrogen atom; and aminocyclopentyl-3-(difluoromethoxy)pyridine-2-carbox 0151) R' and R'' together with the nitrogen atom to amide; which they are attached form a 4- to 6-membered saturated (0175 3-(Difluoromethoxy)-N-(1S,2S)-2-(6-fluoro-1,3- heterocyclic ring optionally substituted by at least one C-C, benzoxazol-2-yl)aminocyclopentylpyridine-2-carboxam alkoxy group. ide; US 2017/0073340 A1 Mar. 16, 2017

(0176 N-(1S,2S)-2-(6-Fluoro-1,3-benzothiazol-2-yl) (0189 removing any protecting groups aminocyclopenyl-3-(1H-1,2,3-triazol-1-yl)pyridine-2-car boxamide; 0190. forming a pharmaceutically acceptable salt. (0177 N-(1S,2S)-2-(6-Chloro-1,3-benzoxazol-2-yl) 0191 Process (i) may conveniently be carried out by aminocyclopentyl-3-(difluoromethoxy)pyridine-2-carbox combining the amine of formula (II) with an acid chloride of amide; formula (III) in the presence of a base such as triethylamine 0.178 3-Ethoxy-6-methyl-N-2-(duinolin-2-ylmethyl)cy or DIPEA (N,N-diisopropylethylamine) in a solvent such as clopentylpyridine-2-carboxamide; . Alternatively the reaction can be carried 0179 3-Ethoxy-6-methyl-M-2-(duinolin-2-ylmethyl) out from the amine of formula (II) and a carboxylic acid of cyclopentylpyridine-2-carboxamide; formula (III) using any of the known coupling reagents such 0180 enantiomers thereof and pharmaceutically accept as EDC (1-ethyl-3-(3-dimethylaminopropyl)carbodiimide) able salts of any of the foregoing. and HOAt (7-aza-1-hydroxybenzotriazole), with or HATU 0181. It should be noted that each of the chemical com (1bis(dimethylamino)methylene)-1H-1,2,3-triazolo 4,5-b] pounds listed above represents a particular and independent pyridinium 3-oxid hexafluorophosphate) with a base Such as aspect of the invention. DIPEA. Another method is to activate the carboxylic acid to 0182. The present invention further provides a process the corresponding acid chloride in situ for example with for the preparation of a compound of formula (I) or a oxalyl chloride in the presence of a catalytic amount of pharmaceutically acceptable salt thereof as defined above DMF. which comprises 0.192 Process (ii) may conveniently be carried out by 0183 (i) reacting a compound of formula mixing the compound of formula (IV) with the compound of formula (V) in a solvent such as DMSO, acetonitrile or (II) and optionally in the presence of a base such as X DIPEA, and heating conventionally or using microwave irradiation. Ra Rb 0193 Compounds of formula (II) in which L represents RNL NH I CH, X represents CH, and R and R are each hydrogen R2 may be prepared according to the scheme below. The heterocyclic bromomethylene compound is likely to be commercially available or can be prepared by bromination 0184 wherein L, X, R", R, R and Rare as defined in of the corresponding heterocyclic methyl compound using, formula (I), with a compound of formula for example, N-bromosuccinimide and benzoyl peroxide in carbon tetrachloride at elevated temperature. Reaction of the heterocyclic bromomethylene compound with triphenyl (III) phosphine in toluene at raised temperature will afford the corresponding phosphonium which on treatment with a base such as n-butyl lithium in the presence of the Boc-protected cyclic ketone will afford the corresponding alkene. The alkene can be reduced by hydrogenation using 0185 wherein R' represents a halogen atom (e.g. chlo hydrogen gas in the presence of a catalyst Such as palladium rine atom) or a hydroxyl group and R is as defined in on carbon. Finally, the Boc protecting group can be removed formula (I), or a salt (e.g. hydrochloride salt) thereof; or using methods known to those skilled in the art, e.g. acid 0186 (ii) when L represents NH or N(CH), reacting a hydrolysis. compound of formula

(IV) 11' --Step (), I-1N. --Step (ii) X O GE O Step (iii) Ra Rb P RI PPh3 Br + -e- R-N125 l RNN2 V R1, R Boc R1 0187 wherein R represents a hydrogen atom or methyl N group and X, R. R. RandR are as defined in formula (I), Step (iv) R. Step (v) with a compound of formula (V), R'-LG', wherein LG' -e- -e- represents a leaving group (e.g. a halogen atom) and R' is as defined in formula (I); and optionally thereafter carrying out R-N RN V V one or more of the following procedures: Boc Boc 0188 converting a compound of formula (I) into another compound of formula (I) US 2017/0073340 A1 Mar. 16, 2017

-continued formula (III) followed by removal of the protecting group, LG', by acid treatment using, for example, an acid such as hydrochloric acid. 0201 Compounds of formula (IV) in which X represents NC(O)R’ may be prepared by acylating a compound of formula (II) wherein L = CH Boc = tert-butyloxycarbonyl (X) H N 0194 Compounds of formula (II) in which L represents an oxygenatom may be prepared by reacting a compound of Ra Rb O formula RSN25 -( RI R' (VI) X (0202 in which R", R. R. R. and Rare as defined in Ra Rb formula (IV), with an acylating agent of formula (IX) as defined above. HO NH I (0203 Compounds of formulae (III), (V), (VI), (VII), R2 (VIII), (IX) and (X) are either commercially available, are well known in the literature or may be prepared using known techniques. (0195 wherein X, R, R and R is as defined in formula 0204. It will be appreciated by those skilled in the art that (II), with a compound of formula (V) as defined above, in in the processes of the present invention certain functional the presence of a base Such as Sodium hydride. groups such as , hydroxyl or amino groups in the 0196) Compounds of formula (IT) in which L represents reagents may need to be protected by protecting groups. NH or N(CH) may be prepared by reacting a compound of Thus, the preparation of the compounds of formula (I) may formula involve, at an appropriate stage, the introduction and/or removal of one or more protecting groups. (VII) 0205 The protection and deprotection of functional X groups is described in Protective Groups in Organic Chem istry, edited by J. W. F. McOmie, Plenum Press (1973) and Ra Rb Protective Groups in Organic Synthesis, 3' edition, T. W. LGNN NH Greene and P. G. M. Wuts, Wiley Interscience (1999). \ f 0206. The compounds of formula (I) above may be R25 R2 converted to a pharmaceutically acceptable salt thereof, preferably an acid addition salt such as a formate, hemi formate, hydrochloride, hydrobromide, benzenesulphonate (0197) in which LG represents a protecting group such as (besylate), Saccharin (e.g. monosaccharin), trifluoroacetate, a tert-butyloxycarbonyl group, and X, R. R. R and Rare Sulphate, nitrate, phosphate, acetate, fumarate, maleate, tar as defined in formula (IV) above, with a compound of trate, lactate, citrate, pyruvate. Succinate, Valerate, propano formula (V) as defined above. ate, butanoate, malonate, oxalate, 1-hydroxy-2-napthoate 0198 Compounds of formula (II) in which X represents (Xinafoate), methanesulphonate or p-toluenesulphonate salt. NC(O)R may be prepared by acylating a compound of 0207. In one aspect of the invention, compounds of formula formula (I) may bear one or more radiolabels. Such radio labels may be introduced by using radiolabel-containing (VIII) reagents in the synthesis of the compounds of formula (I), or H may be introduced by coupling the compounds of formula N (I) to chelating moieties capable of binding to a radioactive metal atom. Such radiolabeled versions of the compounds Ra Rb may be used, for example, in diagnostic imaging studies. RNI NH 0208 Unless stated otherwise, any atom specified herein f may also be an isotope of said atom. For example, the term R2 “hydrogen’ encompasses H., H and H. Similarly carbon atoms are to be understood to include C, C and ''C, (0199 in which L, R, R, R and R are as defined in nitrogen atoms are to be understood to include ''N and 'N, formula (II), with an acylating agent of formula (IX), and oxygen atoms are to be understood to include 'O, ''O RC(O)-LG, in which LG represents a leaving group (e.g. and O. a halogen atom) and R is as defined in formula (I). 0209. In a further aspect of the invention, compounds of 0200 Compounds of formula (IV) may be prepared by formula may be isotopically labelled. As used herein, an reacting a compound of formula (VII) with a compound of “isotopically labelled’ compound is one in which the abun US 2017/0073340 A1 Mar. 16, 2017 dance of a particular nuclide at a particular atomic position include those having a family history of the disorder or within the molecule is increased above the level at which it condition, or those who have been identified by genetic occurs in nature. testing or screening to be particularly Susceptible to devel 0210 Compounds of formula (I) and their salts may be in oping the disorder or condition or those in the prodromal the form of hydrates or solvates which form an aspect of the phase of a disorder. present invention. Such solvates may be formed with com 0218. In particular, the compounds of the invention (in mon organic solvents, including but not limited to, alcoholic cluding pharmaceutically acceptable salts) may be used in Solvents e.g. , ethanol or isopropanol. the treatment of the positive symptoms of Schizophrenia, 0211 Where compounds of formula (I) are capable of schizophreniform disorder or schizoaffective disorder (e.g. existing in stereoisomeric forms, it will be understood that Voices or hallucinations), cognitive disorders (such as the invention encompasses the use of all geometric and dementia and impaired learning), anxiety disorders (such as optical isomers (including atropisomers) of the compounds post-traumatic stress to disorder or panic disorders), or of formula (I) and mixtures thereof including racemates. The addiction. use of tautomers and mixtures thereof also forms an aspect 0219. The invention also provides a method of treating at of the present invention. Enantiomerically pure forms are least one symptom or condition associated with Schizophre particularly desired. nia and other psychotic disorders (e.g., psychotic disorder, 0212 Compounds of formula (I) and their salts may be psychosis or Schizoaffective disorder); dementia and other amorphous or in a polymorphic form or a mixture of any of cognitive disorders; anxiety disorders (e.g., generalized these, each of which forms an aspect of the present inven anxiety disorder, post-traumatic stress disorder, panic disor tion. ders, acute stress disorder, social anxiety disorder, phobias 0213. The compounds of formula (I) and their pharma including agoraphobia, obsessive compulsive disorder, ceutically acceptable salts have activity as pharmaceuticals, trichlofillomania or body dismorphic disorder): mood dis in particular as orexin receptor antagonists, and may be used orders (e.g., depressive disorders, major depressive disor in the treatment of Schizophrenia and other psychotic dis ders, bipolar disorders including bipolar I and II, bipolar orders (e.g., psychotic disorder, psychosis or schizoaffective mania, bipolar depression); addiction including Substance disorder); dementia and other cognitive disorders; anxiety dependence (e.g. cocaine, opiates, or prescription disorders (e.g., generalized anxiety disorder, post-traumatic drug dependence), dependence, nicotine dependence stress disorder, panic disorders, acute stress disorder, social or gambling disorder, eating disorders (e.g., binge eating, anxiety disorder, phobias including agoraphobia, obsessive bulimia nervosa, anorexia nervosa or obesity); sleep disor compulsive disorder, trichlofillomania or body dismorphic ders (e.g. rapid eye movement sleep disorder); disorders disorder): mood disorders (e.g., depressive disorders, major usually first diagnosed in infancy, childhood, or adolescence depressive disorders, bipolar disorders including bipolar I (e.g., attention-deficit disorder, autistic spectrum disorders, and II, bipolar mania, bipolar depression); addiction includ Rett syndrome, Fragile X syndrome, Asperger syndrome and ing Substance dependence (e.g. cocaine, opiates, cannabis or disruptive behaviour disorders); restless leg syndrome; pain prescription drug dependence), alcohol dependence, nico (e.g. neuropathic pain including chemotherapy induced pain tine dependence or gambling disorder, eating disorders (e.g. or migraine); and neurodegenerative disorders (e.g. Parkin binge eating, bulimia nervosa, anorexia nervosa or obesity); son's or Alzheimer's disease) which comprises administer sleep disorders (e.g. rapid eye to movement sleep disorder): ing to a patient in need thereof a therapeutically effective disorders usually first diagnosed in infancy, childhood, or amount of a compound of formula (I) or a pharmaceutically adolescence (e.g., attention-deficit disorder, autistic spec trum disorders, Rett syndrome, Fragile X syndrome, acceptable salt thereof as hereinbefore defined. Asperger syndrome and disruptive behaviour disorders); 0220 Such symptoms and conditions include, but are not restless leg syndrome; pain (e.g. neuropathic pain including limited to, anxiety, agitation, hostility, panic, an eating chemotherapy induced pain or migraine); and neurodegen disorder, an affective symptom, a mood symptom, a negative erative disorders (e.g. Parkinson's or Alzheimer's disease), and positive psychotic symptom commonly associated with 0214 Thus, the present invention provides a compound psychosis and neurodegenerative disorder. of formula (I) or a pharmaceutically acceptable salt thereof 0221 For the above-mentioned therapeutic uses the dos as hereinbefore defined for use in therapy, in particular for age administered will, of course, vary with the compound the treatment of conditions whose development or symp employed, the mode of administration, the treatment desired toms are linked to orexin receptor activity. and the disorder indicated. For example, the daily dosage of 0215. The present invention also provides the use of a the compound of the invention, if inhaled, may be in the compound of formula (I) or a pharmaceutically acceptable range from 0.05 micrograms per kilogram body weight salt thereof as hereinbefore defined for the preparation of a (ug/kg) to 100 micrograms per kilogram body weight (ug/ medicament for the treatment of conditions whose develop kg). Alternatively, if the compound is administered orally, ment or symptoms are linked to orexin receptor activity. then the daily dosage of the compound of the invention may 0216. In the context of the present specification, the term be in the range from 0.01 micrograms per kilogram body “therapy' also includes “prophylaxis' unless there are spe weight (ug/kg) to 100 milligrams per kilogram body weight cific indications to the contrary. The terms “therapeutic' and (mg/kg). “therapeutically should be construed accordingly. 0222. The compounds of formula (I) and pharmaceuti 0217 Prophylaxis is expected to be particularly relevant cally acceptable salts thereof may be used on their own but to the treatment of persons who have suffered a previous will generally be administered in the form of a pharmaceu episode of, or are otherwise considered to be at increased tical composition in which the formula (I) compound/salt risk of the disorder or condition in question. Persons at risk (active ingredient) is in association with a pharmaceutically of developing a particular disorder or condition generally acceptable adjuvant, diluent or carrier. US 2017/0073340 A1 Mar. 16, 2017

