WO2011117254A1 - Piperidine amides as modulators of the ghrelin receptor - Google Patents

Piperidine amides as modulators of the ghrelin receptor Download PDF

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WO2011117254A1
WO2011117254A1 PCT/EP2011/054374 EP2011054374W WO2011117254A1 WO 2011117254 A1 WO2011117254 A1 WO 2011117254A1 EP 2011054374 W EP2011054374 W EP 2011054374W WO 2011117254 A1 WO2011117254 A1 WO 2011117254A1
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alkyl
aryl
heteroaryl
ring
alkoxy
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French (fr)
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Jason Bloxham
Stuart Edward Bradley
Colin Peter Sambrook-Smith
Donald Smyth
John Keily
Graham John Dawson
Chrystelle Marie Rasamison
James Charles Bell
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Prosidion Limited
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/26—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
    • C07D265/30—1,4-Oxazines; Hydrogenated 1,4-oxazines not condensed with other rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention is directed to modulators of the ghrelin receptor.
  • the present invention is directed to ghrelin receptor modulators that are useful for the treatment of diabetes and obesity.
  • Type II diabetes meilitus is a progressive and complex disorder that is difficult to treat effectively in the long term.
  • the majority of patients are overweight or obese at diagnosis and unable to achieve or sustain near norraoglycaemia without oral antidiabetic agents.
  • the frequent need for escalating therapy is presumed due to progressive loss of islet p-cell function, usually in the presence of obesity-related insulin resistance.
  • the current clinical approaches are similar in their modes of action, safety profiles and tolerability.
  • the sulphonylureas and rapid-acting insulin secretogogues aided by DPP -4 inhibitors stimulate insulin secretion, the biguamdes reduce hepatic glucose production, alpha-glucosidase inhibitors delay digestion and absorption of intestinal carbohydrate and the thiazolinediones improve insulin action.
  • a disadvantage of some of these therapies can be their ability to promote weight gain.
  • Obesity is characterized by an excessive adipose tissue mass relative to body size, Clinically, body fat mass is estimated by the body mass index (BM1; weight(kg) height(m) ), or waist circumference. Individuals are considered obese when the BMI is greater than 30 and there are established medical consequences of being overweight. It has been an accepted medical view for some time that an increased body weight, especially as a result of abdominal body fat, is associated with an increased risk for diabetes, hypertension, heart disease, and numerous other health complications, such as arthritis, stroke, gallbladder disease, muscular and respiratory problems, back pain and even certain cancers,
  • hypothalamic centres are also able to sense peripheral hormones involved in the maintenance of body weight and degree of adiposity, such as insulin and leptin, and fat tissue derived peptides.
  • peripheral hormones involved in the maintenance of body weight and degree of adiposity such as insulin and leptin, and fat tissue derived peptides.
  • novel antidiabetic and antiobesity agents particularly ones that are well tolerated with few adverse effects.
  • Ghrelin is a 28-amino acid peptide cleaved from a 117-amino acid precursor, preproghrelm. Ghrelin is predominantly produced by the X/A-ceils in the gastric mucosa of the fundus of the stomach, accounting for approximately two/thirds of circulating ghrelin, with the majority of the remainder being derived from the X/A-ceils of the small intestine. Substantially lower amounts are produced by the bowel, pancreas, pituitary gland, kidney and placenta.
  • Ghrelin affects appetite and body weight. Short term fasting has been demonstrated to cause a rise in circulating ghrelin levels, infusion of ghrelin has also been shown to stimulate appetite and increase spontaneous food intake. Ghrelin signals via the arcuate nucleus of the hypothalamus to activate neurones containing neuropeptide Y and agouti related peptide, which are also orexige ic peptides. In parallel neurones containing the anorexigenic peptides CART and pro-opiom.elanocortin are inhibited. The neuroendocrine effects within the hypothalamus enhance the drive to feed through orexin and ghrelin release itself. Ghrelin can also have long term affects upon body weight.
  • Ghrelin As with short term fasting, it has been shown that after loss of body weight ghrelin levels increase and with body weight gain ghreli levels go down. Ghrelin not only stimulates feeding but it also affects energy homeostasis. This manifests itself in a number of ways by increasing preference for fat, promoting adipogenesis, decreasing lipolysis, inhibiting apopotosis of adipocytes, lowering body temperature and reducing locomotory activity.
  • Ghrelin has also been shown to inhibit the activity of the glucose sensing neurons within the CNS by suppressing both glucose-activated and glucose-inhibited neurons in the dorsal vagal complex. Generally a negative relationship between ghrelin and insulin levels can be demonstrated, with ghrelin inhibiting insulin secretion both in vitro and in vivo although under certain experimental conditions this can be reversed. The release of insulin appears to be controlled by the GHS-Rl receptors in the pancreas.
  • ghrelin impedes insulin's ability to suppress endogenous glucose production, whereas it reinforces the action of insulin on glucose disposal in mice, inhibits secretion of the insulin- sensitizing protein adiponectin produced by the adipocytes and stimulates secretion of counter-regulatory hormones, including growth hormone, Cortisol, epinephrine and possibly glucagon.
  • Acute ghrelin administration in humans increases plasma glucose levels. This may result not only through direct effects on hepatocytes, where it has been shown to be able to modulate glycogen synthesis and gluconeogenesis, stimulating hepatic glucose production.
  • Antagonism of the effects of ghrelin could therefore result in improving the diabetic condition by enhancing glucose dependent insulin secretion and promoting weight loss.
  • Ghrelin is the endogenous ligand for the ghrelin receptor, also known as the growth hormone seereatagougue receptor or GHSR la receptor.
  • the ghrelin receptor has been demonstrated to possess constitutive activity through the Gq PLC pathway, an activity which is approximate to 50% of their maximal capacity. There is also a high constitutive activity through the cAMP response element driven transcription.
  • the high constitutive activity of ghrelin receptors may serve as the signalling set point for appetite and energy expenditure by actions upon neuropeptide Y and agouti-related peptide neurons in the hypothalamus and counter-balancing the effects of inhibitory hormones and neurotransmitters such as leptin, insulin and Ghrelin binds to GHS-RI a and stimulates the release of growth hormone from the somatotrophic ceils of the pituitary gland. This is accompanied by activation of growth hormone releasing neurons and inhibition of somatostatin neurones in the hypothalamus and induction of vagal afferent activation.
  • Ghrelin modulators may have an advantage over current antidiabetic agents in that they could have the ability to reduce hyperglycaemia and have the added advantage of the potential for weight loss.
  • the moqjholino compounds N-((4-benzylmorpholin-2-yl)methyl)-3- phenoxybenzamide and N-((4-berlz l o holm-2-yl)methyl)-3-(berlz lo y)benzamide are also known from CHEMCATS Accession Nos. 20951 13294 and 2095026465 respectively (CAS Registry Nos. 1 182591-75-8 and 1 181183-97-0).
  • the present invention relates to ghrelin receptor modulators that are useful for the treatment of diabetes and obesity,
  • ghrelin receptor modulators that are useful for the treatment of diabetes and obesity.
  • R is C 2- 6 alkyl, C3..7 cycloalkyl, C,.3 alkyl-Cj.y eycloalkyl, €3.3 alkyl-aryl or Ci.j alkyl- heteroaryl, any of which may be optionally substituted with one or more F, OH or C ⁇ ..3 alkoxy groups;
  • R ; and R 2 are independently selected from H, C].$ alkyl, Ci, 3 alkyl-aryl, aryl, C1.3 alkyl- heteroaryl and heteroaryl, or R and taken together may form a 3- to 7-membered carbocyclie ring; optionally substituted with halogen, Cj_3 alkoxy or C1.3 alkyl;
  • R 3 and R 4 are independently selected from H, F, C1-3 alkyl, OH or Ci -3 alkoxy;
  • R ! ; to R 14 are independently selected from H and C3 ⁇ 4; W is C3 ⁇ 4, CHF, CF 2 , O, CH(OH), C(OH)C]. 3 alkyl, CH(OC 1-3 alkyl), C(OC ( .3 alkyl)C,, 3 alkyl, -CH(Cu 3 alkyl) or -C(Ci. 3 alkyl)(C 1-3 alkyl);
  • R 99 is H, Ci-6 alkyl, -(CH ) n -aryl, -(CH 2 ) n -heteroaryl or -(CH 2 ) p -0-aryl where aryl or heteroaryl groups may be optionally substituted with C 1-3 alkyl, C 1 -3 alkoxy or halogen; or R 99 together with R 5 or R 2 form a 5- to 6-membered nitrogen containing ring;
  • Y, ⁇ ', Y 2 and Y 3 are independently N or CR '0 such that the ring contains 0, 1 or 2 nitrogens;
  • R 20 is independently selected from H, halogen. C alkoxy, O-C3-6 cycloalkyl, 0-(4- to 7-membered heterocyelyl), C1.3 alkyl, NR 96 R 97 , Q-(CH 2 ) q -Ci-6 alkoxy, Q ⁇ (CH 2 ) i aryl and Q-(CH 2 ) -heteroaryl;
  • R 96 and R 9 ' are independently selected from H, C 1-3 alkyl and C 3-6 cycloalkyl;
  • R° is H, Ci-3 alkyl, C 3 . 7 cycloalkyl, C1.3 alkyl-C 3 . 7 cycloalkyl, C 1-3 alkyl-aryl or C 1-3 alkyl- heteroaryl, any of which may be optionally substituted with one or more F, OH or Cu alkoxy groups;
  • R' and R 8 independently selected from H, OH, F, Cj -3 alkoxy or Q.3 alkyl, provided that when one of R 7 or R 5 is OH the other cannot be F, OH, or C 1 -3 alkoxy;
  • Ring is a Q.jo carbocyclic, €5-10 aryl, 6- to 10-membered heteroaryl ring or a bicyclic structure comprising a 5- or 6- membered aryl or heteroaryl with a 5 or 6 membered carbocycle or keterocyele fused thereto wherein the bicyclic structure bonds to X via one of the atoms on the aryl or heteroaryl moiety, any of which may be optionally substituted by 1 to 3 groups selected from halogen, C1-3 alkyl optionally substituted by hydroxy or 1 to 3 halogens, C t . 3 alkoxy, CN, C0 2 R i5 , CON(R i 5 ) 2 , SO ? OH, S0 2 N ⁇ R i 5 ) 2 , N(R !5 ) 2 ,
  • R. i5 is independently seletected from H and C 1-3 alkyl
  • n 0, 1, 2 or 3;
  • p 2 or 3
  • q 0, 1 or 2;
  • r is 1 or 2.
  • said compound compound of formula (I) or pharmaceutically acceptable salt thereof may be used in a method for the treatment of diabetes, obesity, metabolic syndrome (syndrome X), impaired glucose tolerance, Prader-Willi syndrome, hyperlipidaemia, hypertriglyceridaemia, hypereholesteroiaemia, low HDL levels, hypertension or abnormal sensitivity to ingested fats.
  • a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined above subject to the proviso that the compound is not N-((4-benzyImorpholin-2-yl)methyl)-3-pherioxybenzaniide or N-((4-benzylmorpholin-2-yl)meihyl)-3-(benzyloxy)benzamide.
  • the molecular weight of the compounds of formula (I) is preferably less than 800, more preferably less than 600, even more preferably less than 500.
  • R is preferably C 2-3 ⁇ 4 alkyl, e.g. isopropyl or pentyl, optionally substituted with one or more F, OH or Ci -3 alkoxy groups.
  • R 1 and R. 2 are preferably independently selected from H and -g alkyl
  • R 3 and R 4 are preferably independently selected from H and F,
  • R n to R ]4 are preferably H.
  • W may be W is C3 ⁇ 4 CHF, CF 2 , CH(OH), C(OH)C 1-3 alkyl, CH(OCi-3 alkyl), C(OC !-3 alkyi)C ]-3 alkyl, ⁇ CH(C>. 3 alkyl) or -C(C 1-3 alkyl)(C 1-3 alkyl).
  • W is preferably CH 2 ,
  • R 99 is preferably H.
  • the ring containing Y, Y ! , Y 2 and Y J preferably contains 1 or 2 nitrogen atoms. When it contains 1 nitrogen atom, this is preferably Y or Y 5 ; when it contains 2 nitrogen atoms these are preferably Y ! and Y 2 .
  • Y is N or C(C !-6 alkoxy); Y ! is CH or N; Y 2 is CH, CMe or N; and Y is CH.
  • R i0 is preferably independently selected from H, Cj. & alkoxy. 0-C 3 . ⁇ s cycloalkyl, O- (CH 2 ) q -Cj, 6 alkoxy and 0 ⁇ (CH 2 ) q -aryl.
  • R 6 , R 7 and R 8 are preferably H.
  • Ring is preferably an optionally substituted C5.10 aryl or 6- to 10-membered heieroaryl ring e.g. a 7- to 10-membered heteroaryl ring.
  • Ring is preferably optionally substituted by 1 to 3 groups selected from halogen, C 1-3 alkyl optionally substituted by OH, C I alkoxy and aryl.
  • Ring is preferably phenyl, napthyl, pyridine or quinoline, optionally substituted with one or more halogen atom, preferably F or CL preferably at least one of which is para or ortho to the X-Ring bond.
  • the phenyl may additionally or alternatively be substituted with one or more C ⁇ to C 3 alkyl, Ci to C alkoxy, nitre, CN, CF 3 , CCHR' 3 , CGN(R !