0223) Therefore the present invention further provides a 0229. The pharmaceutical compositions of this invention pharmaceutical composition comprising a compound of may be orally administered in any orally acceptable dosage formula (I) or a pharmaceutically acceptable salt thereof as form including, but not limited to, capsules, tablets, pow hereinbefore defined, in association with a pharmaceutically ders, granules, and aqueous Suspensions and Solutions. acceptable adjuvant, diluent or carrier. These dosage forms are prepared according to techniques 0224. The invention still further provides a process for well-known in the art of pharmaceutical formulation. In the the preparation of a pharmaceutical composition of the case of tablets for oral use, carriers which are commonly invention which comprises mixing a compound of formula used include lactose and corn starch. Lubricating agents, (I) or a pharmaceutically acceptable salt thereof as herein Such as magnesium Stearate, are also typically added. For before defined with a pharmaceutically acceptable adjuvant, oral administration in a capsule form, useful diluents include diluent or carrier. lactose and dried corn starch. When aqueous Suspensions are 0225 Conventional procedures for the selection and administered orally, the active ingredient is combined with preparation of Suitable pharmaceutical formulations are emulsifying and Suspending agents. If desired, certain described in, for example, “Pharmaceutics. The Science of Sweetening and/or flavouring and/or colouring agents may Dosage Form Design, M. E. Aulton, Churchill Livingstone, be added. 1988. 0230. The pharmaceutical compositions of the invention 0226 Pharmaceutically acceptable adjuvants, diluents or may also be administered in the form of Suppositories for carriers that may be used in the pharmaceutical composi rectal administration. These compositions can be prepared tions of the invention are those conventionally employed in by mixing the active ingredient with a Suitable non-irritating the field of pharmaceutical formulation, and include, but are excipient which is solid at room temperature but liquid at the not limited to, Sugars, Sugar , starches, ion exchang rectal temperature and therefore will melt in the rectum to ers, alumina, aluminium Stearate, lecithin, serum proteins release the active ingredient. Such materials include, but are Such as human serum albumin, buffer Substances such as not limited to, cocoa butter, beeswax and polyethylene phosphates, glycerine, Sorbic acid, potassium Sorbate, partial glycols. glyceride mixtures of Saturated vegetable fatty acids, water, 0231. The pharmaceutical compositions of this invention salts or electrolytes Such as protamine Sulphate, disodium may be administered by nasal aerosol or inhalation. Such hydrogen phosphate, potassium hydrogen phosphate, compositions are prepared according to techniques well Sodium chloride, Zinc salts, colloidal silica, magnesium known in the art of pharmaceutical formulation and may be trisilicate, polyvinyl pyrrolidone, cellulose-based sub prepared as solutions in saline, employing benzyl alcohol or stances, polyethylene glycol, Sodium carboxymethylcellu other Suitable preservatives, absorption promoters to lose, polyacrylates, waxes, polyethylene-polyoxypropylene enhance bioavailability, fluorocarbons, and/or other solu block polymers, polyethylene glycol and wool fat. bilising or dispersing agents known in the art. 0227. The pharmaceutical compositions of the present 0232 Depending on the mode of administration, the invention may be administered orally, parenterally, by inha pharmaceutical composition will preferably comprise from lation spray, rectally, nasally, buccally, vaginally or via an 0.05 to 99% w (per cent by weight), more preferably from implanted reservoir. Oral administration is preferred. The 0.05 to 80% w, still more preferably from 0.10 to 70% w, and pharmaceutical compositions of the invention may contain even more preferably from 0.10 to 50% of active ingredient, any conventional non-toxic pharmaceutically acceptable all percentages by weight being based on total composition. adjuvants, diluents or carriers. The term parenteral as used 0233. The compounds of the invention (that is, com herein includes Subcutaneous, intracutaneous, intravenous, pounds of formula and pharmaceutically acceptable salts intramuscular, intra-articular, intrasynovial, intrasternal, thereof) may also be administered in conjunction with other intrathecal, intralesional and intracranial injection or infu compounds used for the treatment of the above conditions. sion techniques. 0234. The invention therefore further relates to combi 0228. The pharmaceutical compositions may be in the nation therapies wherein a compound of the invention or a form of a sterile injectable preparation, for example, as a pharmaceutical composition or formulation comprising a sterile injectable aqueous or oleaginous Suspension. The compound of the invention is administered with another Suspension may be formulated according to techniques therapeutic agent or agents for the treatment of one or more known in the art using Suitable dispersing or wetting agents of the conditions previously indicated. Such therapeutic (such as, for example, Tween 80) and Suspending agents. agents may be selected from the following: The sterile injectable preparation may also be a sterile 0235 (i) such as, for example, amitrip injectable solution or Suspension in a non-toxic parenterally tyline, amoxapine, bupropion, citalopram, clomipramine, acceptable diluent or solvent, for example, as a solution in desipramine, dulloxetine, elzasonan, escitalopram, 1,3-butanediol. Among the acceptable diluents and solvents fluvoxamine, , gepirone, imipramine, ipsapirone, that may be employed are mannitol, water, Ringer's Solution maprotiline, nortriptyline, , paroxetine, phenel and isotonic sodium chloride solution. In addition, sterile, Zine, protriptyline, reboxetine, robaizotan, Sertraline, fixed oils are conventionally employed as a solvent or Sibutramine, tianeptine, thionisoxetine, tranylcypromaine, Suspending medium. For this purpose, any bland fixed oil , trimipratnine, Venlafaxine, Vortioxetine and may be employed including synthetic mono- or diglycerides. equivalents and pharmaceutically active isomer(s) and/or Fatty acids, such as oleic acid and its glyceride derivatives metabolite(s) thereof; are useful in the preparation of injectables, as are natural 0236 (ii) including, for example, amisul pharmaceutically acceptable oils, such as olive oil or castor pride, aripiprazole, asenapine, benzisoxidil, bifeprunoX, oil, especially in their polyoxyethylated versions. These oil brexpiprazole, , cariprazine, clozapine, chlo Solutions or Suspensions may also contain a long-chain rpromazine, debenzapine, divalproex, dulloxetine, esZopi alcohol diluent or dispersant. clone, haloperidol, illoperidone, lamotrigine, loxapine, lur US 2017/0073340 A1 Mar. 16, 2017 asidone, mesoridazine, , paliperidone, , 0246 (xii) therapies including, for example, perphenazine, phenothiazine, phenylbutlypiperidine, pimoZ , alonimid, , benzoctamine, butabar ide, prochlorperazine, , , sertindole, bital, capuride, , cloperidone, clorethate, dexclamol. Sulpiride, , , , trifluopera , , , , halaze Zine, trimetozine, Valproate, Valproic acid, , pam, hydroxy Zine, lorediplon, , , Zotepine, Zicronapine, Ziprasidone, and equivalents and mephobarbital, , , , pento pharmaceutically active isomer(s) and/or metabolite(s) , , , ralmeteon, roletamide, thereof , , , , and , 0237 (iii) anxiolytics including, for example, alne Zopiclone and equivalents and pharmaceutically active iso spirone, azapirones, , , and mer(s) and/or metabolite(s) thereof; equivalents and pharmaceutically active isomer(s) and/or 0247 (xiii) mood stabilizers including, for example, car metabolite(s) thereof. Example anxiolytics includeadinaZo bamazepine, divalproex, , lamotrigine, lithium, lam, , balezepam, , , olanzapine, quetiapine, Valproate, valproic acid, and Vera , buspirone, , , chlordiaz pamil, and equivalents and pharmaceutically active isomer epoxide, , , , estaZo (s) and/or metabolite(s) thereof; lam, fenobam, , , , lora 0248 (xiv) 5HT1B ligands such as, for example, com Zepam, , , , pounds disclosed in WO99/05134 and WO 02/0821 , , , , , 0249 (XV) mGluR2 agonists: , trepipam, , , , 0250 (xvi) alpha 7 nicotinic agonists such as, for and , and equivalents and pharmaceutically active example, compounds disclosed in WO 96/006098, WO isomer(s) and/or metabolite(s) thereof; 97/030998, WO 99/003859, WO 00/042044, WO 0238 (iv) anticonvulsants including, for example, car 01/029034, WO 01/60821, WO 01/36417, WO 02/096912, bamazepine, valproate, lamotrigine, levetiracetam and gaba WO 03/087102, WO 03/087103, WO 03/087104, WO 2004/ pentin, and equivalents and pharmaceutically active isomer O16617, WO 2004/016616, and WO 2004/019947: (s) ro and/or metabolite(s) thereof; 0251 (xvii) chemokine receptor CCR1 inhibitors; and 0239 (v) Alzheimer's therapies including, for example, 0252 (xviii) delta agonists such as, for example, donepezil, galantamine, memantine, rivastigmine, tacrine, compounds disclosed in WO97/234.66 and WO 02/094794. and equivalents and pharmaceutically active isomer(s) and/ 0253 Such combination products employ the compounds or metabolite(s) thereof; of this invention within the dosage range described herein 0240 (vi) Parkinson's therapies including, for example, and the other pharmaceutically active agent within approved L-dopa, ropinirole, pramipexole, monoamine oxidase type B dosage to ranges and/or the dosage such as described in the (MAO-B) inhibitors such as deprenyl, selegiline and rasa publication reference. giline, catechol-O-methyl transferase (COMT) inhibitors 0254 tin a further aspect the present invention provides Such as entacapone or tolcapone, adenosine A-2 inhibitors, a combination (for example for the treatment of schizophre dopamine re-uptake inhibitors, NMDA antagonists, Nicotine nia, cognitive disorders or pain) of a compound of formula agonists, and Dopamine agonists and inhibitors of neuronal (I) or a pharmaceutically acceptable salt thereof as herein synthase, and equivalents and pharmaceutically before defined and one or more agents selected from car active isomer(s) and/or metabolite(s) thereof; bamazepine, olanzapine, quetiapine, Verapamil, lamotrigine, 0241 (vii) migraine therapies including, for example, oXcarbazepine, risperidone, aripiprazole, Ziprasidone and almotriptan, amantadine, botulinum toxin A, bromocriptine, lithium. , cabergoline, , dihydroergot 0255. The invention also provides a pharmaceutical prod amine, eletriptan, froVatriptan, lisuride, naratriptan, per uct comprising, in combination, a preparation of a first golide, pramipexole, rizatriptan, ropinirole, Sumatriptan, active ingredient which is a compound of formula (I) or a , Zolmitriptan, and Zomitriptan, and equivalents pharmaceutically acceptable salt thereof as hereinbefore and pharmaceutically active isomer(s) and/or metabolite(s) defined, and a preparation of a second active ingredient thereof which is carbamazepine, olanzapine, quetiapine, Verapamil, 0242 (viii) stroke therapies including, for example, lamotrigine, Oxcarbazepine, risperidone, aripiprazole, Zip abciximab, activase, citicoline, desmoteplase, and equiva rasidone or lithium, for simultaneous, sequential or separate lents and pharmaceutically active isomer(s) and/or metabo use in therapy. lite(s) thereof; 0256 In another aspect, the invention provides a kit 0243 (ix) urinary incontinence therapies including, for comprising a preparation of a first active ingredient which is example, darafenacin, duloxetine, falvoxate, mirabegron, a compound of formula (I) or a pharmaceutically acceptable oxybutynin, propiverine, robalZotan, Solifenacin, and tolt salt thereof as hereinbefore defined, and a preparation of a erodine, and equivalents and pharmaceutically active isomer second active ingredient which is carbamazepine, olanzap (s) and/or metabolite(s) thereof; ine, quetiapine, Verapamil, lamotrigine, Oxcarbazepine, ris 0244 (X) neuropathic pain therapies including, for peridone, aripiprazole, Ziprasidone or lithium, and instruc example, capsaicin, gabapentin, lidoderm, and , tions for the simultaneous, sequential or separate and equivalents and pharmaceutically active isomer(s) and/ administration of the preparations to a patient in need or metabolite(s) thereof; thereof. 0245 (xi) nociceptive pain therapies such as, for (0257. The present invention will now be further example, celecoxib, etoricoxib, lumiracoxib, rofecoxib, val explained by reference to the following illustrative decoxib, diclofenac, loxoprofen, naproxen, and paraceta examples. mol, and equivalents and pharmaceutically active isomer(s) 0258. The methods used for synthesis of the compounds and/or metabolite(s) thereof; of the invention are illustrated by the general schemes below US 2017/0073340 A1 Mar. 16, 2017

and the preparative examples that follow. The starting mate 1. INTERMEDIATES rials and reagents used in preparing these compounds are available from commercial Suppliers. These general schemes are merely illustrative of methods by which the Intermediate 1: (1S,2S)-1-N-(6-Fluoro-1,3-benzothi compounds of this invention can be synthesised, and various azol-2-yl)cyclopentane-1,2-diamine hydrochloride modifications to these schemes can be made and will be Suggested to one skilled in the art having referred to this 0278 disclosure. 0259 Nuclear magnetic resonance (NMR) spectra were recorded at 400 MHz; the chemical shifts (8) are reported in parts per million. Spectra were recorded using a Balker 400 Avance instrument fitted with a 5 mm BBFO probe or DUL probe. Instrument control was by Bruker TopSpin 2.1 soft N e ware, unless stated otherwise. 0260 Purity was assessed using UPLC with UV (photo y-f SH, HCI diode array) detection over a wide range of wavelengths, F S normally 220-450 nm, using a Waters Acquity UPLC system equipped with Acquity UPLC BEH or HSS C18 columns (2.1 mm idx50 mm long) operated at 50 or 60° C. Mobile 0279 A microwave vial was charged with tert-butyl phases typically consisted of acetonitrile or methanol mixed N-(1S,2S)-2-aminocyclopentylcarbamate (CAS number with water containing either 0.05% formic acid or 0.025% 586961-34-4; 1.00 g, 4.99 mmol) and 2-chloro-6-fluoro-1, ammonia. 3-benzothiazole (CAS number 399-74-6; 1.03 g, 5.49 mmol) 0261 Mass spectra were recorded with a Waters SQD in dry DMSO (15 ml). DIPEA (2.62 ml, 14.98 mmol) was single quadrupole mass spectrometer using atmospheric added, the vial flushed with nitrogen and sealed. The reac pressure ionisation, unless stated otherwise. tion mixture was subjected to microwave irradiation at 140° 0262 Compounds were purified using normal phase C. for 1.5 hours and upon cooling was dissolved in ethyl chromatography on silica or alumina, or by reverse phase acetate and washed with HCl (0.5 M), water and brine. The chromatographic methods, using Biotage or Isolute KPNH organics were filtered through a hydrophobic frit and con Cartridge, SCX cartridge and SCX-2 solid phase extraction centrated in mow. The crude material was purified by cartridges. column chromatography (silica, 0-50% ethyl acetate/petrol) 0263. Preparative High Performance Liquid Chromatog to afford the Boc-protected intermediate which was dis raphy (HPLC) was performed using an Agilent Technologies solved in 1,4-dioxane (5 ml) and then HCl in 1,4-dioxane (4 1100 Series system or Waters autopurification system M, 4 ml, 16.00 mmol) was added. The reaction was stirred typically using Waters 19 mm idx100 mm or 19 mm idx250 at room temperature for 2 hours and concentrated in vacuo mm C18 columns such as XBridge or SunFire 5 um mate to afford the title compound. rials at 20 mL/min. Mobile phases typically consisted of acetonitrile or methanol mixed with water containing either 0280 MS ES: 252 0.1% formic acid or 0.1% ammonia, unless stated otherwise. 0264. In the following descriptions “room temperature' denotes a temperature in the range from 20° C. to 25°C. 0265. The abbreviations used in the specific examples have the following meanings: 0266 AZa-HOBt (HOAt)=7-Aza-1-hydroxybenzoniaz ole 0267 Boc=tert-Butyloxycarbonyl 0268 DCM=Dichloromethane 0269. DIPEA-N,N-Diisopropylethylamine (0270 DMF-N,N-Dimethylformamide (0271. DMSO–Dimethyl sulfoxide 0272 EDC=1-Ethyl-3-(3-dimethylaminopropyl)carbodi Boc-NH imide (0273 HATU=1-Bis(dimethylamino)methylene)-1H-1,2, 3-triazolo 4,5-b]pyridinium 3-oxid hexafluorophosphate 0274. Herrmanns Catalyst=trans-bis(Acetato)biso-(di-o- tolylphosphino)benzyl dipalladium(II) (0275 RuPhos-Palladacycle-Chloro(2-dicyclohexyl phosphino-2',6'-di-i-propoxy-11'-biphenyl)2-(2-aminoeth CIHHN HN ylphenyl)palladium(II), methyl-t-butylether adduct (0276 TBTU-O-(Benzotriazol-1-yl)-N,N,N',N'-tetram ethyluronium tetrafluoroborate (0277 THF=Tetrahydrofuran US 2017/0073340 A1 Mar. 16, 2017

Intermediate 2: N-(1S,2S)-2-Aminocyclopentyl-3- -continued methoxypyridine-2-carboxamide hydrochloride 0281

CIHHN HN Intermediate 3: (1S,2S)-1-N-(6-Fluoro-1,3-benzothi azol-2-yl)-2-N-methyl-cyclopentane-1,2-diamine 0287

Step (i): tert-Butyl N-(1S,2S)-2-(3-methoxypyri dine-2-amido)cyclopentylcarbamate N 0282. A solution of 3-methoxypyridine-2-carboxylic acid N 2 (CAS number 16478-52-7: 0.84 g, 5.49 mmol), tert-butyl NH N N-(1S,2S)-2-aminocyclopentylcarbamate (CAS number S 586961-34-4; 1.00 g, 4.99 mmol), HARI (2.85 g, 7.49 mmol) and triethylamine (2.09 ml, 14.98 mmol) in dry DMF (0288 Step (i): tert-Butyl N-(1S,2S)-2-(6-fluoro-1,3- (16.6 ml) was stirred at room temperature for 17 hours. The benzothiazol-2-yl)aminocyclopentyl- reaction mixture was partitioned between ethyl acetate and 0289. A microwave vial was charged with tert-butyl water. The organics were washed with water and brine, dried N-(1S,2S)-2-aminocyclopentylcarbamate (CAS number over magnesium sulfate, filtered and concentrated in mow. 586961-34-4; 1.00 g, 4.99 mmol) and 2-chloro-6-fluoro-1, The crude product was purified by column chromatography 3-benzothiazole (CAS number 399-74-6; 1.03 g, 5.49 mmol) (silica, 0-100% ethyl acetate/petrol then 0-30% methanol/ in dry DMSO (16 ml). DIPEA (2.62 ml, 14.98 mmol) was ethyl acetate to afford the title compound. added, the vial flushed with nitrogen and sealed. The reac 0283 MS ES: 336 tion mixture was subjected to microwave irradiation at 140° Step (ii): N-(1S,2S)-2-Aminocyclopentyl-3- C. for 1.5 hours then partitioned between ethyl acetate and methoxypyridine-2-carboxamide hydrochloride water. The organics were washed with brine, filtered through 0284 tert-Butyl N-(1S,2S)-2-(3-methoxypyridine-2- a hydrophobic frit and concentrated in vacuo. The crude amido)cyclopentylcarbamate (880 mg, 2.62 mmol) was material was purified by column chromatography (silica, dissolved in HCl in 1,4-dioxane (4 M, 10 ml. 40.0 mmol) 0-50% ethyl acetate/) to afford the title com and the reaction was stirred at room temperature for 3 hours. pound. The reaction mixture was filtered and the resultant solid was 0290 MS ES: 352 sonicated in ethyl acetate/methanol (10:1) and then filtered 0291 Step (ii): (1S,2S)-1-N-(6-Fluoro1,3-benzothiazol again. Drying afforded the first batch of the title compound. 2-yl)-2-N-methyl-cyclopentane-1,2-diamine The mother liquors from both filtrations were combined, 0292 tert-Butyl N-(1S,2S)-2-(6-fluoro-1,3-benzothi concentrated and azeotropically distilled with toluene fol azol-2-yl)aminocyclopentyl-carbamate (150 mg, 0.43 lowed by acetonitrile. The solvent was evaporated in vacuo mmol) was dissolved in dry THF (1.4 ml). To this was added to afford a second batch of the title compound. drop wise a solution of lithium aluminium hydride in THF 0285 H NMR (DMSO-d) 8 ppm 1.59-1.79 (m, 4H), (1 M. 0.64 ml, 0.64 mmol) and the reaction mixture heated 2.01-2.14 (m, 2H), 3.43-3.51 (m, 1H), 3.90 (s, 3H), 4.15-4. at 60° C. for 3 hours. The reaction was quenched by the 30 (m. 1H), 7.62-7.68 (m, 1H), 7.76-7.83 (m, 1H), 8.21-8.36 addition of sodium sulfate decahydrate and filtered. The (m, 3H), 8.71-8.78 (m, 1H) organics were concentrated in vacuo and the crude material 0286 MS ES: 236 purified by column chromatography (basic silica, 0-100% ethyl acetate/petrol then 0-20% methanol/ethyl acetate) to afford the title compound. 0293 MS ES": 266 Intermediate 4: 2-Chloro-3-methoxy-6-(trifluoromethyl)pyridine 0294

N n N 21 US 2017/0073340 A1 Mar. 16, 2017

0295) To a solution of 2-chloro-6-(trifluoromethyppyri ethyl acetate, the product remained in the aqueous which din-3-ol (CAS number 731002-60-1; 1.00 g, 5.06 mmol) in was concentrated in vacuo to afford the title compound. dry DMF (10 ml) was added potassium carbonate (0.84 g. 0301 H NMR (300 MHz, DMSO-d) 8 ppm 1,21-1.34 6.07 mmol) and methyl iodide (0.38 ml, 6.07 mmol). The (m, , 3H), 3.91-4.06 (m, 2H), 6.98-7.11 (m, 1H), 7.16-7.28 reaction was stirred at room temperature for 72 hours then (m. 1H), 7.82-7.94 (m, 1H) partitioned between ethyl acetate and water. The organics 0302 MS ES: 168 were washed with water and brine, filtered through a hydro phobic frit and concentrated in vacno. The crude material Intermediate 6: Methyl was purified by column chromatography (silica, 0-100% 3-(difluoromethoxy)pyridine-2-carboxylate ethyl acetate/petrol, then 0-20% methanol/ethyl acetate) to afford the title compound. O303 0296 H NMR (400 MHz, DMSO-d) 8 ppm 4.00 (s, 3H), 7.74-7.83 (m, 1H 7.91-8.01 H) O No Nn

N N O n Step (i) O 21 HO 2 ---, O N N 0304) To a solution of methyl 3-hydroxypyridine-2-car boxylate (CAS number 62733-99-7: 500 mg, 3.27 minor) in dry DMF (11 ml) was added 2-chloro-2,2-difluoroacetic 1No 2 1No 21 acid, Sodium (802 mg, 5.22 mmol) and potassium carbonate (812 mg, 5.88 mmol). The reaction mixture was sealed and stirred at 70° C. for 17 hours then partitioned between ethyl Intermediate 5: 3-Ethoxypyridine-2-carboxylic acid acetate and water. The organics were washed with water and hydrochloride brine, filtered through a hydrophobic frit and concentrated in vacuo. The crude material was purified by column chroma 0297 tography (silica, 0-100% ethyl acetate/petrol) to afford the title compound. 0305 MS ES": 204 O

N Intermediate 7: HO S HC 3-(Difluoromethoxy)pyridine-2-carboxylic acid Sodium 1no 2 (0306

Step (i): Methyl 3-ethoxypyridine-2-carboxylate O 0298 To a solution of methyl 3-hydroxypyridine-2-car N boxylate (CAS number 62733-99-7: 1.00 g, 6.53 mmol) in HO oNa dry DMF (22 ml) was added potassium carbonate (1.08 g. O 2 7.84 mmol) and iodoethane (1.22 g, 7.84 mmol). The reaction mixture was stirred at room temperature for 72 hours then partitioned between ethyl acetate and water. The ---, organics were washed with water, filtered through a hydro phobic frit and concentrated in vacuo to afford the title 0307 To a solution of methyl 3-(difluoromethoxy)pyri compound. dine-2-carboxylate (intermediate 6: 200 mg. 0.99 mmol) in 0299 H NMR (400 MHz, DMSO-d) 8 ppm 1.32 (t, THF (3.2 ml) was added NaOH (2 M, 517 ul, 1.034 mmol). J=7.07 Hz, 3H), 3.84 (s, 3H), 4.14 (q, J=7.07 Hz, 2H), The reaction mixture was stirred at room temperature for 4 747-7.56 (m, 1H), 7.60-7.67 (m. 1H), 8.12-8.20 (m, 1H) hours. To this was then added further NaOH (2 M, 100 ul, 0.20 mmol) and the reaction was stirred at room temperature Step (ii): 3-Ethoxypyridine-2-carboxylic acid for a further 2 hours. The reaction mixture was concentrated 0300. A solution of methyl 3-ethoxypyridine-2-carboxy in vacuo and the residue partitioned between ethyl acetate late (1.18 g. 6.53 mmol) and NaOH (2 M, 16.3 ml, 32.6 and water. The aqueous layer was concentrated in vacuo to mmol) in THF (22 ml) was stirred at room temperature for afford the title compound. 17 hours. The reaction mixture was concentrated in vacuo (0308 H NMR (400 MHz, DMSO-d) & ppm 7.02-7.45 and the residue partitioned between ethyl acetate and water. (m. 2H), 7.46-7.55 (m, 1H), 8.22-8.33 (m, 1H) The aqueous layer was acidified to pH 5 and extracted with 0309 MS ES:190 US 2017/0073340 A1 Mar. 16, 2017 14