  • Ring may be selected from pyridine, indole, benzol ,3dioxole, quinoline, benzot iazole, indazole, imidazole, benzoimidazole, dihydx'obenzooxazine, , dihydrobenzodioxine, adarnantane, cyclohexane, 4,4 ⁇ dimethyleyelohexane, 2,3 dihydroindene, all of which may be optionally substituted with one or more halogen or Ci to C alkyl.
  • Ring is preferably phenyl, napthyl. pyridine or quinoline, optionally substituted with one or more halogen atoms, preferably F or CI, preferably at least one of which is para or ortho to the X-Ring bond and additionally or alternatively be substituted with one or more Ci to C 3 alley!.
  • Ring may be 2,3
  • Ring is preferably phenyl, napthyl, pyridine or quinoline, optionally substituted with one or more halogen atoms, preferably F or CI, preferably at least one of which is para or ortho to the X-Ring bond and additionally or alternatively be substituted with one or more Q to C 3 alkyl.
  • the invention also comprehends isotopieally-labelled compounds, which are identical to those recited in formula (I) and following, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number most commonly found in nature.
  • isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, fluorine, such as He, ⁇ C and ⁇ F.
  • Isotopieally-labelled compounds of the present invention for example those into which radioactive isotopes such as ⁇ ll, are incorporated, are useful in drug and/or substrate tissue distribution assays, Tritiated, i.e., 3 ⁇ 4, and carbon-14, i.e., ⁇ C, isotopes are particularly preferred for their ease of preparation and detectability.
  • Tritiated i.e., 3 ⁇ 4
  • carbon-14 i.e., ⁇ C
  • isotopes are particularly preferred for their ease of preparation and detectability.
  • ⁇ and isotopes are particularly useful in PET (positron emission tomography). PET is useful in brain imaging.
  • isotopically labelled compounds of formula (I) and following of this invention can generally be prepared by carr/ing out the procedures disclosed in the Schemes and/or in the Examples below, by substituting a readily available isotopically labelled reagent for a non-isotopically labelled reagent, in one embodiment, the compounds of formula (I), or salts thereof are not. isotopically labelled.
  • preferred compounds of this invention include those in which several or each variable in formula (I) is selected from the preferred, more preferred or particularly listed groups for each variable. Therefore, this invention is intended to include all combinations of preferred, more preferred and particularly listed groups,
  • alkyl means carbon chains which may be linear or branched or combinations thereof.
  • alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec- and tert-buryl, pemyi, hexyi, heptyl and the like.
  • Alkoxy should be construed accordingly. Any alkyl or alkoxy groups may be optionally substituted by one or more fluorine atoms, to form goups such as -CF 3 and -OCF 3 . Generally a -CH3 or CF3 group may be replaced by 8F5 without departing from the present invention.
  • cyeloalkyi and “carbocyelic” mean carbocycles containing no heieroatoms, and includes monocyclic and bicyclic saturated and partially saturated carbocycles.
  • Examples of cyeloalkyi groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cyeloheptyL
  • Examples of partially saturated cyeloalkyi groups include cyclohexene and indane. Cyeloalkyi groups will typically contain from 3 to 7 ring carbon atoms in total, e.g.
  • heterocyclyl includes 4- to IQ-membered monocyclic and bicyclic saturated rings, e.g. 4- to 7-membered monocyclic saturated rings, containing up to three heteroatoms selected from N, O and S.
  • heterocyclic rings include oxetane, tetrahydrofuran, tetrahydropyran, oxepane, oxocane, thietane,
  • heterocyclic rings include the oxidised forms of the sulfur-containing rings.
  • tetrahydrothiopyran 1 ,1 -dioxide are also considered to be heterocyclic rings.
  • halo includes fluorine, chlorine, bromine, and iodine atoms, in particular fluorine or chlorine.
  • aryl includes phenyl and naphthyl, in particular phenyl.
  • heteroaryl includes mono- and bicyclic 5 ⁇ to 10- membered, e.g. monocyclic 5- or 6-niembered, heteroaryl rings containing up to 4 heteroatoms selected from N, O and S.
  • heteroaryl rings are furyl, thienyl, pyrrolyl, pyrazolyl, ixnidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridinyl, pyridazinyl, pyrimidmyl, pyrazinyl and triazinyl.
  • Bicyclic heteroaryl groups include bicyclic heteroaromatie groups where a 5- or 6- membered heteroaryl ring is fused to a phenyl or another heteroaromatie or heterocyclyl group.
  • heterocyclyl rings which may be fused to phenyl or and “heterocyclic ring” includes 5- to 6-membered monocyclic, containing up to three heteroatoms selected from N, O and S.
  • heterocyclic rings examples include tetrahydrofuran, tetrahydropyran, tetrahydrothiophene, tetrahydrothiopyran, pyrrolidine, piperidine, oxazolidine, piperazine, and the like.
  • Other examples of heterocyclic rings include the oxidised forms of the S containing rings.
  • Ring being a bicyclic structure comprising a 5- or 6- membered aryl or heteroaryl with a 5 or 6 membered carbocycle or heterocycle fused thereto
  • fused means that the two cyclic groups of the bicyclic structure share two atoms and the bond between the two atoms.
  • the bicyclic structure contains a heteroaryl ring
  • the heteroaryl may contain up to 4 heteroatoms selected from N, O and S
  • the heterocycle may contain up to three heteroatoms selected from N, O and S, not including any heteroatom which it may share with a heteroaryl moiety.
  • the carbocycie or heterocycle may also contain an unsaturated bond.
  • Compounds described herein may contain one or more asyninietric centers and may thus give rise to diastereomers and optical isomers.
  • the present invention includes all such possible diastereomers as well as their racemic mixtures, their substantially pure resolved enantiomers, all possible geometric isomers, and pharmaceutically acceptable salts thereof.
  • the above formula ( ⁇ ) is shown without a defioitive stereochemistry at certain positions.
  • the present invention includes all stereoisomers of formula ( ⁇ ) and pharmaceutically acceptable salts thereof. Further, mixtures of stereoisomers as well as isolated specific stereoisomers are also included.
  • the products of such procedures can be a mixture of stereoisomers.
  • the present invention includes any possible solvates and polymorphic forms.
  • a type of a solvent that forms the solvate is not particularly limited so long as the solvent is pharmacologically acceptable.
  • water, ethanol, propanol, acetone or the like can be used .
  • Salts derived from bases include those derived from bases such as, for example, potassium and sodium salts and the like.
  • Salts derived from pharmaceutically acceptable non-toxic acids include those derived from inorganic and organic acids such as, for example, hydrochloric, methanesuifomc, sulfuric, p- toluenesulfonic acid and the like.
  • the compounds of formula (I) are intended for pharmaceutical use they are preferably provided in substantially pure form, for example at least 60% pure, more suitably at least 75% pure, especially at least 98% > pure (% are on a weight for weight basis).
  • the compounds of formula ( ⁇ ) can be prepared as described below wherein R, N, W, R 99 , Y, Y 1 , Y 2 , Y 3 , R 20 , X, Ring, R 3 to R 4 , R 6 , R 7 , R 8 and R ! ] to R i4 are as defined above for formula (I).
  • R 1 to R 4 and R n to R 54 are represented as hydrogen, however the procedures described therein are also applicable for the synthesis of compounds where R ! to R 4 and R ! 1 to R 34 are other than hydrogen.
  • Compounds of the formula (I) can be prepared using the methods outlined in Scheme
  • Acids of formula (II) are either readily available, synthesised by known methods or can be synthesised by the methods shown in Schemes 5, 6, 7 and 8.
  • Amines of formula (III) are also either readily available, synthesised by known methods or can be synthesised by the methods shown in Schemes 11, 12, 13 and 14.
  • Acids of formula (IT.) can be reacted with the corresponding amines of formula (III) in a solvent such as DMF in the presence of a base such as DIPEA and with an amide coupling agent such as EDCI and HOBT to give compounds of formula (I).
  • acids of formula (II) can be converted to the corresponding acid chloride using for example oxalyl chloride in a solvent such as DCM and then reacted with amines of formula (III) in the presence of a base such NEtj to give compounds of formula ( ⁇ ).
  • Compounds of formula (VII) can be reacted with a base such as sodium hydride and an electrophile such as 4- fluoronitrobenzene to give compounds of formula (I).
  • a base such as sodium hydride
  • an electrophile such as 4- fluoronitrobenzene
  • compounds of formula (VII) can treated with a boronic acid such as 4 ⁇ fluorobenzene boronic acid in a solvent such as DCM in the presence of a base such as DIPEA and a catalyst such as copper acetate to give compounds of formula (I).
  • Reaction of compounds of formula (X) with oxygen based nucleophiles such as for example phenol using a base such a NaH in a solvent such as NMP and with a catalyst such as Cul gives compounds of formula (I) where Xis O.
  • catalysts such as Pd(OAe) 2 , a ligand such as BINAP and a base such as CS2CO3 m a solvent such as PhMe
  • Compounds of formula (XIV) can be hydrolysed as described previously to give compounds of formula ( ⁇ ).
  • Phenols of formula (VI) are readily available and can treated with a boronic acid such as 4-fluorobenzene boronic acid in a solvent such as DCM in the presence of a base such as D1PEA and a catalyst such as copper acetate to give compounds of formula (II).
  • a boronic acid such as 4-fluorobenzene boronic acid in a solvent such as DCM
  • a base such as D1PEA
  • a catalyst such as copper acetate
  • a Lewis Acid such as aluminium (III) chloride
  • DCE solvent
  • Compounds of formula (XVI) can be reduced to compounds of formula (XVII) using for example trifluroacetic acid and tiethylsilane.
  • N-oxides of formula (XVIII) can be converted to N-oxides of formula (XVIII) using for example m-CPBA in a solvent such as DCM.
  • N-oxides of formula (XVIII) when reacted with TMSCN and DMCC in a solvent such as DCM give compounds of formula (XIX) which can be hydrolysed to compounds of formula (II) using methods outlined above.
  • Aldehydes of formula (XX) can be reacted with Grignard reagents such as phenyl magnesium bromide in a solvent such as THF to give alcohols which either on work-up or in a subsequent oxidation with for example manganese dioxide give ketones of formula (XVI).
  • Grignard reagents such as phenyl magnesium bromide
  • a solvent such as THF
  • ketones of formula (XVI) ketones of formula (XVI).
  • pyridyl halides of formula (XXI) can be reacted with ethyl magnesium bromide in for example THF to form aryi Grignard reagents which can then he treated with aldehydes to give after work-up or subsequent oxidation as outlined previously compounds of formula (XVI).
  • oxidizing agents such as wCPBA
  • DCM a solvent such as DCM
  • compounds of formula (XXIII) can be reacted with TMSCN and N ⁇ -dimethylcarbamoyl chloride in a solvent such as DCM give compounds of formula (XXIV).
  • Nitriles of formula (XXIV) can be hydrolysed using hydrobromic acid to give compounds of formula (VI).
  • Amine of formula (XXV) can be protected with for example a phthalimide group which can be formed by treating the amine with phthalic anhydride in a solvent such as PhMe and heating to give compounds of formula (XXVI).
  • Treating compounds of formula (XXVI) with an acid such as TFA in a solvent such as DCM gives compound of formula (XXVII).
  • Reductive ainination with aldehydes or ketones in a solvent such as DCM and a reducing agent such as NaBH(OAc)3 or alkylation with an alkylating agent and a base such as K 2 CO 3 gives compounds of formula (XVIII).
  • pyridines of formula (XXIX) can be protected using for example di-fcrf-butyl dicarbonate in a solvent such as THF and a base such as Et 3 to give compounds of formula (XXX).
  • Compounds of formula (XXX) can be reduced under pressure, with heating using hydrogen gas and a catalyst such as rhodium on alumina in a solvent such as MeOH to give compounds of formula (XXXI).
  • Compounds of formula (XXXI) can be alkylated with for example and aldehyde or ketone such as Me 2 CO, in a solvent such as DCM with a reducing agent such as to give protected amines of formula (XXXIl).
  • Compounds of formula (XXXII) may be treated with an acid such as TFA in a solvent such as DCM to give amines of formula (III).
  • Piperidones of formula (XXXIII), which are readily available, can be reacted with for example a strong base such as lithium diisopropylamide in a solvent such as THF and with an elecirophile such as 2-bromomethyliso indole- 1,3 -dione (XXXIV) to give compounds of formula (XXXV),
  • Compounds of formula (XXXV) can be reduced with for example hydrazine and potassium hydroxide in a solvent such as diethylene glycol to give compounds of formula (III)
  • the compounds of formula (I) may be prepared singly or as compound libraries comprising at least 2, for example 5 to 1,000, compounds and more preferably 10 to 100 compounds of formula (I).
  • Compound libraries may be prepared by a combinatorial "split and mix” approach or by multiple parallel synthesis using either solution or solid phase chemistry, using procedures known to those skilled i the art.
  • labile functional groups in the intermediate compounds e.g. hydroxy, carboxy and amino groups
  • the protecting groups may be removed at any stage in the synthesis of the compounds of formula (I) or may he present on the final compound of formula (I).
  • a comprehensive discussion of the ways in which various labile functional groups may be protected and methods for cleaving the resulting protected derivatives is given in, for example, Protective Groups in Organic Chemistry, T.W. Greene and P.G.M. Wuts, (1991) Wiley-Interscience, New York, 2 nd edition.
  • the compounds of formula (I) are useful as ghrelin receptor modulators, e.g. ghrelin receptor antagonists, for the treatment and/or prophylaxis of diabetes and obesity.
  • the compounds of formula (I) will generally be administered in the form of a pharmaceutical composition.
  • the invention also provides a compound of formula (1), or a phannaceutically acceptable salt thereof, for use as a pharmaceutical .
  • the invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (i), in combination with a pharmaceutically acceptable carrier.
  • composition is comprised of a pharmaceutically acceptable carrier and a non-toxic therapeutically effective amount of a compound of formula (I), or a
  • the invention also provides a pharmaceutical composition for the treatment of disease by modulating the ghrelin receptor, resulting in the prophylactic or therapeutic treatment of diabetes or obesity, comprising a phannaceutically acceptable carrier and a nontoxic therapeutically effective amount of compound of formula (I), or a pharmaceutically acceptable salt thereof
  • compositions may optionally comprise other therapeutic ingredients or adjuvants.
  • the compositions include compositions suitable for oral, rectal, topical, and parenteral (including subcutaneous, intramuscular, and intravenous) administration, although the most suitable route in any given case will depend on the particular host, and nature and severity of the conditions for which the active ingredient is being administered.
  • the pharmaceutical compositions may be conveniently presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy.
  • the compounds of formula (I), or pharmaceutically acceptable salts thereof can be combined as the active ingredient in intimate admixture with a
  • the carrier may take a wide variety of forms depending on th e form of preparation desired for administration, e.g. oral or parenteral (including intravenous).
  • compositions can be presented as discrete units suitable for oral administration such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient. Further, the compositions can be presented as a powder, as granules, as a solution, as a suspension in an aqueous liquid, as a non-aqueous liquid, as an oil-in-water emulsion, or as a water-in-oil liquid emulsion.
  • the compound of formula (I), or a pharmaceutically acceptable salt thereof may also be administered by controlled release means and/or deliver - devices.
  • compositions may be prepared by any of the methods of pharmacy, in general, such methods include a step of bringing into association the active ingredient with the carrier that constitutes one or more necessary ingredients, in general, the compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both. The product can then be conveniently shaped into the desired presentation,
  • the compounds of formula ( ⁇ ), or pharmaceutically acceptable salts thereof, can also be included in pharmaceutical compositions in combination with one or more other therapeutically active compounds.
  • the pharmaceutical carrier employed can be, for example, a solid, liquid, or gas.
  • solid carriers include lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid.
  • liquid carriers are sugar syrup, peanut oil, olive oil, and water.
  • gaseous carriers ixiclude carbon dioxide and nitrogen.
  • any convenient pharmaceutical media may be employed.
  • water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, and the like may be used to form oral liquid preparations such as suspensions, elixirs and solutions; while carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like may be used to form oral solid preparations such as powders, capsules and tablets. Because of their ease of administration, tablets and capsules are the preferred oral dosage units whereby solid pharmaceutical carriers are employed.
  • tablets may be coated by standard aqueous or nonaqueous techniques.
  • a tablet containing the composition of this invention may be prepared by compression or molding, optionally with one or more accessory ingredients or adjuvants.
  • Compressed tablets may be prepared by compressing, in a suitable machine, the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent. Molded tablets may be made by molding in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent.
  • Each tablet preferably contains from about 0,05mg to about 5g of the active ingredient and each cachet or capsule preferably containing from about O.Q5mg to about 5g of the active ingredient.
  • a formulation intended for the oral administration to humans may contain from about 0.5mg to about 5g of active agent, compounded with an appropriate and convenient amount of carrier material which may vary from about 5 to about 95 percent of the total composition.
  • Unit dosage forms will generally contain between from about Img to about 2g of the active ingredient, typically 25mg, 50mg, lOOmg, 200mg, 300mg, 400mg, 500m g, 600mg, SOOmg, or lOOOmg.
  • compositions of the present invention suitable for parenteral administration may be prepared as solutions or suspensions of the active compounds in water.
  • a suitable surfactant can be included such as, for example, hydroxypropylcellulose.
  • Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils. Further, a preservati ve can be included to prevent the detrimental growth of microorganisms.
  • compositions of the present invention suitable for injectable use include sterile aqueous solutions or dispersions.
  • the compositions can be in the form of sterile powders for the extemporaneous preparation of such sterile injectable solutions or dispersions, in all cases, the final injectable form must be sterile and must be effectively fluid for easy syringability.
  • the pharmaceutical compositions must be stable under the conditions of manufacture and storage; thus, preferably should be preserved against the contaminating action of microorganisms such as bacteria and fungi.
  • the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g. glycerol, propylene glycol and liquid polyethylene glycol), vegetable oils, and suitable mixtures thereof.
  • compositions of the present invention can be in a form suitable for topical use such as, for example, an aerosol, cream, ointment, lotion, dusting powder, or the like. Further, the compositions can be in a form suitable for use in transdermal devices. These formulations may be prepared, using a compound of formula (I), or a pharmaceutically acceptable salt thereof, via conventional processing methods. As an example, a cream or ointment is prepared by admixing hydrophilic material and water, together with about 5wt% to about 10wt% of the compound, to produce a cream or ointment having a desired consistency.
  • compositions of this invention can be in a form suitable for rectal administration wherein the carrier is a solid. It is preferable that the mixture forms unit dose suppositories. Suitable carriers include cocoa butter and other materials commonly used in the art. The suppositories may be conveniently formed by first admixing the composition with the softened or melted carrier(s) followed by chilling and shaping in molds.
  • the pharmaceutical formulations described above may include, as appropriate, one or more additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, preservatives (including anti-oxidants) and the like.
  • additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, preservatives (including anti-oxidants) and the like.
  • additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, preservatives (including anti-oxidants) and the like.
  • additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, preservatives (including anti-oxidants) and the like.
  • other adjuvants can be included to render the formulation isotonic with the blood of the intended recipient
  • compositions containing a compound of formula (I), or pharmaceutically acceptable salts thereof may also be prepared in powder or liquid concentrate form.
  • dosage levels on the order of O.Qlmg/kg to about 150mg kg of body weight per day are useful in the treatment of the above-indicated conditions, or alternatively about 0.5mg to about 7g per patient per day.
  • diabetes may be effectively treated by the administration of from about 0.01 to 50mg of the compound per kilogram of body weight per day, or alternatively about 0.5mg to about 3.5g per patient per day.
  • the specific dose level for any particular patient will depend upon a variety of factors including the age, body weight, general heal th, sex, diet time of administration, route of administration, rate of excretion, drug combination and the severity of the particular disease undergoing therapy.
  • the compounds of formula (I) may be used in the treatment of diseases or conditions in which the ghrelin receptor plays a role,
  • the invention also pro vides a method for the treatment of a disease or condition in which the ghrelin receptor plays a role comprising a step of administering to a subject hi need thereof an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof.
  • diabetes diseases or conditions in which the ghrelin receptor plays a role include diabetes and obesity.
  • the treatment of diabetes includes impaired glucose tolerance, insulin resistance and diabetic complications such as neuropathy, nephropathy, retinopathy, cataracts, cardiovascular complications and dyslipidaemia).
  • the treatment of obesity is intended to encompass the treatment of diseases or conditions such as obesity and other eating disorders associated with excessive food intake e.g. by reduction of appetite and body weight, maintenance of weight reduction and prevention of rebound.
  • the compounds of the invention may also be used for treating metabolic diseases such as metabolic syndrome (syndrome X), impaired glucose tolerance, Prader-Willi syndrome, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, low HDL levels and hypertension, and and for the treatment of patients who have an abnormal sensitivity to ingested fats leading to functional dyspepsia.
  • metabolic syndrome simple X
  • Prader-Willi syndrome hyperlipidemia
  • hypertriglyceridemia hypercholesterolemia
  • the invention also provides a method for the treatment of diabetes, particularly type 2 diabetes, comprising a step of administering to a subject in need thereof an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof.
  • the invention also provides a method for the treatment of obesity comprising a step of administering to a subject in need thereof an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof.
  • the invention also provides a method for the treatment of metabolic syndrome
  • the invention also provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of a condition as defined above.
  • the invention also provides the use of a compound of formula (I), or a
  • treatment includes both therapeutic and prophylactic treatment.
  • the compounds of formula (I) may exhibit advantageous properties compared to known ghrelin receptor modulators, for example, the compounds may exhibit improved solubility thus improving absorption properties and bioavailability, or other advantageous properties for compounds to be used as pharmaceuticals,
  • the compounds of formula (I), or pharmaceutically acceptable salts thereof, may be administered alone or in combination with one or more other therapeutically active compounds.
  • the other therapeutically active compounds may be for the treatment of the same disease or condition as the compounds of formula (I) or a different disease or condition.
  • the therapeutically active compounds may be administered simultaneously, sequentially or separately.
  • the compounds of formula (I) may be administered with other active compounds for the treatment of diabetes and/or obesity, for example insulin and insulin analogs, gastric lipase inhibitors, pancreatic lipase inhibitors, sulfonyl ureas and analogs, biguamdes, 2 agonists, glitazones, PPAR-y agonists, mixed PPAR- ⁇ ⁇ agonists, RXR agonists, fatty acid oxidation inhibitors, -glucosidase inhibitors, dipeptidyl peptidase IV inhibitors, GPR119 agonists, GLP-1 agonists e.g.
  • active compounds for the treatment of diabetes and/or obesity for example insulin and insulin analogs, gastric lipase inhibitors, pancreatic lipase inhibitors, sulfonyl ureas and analogs, biguamdes, 2 agonists, glitazones, PPAR-y agonists, mixed PPAR- ⁇ ⁇ agonists
  • GLP-1 analogues and mimetics ⁇ -agonists, phosphodiesterase inhibitors, lipid lowering agents, glycogen phosphorylase inhibitors, antiobesity agents e.g. pancreatic lipase inhibitors, MCH-1 antagonists and CB-1 antagonists (or inverse agonists), arnylm antagonists, lipoxygenase inhibitors, somostatin analogs, glucokinase activators, glucagon antagonists, insulin signalling agonists, PTP1B inhibitors, gluconeogenesis inhibitors, antilypolitic agents, GSK inhibitors, galanin receptor agonists, anorectic agents, CCK receptor agonists, ieptin, serotonergic/dopaminergic antiobesity drags, reuptake inhibitors e.g.
  • sibutramme CRF antagonists, CRF binding proteins, thyromimetic compounds, aldose reductase inhibitors, glucocorticoid receptor antagonists, NHE-1 inhibitors or sorbitol dehydrogenase inhibitors.
  • Combination therapy comprising the administration of a compound of formula (I), or a pharmaceutically acceptable salt tliereof, and at least one other antidiabetic or antiobesity agent represents a further aspect of the invention.
  • the present invention also provides a method for the treatment of obesity in a mammal, such as a human, which method comprises adminisiermg an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, and another antidiabetic or antiobesity agent, to a mammal in need thereof.
  • the invention also provides the use of a compound of formula (I), or a
  • the invention also provides the use of a compound of formula (I), or a
  • the compound of formula (I), or a pharmaceutically acceptable salt thereof, and the other antidiabetic or antiobesity agent(s) may be co-administered or administered sequentially or separately.
  • Co-administration includes administration of a formulation which includes both the compound of formula (I), or a pharmaceutically acceptable salt thereof, and the other antidiabetic or antiobesity agent(s), or the simultaneous or separate administration of different formulations of each agent. Where the pharmacological profiles of the compound of formula (I), or a pharmaceutically acceptable salt thereof, and the other antidiabetic or antiobesity agent(s) allow it, coadministration of the two agents may be preferred.
  • the invention also provides the use of a compound of formula (I), or a
  • the invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and another antidiabetic or antiobesity agent, and a pharmaceutically acceptable carrier.
  • the invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and another antidiabetic or antiobesity agent, and a pharmaceutically acceptable carrier.
  • the mass spectra were obtained using an electrospray ionisation source in either the positive (ES 4 ) or negative (ES ) ion modes.
  • Standard method eluting with solvent A (water+0.1% formic acid) and solvent B (MeCN+0.1% formic acid).
  • Basic method eluting with solvent A (water+0.2% NH 4 OH) and solvent B (MeCN (or MeOH)+0.2% NH 4 OH). Unless otherwise stated standard method was employed for purification.
  • Prep Cliiral HPLC was carried out using Daieel Chiralpack IA, 250x20mm, 5 ⁇ , Flow rate: 12-15.0 mL/min.
  • Abbreviations and acronyms AcOH: Acetic acid; Me 2 CO: Acetone; MeCN: Acetonitrile;
  • HATU 0-(7-Azabenzotriazoie-l-yl)-N,N, N, A etramethy roriium hexafiuorophosphate; cone: concentrated; CS2CO3: Cesium carbonate; Cul: Copper iodide; DCE: Diehloroethane;
  • DCM Dichloromethane
  • DEA Diethylamine
  • DAST Diethylaminosulfur trifluoride
  • DIBAL-H diisobutyialuminium hydride
  • DIPEA N,N-
  • EDCI N-(3-Dimethylaminopropyl)-.V-ethyi carbodiimide hydrochloride
  • DMCC AvV-Dimethylcarbamo l chloride
  • DMSO Dimethylsulfoxide
  • DMF NjN-Dimethylfonnamide
  • Et 2 0 Diethyl ether
  • BINAP 2,2'-3 ⁇ 4s(Diphenylphosphmo) ⁇ ⁇ , ⁇ -binaphthaiene
  • EtOH Ethanol
  • EtOAc Ethyl acetate
  • h hoisr(s): HC1: Hydrogen chloride
  • L1AIH 4 Lithium aluminium hydride
  • HOBt Hydroxybenzotriazole
  • LiOU LiOU:
  • Preparations 21-25 were prepared from C-((i?)-l-isopropylpiperidin-3-yl)meth.ylamine phthalazmedione salt (Preparation 5) and the corresponding aldehyde (Table 1).