Intermediate 8: 3-(Difluoromethoxy)pyridine-2-carboxylic acid f \

0310 Br NN s s O N step (i) step (ii) r N N 2 N 21 N N 1. 2 O NY F F HO N 0311. To a solution of methyl 3-(difluoromethoxy)pyri N 2 dine-2-carboxylate (intermediate 6: 221 mg, 1.09 mmol) in THF (1.5 ml) and water (0.2 ml) was added lithium hydrox ide (78 mg, 3.26 mmol). The reaction mixture was stirred at Intermediate 10: room temperature for 2 hours then concentrated in vacuo. 3-(2H-1,2,3-Triazol-2-yl)pyridine-2-carboxylic acid The residue was acidified with HCl (aq, 2M) and extracted with ethyl acetate. The organics were dried over sodium 0318 sulfate and concentrated in mow to afford the title com pound. 0312 H NMR (400 MHz, DMSO-d) 8 ppm 7.06-7.50 W \ (m. 1H), 7.59-7.69 (m, 1H, 7.77-7.88 (m. 1H), 8.44-8.56 (m, NNN 1H) O N 0313 MS ES:190 HO N Intermediate 9: (1S,2S)-1-N-(6-Chloro-1,3-benzo thiazol-2-yl)cyclopentane-1,2-diamine hydrochlo- Na2 ride 0314) Step (i): 3-(2H-1,2,3-Triazol-2-yl)pyridine-2-carbo nitrile 0319. A microwave vial was charged with 3-bromopyri N dine-2-carbonitrile (CAS number 55758-02-6; 500 mg, 2.73 N % mmol), 2H-1,2,3-triazole (CAS number 288-36-8; 377 mg, y-f NHHCI 5.46 mmol), trans-1-N.2-N-dimethylcyclohexane-1,2-di C S amine (78 mg 0.55 mmol), copper (I) trifluoromethanesul fonate complex (70 mg, 0.14 minor), cesium car bonate (1.78 g. 5.46 mmol) and DMF (5 ml). The mixture 0315. A microwave vial was charged with tert-butyl was degassed and Subjected to microwave irradiation at 120° N-(1S,2S)-2-aminocyclopentylcarbamate (CAS number C. for 45 minutes. The reaction mixture was diluted with 586961-34-4: 500 mg, 2.50 mmol), 2,6-dichloro-1,3-benzo- water and extracted with ethyl acetate. The organics were thiazole (CAS number 3622-23-9; 560 mg, 2.75 mmol) and washed with water and brine, dried over sodium sulfate, DIPEA (1308 ul, 7.49 mmol) in dry DMSO (8.3 ml). The filtered and concentrated in vacuo. The crude material was reaction mixture was subjected to microwave irradiation at purified by column chromatography (silica, 0-50% ethyl 140° C. for 2 hours then partitioned between ethyl acetate acetate/petrol) to afford the title compound. and water. The organics were washed with water and brine, 0320 "H NMR (400 MHz, DMSO-d) & ppm 7.94-8.02 dried over magnesium Sulfate, filtered and concentrated in (m. 1H), 8.37(s, 2H), 8.55-8.62 (m, 1H), 8.78-8.86 (m, 1H) mow. The crude material was purified by column chroma- 0321 Step (ii): 3-(2H-1,2,3-Triazol-2-yl)pyridine-2-car tography (silica, 0-100% ethyl acetate/petrol). The resultant boxylic acid solid was then stirred in HCl in 1,4-dioxane (4M, 6 ml) and 0322 To a solution of 3-(2H-1,2,3-triazol-2-yl)pyridine methanol (6 ml) at room temperature for 4 hours. The 2-carbonitrile (250 mg, 1.46 mmol) ethanol (2 ml) and water reaction m1Xture Was concentrated 1n Vacuo, azeotroping (2.5 ml) was added NaOH (8 M, 0.91 ml, 7.30 mmol). The with toluene to afford the title compound. reaction mixture was heated to 100° C. for 15 hours then 0316 H NMR (400 MHz, DMSO-d) 8 ppm 1.59-1.84 concentrated in vacuo to give the sodium salt of the title (m, 4H), 2.03-2.25 (m, 2H)3.40-3.51 (m. 1H), 4.13-4.27 (m, compound. The crude material was acidified to pH 4 with 1H), 7.27-7.34 (m. 1H), 7.45-7.53 (m. 1H), 7.80-7.91 (m, HCl (2 M) then purified by reverse phase chromatography 1H), 8.22-8.33 (m, 2F), 8.68-8.82 (m, 1H) (C18 silica, 0-100% water (with 0.1% formic acid)/acetoni 0317 MS ES: 268 trile) to afford the title compound. US 2017/0073340 A1 Mar. 16, 2017

0323 "H NMR (400 MHz, DMSO-d) 8 ppm 7.67-7.83 Step (ii): N-(1S,2S)-2-Aminocyclopentyl-2-(dif (m. 1H), 8.19 (s. 2H 8.28-8.41 H), 8.65-8.75 (m, 1H), 13.54 luoromethoxy)benzamide hydrochloride (br. S., 1H) 0328. A mixture of tert-butyl N-(1S,2S)-2-[2-(difluo romethoxy)benzamidocyclopentyl-carbamate (221 mg, 0.60 mmol) and HCl in 1,4-dioxane (4 M, 1.5 ml, 6.00 O mmol) was stirred at room temperature for 18 hours. Diethyl y step (i) ether was added to the reaction mixture and the resultant solid was filtered to afford the title compound. X. 0329 H NMR (400 MHz, DMSO-d) 8 ppm 1.59-183 (m, 4H), 1.99-2.14 (m, 2H), 3.42-3.53 (m. 1H), 4.19-4.38 O (m. 1H), 7.01-7.49 (m, 1H), 7.61-7.72 (m, 1H), 7.76-7.88 (m. 1H), 8.16-8.31 (m, 2H), 8.48-8.61 (m. 1H), 8.83-8.96 X-Y / / step (ii) (m. 1H) y's i-K - rol. 0330 MS ES: 271 F

N n Step (i) -e- 2 O F N 2. CIHHN HN n Br Step (ii) p-( Her 21 N n Ph. BP Step (iii) 21 HN -Boc Intermediate 11: N-(1S,2S)-2-Aminocyclopentyl N 2-(difluoromethoxy)benzamide hydrochloride N1 N Step (iv) 0324 -e- 21 N n Step (v) Hs 21 HN CIHHN V i. Boc N n 21 CIHHN Step (i): tert-Butyl N-(1S,2S)-2-[2-(difluo romethoxy)benzamido-cyclopentylcarbamate Intermediate 12: 0325 A solution of tert-butyl N-(1S,2S)-2-aminocyclo 2-(Quinolin-2-ylmethyl)cyclopentan-1-amine pentylcarbamate (CAS number 586961-34-4, 150 mg, 0.75 hydrochloride mmol), 3-(difluoromethoxy)pyridine-2-carboxylic acid (In termediate 8; 177 mg, 0.94 mmol), EDC (161 mg 0.840 0331 mmol) and 3H-1.2.3 triazolo 4,5-b]pyridin-3-ol (101 mg, 0.750 mmol) in DMF (6 ml) was stirred at room temperature N for 18 hours. The reaction mixture was diluted with ethyl n acetate and washed with water, brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude prod 2 uct was purified by column chromatography (silica, 0-80% ethyl acetate/petrol) to afford the title compound. CIHHN 0326) "H NMR (400 MHz, DCM-d) 8 ppm 1.41 (s.9H), 1.45-1.69 (m, 2H), 1.75-1.90 (m, 2 H), 2.15-2.32 (m, 2H), 3.78-3.93 (m. 1H), 4.02-4.18 (m, 1H), 4.89-5.03 (m, 1H), Step (i): 2-(Bromomethyl)cquinoline 6.64-7.11 (m, 1H), 7.47-7.60 (m, 1H), 7.66-7.76 (m. 1H), 8.08-8.24 (m, 1H), 8.49-8.57 (m, 1H) 0332 To a solution of 2-methylduinoline (CAS number 0327 MS ES": 371 91-63-4; 40 g, 279 mmol) in carbon tetrachloride (700 ml) US 2017/0073340 A1 Mar. 16, 2017

was added benzoyl peroxide (1.69 g, 6.99 mmol) and ane (5 ml) was added HCl in 1,4-dioxane (12%, 20 ml) at 0° 1-bromopyrrolidine-2,5-dione (CAS number 128-08-5; C. and the resulting mixture was stirred at room temperature 59.74g, 335 mmol) and the resulting mixture was heated to for 1 hour. The reaction mixture was concentrated in vacuo reflux for 18 hours. The reaction mixture was filtered and the crude material purified by column chromatography through diatomaceous earth (commercially sold under the (silica, 0-2% methanol/DCM) to afford the cis- and trans trade mark “Celite'), washed with DCM and concentrated in isomers of the title compound. vacuo. The crude material was purified by column chroma 0341 Isomer 1 Racemic tography (silica, 0-15% ethyl acetate/n-hexane) to afford the 0342 H NMR (DMSO-d) 8 ppm 150-1.70 (m, 2H), title compound. 175-1.86 (m, 2H), 1.94-2.02 (m, 1H), 2.61-2.68 (m, 1H), 0333 H NMR (CDC1) 8 ppm 4.74 (s. 2H), 7.58-7.61 3.17-3.25 (m, 2H), 3.46-3,60 (m, 1H), 3.63-3.70 (m, 1H), (m. 2H), 7.74-7.78 (m, 1H), 7.83-7.85 (m. 1H)808-8.11 (m, 7.82-7.89 (m. 1H), 7.90-7.96 (m, 1H), 8.04-8.06 (m, 1H), 1H), 8.19-8.21 (m, 1H) 8.20-8.45 (m, 5H), 8.85-9.01 (br, S., 1H) 0343 MS ES": 228 Step (ii): 0344 Isomer 2 Racemic Triphenyl(quinolin-2-ylmethyl)phosphonium (0345 H NMR (DMSO-d) 8 ppm 1.39-1.50 (m, 1H), bromide 1.60- 1.72 (m, 3H), 1.72-1.83 (m. 1H), 2.02-2.15 (m. 1H), 0334) To a solution of 2-(bromomethyl)guinoline (25 g, 3.14-3.25 (m. 1H), 3.32-3.44 (m, 1H), 3.60-3.90 (m, 1H), 112 mmol) in toluene (500 ml) was added triphenylphos 7.81-8.01 (m, 2H), 8.02-8.12 (m, 1H), 8.23-8.49 (m, 5H), phine (35 g, 135 mmol) and the resulting mixture was heated 8.85-9.05 (br. s. 1H) to reflux for 16 hours and then concentrated in vacuo. The 0346 MS ES": 228 crude material was purified by triturating with diethyl ether to afford the title compound. 0335 H NMR (DMSO-d) 8 ppm 5.74-5.78 (m, 2H), 7.50-7.58 (m. 1H), 7.60-7.69 (m, 2H), 7.70-7.74 (m, 7H), 7.82-795 (m, 10 H), 8.34-8.36 (m. 1H) OH ls, Step (iii): tert-Butyl N-2-(E)-2-(duinolin-2-ylmeth ylidene)cyclopentylcarbamate HO N step () HO S. step (ii) -- -> 0336 To a suspension of triphenyl(quinolin-2-ylmethyl) N 2 N 2 phosphonium bromide (40 g, 82.47 mmol) in THF (400 ml) was added n-butyl lithium (23%, 45.56 ml, 164.9 mmol) at 0° C. and the resulting mixture was stirred at room tem perature for 2 hours. A solution of tert-butyl 2-oxocyclo pentylcarbamate (CAS number 477585-30-1; 16.41 g, 82.47 O ls, mmol) in THF (50 ml) was added and the resulting mixture was stirred at room temperature for 14 hours before being HO N quenched with a saturated Solution of ammonium chloride (aq. 50 ml). The resulting mixture was then poured into N 2 water and extracted with ethyl acetate. The organics were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by column chromatography (silica, 0-15% ethyl acetate/n- hexane) to afford the title compound. Intermediate 13: 0337. MS ES": 325 3-Ethoxy-6-methylpyridine-2-carboxylic acid Step (iv): tert-Butyl N-2-(duinolin-2-ylmethyl)cyclopentylcarbamate 0347 0338 To a solution of tert-butyl N-2-(E)-2-(duinolin-2- ylmethylidene)cyclopentylcarbamate (15g, 46.3 mmol) in methanol (60 ml) was added palladium on carbon (2.0 g) and the resulting reaction was stirred under a balloon of hydro gen gas for 2 hours. The reaction mixture was filtered through diatomaceous earth (commercially sold under the HO N trade mark “Celite'), washed with methanol and concen trated in vacuo. The crude product was purified by column 2 chromatography (silica, 0-20% ethyl acetate/n-hexane) to afford the title compound. 0339. MS ES: 327 Step (v): 2-(Quinolin-2-ylmethyl)cyclopentan-1-amine Step (i): (3-Ethoxy-6-methylpyridin-2-yl)methanol hydrochloride 0348. To a solution of 2-(hydroxymethyl)-6-methylpyri 0340. To a solution of tert-butyl N-2-(duinolin-2-ylm din-3-ol (CAS number 42097-42-7: 1.00 g, 7.19 mmol) in ethyl)cyclopentylcarbamate (14g, 4.28 mmol) in 1,4-diox DMF (10 ml) was added iodoethane (0.69 ml, 8.62 mmol) US 2017/0073340 A1 Mar. 16, 2017