  • Preparation 3i 4-ChIoropyridiMe ⁇ 2 ⁇ earbosylic acid (( «S)-l-pipendin ⁇ 3 ⁇ ylmethyI)amide
  • Preparation! 77 2-Amiso-5-(4-f!aoropheiioxy)siic0tii-Ic add To 2-ammo-5-(4-fluorophenoxy)fiicoiinie acid methyl ester (Preparation 76) (125mg, 0,48irmiol) in MeOH (lOmL) and water (5mL) was added LiOH (87mg, 3.8mmol). After 6h the solvent was removed in vacuo and the residue was partitioned between EtOAc and water.
  • Examples 3-16 were prepared from the corresponding acid (Preparation X in Table 2) and the appropriate amine:
  • Example 17 4-(4-FIuoroph3 ⁇ 4n xy)pyridine-2-earboxylic add ( 1 -isopr op lpiperi di n-3- ylhurlsy!amide
  • Example 18 4-(4-Fluorop!ieiioxy)pyridiiie ⁇ 2 ⁇ €arboxylie acid ((sS)-l-isopropylpiperidm- 3-ylmethy!)amide
  • Example 22 4 ⁇ (4.4-DimethyIcycioliexyloxy)pyridiBe-2-£arboxyiic acid (l-lsopropyl plper i -3 ⁇ ylmethyl)amide
  • Example 23 4-Phenoxypyridine ⁇ 2 ⁇ carboxy]ic add (l-isopropylpiperidin-3- ylmethyl)aimde
  • phenol (30 ⁇ protagonist, G,34mmol
  • 4-chloropyridine-2-carboxylic acid (1- isopropyipiperidin-3 ⁇ ylmethyl)amide (Preparation 27) (lOOmg, 0.34mmol) in DMSO (2mL) were added NaO'Bu (65mg, 0.68mmol) and potassium benzoate (108mg, 0.68mmol).
  • the mixture was heated at 65°C for 16h before cooling to rt and adding water (5mL).
  • Example 25 4-(3-Fluorophenoxy)pyridine-2-carboxylic add (l-isopropylpiperidiii ⁇ 3-yi- methyl)amide
  • Examples 36-41 were prepared from the corresponding chloropyridine amide (Preparation X in Table 4) and the appropriate phenol: Table 4
  • Example 49 4-(4-Fli_orophesoxy)pyri iiBe-2-earboxylic acid ((i?)-l- €yelope tylpiperidin-3-yls3 ⁇ 4etli l)am de
  • Examples 50-58 were prepared from the appropriate amine (Preparation X in Table 6) and the corresponding alkylating agents:
  • Examples 60-72 were prepared from 4- chloropyridme-2-carboxylic acid ((/?)- l-isopropylpiperidin-3-ylmethyl)amide (Preparation 31) and the corresponding phenol (Table 7):
  • Examples 74-122 were prepared from 4-chloropyridine-2-carboxylic acid ((i?)-l -isopropylpiperidin-3 -ylme ⁇ hyl)arnide (Preparation 31) and the corresponding phenol (Table 8): Table 8
  • Example 123 4-(4-Mctis icy !ohexylox )pyridku > -2-carboxyIic acid ((JQ-l-isopropyi- piperidm-3-ylmethyl)amide formic acid salt
  • Examples 124 and 125 were prepared from 4-chloropyridine-2-carboxylic acid ((R)- 1 -isopropylpiperidin-3-ylmethyl)amide
  • Example 126 4-(4-Methoxypheiiylarain )pyridlne-2-carboxylic acid ((It)-l-isopropyl piper m-3-ylmethyl)amIde bis formic add salt
  • Example 128 [3-(4-Fluorophenoxy)phenyl] [2-(l-isopropylplperidiii-3-yI)pyrr lidin-l- yljmethanone
  • Examples 132-135 were prepared from 4-
  • Examples 136-140 were prepared from 3- (4 ⁇ fluorophenoxy)benzoic acid and the corresponding amine (Preparation X in Table 11): Table 11
  • Examples 141 asid 142 4-(4-Fluorophenoxy)pyridine-2-carboxylic add (( ⁇ )-4,4 ⁇ difliioro-l-isopropylpiperidi!i-3-ylmetliyl)amide aed 4-(4-Fluorophenoxy)pyridiue-2- carboxylic acid (i.S) ⁇ 4,4 ⁇ difliioro-l-isopropylpiperidii ⁇ 3 ⁇ ylmetliyI)am de
  • Example 143' 4-(4-Fl oropheMoxy)pyridiiie ⁇ 2 ⁇ earboxylk add ((i?)-l-pyridin-3- ylmethyl-piperidia ⁇ 3 ⁇ ylmethyl)amide
  • pyridine-3-carbaldehyde 27mg, 0.25mmol
  • DCE dimethyl sulfoxide
  • 4-(4- fluorophenoxy)pyridine-2-carboxylic acid ((iS -l-piperidin-3-ylmethyl)amide
  • Preparation 79) 40mg, 0.12mmol
  • NaBH(OAc) 3 53mg, 0.25mmol
  • Example 148 4-(4-Fluorophenoxy)pyridine-2-carboxylic acid ((jR)-l-ethylpiperidin-3- ylHiethyI)amide
  • Example 150 4-(4-Fluorophenoxy)pyridine-2-carboxylic add [(R)-l-(l-phenylethyl)- p!peridra-3-ylmetbyl] amide
  • Example 151 and Example 152 4 ⁇ (4-Ftaorophenoxy)pyridine ⁇ 2-earboxy!ie add (( ⁇ )-l,2-dimefliyl-propyl)piperidta-3-ylmetayl]amide aad 4-(4-
  • Example 153 4-(4-FInorophenoxy)pyrMme-2 ⁇ carboxylk add [(3 ⁇ 4 ⁇ l ⁇ (l ⁇ pyridiH-3- ylethyI)-piperidiH ⁇ 3 ⁇ ylmeth ]]amide
  • Example 15S 6-(4-F!iioropliei oxy)-3-isopropoxypyrida3 ⁇ 4tae ⁇ 4-earboxyIie acid ⁇ (R ⁇ isopropyIpiperldiii-3-ylmethyI)amide
  • 6-chloro-3-isopropoxypyridazine-4-carboxylie acid ((i?)-l-isopropylpiperidin-3- ylmethyl)amide (Preparation 37) (39mg, 0.1 1 mmol) and 4-fluorophenol (123rag, l . lmraol) in NMP (ImL) was added NaH (60% mineral dispersion in oil, 13mg, 0.33mmol).
  • Examples 156-159 were obtained from the respective 6-chloropyridazin.e-4-carboxylic acid (( ?)- l -isopropylpiperidin-3- ylmethyl)amides (Preparation X in Table 13) and the corresponding phenol:
  • Examples 61-164 were obtained from 6-chloro-3 -isopropoxypyridazine-4-carboxylic acid ⁇ (R) ⁇ 1 -isopropylpiperidin-3 - ylmethyl)amide (Preparation 37) and the corresponding aniline (Table 14): 6-[(4-Fluorophenyl)
  • Example 168 2-Amino-5-(4-fliiorop eBoxy)-iV-(l-isopropylpiperidia-3-ylmettiyl)- benzamide
  • Example 171 4-(4-FIuoroptseHoxy)pyridiiie-2-carboxylic acid [l-(l-isopropylpiperidin- 3-yl)ethyl] amide
  • the biological activity of the compounds of the invention may be tested in the following assay systems:
  • GHSR membranes (Millipore. prepared from Chem-1 cells stably overexpressing GHS-Rla), 0.025nM human i25 i ⁇ Ghrelin (Perkin Elmer) and the compound of interest were incubated in 25 mM Hepes pH 7.4 containing 5 mM MgCl 2 , 1 mM Ca €l 2 , 2.5 mM EDTA and 0.2% BSA for 2h at room temperature. Radioligand bound to the membrane was trapped onto a 0.5% PEI presoaked filtermat B (Perkin Elmer) using a Filtermate harvester (Perkin Elmer). The effect of compound upon the specific binding of !
  • the binding assay was initiated by the addition of [ i3 S]-GTPyS (Perkin Elmer) to a final concentration of 150 pM in a 100 ⁇ assay solution containing 24 mM HEPES pH 7.1, 49 mM NaCL 10 mM MgCl ? , 0.1% BSA, 0.5% DMSO, 10 ⁇ / ⁇ £ saponin, 1 ⁇ GDP, 20 ⁇ / ⁇ 1 membranes (Milltpore, prepared from Chem ⁇ l cells stably overexpressing GHS ⁇ Rl a), 10 nM human ghrelin (Peptides International) and the compound of interest. The assay was incubated at 30°C for 30 min.
  • membranes, saponin and GDP were pre-incubated for 10 min, and a further 15 min after the addition of ghrelin. 10 ⁇ unlabelled GTPyS was used instead of compound and ghrelin to determine non-specific binding.
  • Membranes were captured on wheatgerm agglutinin SPA beads (4 mg/mL, GE Healthcare) in a 30 min incubation at room temperature.
  • Th beads were pelleted by centrifugation at 1,300 g for 5 min at room temperature and bound [ 3S S]-GTPyS was measured by scintillation counting using a Wallac Microbeta® TriLux counter (Perldn Elmer), The effect of compound upon the specific binding of [ j5 S]-GTPyS was utilized to determine the IC 50 by fitting the data to a hyperbolic model.
  • K and IC 50 values determined respectively by the GHSR Ghrelin competition assay and the [35S]GTPgS binding assay described above are provided for compounds of the present invention in Table 15.
  • the effects of the compounds of invention on body weight, food and water intake and postprandial glucose handling may be examined in diet induced obese (DIO) mouse. Tes compounds and reference compounds are dosed by appropriate routes of administration (e.g. intraperitonally or orally) for up to two weeks. During the baseline and treatment period body weight, food intake and water intake is measured daily and any significant differences between treatment groups and control group are analysed. All animals have free access to a high fat diet (45% kcal) and water and will be maintained on a normal phase 12h light-dark cycle. Animals will be exposed to the appropriate diet for at least 15 weeks before experiment. In the end of the experiment, the animals may be fasted over night and the next day an oral glucose tolerance test (OGTT) performed.
  • OGTT oral glucose tolerance test
  • a bolus dose of glucose (eg 2g/kg) is given by oral gavage.
  • the level of blood glucose and insulin are measured at predefined time intervals before and after the bolus glucose dose. Any significant difference in glucose excursion between treatment groups and control group are analysed.

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Abstract

Compounds of formula (I) or pharmaceutically acceptable salts thereof, are useful for the treatment of diabetes and obesity.

Description

PIPERIDINE AMIDES AS MODULATORS OF THE GHRELIN RECEPTOR
BACKGROUND OF THE INVENTION
The present invention is directed to modulators of the ghrelin receptor. In particular, the present invention is directed to ghrelin receptor modulators that are useful for the treatment of diabetes and obesity.
Type II diabetes meilitus is a progressive and complex disorder that is difficult to treat effectively in the long term. The majority of patients are overweight or obese at diagnosis and unable to achieve or sustain near norraoglycaemia without oral antidiabetic agents. The frequent need for escalating therapy is presumed due to progressive loss of islet p-cell function, usually in the presence of obesity-related insulin resistance. The current clinical approaches are similar in their modes of action, safety profiles and tolerability. The sulphonylureas and rapid-acting insulin secretogogues aided by DPP -4 inhibitors stimulate insulin secretion, the biguamdes reduce hepatic glucose production, alpha-glucosidase inhibitors delay digestion and absorption of intestinal carbohydrate and the thiazolinediones improve insulin action. A disadvantage of some of these therapies can be their ability to promote weight gain.
Obesity is characterized by an excessive adipose tissue mass relative to body size, Clinically, body fat mass is estimated by the body mass index (BM1; weight(kg) height(m) ), or waist circumference. Individuals are considered obese when the BMI is greater than 30 and there are established medical consequences of being overweight. It has been an accepted medical view for some time that an increased body weight, especially as a result of abdominal body fat, is associated with an increased risk for diabetes, hypertension, heart disease, and numerous other health complications, such as arthritis, stroke, gallbladder disease, muscular and respiratory problems, back pain and even certain cancers,
Pharmacological approaches to the treatment of obesity have been mainly concerned with reducing fat mass by altering the balance between energy intake and expenditure. Many studies have clearly established the link between adiposity and the brain circuitry involved in the regulation of energy homeostasis. Direct arid indirect evidence suggest that serotonergic, dopaminergic, adrenergic, cholinergic, endocannabinoid, opioid, and histaminergic pathways in addition to many neuropeptide pathways (e.g. neuropeptide Y and melanocortms) are implicated in the central control of energy intake and expenditure. Hypothalamic centres are also able to sense peripheral hormones involved in the maintenance of body weight and degree of adiposity, such as insulin and leptin, and fat tissue derived peptides. There is a continuing need for novel antidiabetic and antiobesity agents, particularly ones that are well tolerated with few adverse effects.
Ghrelin is a 28-amino acid peptide cleaved from a 117-amino acid precursor, preproghrelm. Ghrelin is predominantly produced by the X/A-ceils in the gastric mucosa of the fundus of the stomach, accounting for approximately two/thirds of circulating ghrelin, with the majority of the remainder being derived from the X/A-ceils of the small intestine. Substantially lower amounts are produced by the bowel, pancreas, pituitary gland, kidney and placenta.
Ghrelin affects appetite and body weight. Short term fasting has been demonstrated to cause a rise in circulating ghrelin levels, infusion of ghrelin has also been shown to stimulate appetite and increase spontaneous food intake. Ghrelin signals via the arcuate nucleus of the hypothalamus to activate neurones containing neuropeptide Y and agouti related peptide, which are also orexige ic peptides. In parallel neurones containing the anorexigenic peptides CART and pro-opiom.elanocortin are inhibited. The neuroendocrine effects within the hypothalamus enhance the drive to feed through orexin and ghrelin release itself. Ghrelin can also have long term affects upon body weight. As with short term fasting, it has been shown that after loss of body weight ghrelin levels increase and with body weight gain ghreli levels go down. Ghrelin not only stimulates feeding but it also affects energy homeostasis. This manifests itself in a number of ways by increasing preference for fat, promoting adipogenesis, decreasing lipolysis, inhibiting apopotosis of adipocytes, lowering body temperature and reducing locomotory activity.
Ghrelin has also been shown to inhibit the activity of the glucose sensing neurons within the CNS by suppressing both glucose-activated and glucose-inhibited neurons in the dorsal vagal complex. Generally a negative relationship between ghrelin and insulin levels can be demonstrated, with ghrelin inhibiting insulin secretion both in vitro and in vivo although under certain experimental conditions this can be reversed. The release of insulin appears to be controlled by the GHS-Rl receptors in the pancreas. It has also been shown that ghrelin impedes insulin's ability to suppress endogenous glucose production, whereas it reinforces the action of insulin on glucose disposal in mice, inhibits secretion of the insulin- sensitizing protein adiponectin produced by the adipocytes and stimulates secretion of counter-regulatory hormones, including growth hormone, Cortisol, epinephrine and possibly glucagon. Acute ghrelin administration in humans increases plasma glucose levels. This may result not only through direct effects on hepatocytes, where it has been shown to be able to modulate glycogen synthesis and gluconeogenesis, stimulating hepatic glucose production.
Antagonism of the effects of ghrelin could therefore result in improving the diabetic condition by enhancing glucose dependent insulin secretion and promoting weight loss.
Ghrelin is the endogenous ligand for the ghrelin receptor, also known as the growth hormone seereatagougue receptor or GHSR la receptor. The ghrelin receptor has been demonstrated to possess constitutive activity through the Gq PLC pathway, an activity which is approximate to 50% of their maximal capacity. There is also a high constitutive activity through the cAMP response element driven transcription. The high constitutive activity of ghrelin receptors may serve as the signalling set point for appetite and energy expenditure by actions upon neuropeptide Y and agouti-related peptide neurons in the hypothalamus and counter-balancing the effects of inhibitory hormones and neurotransmitters such as leptin, insulin and
Figure imgf000005_0001
Ghrelin binds to GHS-RI a and stimulates the release of growth hormone from the somatotrophic ceils of the pituitary gland. This is accompanied by activation of growth hormone releasing neurons and inhibition of somatostatin neurones in the hypothalamus and induction of vagal afferent activation.
Ghrelin modulators may have an advantage over current antidiabetic agents in that they could have the ability to reduce hyperglycaemia and have the added advantage of the potential for weight loss.
international patent applications WO2005/035498, WO2005/048916,
WO2006/012577, WO2006/020959, WO2006/079077, WO2007/020013, WO2007/032371, WO2007/079239, WO2007/146914, WO2008/008286, WO2008/141189, WO2008/148853, WO2008/148854, WO2008/148856, WO2009/047558, WO2009/1 15503, WO2009/133052 and WO2010/022213 disclose ghrelin receptor modulators.
Sun, et al., J. Pharm. Biomed. Anal., 2009; 50: 27-34 reports on the identification and structure elucidatio of metabolites of mosapride, a selective gastroprokinetic agent, in rats. One metabolite was assumed to be the O-glucuronide conjugate of 3-hydroxymosapride. However, the exact phenolic hydroxy! position at C-3 or C-6 could not be fully ascertained from the data. The glucoside moiety is not a carbocycle.
The moqjholino compounds N-((4-benzylmorpholin-2-yl)methyl)-3- phenoxybenzamide and N-((4-berlz l o holm-2-yl)methyl)-3-(berlz lo y)benzamide are also known from CHEMCATS Accession Nos. 20951 13294 and 2095026465 respectively (CAS Registry Nos. 1 182591-75-8 and 1 181183-97-0). The present invention relates to ghrelin receptor modulators that are useful for the treatment of diabetes and obesity,
SUMMARY OF THE INVENTION
Compounds of formula (i):
Figure imgf000006_0001
or pharmaceutically acceptable salts thereof, are ghrelin receptor modulators that are useful for the treatment of diabetes and obesity.
DETAILED DESCRIPTION OF THE INVENTION
In one aspect of the present invention there is provided a compound of formula (I):
Figure imgf000006_0002
or a pharmaceutically acceptable salt thereof, for use in a method of treatment of the human or animal body by therapy, wherein:
R is C2-6 alkyl, C3..7 cycloalkyl, C,.3 alkyl-Cj.y eycloalkyl,€3.3 alkyl-aryl or Ci.j alkyl- heteroaryl, any of which may be optionally substituted with one or more F, OH or C\ ..3 alkoxy groups;
R; and R2 are independently selected from H, C].$ alkyl, Ci,3 alkyl-aryl, aryl, C1.3 alkyl- heteroaryl and heteroaryl, or R and taken together may form a 3- to 7-membered carbocyclie ring; optionally substituted with halogen, Cj_3 alkoxy or C1.3 alkyl;
R3 and R4 are independently selected from H, F, C1-3 alkyl, OH or Ci-3 alkoxy;
R! ; to R14 are independently selected from H and C¾; W is C¾, CHF, CF2, O, CH(OH), C(OH)C].3 alkyl, CH(OC1-3 alkyl), C(OC(.3 alkyl)C,,3 alkyl, -CH(Cu3 alkyl) or -C(Ci.3 alkyl)(C1-3 alkyl);
R99 is H, Ci-6 alkyl, -(CH )n-aryl, -(CH2)n-heteroaryl or -(CH2)p-0-aryl where aryl or heteroaryl groups may be optionally substituted with C1-3 alkyl, C1 -3 alkoxy or halogen; or R99 together with R5 or R2 form a 5- to 6-membered nitrogen containing ring;
Y, Υ', Y2 and Y3 are independently N or CR'0 such that the ring contains 0, 1 or 2 nitrogens;
R20 is independently selected from H, halogen. C alkoxy, O-C3-6 cycloalkyl, 0-(4- to 7-membered heterocyelyl), C1.3 alkyl, NR96R97, Q-(CH2)q-Ci-6 alkoxy, Q~(CH2)i aryl and Q-(CH2) -heteroaryl;
R96 and R9 'are independently selected from H, C1-3 alkyl and C3-6 cycloalkyl;
X is O, NR6, CR7R8, or C===0 and when Ring is aryl then X can be 0(CH2)r;
R° is H, Ci-3 alkyl, C3.7 cycloalkyl, C1.3 alkyl-C3.7 cycloalkyl, C1-3 alkyl-aryl or C1-3 alkyl- heteroaryl, any of which may be optionally substituted with one or more F, OH or Cu alkoxy groups;
R' and R8 independently selected from H, OH, F, Cj-3 alkoxy or Q.3 alkyl, provided that when one of R7 or R5 is OH the other cannot be F, OH, or C1 -3 alkoxy;
Ring is a Q.jo carbocyclic,€5-10 aryl, 6- to 10-membered heteroaryl ring or a bicyclic structure comprising a 5- or 6- membered aryl or heteroaryl with a 5 or 6 membered carbocycle or keterocyele fused thereto wherein the bicyclic structure bonds to X via one of the atoms on the aryl or heteroaryl moiety, any of which may be optionally substituted by 1 to 3 groups selected from halogen, C1-3 alkyl optionally substituted by hydroxy or 1 to 3 halogens, Ct.3 alkoxy, CN, C02Ri5, CON(Ri 5)2, SO?OH, S02N{Ri 5)2, N(R!5)2,
N(Ri5)2(CQ)N(R15)2, 0(CH2)q-aryl, 0(CH2)q-heteroaryl, H(CO)Cw alkyl, OH, aryl, heteroaryl and COCi-3alkyl; provided that Ring is not unsubstituted 4-pyridyl;
R.i5 is independently seletected from H and C1-3 alkyl;
n is 0, 1, 2 or 3;
p is 2 or 3;
q is 0, 1 or 2; and
r is 1 or 2.
In some embodiments said compound compound of formula (I) or pharmaceutically acceptable salt thereof may be used in a method for the treatment of diabetes, obesity, metabolic syndrome (syndrome X), impaired glucose tolerance, Prader-Willi syndrome, hyperlipidaemia, hypertriglyceridaemia, hypereholesteroiaemia, low HDL levels, hypertension or abnormal sensitivity to ingested fats.
According to another aspect of the present invention there is provided a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined above, subject to the proviso that the compound is not N-((4-benzyImorpholin-2-yl)methyl)-3-pherioxybenzaniide or N-((4-benzylmorpholin-2-yl)meihyl)-3-(benzyloxy)benzamide.
The molecular weight of the compounds of formula (I) is preferably less than 800, more preferably less than 600, even more preferably less than 500.
R is preferably C2-¾ alkyl, e.g. isopropyl or pentyl, optionally substituted with one or more F, OH or Ci-3 alkoxy groups.
R1 and R.2 are preferably independently selected from H and -g alkyl
R3 and R4 are preferably independently selected from H and F,
Rn to R]4 are preferably H.
In some embodiments, W may be W is C¾ CHF, CF2, CH(OH), C(OH)C1-3 alkyl, CH(OCi-3 alkyl), C(OC!-3 alkyi)C]-3 alkyl, ~CH(C>.3 alkyl) or -C(C1-3 alkyl)(C1-3 alkyl). W is preferably CH2,
R99 is preferably H.
The ring containing Y, Y!, Y2 and YJ preferably contains 1 or 2 nitrogen atoms. When it contains 1 nitrogen atom, this is preferably Y or Y5; when it contains 2 nitrogen atoms these are preferably Y! and Y2.
Other preferred compounds of the invention are independently selected from those where: Y is N or C(C!-6 alkoxy); Y! is CH or N; Y2 is CH, CMe or N; and Y is CH.
Ri0 is preferably independently selected from H, Cj.& alkoxy. 0-C3.<s cycloalkyl, O- (CH2)q-Cj,6 alkoxy and 0~(CH2)q-aryl.
X is preferably O, NR6 or CR7RS, preferably C¾, C(Hal)2, or CHOH, or C=0, more preferably O.
R6, R7 and R8 are preferably H.
Ring is preferably an optionally substituted C5.10 aryl or 6- to 10-membered heieroaryl ring e.g. a 7- to 10-membered heteroaryl ring.
Ring is preferably optionally substituted by 1 to 3 groups selected from halogen, C1-3 alkyl optionally substituted by OH, C I alkoxy and aryl.
ie X is O, NR.6, CR7R¾, C¾, C(Hai)2, CHOH or C=0, Ring is preferably phenyl napthyl, pyri.dine or quinoline, optionally substituted with one or more halogen atoms, preferably F or CL preferably at least one of which is para or ortho to the X-Ring bond and additionally or alternatively be substituted with one or more to C3 alkyl.
When X is O, Ring is preferably phenyl, napthyl, pyridine or quinoline, optionally substituted with one or more halogen atom, preferably F or CL preferably at least one of which is para or ortho to the X-Ring bond. The phenyl may additionally or alternatively be substituted with one or more C\ to C3 alkyl, Ci to C alkoxy, nitre, CN, CF3, CCHR'3, CGN(R!¾, S<¾OH, S02N(Ri5)2) N(Rls)2, (Ri5)2(CO) (Ri5)2, aryl, 0(CH2)q-aryl, heteroaryl, 0(CH2)q-heteroaryl. Alternatively, when X is O, Ring may be selected from pyridine, indole, benzol ,3dioxole, quinoline, benzot iazole, indazole, imidazole, benzoimidazole, dihydx'obenzooxazine, , dihydrobenzodioxine, adarnantane, cyclohexane, 4,4~dimethyleyelohexane, 2,3 dihydroindene, all of which may be optionally substituted with one or more halogen or Ci to C alkyl.
When X is NR.6 Ring is preferably phenyl, napthyl. pyridine or quinoline, optionally substituted with one or more halogen atoms, preferably F or CI, preferably at least one of which is para or ortho to the X-Ring bond and additionally or alternatively be substituted with one or more Ci to C3 alley!. Alternatively, when X is NRb, Ring may be 2,3
dihydroindene.
When X is C¾, Ring is preferably phenyl, napthyl, pyridine or quinoline, optionally substituted with one or more halogen atoms, preferably F or CI, preferably at least one of which is para or ortho to the X-Ring bond and additionally or alternatively be substituted with one or more Q to C3 alkyl.
The invention also comprehends isotopieally-labelled compounds, which are identical to those recited in formula (I) and following, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number most commonly found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, fluorine, such as He, ^C and ^F.
Compounds of the present invention and salts of said compounds that contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of the present invention, Isotopieally-labelled compounds of the present invention, for example those into which radioactive isotopes such as ^ll, are incorporated, are useful in drug and/or substrate tissue distribution assays, Tritiated, i.e., ¾, and carbon-14, i.e., ^C, isotopes are particularly preferred for their ease of preparation and detectability. ^ and isotopes are particularly useful in PET (positron emission tomography). PET is useful in brain imaging. Further, substitution with heavier isotopes such as deuterium, i.e., ¾, can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances, isotopically labelled compounds of formula (I) and following of this invention can generally be prepared by carr/ing out the procedures disclosed in the Schemes and/or in the Examples below, by substituting a readily available isotopically labelled reagent for a non-isotopically labelled reagent, in one embodiment, the compounds of formula (I), or salts thereof are not. isotopically labelled.