and potassium carbonate (4.97g, 35.9 mmol). The reaction 7.56-7.60 (m. 1H), 8.10-8.14 (m, 1H), 8.16-8.20 (m, 1H), mixture was stirred at room temperature for 24 hours then 8.51-8.55 (m, 1H), 8.78-8.88 (m, 1H) partitioned between diethyl ether and water. The organics 0355 MS ES": 436/437 were washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The crude material was Example 2 purified by column chromatography (silica, 0-100% ethyl acetate/petrol) to afford the title compound. 0349 H NMR (400 MHz, DCM-d) 8 ppm 1.39-1.51 6-Bromo-N-(1S,2S)-2-(6-fluoro-1,3-benzothiazol (m, 3H), 2.55 (s, 3H), 4.02-4.14 (m, 2H), 4.71 (s. 2H), 2-yl)aminocyclopentyl-3-methoxypyridine-2-car 7.06-7.13 (m, 1H), 7.14-7.20 (m. 1H) boxamide Step (ii): 3-Ethoxy-6-methylpyridine-2-carboxylic 0356 acid 0350. To a suspension of (3-ethoxy-6-methylpyridin-2- yl)methanol in water (780 ul) was added potassium hydrox ide (57 mg, 1.02 mmol) and KMnO (297 mg, 1.881 mmol) N and the resultant mixture was stirred at room temperature for NH 2 hours. The reaction mixture was acidified to pH 4, diluted S with methanol, filtered through diatomaceous earth (com mercially sold under the trade mark “Celite') and concen trated in vacuo to remove any volatiles. The remaining aqueous layer was washed with DCM then concentrated in vacuo. Water was added to form a suspension. The solids were filtered off and the filtrate was adjusted to give pH 4 and extracted with DCM. The organics were concentrated in 0357 To a solution of (1S,2S)-1-N-(6-fluoro-1,3-benzo vacuo to afford the title compound. thiazol-2-yl)cyclopentane-1,2-diamine hydrochloride (Inter 0351 H NMR (400 MHz, DCM-d) 8 ppm 1.46-1.58 mediate 1; 343 mg, 1.19 mmol) in dry DCM (4 ml) and THF (m, 3 H), 2.59 (s.3H), 4.15-4.33 (m, 2H), 7.40-7.54 (m, 2H) (2 ml) was added 6-bromo-3-methoxypyridine-2-carboxylic acid (CAS number 1256810-26-0; 349 mg, 1.50 mmol), 2. EXAMPLES HATU (680 mg, 1.79 mmol) and triethylamine (498 ul, 3.58 mmol). The reaction mixture was stirred at room tempera Example 1 ture for 72 hours then partitioned between DCM and a saturated Solution of sodium bicarbonate. The organics were 3-Bromo-N-(1S,2S)-2-(6-fluoro-1,3-benzothiazol filtered through a hydrophobic frit and concentrated in 2-yl)aminocyclopentyl-pyridine-2-carboxamide vacuo. The crude material was purified by column chroma O352 tography (silica, 0-100% ethyl acetate/petrol then 0-30% methanol/ethyl acetate) and then further purified by column chromatography (silica, 0-100% ethyl acetate/petrol then 0-30% methanol/ethyl acetate) to afford the title compound. O 0358 H NMR (DMSO-d) 8 ppm 1.50-1.72 (m, 2H), Br 1.69-1.78 (m, 2H), 2.05-2.18 (m, 2H), 3.72 (s, 3H), 4.14-4. F 25 (m, 2H), 6.99-7.08 (m, 1H), 7.29-7.34 (m, 1H), 7.50-7.69 e (m, 3H), 8.13-8.21 (m, 1H), 8.54-8.62 (m, 1H) N NJ 0359 MS ES": 466/468 Example 3 0353. To a solution of (1S,2S)-1-N-(6-fluoro-1,3-benzo thiazol-2-yl)cyclopentane-1,2-diamine hydrochloride (Inter N-(1S,2S)-2-(6-Fluoro-1,3-benzothiazol-2-yl) mediate 1: 1.00 g, 3.47 mmol) in dry DCM (11.6 ml) was aminocyclopentyl-3-methoxypyridine-2-carboxam added 3-bromopyridine-2-carboxylic acid (CAS number ide 30683-23-9; 0.84g, 4.17 mmol), HATU (1.98g, 5.21 mmol) and DIPEA. (1.82 ml, 10.42 mmol). The reaction mixture 0360 was stirred at room temperature for 3 hours then partitioned between DCM and a saturated solution of sodium bicarbon ate. The organics were filtered through a hydrophobic frit and concentrated in vacuo. The crude material was purified by column chromatography (silica, 0-100% ethyl acetate/ F O N petrol then 0-20% methanol/ethyl acetate) then by reverse phase preparative HPLC (eluted with acetonitrile/water con e taining 0.1% ammonia) to afford the title compound. 0354 H NMR (DMSO-d) 8 ppm 1.48-1.61 (m. 2H), N h 1.70-1.83 (m, 2H), 2.06-2.20 (m, 2H), 4.15-4.28 (m, 2H), 7.00-7.07 (m. 1H), 7.28-7.35 (m, 1H), 7.38-7.43 (m, 1H), US 2017/0073340 A1 Mar. 16, 2017

0361. To a solution of (1S,2S)-1-N-(6-fluoro-1,3-benzo Example 5 thiazol-2-yl)cyclopentane-1,2-diamine hydrochloride (Inter mediate 1: 250 mg, 0.87 mmol), 3-methoxypyridine-2- N-(1S,2S)-2-(6-Fluoro-1,3-benzothiazol-2-yl) carboxylic acid (CAS number 16478-52-7; 160 mg, 1.04 aminocyclopentyl-3-methoxy-N-methylpyridine-2- mmol) and triethylamine (363 ul. 2.61 mmol) in DMF (3 ml) carboxamide was added HATU (495 mg, 1.30 mmol). The resultant 0368 mixture was stirred at room temperature for 18 hours then

partitioned between ethyl acetate and water. The organics were washed with water and a saturated solution of sodium bicarbonate, and then extracted with HCl (1 M, 20 ml). The 9 N resulting aqueous layer was concentrated in vacuo, basified F O with NaOH (2 M) and extracted with ethyl acetate. The organics were filtered through a hydrophobic frit and con e centrated in vacuo. The crude product was purified by N column chromatography (silica, 20-100% ethyl acetate/pet NJ rol) to afford the title compound. 0362) H (DMSO-d) (3 ppm 1.48-1.61 (m. 2H), 1.65-1. 0369 To a solution of (1S,2S)-1-N-(6-fluoro-1,3-benzo 79 (m, 2H), 2.27-2.20 (m, 2H), 3.73 (s, 3H), 4.13-4.27 (m, thiazol-2-yl)-2-N-methyl-cyclopentane-1,2-diamine (Inter 2H), 7.00-7.08 (m. 1H), 7.29-7.33 (m, 7.39-7.45 (m, 1H), mediate 3: 50 mg, 0.17 mmol), 3-methoxypyridine-2-car 747-7.53 (m. 1H), 7.56-7.61 (m. 1H), 8.09-8.11 (m, 1H), boxylic acid (CAS number 16478-52-7:30 mg, 0.20 mmol) 8.13-8.16 (m, 1H), 8.52-8.58 (m, 1H) and triethylamine (0.069 ml, 0.50 mmol) in DMF (1 ml) was added HAM (94 mg., 0.25 mmol). The reaction mixture was 0363 MS ES: 387 stirred at room temperature for 18 hours then partitioned between DCM and water. The organics were washed with a Example 4 saturated solution of sodium bicarbonate, filtered through a hydrophobic frit and concentrated in vacuo. The crude 3-Chloro-N-(1S,2S)-2-(6-fluoro-1,3-benzothiazol material was purified by reverse phase preparative HPLC 2-yl)amino cyclopentyl-pyridine-2-carboxamide (eluted with acetonitrile/water containing 0.1% ammonia) to afford the title compound. 0364 0370 "H NMR (400 MHz, DMSO-d) 8 ppm 1.45-2.18 (m, 6H), 2.63-2.99 (m, 3H), 3.47-3.66 (m, 3H), 3.70-4.89 (m. 2H), 6.97-8.17 (m, 7H)

0371 MS ES": 401

O Example 6 F C N-(1S,2S)-2-(6-Fluoro-1,3-benzothiazol-2-yl) e aminocyclopentyl-3-(2H-1,2,3-triazol-2-yl)pyri N h dine-2-carboxamide 0372 0365. To a solution of (1S,2S)-1-N-(6-fluoro-1,3-benzo thiazol-2-yl)cyclopentane-1,2-diamine hydrochloride (Inter mediate 1: 50 mg, 0.17 mmol), 3-chloropyridine-2-carbox N O ( ylic acid is (CAS number 57266-69-0; 41 mg, 0.26 mmol) F y 1 a N-N NH HN and triethylamine (0.073 ml, 0.52 mmol) in DCM (2 ml) was S e added HATU (99 mg, 0.26 mmol). The reaction mixture was stirred at room temperature for 3 hours then partitioned N between DCM and a saturated solution of sodium bicarbon NJ ate. The organics were filtered through a hydrophobic frit and concentrated in vacuo. The crude material was purified 0373) A microwave vial was charged with 3-bromo-N- by reverse phase preparative HPLC (eluted with acetonitrile/ (1S,2S)-2-(6-fluoro-1,3-benzothiazol-2-yl)aminocyclo water containing 0.1% ammonia) to afford the title com pentylpyridine-2-carboxamide (Example 1: 900 mg, 2.07 pound. mmol), 2H-1,2,3-triazole (CAS number 288-36-8; 286 mg, 4.13 mmol), cesium carbonate (1347 mg, 4.13 mmol), 0366 "H NMR (MeOH-da) 8 ppm 1.65-1.80 (m. 2H), copper(I) iodide (20 mg, 0.10 mmol) and trans-1-N.2-N- 1.85-1.95 (m. 2H), 2.14-2.26 (m. 2H), 4.14-4.24 (m. 2H), dimethylcyclohexane-1,2-diamine (59 mg, 0.41 mmol) in 6.93-7.01 (m. 1H), 7.25-7.40 (m, 2H), 743-748 (m. 1H), DMF (7 The reaction mixture was subjected to microwave 7.88-7.94 (m, 1H), 8.46-8.49 (m, 1H). irradiation at 120° C. for 1 hour then partitioned between 0367 MS ES: 391 ethyl acetate and water. The organics were washed with US 2017/0073340 A1 Mar. 16, 2017

water and brine, dried over magnesium Sulfate, filtered and (0381) To a slurry of (1S,2S)-1-N-(6-fluoro-1,3-benzothi concentrated in vacuo. The crude product was purified by azol-2-yl)cyclopentane-1,2-diamine hydrochloride (Inter column chromatography (silica, 50-100% ethyl acetate/pet mediate 1; 100 mg, 0.35 mmol) in dry DCM (1.2 ml) was rol then 0-30% methanol/ethyl acetate), the resultant solid added 3-isopropoxypyridine-2-carboxylic acid (CAS num was recrystallised from ethyl acetate to afford the title ber 317334-97-7: 70 mg, 0.39 mmol), HATU (198 mg, 0.52 compound. mmol) and triethylamine (145ul, 1.04 mmol). The reaction 0374 H NMR (DMSO-d) 8 ppm 1.45-1.55 (m, 2H), mixture was stirred at room temperature for 72 hours then 1.64-1.73 (m, 2H), 1.96-2.15 (m, 2H), 3.99-4.08 (m. 1H), partitioned between DCM and a saturated solution of 4.16-4.26 (m. 1H), 7.01-7.08 (m, 1H), 7.32-7.36 (m, 1H), Sodium carbonate. The organics were filtered through a 7.56-7.61 (m, 1H), 7.75-7.78 (m, 1H), 7.81 (s, 1H), 8.10-8. hydrophobic frit and concentrated in vacuo. The crude 19 (m, 2H), 8.45 (s, 1H), 8.86-8.88 (m. 1H), 9.05-9.09 (m, product was purified by column chromatography (silica, 1H) 0-100% ethyl acetate/petrol then 0-30% methanol/ethyl 0375 MS ES: 424 acetate) then by reverse phase preparative HPLC (eluted Example 7 with acetonitrile/water containing 0.1% ammonia) to afford N-(1S,2S)-2-(6-Fluoro-1,3-benzoxazol-2-yl)amino the title compound. cyclopentyl-3-methoxypyridine-2-carboxamide 0382 "H NMR (DMSO-d) 8 ppm 1.15-121 (m, 6H), 0376 1.51-1.65 (m, 2H), 1.68-1.78 (m, 2H), 2.15-2.21 (m, 2H) 4.14-4.23 (m, 2H) 4.53-4.68 (m, 1H), 6.95-7.08 (m, 1H) 7.28-7.33 (m. 1H), 7.35-742 (m, 1H), 7.50-7.56 (m, 1H), 7.58-7.61 (m. 1H), 8.08-8.12 (m, 1H), 8.16-8.19 (m, 1H), 8.43-8.48 (m, 1H) 0383 MS ES": 415 Example 9 N-(1S,2S)-2-(6-Fluoro-1,3-benzothiazol-2-yl) aminocyclopentyl-3-methoxy-6-methylpyridine-2- carboxamide 0377 To a solution of N-(1S,2S)-2-aminocyclopentyl 3-methoxypyridine-2-carboxamide hydrochloride (Interme 0384 diate 2: 75 mg, 0.28 mmol) and DIPEA (0.15 ml, 0.83 mmol) in DMSO (1 ml) was added 2-chloro-6-fluoro-1,3-benzox azole (CAS number 153403-53-3; 57 mg, 0.33 mmol) and the reaction mixture was subjected to microwave irradiation at 140°C., for 2 hours. The reaction mixture was partitioned N O between DCM and water. The 1.5 organics were filtered NI fin through a hydrophobic frit and concentrated in vacuo. The -OstS e - crude material was purified by reverse phase preparative HPLC (eluted with acetonitrile/water containing 0.1% ammonia) to afford the title compound. N h 0378 H NMR (DCM-d) 8 ppm 1.66-1.82 (m. 2H), 1.86-1.94 (m, 2H), 2.21-2.32 (m. 1H), 2.46-2.58 (m. 1H), 3.91 (s, 3H), 3.91-3.99 (m. 1H), 4.35-4.45 (m, 1H), 6.55-6. 66 (m. 1H), 6.85-6.93 (m. 1H), 6.98-7.02 (m. 1H), 7.16-7.20 0385. A microwave vial was charged with 6-bromo-N- (m. 1H), 7.45-7.56 (m, 2H), 8.08-8.19 (m. 1H), 8.15-8.23 (1S,2S)-2-(6-fluoro-1,3-benzothiazol-2-yl)aminocyclo (m. 1H) pentyl-3-methoxypyridine-2-carboxamide (Example 2: 80 0379 MS ES": 371 mg, 0.17 mmol), methyl boronic acid (21 mg, 0.35 mmol), Example 8 potassium carbonate (95 mg. 0.69 mmol), tetrakis(triphenyl phosphine)palladium(0) (20 mg 0.017 mmol), 1,4-dioxane N-(1S,2S)-2-(6-Fluoro-1,3-benzothiazol-2-yl) (500 ul) and water (115 ul). The reaction was sealed, aminocyclopentyl-3-(propan-2-yloxy)pyridine-2- evacuated and purged with nitrogen and Subjected to micro carboxamide wave irradiation at 100° C. for 1 hour. The reaction mixture 0380 was partitioned between ethyl acetate and water then the organics washed with water, filtered through a hydrophobic frit and concentrated in vacuo. The crude material was purified by column chromatography (silica, 0-100% ethyl acetate/petrol then 0-20% methanol/ethyl acetate) to afford N O the title compound. NH HN (0386 H NMR (DMSO-d) 8 ppm 1.56-1.71 (m, 2H), S e 1.69-1.78 (m, 2H), 2.06-2.18 (m, 2H), 2.38 (s, 3H), 3.69 (s. 3H), 4.12-4.28 (m, 2H), 6.99-7.08 (m, 1H), 7.23-7.35 (m, N NJ 2H), 7.38-741 (m, 1H) 7.56-7.60 (m. 1H) 8.15-8.19 (m, 1H), 8.43-8.46 (m, 1H) 0387 MS ES": 401 US 2017/0073340 A1 Mar. 16, 2017 20