While the preferred groups for each variable have generally been listed above separately for each variable, preferred compounds of this invention include those in which several or each variable in formula (I) is selected from the preferred, more preferred or particularly listed groups for each variable. Therefore, this invention is intended to include all combinations of preferred, more preferred and particularly listed groups,
Specific compounds of the invention which may be mentioned are those included in the Examples and pharmaceutically acceptable salts thereof.
As used herein, unless stated otherwise, "alkyl" means carbon chains which may be linear or branched or combinations thereof. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec- and tert-buryl, pemyi, hexyi, heptyl and the like. "Alkoxy" should be construed accordingly. Any alkyl or alkoxy groups may be optionally substituted by one or more fluorine atoms, to form goups such as -CF3 and -OCF3. Generally a -CH3 or CF3 group may be replaced by 8F5 without departing from the present invention.
The terms "cyeloalkyi" and "carbocyelic" mean carbocycles containing no heieroatoms, and includes monocyclic and bicyclic saturated and partially saturated carbocycles. Examples of cyeloalkyi groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cyeloheptyL Examples of partially saturated cyeloalkyi groups include cyclohexene and indane. Cyeloalkyi groups will typically contain from 3 to 7 ring carbon atoms in total, e.g. 3 to 6 ring carbon atoms, A glucoside such, for example, as the one found in some of the metabolites reported in Sun, et ah, 2009 (see above) is not carbocyelic, because it contains a heteroatom - oxygen■■■ and is not included in the definition of "Ring" in accordance with the invention. Neither is a glucoside a "heteroaryl" group.
Unless otherwise indicated the term "heterocyclyl" includes 4- to IQ-membered monocyclic and bicyclic saturated rings, e.g. 4- to 7-membered monocyclic saturated rings, containing up to three heteroatoms selected from N, O and S. Examples of heterocyclic rings include oxetane, tetrahydrofuran, tetrahydropyran, oxepane, oxocane, thietane,
tetrahydrothiophene, tetrahydrothiopyran, thiepane, thiocane, azetidine, pyrrolidine, piperidine, azepane, azocane, [] ,3]dioxane, oxazolidine, piperazine, and the like. Other examples of heterocyclic rings include the oxidised forms of the sulfur-containing rings. Thus, tetrahydrothiophene 1 -oxide, tetrahydrothiophene 1,1 -dioxide, tetrahydrothiopyran 1- oxide. and tetrahydrothiopyran 1 ,1 -dioxide are also considered to be heterocyclic rings.
The term "halo" includes fluorine, chlorine, bromine, and iodine atoms, in particular fluorine or chlorine.
The term "aryl" includes phenyl and naphthyl, in particular phenyl.
Unless otherwise stated, the term "heteroaryl" includes mono- and bicyclic 5~ to 10- membered, e.g. monocyclic 5- or 6-niembered, heteroaryl rings containing up to 4 heteroatoms selected from N, O and S. Examples of such heteroaryl rings are furyl, thienyl, pyrrolyl, pyrazolyl, ixnidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridinyl, pyridazinyl, pyrimidmyl, pyrazinyl and triazinyl. Bicyclic heteroaryl groups include bicyclic heteroaromatie groups where a 5- or 6- membered heteroaryl ring is fused to a phenyl or another heteroaromatie or heterocyclyl group. Examples of such bicyclic heteroaromatie rings are benzofuran, benzothiophene, indole, benzoxazole, benzothiazole, indazole, benzimidazole, benzotriazole, quinoline, isoquinoline, quinazoline, quinoxaline and purine. "Heterocyclyl" rings which may be fused to phenyl or and "heterocyclic ring" includes 5- to 6-membered monocyclic, containing up to three heteroatoms selected from N, O and S. Examples of heterocyclic rings include tetrahydrofuran, tetrahydropyran, tetrahydrothiophene, tetrahydrothiopyran, pyrrolidine, piperidine, oxazolidine, piperazine, and the like. Other examples of heterocyclic rings include the oxidised forms of the S containing rings.
In the context of Ring being a bicyclic structure comprising a 5- or 6- membered aryl or heteroaryl with a 5 or 6 membered carbocycle or heterocycle fused thereto, the term fused means that the two cyclic groups of the bicyclic structure share two atoms and the bond between the two atoms. When the bicyclic structure contains a heteroaryl ring, the heteroaryl may contain up to 4 heteroatoms selected from N, O and S, and the heterocycle may contain up to three heteroatoms selected from N, O and S, not including any heteroatom which it may share with a heteroaryl moiety. The carbocycie or heterocycle may also contain an unsaturated bond.
Compounds described herein may contain one or more asyninietric centers and may thus give rise to diastereomers and optical isomers. The present invention includes all such possible diastereomers as well as their racemic mixtures, their substantially pure resolved enantiomers, all possible geometric isomers, and pharmaceutically acceptable salts thereof. The above formula (Ϊ) is shown without a defioitive stereochemistry at certain positions. The present invention includes all stereoisomers of formula (Ϊ) and pharmaceutically acceptable salts thereof. Further, mixtures of stereoisomers as well as isolated specific stereoisomers are also included. During the course of the synthetic procedures used to prepare such compounds, or i using racemization or epimerization procedures known to those skilled in the art, the products of such procedures can be a mixture of stereoisomers.
When the compound of formula (1) and pharmaceutically acceptable salts thereof exist in the form of solvates or polymorphic forms, the present invention includes any possible solvates and polymorphic forms. A type of a solvent that forms the solvate is not particularly limited so long as the solvent is pharmacologically acceptable. For example, water, ethanol, propanol, acetone or the like can be used .
The term "pharmaceutically acceptable salts" refers to salts prepared from
pharmaceutically acceptable non-toxic bases or acids. Salts derived from bases include those derived from bases such as, for example, potassium and sodium salts and the like. Salts derived from pharmaceutically acceptable non-toxic acids, include those derived from inorganic and organic acids such as, for example, hydrochloric, methanesuifomc, sulfuric, p- toluenesulfonic acid and the like.
Since the compounds of formula (I) are intended for pharmaceutical use they are preferably provided in substantially pure form, for example at least 60% pure, more suitably at least 75% pure, especially at least 98%> pure (% are on a weight for weight basis).
The compounds of formula (Ϊ) can be prepared as described below wherein R, N, W, R99, Y, Y1 , Y2, Y3, R20, X, Ring, R3 to R4, R6, R7, R8 and R! ] to Ri4 are as defined above for formula (I). In some of the Schemes, R1 to R4 and Rn to R54 are represented as hydrogen, however the procedures described therein are also applicable for the synthesis of compounds where R! to R4 and R! 1 to R34 are other than hydrogen. Compounds of the formula (I) can be prepared using the methods outlined in Scheme
1:
Scheme 1
Figure imgf000013_0001
Acids of formula (II) are either readily available, synthesised by known methods or can be synthesised by the methods shown in Schemes 5, 6, 7 and 8. Amines of formula (III) are also either readily available, synthesised by known methods or can be synthesised by the methods shown in Schemes 11, 12, 13 and 14. Acids of formula (IT.) can be reacted with the corresponding amines of formula (III) in a solvent such as DMF in the presence of a base such as DIPEA and with an amide coupling agent such as EDCI and HOBT to give compounds of formula (I). Alternatively acids of formula (II) can be converted to the corresponding acid chloride using for example oxalyl chloride in a solvent such as DCM and then reacted with amines of formula (III) in the presence of a base such NEtj to give compounds of formula (Γ).
Compounds of the formula (Ϊ) can be prepared using the methods outlined in Scheme
Figure imgf000013_0002
IV V !
Acids of formula (IV), which are either readily available or synthesised by known methods, can be coupled with amines of formula (III) using methods described above to give compounds of formula (V). Compounds of formula (V) can be reacted with oxygen (X - O) or nitrogen (X = NR6) based nucleophi!es, for example with phenol in the presence of a base such as NaH and in a solvent such as THF to give, after heating, compounds of formula (I), Alternatively compounds of formula (V) can be reacted with for example benzyl boronates using a catalyst such PdCl2(dppf) with a base such as K2CO3 and in a solvent system such as PhMe/dioxane/water to give compounds of formula (Ϊ) (X = C¾).
Compounds of the formula (I) can be prepared using the methods outlined in Scheme Scheme 3
Figure imgf000014_0001
VI VH Ϊ
Hydroxy acids of formula (VI), which are either readily available, synthesised by known methods or can be synthesised by the method shown in Scheme 10, can be coupled to amines as described above to give compounds of formula (VII). Compounds of formula (VII) can be reacted with a base such as sodium hydride and an electrophile such as 4- fluoronitrobenzene to give compounds of formula (I). Alternatively compounds of formula (VII) can treated with a boronic acid such as 4~fluorobenzene boronic acid in a solvent such as DCM in the presence of a base such as DIPEA and a catalyst such as copper acetate to give compounds of formula (I).
Compounds of the formula (I) can be prepared using the methods outlined i Scheme
Figure imgf000014_0002
Acids of formula (VIII) (Y = N or CH), which are readily available, can be coupled with amines using conditions outlined above to give amides of formula (IX). Reaction of compounds of formula (IX) with oxygen or nitrogen nucleophiles, for example sodium methoxide in a solvent such as methanol, gives compounds of formula (X). Reaction of compounds of formula (X) with oxygen based nucleophiles such as for example phenol using a base such a NaH in a solvent such as NMP and with a catalyst such as Cul gives compounds of formula (I) where Xis O. Compounds of formula (X) can also be reacted with nitrogen based nucleophiles such as anilines with a ligand such as biphenyl-2-yl-di-tert- butylphosphane, a catalyst such as Pd2dba3 and a base such as NaO'Bu in a solvent such as PhMe to give, after heating, compounds of formula (I) where X = NR6. Compounds of formula (I) (X = CR'R*) can be synthesized by reacting compounds of formula (X) with for example benzyl boronaies in the presence of a catalyst such as Pd(¾(dppf) with a base such as K2CO3 in a solvent such as PhMe and dioxane,
Compounds of formula (II) can be prepared using the methods outlined in Scheme 5:
Figure imgf000015_0001
ΧΪ ΧΪΪ
Cyano compounds of formula (XI) (where at least one of Y, Y1, Y or Y3 are N), which are readily available or can be synthesised using known methods, can be reacted with oxygen (X - O) or nitrogen ( = NR6) based nucleophiles for example with phenol in the presence of a base such as NaH and in a solvent such as THF to give after heating compounds of formula (XII), Hydrolysis of compounds of formula (XII) with for example NaOH in a solvent such as EtOH gives compounds of formula (II).
Compounds of formula (II) can be prepared using the methods outlined in Scheme 6:
Figure imgf000015_0002
Χίΐί XIV U
Esters of formula (XIII) which are readily available, can be reacted with oxygen (X - O) or nitrogen (X = NR6) based nucleophiles, for example anilines in the presence of catalysts such as Pd(OAe)2, a ligand such as BINAP and a base such as CS2CO3 m a solvent such as PhMe to give after heating compounds of formula (XIV). Compounds of formula (XIV) can be hydrolysed as described previously to give compounds of formula (Π).
Compounds of formula (II) can be prepared using the methods outlined in Scheme 7
Schem
Figure imgf000015_0003
VI Phenols of formula (VI) are readily available and can treated with a boronic acid such as 4-fluorobenzene boronic acid in a solvent such as DCM in the presence of a base such as D1PEA and a catalyst such as copper acetate to give compounds of formula (II).
Compounds of formula (II) can be prepared using the methods outlined in Scheme 8:
Figure imgf000016_0001
XV XVII
Figure imgf000016_0002
55 xix xvm
Pyridyl acids of formula (XV), which are either readily available or can synthesised using known methods, can be converted to the acid chloride by treatment with for example oxalyl chloride and can then undergo a Friedel-Craft reaction with ArH in the presence of a Lewis Acid such as aluminium (III) chloride and in a solvent such as DCE to give compounds of formula (XVI) (Ring = aryl). Compounds of formula (XVI) can be reduced to compounds of formula (XVII) using for example trifluroacetic acid and tiethylsilane.
Compounds of formula (XVII) can be converted to N-oxides of formula (XVIII) using for example m-CPBA in a solvent such as DCM. N-oxides of formula (XVIII) when reacted with TMSCN and DMCC in a solvent such as DCM give compounds of formula (XIX) which can be hydrolysed to compounds of formula (II) using methods outlined above.
Alternatively compounds of formula (XVI) can be prepared using the methods outlined in Scheme 9:
SeSieme 9
Figure imgf000016_0003
XX XVI ΧΧί
Aldehydes of formula (XX) can be reacted with Grignard reagents such as phenyl magnesium bromide in a solvent such as THF to give alcohols which either on work-up or in a subsequent oxidation with for example manganese dioxide give ketones of formula (XVI). Alternatively pyridyl halides of formula (XXI) can be reacted with ethyl magnesium bromide in for example THF to form aryi Grignard reagents which can then he treated with aldehydes to give after work-up or subsequent oxidation as outlined previously compounds of formula (XVI).
Compounds of formula (VI) can he prepared by the route outlined in Scheme 10:
Scheme 10
Figure imgf000017_0001
Ethers of formula (XXII), which are either readily available or can be synthesised using known methods, can be treated with oxidizing agents such as wCPBA in a solvent such as DCM to give N-oxides of the formula (XXIII). Compounds of formula (XXIII) can be reacted with TMSCN and N^ -dimethylcarbamoyl chloride in a solvent such as DCM give compounds of formula (XXIV). Nitriles of formula (XXIV) can be hydrolysed using hydrobromic acid to give compounds of formula (VI).
Compounds of formula (III) can be prepared by the route outlined in Scheme 11:
Figure imgf000017_0002
XXV XXVI XXVH
Figure imgf000017_0003
m XVIII
Amine of formula (XXV) can be protected with for example a phthalimide group which can be formed by treating the amine with phthalic anhydride in a solvent such as PhMe and heating to give compounds of formula (XXVI). Treating compounds of formula (XXVI) with an acid such as TFA in a solvent such as DCM gives compound of formula (XXVII). Reductive ainination with aldehydes or ketones in a solvent such as DCM and a reducing agent such as NaBH(OAc)3 or alkylation with an alkylating agent and a base such as K2CO3 gives compounds of formula (XVIII). Removal of the protecting group from compounds of formula (XVIIi). for example reacting with hydrazine in EtOH in the case of a phthaiimide, gives amines of formula (III).
Compounds of formula (III) can be prepared by the route outlined in Scheme 12:
Scheme 12
Figure imgf000018_0001
III
Readily available pyridines of formula (XXIX) can be protected using for example di-fcrf-butyl dicarbonate in a solvent such as THF and a base such as Et3 to give compounds of formula (XXX). Compounds of formula (XXX) can be reduced under pressure, with heating using hydrogen gas and a catalyst such as rhodium on alumina in a solvent such as MeOH to give compounds of formula (XXXI). Compounds of formula (XXXI) can be alkylated with for example and aldehyde or ketone such as Me2CO, in a solvent such as DCM with a reducing agent such as
Figure imgf000018_0002
to give protected amines of formula (XXXIl). Compounds of formula (XXXII) may be treated with an acid such as TFA in a solvent such as DCM to give amines of formula (III).
Compounds of formula (III) can be prepared by the route outlined in Scheme 13:
Scheme 13
Figure imgf000019_0001
Figure imgf000019_0002
XXXVI III
Piperidones of formula (XXXIII), which are readily available, can be reacted with for example a strong base such as lithium diisopropylamide in a solvent such as THF and with an elecirophile such as 2-bromomethyliso indole- 1,3 -dione (XXXIV) to give compounds of formula (XXXV), Compounds of formula (XXXV) can be reduced with for example hydrazine and potassium hydroxide in a solvent such as diethylene glycol to give compounds of formula (III)
Figure imgf000019_0003
Compounds of formula (XXXV) can also be reacted with reducing agents such as NaB¾ or methyl magnesium bromide in solvent such as THF to give compounds of formula (ill) (W = CH(OH) or C(OH)Cj.3 alkyl). Alternatively compounds of formula (XXXV) can be treated with a fluorinating agent such as DAST in a solvent such as DCM to give compounds of formula (XXXVI) which can be reacted with hydrazine in a solvent such as ethanol give amines of formula (III) (W = CF2).
Compounds of formula III can be prepared by the route outlined in Scheme 14:
Figure imgf000019_0004
Hi HI
Amines of formula (ΙΤΪ) (RQ9 = H) can be alkylated by for example reaction with an aldehyde in a solvent such as DCM and a reducing agent such as NaBH(OAc)3 to give compounds of formula (III) (Ry9 .5 alkyl).
The compounds of formula (I) may be prepared singly or as compound libraries comprising at least 2, for example 5 to 1,000, compounds and more preferably 10 to 100 compounds of formula (I). Compound libraries may be prepared by a combinatorial "split and mix" approach or by multiple parallel synthesis using either solution or solid phase chemistry, using procedures known to those skilled i the art.
During the synthesis of the compounds of formula (I), labile functional groups in the intermediate compounds, e.g. hydroxy, carboxy and amino groups, may be protected. The protecting groups may be removed at any stage in the synthesis of the compounds of formula (I) or may he present on the final compound of formula (I). A comprehensive discussion of the ways in which various labile functional groups may be protected and methods for cleaving the resulting protected derivatives is given in, for example, Protective Groups in Organic Chemistry, T.W. Greene and P.G.M. Wuts, (1991) Wiley-Interscience, New York, 2nd edition.
Any novel intermediates, such as those defined above, may be of use in the synthesis of compounds of formula (I) and are therefore also included within the scope of the invention, for example compounds of formulae (V), (VII), (IX) and (X) or a salt or protected derivative thereof.
As indicated above the compounds of formula (I) are useful as ghrelin receptor modulators, e.g. ghrelin receptor antagonists, for the treatment and/or prophylaxis of diabetes and obesity. For such use the compounds of formula (I) will generally be administered in the form of a pharmaceutical composition.
The invention also provides a compound of formula (1), or a phannaceutically acceptable salt thereof, for use as a pharmaceutical .
The invention also provides a pharmaceutical composition comprising a compound of formula (i), in combination with a pharmaceutically acceptable carrier.
Preferably the composition is comprised of a pharmaceutically acceptable carrier and a non-toxic therapeutically effective amount of a compound of formula (I), or a
phannaceutically acceptable salt thereof.
Moreover, the invention also provides a pharmaceutical composition for the treatment of disease by modulating the ghrelin receptor, resulting in the prophylactic or therapeutic treatment of diabetes or obesity, comprising a phannaceutically acceptable carrier and a nontoxic therapeutically effective amount of compound of formula (I), or a pharmaceutically acceptable salt thereof
The pharmaceutical compositions may optionally comprise other therapeutic ingredients or adjuvants. The compositions include compositions suitable for oral, rectal, topical, and parenteral (including subcutaneous, intramuscular, and intravenous) administration, although the most suitable route in any given case will depend on the particular host, and nature and severity of the conditions for which the active ingredient is being administered. The pharmaceutical compositions may be conveniently presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy.
In practice, the compounds of formula (I), or pharmaceutically acceptable salts thereof, can be combined as the active ingredient in intimate admixture with a
pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier may take a wide variety of forms depending on th e form of preparation desired for administration, e.g. oral or parenteral (including intravenous).
Thus, the pharmaceutical compositions can be presented as discrete units suitable for oral administration such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient. Further, the compositions can be presented as a powder, as granules, as a solution, as a suspension in an aqueous liquid, as a non-aqueous liquid, as an oil-in-water emulsion, or as a water-in-oil liquid emulsion. In addition to the common dosage forms set out above, the compound of formula (I), or a pharmaceutically acceptable salt thereof, may also be administered by controlled release means and/or deliver - devices. The compositions may be prepared by any of the methods of pharmacy, in general, such methods include a step of bringing into association the active ingredient with the carrier that constitutes one or more necessary ingredients, in general, the compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both. The product can then be conveniently shaped into the desired presentation,
The compounds of formula (Ϊ), or pharmaceutically acceptable salts thereof, can also be included in pharmaceutical compositions in combination with one or more other therapeutically active compounds.
The pharmaceutical carrier employed can be, for example, a solid, liquid, or gas. Examples of solid carriers include lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid. Examples of liquid carriers are sugar syrup, peanut oil, olive oil, and water. Examples of gaseous carriers ixiclude carbon dioxide and nitrogen.
In preparing the compositions for oral dosage form, any convenient pharmaceutical media may be employed. For example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, and the like may be used to form oral liquid preparations such as suspensions, elixirs and solutions; while carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like may be used to form oral solid preparations such as powders, capsules and tablets. Because of their ease of administration, tablets and capsules are the preferred oral dosage units whereby solid pharmaceutical carriers are employed. Optionally, tablets may be coated by standard aqueous or nonaqueous techniques.
A tablet containing the composition of this invention may be prepared by compression or molding, optionally with one or more accessory ingredients or adjuvants. Compressed tablets may be prepared by compressing, in a suitable machine, the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent. Molded tablets may be made by molding in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent. Each tablet preferably contains from about 0,05mg to about 5g of the active ingredient and each cachet or capsule preferably containing from about O.Q5mg to about 5g of the active ingredient.
For example, a formulation intended for the oral administration to humans may contain from about 0.5mg to about 5g of active agent, compounded with an appropriate and convenient amount of carrier material which may vary from about 5 to about 95 percent of the total composition. Unit dosage forms will generally contain between from about Img to about 2g of the active ingredient, typically 25mg, 50mg, lOOmg, 200mg, 300mg, 400mg, 500m g, 600mg, SOOmg, or lOOOmg.
Pharmaceutical compositions of the present invention suitable for parenteral administration may be prepared as solutions or suspensions of the active compounds in water. A suitable surfactant can be included such as, for example, hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils. Further, a preservati ve can be included to prevent the detrimental growth of microorganisms.
Pharmaceutical compositions of the present invention suitable for injectable use include sterile aqueous solutions or dispersions. Furthermore, the compositions can be in the form of sterile powders for the extemporaneous preparation of such sterile injectable solutions or dispersions, in all cases, the final injectable form must be sterile and must be effectively fluid for easy syringability. The pharmaceutical compositions must be stable under the conditions of manufacture and storage; thus, preferably should be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g. glycerol, propylene glycol and liquid polyethylene glycol), vegetable oils, and suitable mixtures thereof.
Pharmaceutical compositions of the present invention can be in a form suitable for topical use such as, for example, an aerosol, cream, ointment, lotion, dusting powder, or the like. Further, the compositions can be in a form suitable for use in transdermal devices. These formulations may be prepared, using a compound of formula (I), or a pharmaceutically acceptable salt thereof, via conventional processing methods. As an example, a cream or ointment is prepared by admixing hydrophilic material and water, together with about 5wt% to about 10wt% of the compound, to produce a cream or ointment having a desired consistency.
Pharmaceutical compositions of this invention can be in a form suitable for rectal administration wherein the carrier is a solid. It is preferable that the mixture forms unit dose suppositories. Suitable carriers include cocoa butter and other materials commonly used in the art. The suppositories may be conveniently formed by first admixing the composition with the softened or melted carrier(s) followed by chilling and shaping in molds.
In addition to the aforementioned carrier ingredients, the pharmaceutical formulations described above may include, as appropriate, one or more additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, preservatives (including anti-oxidants) and the like. Furthermore, other adjuvants can be included to render the formulation isotonic with the blood of the intended recipient.
Compositions containing a compound of formula (I), or pharmaceutically acceptable salts thereof, may also be prepared in powder or liquid concentrate form.
Generally, dosage levels on the order of O.Qlmg/kg to about 150mg kg of body weight per day are useful in the treatment of the above-indicated conditions, or alternatively about 0.5mg to about 7g per patient per day. For example, diabetes may be effectively treated by the administration of from about 0.01 to 50mg of the compound per kilogram of body weight per day, or alternatively about 0.5mg to about 3.5g per patient per day.
It is understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the age, body weight, general heal th, sex, diet time of administration, route of administration, rate of excretion, drug combination and the severity of the particular disease undergoing therapy. The compounds of formula (I) may be used in the treatment of diseases or conditions in which the ghrelin receptor plays a role,
Thus the invention also pro vides a method for the treatment of a disease or condition in which the ghrelin receptor plays a role comprising a step of administering to a subject hi need thereof an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof.
Diseases or conditions in which the ghrelin receptor plays a role include diabetes and obesity. In the context of the present application the treatment of diabetes (including Type 2 diabetes) includes impaired glucose tolerance, insulin resistance and diabetic complications such as neuropathy, nephropathy, retinopathy, cataracts, cardiovascular complications and dyslipidaemia). The treatment of obesity is intended to encompass the treatment of diseases or conditions such as obesity and other eating disorders associated with excessive food intake e.g. by reduction of appetite and body weight, maintenance of weight reduction and prevention of rebound. The compounds of the invention may also be used for treating metabolic diseases such as metabolic syndrome (syndrome X), impaired glucose tolerance, Prader-Willi syndrome, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, low HDL levels and hypertension, and and for the treatment of patients who have an abnormal sensitivity to ingested fats leading to functional dyspepsia.
The invention also provides a method for the treatment of diabetes, particularly type 2 diabetes, comprising a step of administering to a subject in need thereof an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof.
The invention also provides a method for the treatment of obesity comprising a step of administering to a subject in need thereof an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof.
The invention also provides a method for the treatment of metabolic syndrome
(syndrome X), impaired glucose tolerance, hyperlipidemia, hj'pertriglyceridemia, hypercholesterolemia, low HDL levels, hypertension, or abnormal sensitivity to ingested fats comprising a step of administering to a patient in need thereof an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof,
The invention also provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of a condition as defined above. The invention also provides the use of a compound of formula (I), or a
pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a condition as defined above.
In the methods of the invention the term "treatment" includes both therapeutic and prophylactic treatment.
The compounds of formula (I) may exhibit advantageous properties compared to known ghrelin receptor modulators, for example, the compounds may exhibit improved solubility thus improving absorption properties and bioavailability, or other advantageous properties for compounds to be used as pharmaceuticals,
The compounds of formula (I), or pharmaceutically acceptable salts thereof, may be administered alone or in combination with one or more other therapeutically active compounds. The other therapeutically active compounds may be for the treatment of the same disease or condition as the compounds of formula (I) or a different disease or condition. The therapeutically active compounds may be administered simultaneously, sequentially or separately.