Example 10 and triethylamine (0.073 ml, 0.52 mmol) in DCM (2 ml) was N-(1S,2S)-2-(6-Fluoro-1,3-benzothiazol-2-yl) added HATU (99 mg, 0.26 mmol). The reaction mixture was aminocyclopentyl-3-(1H-pyrazol-1-yl)pyridine-2- stirred at room temperature for 24 hours then partitioned carboxamide between DCM and water. The organics were filtered through a hydrophobic frit and concentrated in vacuo. The crude 0388 material was purified by reverse phase preparative HPLC (eluted with acetonitrile/water containing 0.1% ammonia) to afford the title compound. 0394 H NMR (400 MHz, DMSO-d) 8 ppm 1.46-1.67 (m. 2H), 1.68-1.82 (m, 2H), 2.05-2.25 (m, 2H), 4.09-4.23 F y 1 a N-N 1H), 4.25-4.38 (m, 1H), 6.98-7.10 (m. 1H), 7.29-7.37 a NH HN 1H), 7.54-7.60 (m, 1H), 7.61-7.69 (m. 1H), 7.75-7.89 S e 1H), 8.14-8.26 (m. 1H), 8.38-8.49 (m. 1H), 8.94-9.06 N 1H) NJ 0395 MS ES": 375 0389. A microwave vial was charged with 3-bromo-N- Example 12 (1S,2S)-2-(6-fluoro-1,3-benzothiazol-2-yl)aminocyclo pentylpyridine-2-carboxamide (Example 1: 100 mg, 0.23 N-MS,2S)-2-(6-Fluoro-1,3-benzothiazol-2-yl) mmol), 1H-pyrazole (CAS number 288-13-1; 31 mg, 0.46 aminocyclopentyl-3-(piperidin-1-yl)pyridine-2- mmol), cesium carbonate (150 mg, 0.46 mmol), copper (I) iodide (2 mg 0.010 mmol) and trans-1-N.2-N-dimethylcy carboxamide clohexane-1,2-diamine (2 mg, 0.013 mmol) in DMF (780 0396 ul). The reaction mixture was subjected to microwave irra diation at 120° C. for 1 hour then partitioned between ethyl acetate and water. The organics were washed with brine, filtered through a hydrophobic frit and concentrated in vacuo. The crude material was purified by reverse phase preparative HPLC (eluted with acetonitrile/water containing N O O 0.1% ammonia) to afford the title compound. 0390 "H NMR (400 MHz, DCM-d) 8 ppm 1.46-1.80 NH HN (m. 2H), 1.82-2.01 (m, 2H), 2.19-2.50 (m, 2H), 4.05-4.21 S e (m. 1H), 4.23-4.40 (m, 1H), 6.23-6.40 (m. 1H), 6.40-6.51 (m, H), 7.52-7.63 (m, 1H), 7.65-7.71 (m, 1H), 7.74-7.82 (m, N h 1H), 7.87-7.93 (m. 1H), 7.94-8.01 (m. 1H), 8.03-8.13 (m, 1H), 8.25-8.33 (m, 1H), 8.54-8.64 (m, 1H) 0391 MS ES: 423 0397. A mixture of 3-(piperidin-1-yl)pyridine-2-carbox ylic acid (CAS number 898.289-01-5; 59 mg, 0.29 mmol), Example 11 (1S,2S)-1-N-(6-fluoro-1,3-benzothiazol-2-yl)cyclopentane L2-diamine hydrochloride (Intermediate 1: 75 mg, 0.26 3-Fluoro-N-(1S,2S)-2-(6-fluoro-1,3-benzothiazol mmol), EDC (75 mg, 0.392 mmol), 3H-1.2.3 triazolo 4.5- 2-yl)aminocyclopentylpyridine-2-carboxamide bipyridin-3-ol (53 mg 0.390 mmol) and triethylamine (0.11 0392 ml, 0.78 minor) in dry DCM (1 ml) was stirred at room temperature for 18 hours then partitioned between DCM and a saturated Solution of sodium bicarbonate. The organics

were filtered through a hydrophobic frit and concentrated in vacuo. The crude material was purified by column chroma O tography (silica, 40-100% ethyl acetate/petrol) and then F F purified further by reverse phase preparative HPLC (eluted e with acetonitrile/water containing 0.1% ammonia) to afford the title compound. N NJ 0398 H NMR (400 MHz, DCM-d) 8 ppm 1.54-1.67 (m. 2H), 1.69-1.85 (m, 6H), 1.87-2.04 (m, 2H), 2.21-2.40 0393 To a solution of (1S,2S)-1-N-(6-Fluoro-1,3-benzo (m. 1H), 2.49-2.65 (m, 1H), 2.92-3.11 (m, 4H), 3.93 -4.11 thiazol-2-yl)cyclopentane-1,2-diamine hydrochloride (Inter (m. 1H), 4.34-4.52 (m, 1H), 6.90-7.09 (m. 1H), 7.24-7.45 mediate 1: 50 mg, 0.17 mmol), 3-fluoropyridine-2-carbox (m, 3H), 7.46-7.56 (m, 1H), 8.17-8.34 (m, 1H) ylic acid (CAS number 152126-31-3; 37 mg, 0.26 mmol) 0399. MS ES": 440 US 2017/0073340 A1 Mar. 16, 2017 21

Example 13 propoxy-1, 1'-biphenyl-2-yl)phosphine (7 mg, 0.015 mmol) and pyrrolidine (CAS number 123-75-1: 490 mg. 3-(AZetidin-1-yl)-N-(1S,2S)-2-(6-fluoro-1,3-benzo 6.89 mmol) in THF (1.5 ml).The reaction mixture was thiazol-2-yl)aminocyclopentylpyridine-2-carbox subjected to microwave irradiation at 100° C. for 1 hour then amide partitioned between ethyl acetate and water. The organics were washed with water then brine, filtered through a 04.00 hydrophobic frit and concentrated in vacuo. The crude material was purified by reverse phase preparative HPLC (eluted with acetonitrile/water containing 0.1% ammonia) to afford the title compound. F 0406 H NMR (400 MHz, DCM-d) 8 ppm 1.71-2.04 (m, 8H), 2.25-2.39 (m, 1H), 2.41-2.55 (m. 1H), 3.15-3.27 (m. 2H), 3.28-3.42 (m, 2H), 3.98-4.11 (m. 1H), 4.29-4.42 (m. 1H), 7.02-7.11 (m. 1H), 7.17-7.21 (m. 1H), 7.22-7.28 (m. 1H), 7.31-7.37 (m, 1H), 7.40-7.46 (m. 1H), 7.70-7.77 (m, 1H), 7.86-7.92 (m. 1H) 04.01. A microwave vial was charged with 3-bromo-N- 0407. MS ES": 426 (1S,2S)-2-(6-fluoro-1,3-benzothiazol-yl)aminocyclopen tyl-pyridine-2-carboxamide (Example 1: 200 mg, 0.46 Example 15 mmol), azetidine (CAS number 503-29-7: 393 mg, 6.89 mmol), RuPhos-Palladacycle (4 mg, 5.48 umol), sodium tent-butoxide (88 mg, 0.92 mmol) and dicyclohexyl(2,6'- N-(1S,2S)-2-(6-Fluoro-1,3-benzothiazol-2-yl) diisopropoxy-1, 1'-biphenyl-2-yl)phosphine (7 mg, 0.015 aminocyclopentyl-3-(3-methoxyaZetidin-1-yl)pyri mmol) in THF (1.5 ml). The reaction mixture was subjected dine-2-carboxamide to microwave irradiation at 100° C. for 1 hour then parti tioned between ethyl acetate and water. The organics were 04.08 washed with water then brine, filtered through a is hydro phobic frit and concentrated in vacuo. The crude material was purified by reverse phase preparative HPLC (eluted N with acetonitrile/water containing 0.1% ammonia) to afford the title compound. 0402 "H NMR (400 MHz, DCM-d) 8 ppm 1.68-1.83 O (m. 2H), 1.89-2.00 (m, 2H), 2.21-2.38 (m, 3 H), 2.44-2.56 F N (m. 1H), 3.89-4.10 (m, 5H), 4.27-4.40 (m. 1H), 6.87-6.94 (m. 1H), 6.98-7.08 (m, 1H), 7.22-7.29 (m, 2H), 7.29-7.35 e (m. 1H), 7.38-7.46 (m, 1H), 7.86-7.92 (m. 1H), 7.93-8.04 (m. 1H) N h 0403 MS ES: 412 Example 14 04.09. A microwave vial was charged with 3-bromo-N- (1S,2S)-2-(6-fluoro-1,3-benzothiazol-2-yl)aminocyclo N-(1S,2S)-2-(6-Fluoro-1,3-benzothiazol-2-yl) pentyl-pyridine-2-carboxamide (Example 1: 200 mg. 0.46 aminocyclopentyl-3-(pyrrolidin-1-yl)pyridine-2- mmol), 3-methoxyazetidine (CAS number 110925-17-2: carboxamide 600 mg, 6.89 mmol), RuPhos-Palladacycle (4 mg, 5.48 umol), sodium tert-butoxide (530 mg, 5.51 mmol), dicyclo 04.04 hexyl(2,6'-diisopropoxy-1,1'-biphenyl-2-yl)phosphine (7 mg, 0.015 mmol) and THF (1.5 ml). The reaction mixture was subjected to microwave irradiation at 100° C. for 1 hour then partitioned between ethyl acetate and water. The organ ics were washed with water then brine, filtered through a N KD hydrophobic frit and concentrated in vacuo. The crude NH HN material was purified by reverse phase preparative HPLC S e (eluted with acetonitrile/water containing 0.1% ammonia) to afford the title compound. N f 0410 "H NMR (400 MHz, DCM-d) 8 ppm 1.68-1.83 (m. 2H), 1.89-2.00 (m, 2H), 2.22-2.37 (m. 1H), 2.45-2.59 0405. A microwave vial was charged with 3-bromo-N- 1H), 3.70-3.77 (m, 1H), 3.79-3.88 (m. 1H), 3.94-405 (1S,2S)-2-(6-fluoro-1,3-benzothiazol-2-yl)aminocyclo 1H), 4.12-4.41 (m, 5H), 6.85-6.95 (m. 1H), 6.98-7.07 pentyl-pyridine-2-carboxamide (Example 1: 200 mg, 0.46 1H), 7.21-7.36 (m, 2H), 7.38-7.47 (m. 1H), 7.88-7.95 mmol), RuPhos-Palladacycle (4 mg, 5.48 umol), sodium 1H), 7.98-8.06 (m, 1H) tert-butoxide (88 mg, 0.92 mmol), dicyclohexyl (2,6'-diiso 0411 MS ES: 442 US 2017/0073340 A1 Mar. 16, 2017 22

Example 16 denum hexacarbonyl (437 mg, 1.65 mmol), tri-tent-butyl phosphonium tetrafluoroborate (29 mg, 0.10 mmol), 3-Methoxy-N-(1S,2S)-2-(duinoxalin-2-yl)amino 2-chloro-3-methoxy-6-(trifluoromethyl)pyridine (Interme cyclopentylpyridine-2-carboxamide diate 4: 700 mg, 3.31 mmol), Herrmanns Catalyst (31 mg, 0412 0.033 mmol) and DBU (0.83 ml, 5.53 mmol) in dry 1,4- dioxane (13 ml). The reaction mixture was subjected to microwave irradiation at 125° C. for 1 hour then partitioned between ethyl acetate and water. The organics were washed with water and brine, filtered through a hydrophobic frit and

concentrated in vacuo. The crude material was purified by reverse phase preparative HPLC (eluted with acetonitrile/ water containing 0.1% ammonia) then further purified by column chromatography (silica, 0-100% ethyl acetate/petrol then 0-30% methanol/ethyl acetate) to afford the tide com pound. 0418 H NMR (400 MHz, DMSO-d) 8 ppm 1.49-1.64 (m. 2H), 1.68-1.81 (m, 2H), 2.04-2.22 (m, 2H), 3.78 (s.3H), 0413. A microwave vial was charged with N-(1S,2S)-2- 4.12-4.27 (m, 2H), 6.97-7.09 (m, 1H), 7.24-7.35 (m, 1H), aminocyclopentyl-3-methoxypyridine-2-carboxamide 7.53-7.62 (m. 1H), 7.66-7.75 (m, 1H), 7.88-7.99 (m, 1H), hydrochloride (Intermediate 2: 75 mg, 0.28 mmol) and 8.13-8.25 (m, 1H), 8.56-8.71 (m, 1H) DIPEA (0.15 ml, 0.83 mmol) in DMSO (1.0 ml). 2-chloro quinoxaline (CAS number 1448-87-9: 54 mg. 0.33 mmol) 0419 MS ES":455 was added and the reaction mixture Subjected to microwave irradiation at 140°C. for 2 hours. The reaction mixture was Example 18 partitioned between DCM and water then the organics filtered through a hydrophobic frit and concentrated in vacuo. The crude material was purified by reverse phase 3-Ethoxy-N-(1S,2S)-2(6-fluoro-1,3-benzothiazol-2- preparative HPLC (eluted with acetonitrile/water containing yl)aminocyclopentylpyridine-2-carboxamide 0.1% ammonia) then purified further by column chromatog raphy (silica, 0-15% methanol/DCM) to afford the title 0420 compound. 0414. "H NMR (400 MHz, DCM-d) 8 ppm 1.66-1.83 (m. 2H), 1.88-2.03 (m, 2H), 2.31-2.44 (m. 1H), 2.48-2.61 (m. 1H), 3.85 (s.3H), 4.27-4.44 (m, 2H), 6.02-6.17 (m. 1H), 7.29-7.43 (m, 3H), 7.49-7.59 (m, 1H), 7.60-7.69 (m, 1H), 7.78-7.88 (m. 1H), 8.06-8.16 (m, 1H), 8.20-8.29 (m, 1H), 8.34-8.45 (m, 1H) N O ( 0415 MS ES: 364 y-f If O F S o Example 17 N N-(1S,2S)-2-(6-Fluoro-1,3-benzothiazol-2-yl) \ / aminocyclopentyl-3-methoxy-6-(trifluoromethyl) pyridine-2-carboxamide 0421. To a slurry of (1S,2S)-1-N-(6-fluoro-1,3-benzo 0416 thiazol-2-yl)cyclopentane-1,2-diamine hydrochloride (Inter mediate 1; 100 mg, 0.35 mmol) in dry DCM (1.2 ml) was added 3-ethoxypyridine-2-carboxylic acid hydrochloride (Intermediate 5, 78 mg, 0.38 mmol), HATU (198 mg 0.52 mmol) and triethylamine (145ul, 1.04 mmol). The reaction mixture was stirred at room temperature for 17 hours then partitioned between DCM and a saturated solution of Sodium bicarbonate. The organics were filtered through a hydrophobic frit and concentrated in vacuo. The crude material was purified by reverse phase preparative HPLC (eluted with acetonitrile/water containing 0.1% ammonia) to afford the title compound. 0422 H NMR (400 MHz, DCM-d) 8 ppm 1.43-1.55 (m,3H), 1.64-1.77 (m, 2H), 1.86-198(m, 2H), 2.23-2.36 (m, 1H), 2.45-2.60 (m, 1H), 3.96-4.00 (m, 1H), 4.10 -4.23 (m, 0417. A microwave vial was charged with (1S,2S)-1-N- 2H), 4.31-4.48 (m, 1H), 6.94-7.07 (m, 1H), 7.24-7.33 (m, (6-fluoro-1,3-benzothiazol-2-yl)cyclopentane-1,2-diamine 1H), 7.35-7.46 (m, 3H), 8.06-8.24 (m, 2H) hydrochloride (Intermediate 1; 952 mg, 3.31 mmol), molyb 0423 MS ES": 401 US 2017/0073340 A1 Mar. 16, 2017 23

Example 19 0429 To a solution of (1S,2S)-1-N-(6-fluoro-1,3-benzo thiazol-2-yl)cyclopentane-1,2-diamine hydrochloride (Inter N-(1S,2S)-2-(6-Fluoro-1,3-benzothiazol-2-yl) mediate 1: 284 mg. 0.99 mmol) in dry DCM (3.3 ml) was aminocyclopentyl-3-(trifluoromethoxy)pyridine-2- added 3-(difluoromethoxy)pyridine-2-carboxylic acid, carboxamide sodium (Intermediate 7: 209 mg 0.99 mmol), 3H-1.2.3 0424 triazolo 4,5-b]pyridin-3-ol (201 mg, 1.48 mmol), EDC (283 mg, 1.48 mmol) and DIPEA (516 ul, 2.96 mmol). The reaction mixture was stirred at room temperature for 72 hours then partitioned between DCM and a saturated solu tion of sodium bicarbonate. The organics were filtered N O F through a hydrophobic frit and concentrated in vacuo. The y-f Ifn p-(-f crude material was purified by column chromatography F S o F (silica, 0-100% ethyl acetate/petrol, then 0-30% methanol/ N ethyl acetate) to afford the title compound. \ / 0430 "H NMR (400 MHz, DMSO-d) 8 ppm 1.51-1.65 (m. 2H), 1.68-1.80 (m, 2H), 2.08-2.22 (m, 2H), 4.13-4.22 0425. A microwave vial was charged with (1S,2S)-1-N- (m. 1H), 4.22-4.31 (m, 1H), 6.89-7.17 (m, 2H), 7.29-7.37 (6-fluoro-1,3-benzothiazol-2-yl)cyclopentane-1,2-diamine (m. 1H), 7.53-7.66 (m, 2H), 7.69-7.79 (m, 1H), 8.15-8.24 hydrochloride (Intermediate 1: 172 mg, 0.60 mmol), molyb (m. 1H), 8.43-8.52 (m, 1H), 8.80-8.96 (m, 1H) denum hexacarbonyl (79 mg, 0.30 mmol), tri-tert-butylphos 0431 MS ES": 423 phonium tetrafluoroborate (5 mg, 0.018 mmol), 2-bromo-3- (trifluoromethoxy)pyridine (145 mg, 0.60 mmol), Herrmanns Catalyst (6 mg, 6.41 umol) and DBU (150 ul, Example 21 0.998 mmol) in dry 1,4-dioxane (2.4 ml). The reaction was subjected to microwave irradiation at 125° C. for 25 minutes N-(1S,2S)-2-(6-Chloro-1,3-benzothiazol-2yl) then partitioned between ethyl acetate and water. The organ aminocyclopentyl-3-(2H-1,2,3-triazol-2-yl)pyri ics were washed with water and brine, filtered through a dine-2-carboxamide hydrophobic frit and concentrated in vacuo. The crude material was purified by column chromatography (silica, 0432 0-100% ethyl acetate/petrol then 0-30% methanol/ethyl acetate) then further purified by reverse phase preparative HPLC (eluted with acetonitrile/water containing 0.1% ammonia) to afford the title compound. 0426 H NMR (400 MHz, DMSO-d) 8 ppm 1.50-1.64 (m. 2R), 1.68-1.80 (m. 2E), 2.07-2.21 (m. 2H), 4.13-4.23 (m, 1H), 4.23-4.33 (m. 1H), 6.97-7.10 (m. 1H), 7.26-7.37 (m, 1H), 7.52-7.62 (m. 1H), 7.64-7.74 (m. 1H), 7.90-8.03 (m, 1H), 8.14-8.23 (m. 1H), 8.55-8.69 (m. 1H), 8.92-9.02 (m, 1H) 0427 MS ES": 441 0433) To a solution of (1S, 2S)-1-N-(6-chloro-1,3-ben Example 20 Zothiazol-2-yl)cyclopentane-1,2-diamine hydrochloride (In termediate 9; 100 mg, 0.329 mmol) in dry DCM (1.1 ml) 3-(Difluoromethoxy)-N-(1S,2S)-2-(6-fluoro-1,3- was added 3-(2H-1,2,3-triazol-2-yl)pyridine-2-carboxylic benzothiazol-2-yl)aminocyclopentylpyridine-2- acid (Intermediate 10; 70 mg, 0.37 mmol), EDC (95 mg. carboxamide 0.49 mmol), 3H-1.2.3 triazolo 4,5-b]pyridin-3-ol (67 mg, 0.49 mmol) and DIPEA (172 ul, 0.99 mmol). The reaction 0428 mixture was stirred at room temperature for 4 hours then partitioned between DCM and water. The organics were

filtered through a hydrophobic frit and concentrated in vacuo. The crude material was purified by column chroma tography (basic silica. 0-100% ethyl acetate/petrol) to afford the title compound. 0434 H NMR (400 MHz, DMSO-d) oppm 1.49-1.65 (m. 2H), 1.66-1.76 (m, 2H), 2.01-2.19 (m, 2H), 4.09-4.17 (m. 1H), 4.18-4.25 (m, 1H), 7.17-7.27 (m, 1H), 7.30-7.38 (m. 1H), 7.64-7.75 (m, 1H), 7.76-7.83 (m, 1H), 8.04 (s. 2H), 8.17-8.35 (m, 2H), 8.59-8.71 (m, 1H), 8.73-8.88 (m. 1H) 0435 MS ES": 440 US 2017/0073340 A1 Mar. 16, 2017 24

Example 22 partitioned between ethyl acetate and water. The organics were washed with water and brine, dried over sodium N-(1S,2S)-2-(6-Chloro-1,3-benzothiazol-2-yl) sulfate, filtered and concentrated in vacuo. The crude mate aminocyclopentyl-3-(difluoromethoxy)pyridine-2- rial was purified by o column chromatography (silica, carboxamide 30-80% ethyl acetate/petrol) then purified further by reverse 0436 phase chromatography (C18 silica, 5-95% water (with 005% ammonia)/acetonitrile) to afford the title compound. 0442 H NMR (400 MHz, DMSO-d) 8 ppm 1.53-1.67 (m. 2H), 1.67-1.81 (m, 2H), 2.01-2.18 (m, 2H), 406-4.19 (m. 1H), 4.22-4.32 (m, 1H), 6.88-7.38 (m, 4 H), 7.52-7.65 (m. 1H), 7.67-7.79 (m, 1H), 8.03-8.17 (m, 1H), 8.44-8.53 N O F (m. 1H), 8.77-8.87 (n, 1H) y-f If p-( 0443 MS ES": 407 C S o F N \ / Example 24 N-(1S,2S)-2-(6-Fluoro-1,3-benzothiazol-2-yl) 0437. To a solution of N-(1S,2S)-2-aminocyclopentyl aminocyclopentyl-3-(1H-1,2,3-triazol-1-yl)pyri 2-(difluoromethoxy)benzamide hydrochloride (Intermediate dine-2-carboxamide 11:45 mg, 0.15 mmol) in DMSO (0.5 ml) was added DIPEA (0.077 ml, 0.44 mmol) and 2,6-dichloro-1,3-benzothiazole 0444 (CAS number 3622-23-9; 36 mg, 0.18 mmol). The reaction mixture was heated to 140° C. for 4 hours then partitioned between ethyl acetate and water. The organics were washed with water and brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by column chromatography (silica, 30-70% ethyl acetate/pet N rol) then purified further by reverse phase chromatography N 9 ? (C18 silica. 0-100% water (with 0.05% ammonia)/acetoni trile) to afford the title compound. y-f If N-N 0438 H NMR (400 MHz, DMSO-d) 8 ppm 1.51-1.66 F S o (m. 2H), 1.68-1.79 (m, 2H), 2.06-2.23 (m, 2H), 4.14-4.22 N (m. 1H), 4.23-4.32 (m, 1H), 6.89-7.37 (m, 3 H), 7.57-7.66 \ / (m. 1H), 7.70-7.80 (m, 2H), 8.27-8.38 (m. 1H), 8.44-8.55 (m. 1H), 8.85-8.98 (m, 1H) 0439 MS ES": 439 0445. A microwave vial was charged with 3-bromo-N- (1S,2S)-2-(6-fluoro-1,3-benzothiazol-2-yl)aminocyclo Example 23 pentyl-pyridine-2-carboxamide (Example 1,900 mg, 2.07 3-(Difluoromethoxy)-N-(1S,2S)-2-(6-fluoro-1,3- mmol), 2H-1,2,3-triazole (CAS number 288-36-8; 286 mg, benzoxazol-2-yl)aminocyclopentylpyridine-2-car 4.13 mmol), cesium carbonate (1347 mg, 4.13 mmol), copper (I) iodide (20 mg, 0.11 mmol) and trans-1-N.2-N- boxamide dimethylcyclohexane-1,2-diamine (59 mg, 0.41 mmol) in 0440 DMF (6.9 ml). The reaction mixture was subjected to microwave irradiation at 120° C. for 1 hour then partitioned between ethyl acetate and water. The organics were washed with water and brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The crude material was purified by column chromatography (silica, 50-100% ethyl acetate/ N O F petrol then 0-30% methanol/ethyl acetate) then purified further by column chromatography (silica, 50-100% ethyl y-f If p-( acetate/petrol then 0-20% methanol/ethyl acetate).The resul F O F tant material was recrystallised from ethyl acetate to afford N \ / the title compound. 0446 H NMR (400 MHz, DMSO-d) 8 ppm 1.48-1.64 (m. 2H), 1.65-1.75 (m, 2H), 2.01-2.17 (m, 2H), 408-4.16 0441. To a solution of N-(1S,2S)-2-aminocyclopentyl (m. 1H), 416-4.25 (m. 1H), 6.96-7.11 (m, 1 11), 7.30-7.41 2-(difluoromethoxy)benzamide hydrochloride (Intermediate (m. 1H), 7.54-7.65 (m, 1H), 7.67-7.75 (m. 1H), 8.05 (s. 2H), 11:45 mg, 0.15 mmol) in DMSO (0.5 ml) was added DIPEA (57 mg, 0.44 mmol) and 2-chloro-6-fluoro-1,3-benzoxazole 8.10-8.18 (m. 1H), 8.20-8.30 (m, 1H), 8.61-8.72 (m. 1H), (CAS number 153403-53-3; 30 mg, 0.17 mmol). The reac 8.77-8.86 (m, 1H) tion mixture was heated to 140° C. for 4 hours then 0447. MS ES": 424 US 2017/0073340 A1 Mar. 16, 2017 25

Example 25 0.86 mmol). The reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was washed N-(1S,2S)-2-(6-Chloro-1,3-benzoxazol-2-yl) with water, filtered through a hydrophobic frit and concen aminocyclopentyl-3-(difluoromethoxy)pyridine-2- trated in vacuo. The crude material was purified by column carboxamide chromatography (silica, 50-100% ethyl acetate/petrol, then 0-20% methanol/ethyl acetate) to afford the title compound. 0448 0454 H NMR (400 MHz, DCM-d) 8 ppm 1.45-1.53 (m, 3H), 1.54-1.62 (m, 1H), 1.65-193 (m, 4H), 2.04-2.19 (m. 1H), 2.53 (s.3H), 2.70-2.82 (m. 1H), 2.88-3.02 (m. 1H), 3.21-3.36 (m. 1H), 4.04-4.23 (m, 2H), 4.54-4.67 (m, 1H), 7.19-7.25 (m. 1H), 7.26-7.31 (m, 1H), 7.35-742 (m, 1H), N O F 7.49-7.57 (m. 1H), 7.66-7.73 (m, 1H), 7.79-7.86 (m, 1H), y-f If p-( 794-8.03 (m, 1H), 8.08-8.17 (m. 1H) C O o F 0455 MS ES": 390 N \ / Example 27 3-Ethoxy-6-methyl-N2-(duinolin-2-ylmethyl)cyclo pentylpyridine-2-carboxamide 0449 To a solution of N-(1S,2S)-2-aminocyclopentyl 2-(difluoromethoxy)benzamide hydrochloride (Intermediate 0456 11:49 mg, 0.16 mmol) in DMSO (0.5 ml) was added DIPEA (0.083 ml, 0.48 mmol) and 2,6-dichloro-1,3-benzoxazole (CAS number 3621-82-7; 36 mg, 0.19 mmol). The reaction mixture was heated at 140°C. for 4 hours then partitioned between ethyl acetate and water. The organics were washed o O with water and brine, dried over sodium sulfate and con HN o-/ centrated in vacuo. The crude material was purified by / reverse phase chromatography (C18 silica, 0-100% water N (with 0.05% ammonia)/acetonitrile) then further purified by / \ column chromatography (basic silica, 0-35% ethyl acetate/ petrol) to afford the title compound. 0450 "H NMR (400 MHz, DMSO-d) 8 ppm 1.53-1.68 (m. 2H), 1.68-1.81 (m, 2H), 2.03-2.18 (m, 2H), 4.07-4.21 (m. 1H), 4.23-4.34 (m, 1H), 6.86-7.36 (m, 3 H), 7.43-7.51 0457 To a solution of 3-ethoxy-6-methylpyridine-2-car (m. 1H), 7.55-7.65 (m, 1H), 7.68-7.79 (m, 1H), 8.17-8.31 boxylic acid (Intermediate 13; 51 mg, 0.29 mmol) in DMF (m. 1H), 8.41-8.53 (m, 1H), 8.72-8.84 (m, 1H) (3 ml) was added DIPEA (0.15g, 1.14 mmol), TBTU (0.11 g, 0.34 mmol) and 2-(duinolin-2-ylmethyl)cyclopentan-1- 0451 MS ES": 423 amine hydrochloride (Intermediate 12, Isomer 2; 75 mg. 0.29 mmol). The reaction mixture was stirred at room Example 26 temperature for 5 hours then poured into water and extracted with ethyl acetate. The organics were washed with brine, 3-Ethoxy-6-methyl-N-2-(duinolin-2-ylmethyl)cy dried over sodium sulfate, filtered and concentrated in clopentylpyridine-2-carboxamide vacuo. The crude material was purified by column chroma tography (silica, 0-70% ethyl acetate/n-hexane) to afford the 0452 title compound. 0458 H NMR (400 MHz, DMSO-d) 8 ppm 1.24-127 (m, 3H), 1.32-1.36 (m, 1H), 1.50-1.67 (m, 4H), 1.99-2.01 (m. 1H), 2.33-2.39 (m, 4H), 2.75-2.81 (m. 1H), 3.26-3.27 (m. 1H), 4.00-4.05 (m, 3H), 7.22-7.28 (m. 1H), 7.41-7.45 (m. 2H), 7.51-7.55 (m, 1H), 7.68-7.72 (m, 1H), 7.91-7.96 (m. 2H), 8.24-8.30 (m, 2H) 0459 MS ES": 390 3. BIOLOGICAL EFFICACY OF COMPOUNDS OF THE INVENTION 0460 Orexin antagonist activity was determined by mea Suring changes in intracellular calcium levels using a Ca" 0453 To a solution of 2-(duinolin-2-ylmethyl)cyclopen sensitive fluorescent dye. The changes in fluorescent signal tan-1-amine hydrochloride (Intermediate 12, Isomer 1: 75 were monitored by Fluorescent Imaging Plate Reader mg, 0.29 mmol) in DCM (950 ul) was added 3-ethoxy-6- (FLIPRTM) technology available from Molecular Devices, methylpyridine-2-carboxylic acid (Intermediate 13; 57 mg, LLC, U.S.A. Orexin mediated increases in intracellular Ca" 0.32 mmol), EDC (60 mg, 0.31 mmol), 3H-1.2.3 triazolo concentration were readily detected upon activation with 4,5-b]pyridin-3-ol (43 mg, 0.32 mmol) and DIPEA (150 ul, orexin-A. Twenty-four hours prior to the assay, RBL-2H3 US 2017/0073340 A1 Mar. 16, 2017 26 cells stably expressing either human orexin receptor 1 or alkoxy, C-C alkoxycarbonyl, C-C alkoxycarbo human orexin receptor 2 were seeded in cell culture medium nylamino, C-C haloalkoxy, NR'R. C-C, in black, clear-bottom 384-well plates (commercially avail cycloalkylamino, C-C alkylcarbonyloxy, C-C alky able from Corning Inc., U.S.A.) and grown overnight at 37° lcarbonylamino, Sulphonamido, C-C alkylsulphonyl, C., 5% CO. On the day of the assay, cell culture media was C-C alkylsulphonylamino and C(O)NR'R''. removed and cells were loaded with Calcium 5 Dye (com L represents a bond, CH, O, NH or N(CH): mercially sold by Molecular Devices, LLC, U.S.A.) for 1 R" represents a hydrogen atom or a C-C alkyl or C-C, hour at 37° C., 5% CO. Test compounds (at 10 point half haloalkyl group; log concentration response curves from 10LM) were added R” represents a hydrogen atom or a C-C alkyl or C-C, to cells for 15 minutes prior to the addition of orexin-A to all haloalkyl group; wells, to achieve a final concentration that produces approxi X represents CF, CHR, O or NC(O)R’: mately an 80% maximal response. The ICs values were R represents a hydrogen atom or a C-C alkyl or C-C, determined from ten point concentration response curves. cycloalkyl group; Curves were generated using the average of two wells for R represents a 5- or 6-membered monocyclic heteroaro each data point. The results obtained are shown in the table matic group optionally substituted by at least one below in which NT denotes Not Tested. Substituent independently selected from halogen, hydroxyl, cyano, C-C alkyl, C-C haloalkyl, C-C Results hydroxyalkyl, C-C alkoxy, C-C haloalkoxy, C-C alkenyl, C-C alkylcarbonyloxy, C-C alkoxycarbo 0461) nyl, - NR'R'', C(O)NR'R'', C-C cycloalkyl, C-C cycloalkyloxy, C-C cycloalkylmethyl or a 5- or Example Human Orexin1R Human Orexin2R 6-membered heteroaryl group, the heteroaryl group Number ICso (nM) ICso (nM) being optionally substituted by at least one substituent independently selected from C-C alkyl, C-C alkoxy 1 43 >10,000 2 128 NT and C-C haloalkoxy; 3 170 >10,000 R" and Reach independently represent a hydrogen atom 4 NT NT or a C-C alkyl or C-C cycloalkyl group, or R and 5 14 2800 6 8.6 >10,000 R may together with the nitrogen atom to which they 7 540 >10,000 are attached form a 4- to 7-membered saturated het 8 34 3300 erocyclic ring optionally Substituted by at least one 9 84 >10,000 Substituent independently selected from halogen, 10 21 >10,000 11 330 >10,000 hydroxyl and C-C alkoxy; 12 42 >10,000 R. R. each independently represent a hydrogen atom 13 69 >10,000 or a C-C alkyl or C-C cycloalkyl group, or R and 14 170 >10,000 R"may together with the nitrogen atom to which they 15 150 >10,000 16 630 NT are attached form a 4- to 7-membered saturated het 17 210 96.OO erocyclic ring optionally Substituted by at least one 18 41 88.00 Substituent independently selected from halogen and 19 33 36OO hydroxyl: 2O 1OO >10,000 21 24 >10,000 R represents a hydrogen or halogen atom or a hydroxyl 22 3OO >10,000 group; 23 290 >10,000 R represents a C-C alkyl, C-C alkoxy, benzyloxy, 24 86 >10,000 C-C aryl, or heteroaryl group; 25 660 >10,000 26 910 NT R" and R' each independently represent a hydrogen 27 71 6000 atom or a C-C alkyl or C-C cycloalkyl group, or R' and R' may together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated 1.-15. (canceled) heterocyclic ring optionally Substituted by at least one 16. A compound of formula Substituent independently selected from halogen, hydroxyl and C-C alkoxy; and R'' and R' each independently represent a hydrogen (I) atom or a C-C alkyl or C-C cycloalkyl group, or R' and R'may together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring optionally Substituted by at least one Substituent independently selected from halogen and hydroxyl: or a pharmaceutically acceptable salt thereof. 17. A compound according to claim 16, wherein R' wherein represents a 9- or 10-membered fused bicyclic heteroaro R" represents an 8- to 10-membered fused bicyclic het matic group containing one or two ring heteroatoms inde eroaromatic group optionally Substituted by at least one pendently selected from nitrogen, oxygen and Sulphur, the Substituent independently selected from halogen, heteroaromatic group being optionally Substituted by one or cyano, hydroxyl, C-C cycloalkyl, C-C alkyl, C-C more halogen atoms.

US 2017/0073340 A1 Mar. 16, 2017 28

wherein R” represents a halogen atom or a hydroxyl removing any protecting groups group and R is as claimed in formula (I), forming a pharmaceutically acceptable salt. or a salt thereof; or 27. A pharmaceutical composition comprising a com (ii) when L represents NH or N(CH), reacting a com pound of formula (I) or a pharmaceutically acceptable salt pound of formula thereof as claimed in claim 16, in association with a phar maceutically acceptable adjuvant, diluent or carrier, and optionally one or more other therapeutic agents. (IV) 28. A composition according to claim 27, wherein the one X or more other therapeutic agents are selected from carbam aZepine, olanzapine, quetiapine, Verapamil, lamotrigine, Ra R! ? oXcarbazepine, risperidone, aripiprazole, Ziprasidone and 25 lithium. s? Sl 29. A method of treating schizophrenia, schizophreniform R1, R disorder, schizoaffective disorder, cognitive disorders or pain, comprising administering to an individual in need wherein R represents a hydrogen atom or methyl group thereof a therapeutically effective amount of a compound of and X, R", R, R and Rare as claimed in formula (I), formula (I) or a pharmaceutically acceptable salt thereof as with a compound of formula (V), R'-LG' , wherein claimed in claim 16. LG' represents a leaving group and R' is as claimed in 30. A method of treating post-traumatic stress disorder, formula (I); panic disorders or addiction, comprising administering to an and optionally thereafter carrying out one or more of the individual in need thereof a therapeutically effective amount following procedures: of a compound of formula (I) or a pharmaceutically accept converting a compound of formula (I) into another able salt thereof as claimed in claim 16. compound of formula (I) k k k k k