The compounds of formula (I) may be administered with other active compounds for the treatment of diabetes and/or obesity, for example insulin and insulin analogs, gastric lipase inhibitors, pancreatic lipase inhibitors, sulfonyl ureas and analogs, biguamdes, 2 agonists, glitazones, PPAR-y agonists, mixed PPAR-α γ agonists, RXR agonists, fatty acid oxidation inhibitors, -glucosidase inhibitors, dipeptidyl peptidase IV inhibitors, GPR119 agonists, GLP-1 agonists e.g. GLP-1 analogues and mimetics, β-agonists, phosphodiesterase inhibitors, lipid lowering agents, glycogen phosphorylase inhibitors, antiobesity agents e.g. pancreatic lipase inhibitors, MCH-1 antagonists and CB-1 antagonists (or inverse agonists), arnylm antagonists, lipoxygenase inhibitors, somostatin analogs, glucokinase activators, glucagon antagonists, insulin signalling agonists, PTP1B inhibitors, gluconeogenesis inhibitors, antilypolitic agents, GSK inhibitors, galanin receptor agonists, anorectic agents, CCK receptor agonists, ieptin, serotonergic/dopaminergic antiobesity drags, reuptake inhibitors e.g. sibutramme, CRF antagonists, CRF binding proteins, thyromimetic compounds, aldose reductase inhibitors, glucocorticoid receptor antagonists, NHE-1 inhibitors or sorbitol dehydrogenase inhibitors.
Combination therapy comprising the administration of a compound of formula (I), or a pharmaceutically acceptable salt tliereof, and at least one other antidiabetic or antiobesity agent represents a further aspect of the invention. The present invention also provides a method for the treatment of obesity in a mammal, such as a human, which method comprises adminisiermg an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, and another antidiabetic or antiobesity agent, to a mammal in need thereof.
The invention also provides the use of a compound of formula (I), or a
pharmaceutically acceptable salt tliereof, and another antidiabetic or antiobesity agent for the treatment of diabetes or obesity .
The invention also provides the use of a compound of formula (I), or a
pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in combination with another antidiabetic or antiobesity agent, for the treatment of diabetes or obesity.
The compound of formula (I), or a pharmaceutically acceptable salt thereof, and the other antidiabetic or antiobesity agent(s) may be co-administered or administered sequentially or separately.
Co-administration includes administration of a formulation which includes both the compound of formula (I), or a pharmaceutically acceptable salt thereof, and the other antidiabetic or antiobesity agent(s), or the simultaneous or separate administration of different formulations of each agent. Where the pharmacological profiles of the compound of formula (I), or a pharmaceutically acceptable salt thereof, and the other antidiabetic or antiobesity agent(s) allow it, coadministration of the two agents may be preferred.
The invention also provides the use of a compound of formula (I), or a
pharmaceutically acceptable salt thereof, and another antidiabetic or antiobesity agent in the manufacture of a medicament for the treatment of diabetes or obesity.
The invention also provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and another antidiabetic or antiobesity agent, and a pharmaceutically acceptable carrier. The invention also
encompasses the use of such compositions in the methods described above.
All publications, including, but not limited to, patents and patent application cited in this specification, are herein incorporated by reference as if each individual publication were specifically and individually indicated to be incorporated by reference herein as fully set forth. The invention will now be described by reference to the following examples which are for illustrative purposes and are not to be construed as a limitation of the scope of the present invention. Examples
Materials and methods:
Column chromatography was carried out on SiC½ (40-63 mesh) unless specified otherwise. LCMS data were obtained as follows: Atlantis 3μ g column (3.0 x 20.0 mm, flow rate = 0.85 mL min) eluting with a water-MeCN solution containing 0.1% formic acid over 6 min with UV detection at 220 nm. Gradient information: 0.0-0.3 min 100% water; 0.3-4.25 min: Ramp up to 10% water-90% MeCN; 4.25-4.4 min: Ramp up to 100% MeCN; 4.4-4.9 min: Hold at 100% MeCN; 4.9-6.0 min: Return to 100% water. The mass spectra were obtained using an electrospray ionisation source in either the positive (ES4) or negative (ES ) ion modes.
Where chlorine is present in the molecule the masses are quoted for 3SC1 and when bromine is present 81 Br has been quoted.
Prep HPLC purification was earned out using a CI S column; Flow rate = 20mL mm, UV detection at 220 nM using a 8-10 min gradient. Standard method: eluting with solvent A (water+0.1% formic acid) and solvent B (MeCN+0.1% formic acid). Basic method: eluting with solvent A (water+0.2% NH4OH) and solvent B (MeCN (or MeOH)+0.2% NH4OH). Unless otherwise stated standard method was employed for purification.
Prep Cliiral HPLC was carried out using Daieel Chiralpack IA, 250x20mm, 5μΜ, Flow rate: 12-15.0 mL/min. Abbreviations and acronyms: AcOH: Acetic acid; Me2CO: Acetone; MeCN: Acetonitrile;
NH3: Ammonia; NH4CI: Ammonium chloride NH4OH: Ammonium hydroxide; An Argon;
HATU: 0-(7-Azabenzotriazoie-l-yl)-N,N, N, A etramethy roriium hexafiuorophosphate; cone: concentrated; CS2CO3: Cesium carbonate; Cul: Copper iodide; DCE: Diehloroethane;
DCM: Dichloromethane; DEA: Diethylamine; DAST: Diethylaminosulfur trifluoride;
DEAD: Diethyl azodicarboxylate DIBAL-H: diisobutyialuminium hydride; DIPEA: N,N-
Diisopropylethylamine; EDCI: N-(3-Dimethylaminopropyl)-.V-ethyi carbodiimide hydrochloride; DMCC: AvV-Dimethylcarbamo l chloride; DMSO: Dimethylsulfoxide;
DMF: NjN-Dimethylfonnamide; Et20: Diethyl ether; BINAP: 2,2'-¾s(Diphenylphosphmo)~ Ι,Γ-binaphthaiene; EtOH; Ethanol; EtOAc: Ethyl acetate; h; hoisr(s): HC1: Hydrogen chloride; L1AIH4; Lithium aluminium hydride; HOBt: Hydroxybenzotriazole; LiOU:
Lithium hydroxide; MP-Carbonate: Macroporous polymer bound carbonate resin; MP- TsOH: Macroporous polymer bound toluenesulfonic acid resin; MgS0 : Magnesium sulphate; /n-CPBA: weto-chioroperbenzoic acid; MeOH: Methanol; NMP: N- Methylpyrrolidone; MTBE: Methyl tert-butyl ether; Pd(OAc)2: Palladium acetate;
PdCl2(dppf): Palladium dichlox'o [i, -ft«'(diphenylphosphmo)ferrocene|; K2C03: Potassium Carbonate; KO'Bu: Potassium ierr-butoxide; rt: room temperature; RT: Retention time; sat.: saturated; NaBH^: Sodium borohydride; Na2C03: Sodium carbonate; NaH: Sodium hydride; NaHC03: Sodium hydrogen carbonate; NaOH: Sodium hydroxide; a2S04: Sodium sulfate; NaO'Bu: Sodium tert-butoxide; NaBH(OAc)3: Sodium triacetoxyborohydride; SCX: Strong cation exchange resin; THF: Tetrahydrofuran; PhMe: Toluene; TFA: Trifluoroacetie acid; NEt3: Triethylamine; TMSC : Trimethylsilyl cyanide; PPh3: Triphenylphosphine; Pd2dba3: Tris(dibenzylideneacetone)-dipalladium(0).
Preparation 1: (5')-l-Fiperidia-3 etie add salt
Figure imgf000028_0001
To (5)-3-hydroxymethylpiperidine-l-carboxyIic acid teri-butyl ester (lOOg,
464mmol) in DCM (500mL) at 0°C was added, via a dropping funnel, TFA (250mL), After addition the mixture was stirred at rt for 6h before the solvent was removed in vacuo. PhMe (50GmL) was added and the solvent removed in vacuo. This process was repeated three times to give the title compound: RT = 0.78min; m/z (ES+) ~ 116.1 [M+ H]+.
Preparation 2: ((5)-1-Isopropylpiperidiii-3- l)meiliaBol
Figure imgf000028_0002
To (iS)-l-piperidin-3-ylmethanol trifluoroacetie acid salt (Preparation 1) (464mmol) in Me2CO (500ml.) and THF (400mL) at 0°C under a flow of Ar was added NaBH(OAc)3 (1 7g, 928mmol) in portions. After addition the mixture was stirred at rt for 2h before 2M NaOH was added carefully and the organic solvent removed in vacuo. The aqueous phase was basified to pH~12 using solid NaOH, extracted with 9:1 DCM:MeOH and then 1:1 EtOAcrTHF. The combined organic phase was dried (MgS04) and the solvent removed in vacuo to give the title compound: RT = 0.48min; m/z (ES") = 158.1 [M + iff.
Preparation 3: l-C^-l-Pfperidiii-S-yiiiietliylisoiKdo!e-ljS-diooe
Figure imgf000029_0001
To (jR)-3-aminomethylpiperidine-l-carboxylic acid ½ri-butyl ester (lOg, 46.7mmol) in PhMe (lOOmL) was added phthalic anhydride (6.92g (46,7mmol). The mixture was heated under reflux for 3h in a flask fitted to a Dean-Stark trap and then stirred at rt for 64h, The solvent was removed in vacuo to give (i?)-3-(l,3-dioxo ,3-dihydroisomdol-2- ylrnethyl)piperidine-1 -carboxylic acid /en-butyl ester to which was added DCM (lOOmL). TFA (50mL) was then added over 0.5h at rt and after Ih the solvent was removed in vacuo. DCM and 2M K7CO3 were added and the mixture extracted, with DCM. The combined organic phase was washed with 2M K2CO3, brine and dried (MgS04). The solvent was removed in vacuo to give the title compound: RT - 1.93mm; m/z (ES+) = 245.1 [M + H]+.
Preparation 4t -C^-l-isopropyl iperidiii-S-ylmetliy^isolndoJe-ljS-dioise
Figure imgf000029_0002
Method 1 : To ((5)-l-isopropylpiperidin-3-yl)methanol (Preparation 2) (crude 464mmol) in THF (lOOOmL) was added isoindole-l ,3-dione (102.4g, 696mmol) and Ρ1¾ (140g, 534mmol). The mixture was cooled to 0°C, DEAD (97g, 557mmol) added slowly via a cannulated needle before the mixture was stirred at it for 16h. The mixture was cooled to 0°C, PPhj (122g, 464mmol) and DEAD (97g, 557rmnol) were added before stirring at rt for 0.5h. The mixture was cooled to 0°C, PPh3 (61g, 232mmol) and DEAD (48.5g, 278mmol) were added and after stirring for a further O.Sh at rt PPh.3 (122g, 464mmol) was added. The mixture was stirred at rt for 1.5h and then the solvent was removed in vacuo. The residue was triturated with Et2Q to give a solid which after filtration was discarded. The solvent was removed in vacuo and the residue further triturated with EtiO/Hexane to give further solid which was discarded after filtration. The solvent was removed in vacuo and the residue purified by column chromatography (DCM then inceasing EtOAc upto 1 % NEt3 in EtOAc) to give, after removal of the solvent in vacuo, the title compound: RT = 2.00min; m z (ES+) = 287.1 [ t H ,
Method 2: To 2-(S)-l-piperidm-3-ylmethylisoitidole-l,3-dione (Preparation 3) (9.3g, 38.1mmol) in THF (SOrnL) and Me2CO (25mL) was added NaBH(OAc)3 (8.48g, 40.0mmol), After 16h at rt EtOAc and 2M 2CQ3 were added and the phases separated. The aqueous phase was extracted with EtOAc and the combined organic phase was washed with 2M
K2CO3, brine and dried (MgS04). The solvent was removed in vacuo to give the title compound: RT = 2.04min; m/z (ES÷) - 287.1 [M+ H]+. Preparation St C-((^)~l~isopropy!piperidiii-3-yl)meiisylai}iiHe phthalazmedioae salt
Figure imgf000030_0001
To 2-((jS)-l-isopropylpiperidhi-3-ylmemyl)isomdole-l,3-dione (Preparation 4) (79.3g, 277mmol) in EtOH (300mL) was added hydrazine monohydrate (12.1mL,
249mmol). The mixture was heated under reflux for 3h, then cooled and the solvent was removed in vacuo to give the title compound: RT === 0.22rain; m/z (ES+) = 157.1 [M÷ H] RT=2.02niin; m/z (ES+) 163.0 [M + H]+ (Phthalazinedione).
Preparation 6: Fiperidin-3-ylmethykarbamic acid ferf-butyl ester
Figure imgf000030_0002
Pyridin-3-ylmethylcarbamic acid teri-buiyl ester (81g. 389mmol), MeOH (200mL), water (30mL) and rhodium on alumina (8g) were heated to 50°C under a hydrogen atmosphere (40 bar) in a Parr hydro genator. After 16h the mixture was filtered through celite washed with MeOH and the solvent removed in vacuo from the filtrate to gi e the title compound: RT ~ 1.71min; m/z (ES+) = 215.1 [M+ H]+.
Preparation 7: (l~isopr py!piperidii¾~3~ylmetliyl)carbamje add tert-l tyl ester
Figure imgf000030_0003
To piperidin-3-ylmeihylearbamic acid tert-biityl ester (Preparation 6) (83.3g,
389mmol) in THF (SOOmL) and M<¾CO (SOOmL) was added NaBH(OAc)3 (124g, 584mmol) in portions. As the mixture thickened additional Me2CO (300mL) and THF (lOOmL) were added to maintain stirring. After 16h the solvent was removed in vacuo and the residue partitioned between 2M NaOH (to achieve pH~14) and Et20. The aqueous phase was extracted twice with Et20 and the combined organic phase washed with brine and dried (MgS04). The solvent was removed in vacuo to give the title compound: RT = l .SSmin; m/z (ES+) = 257.2 [M+ H]+. Preparation 8: C~((/l.)-l-IsopiOpylpiper!din-3-yl)methylamine (25,3S)-2,3-6«- benzoyloxysuccinic aeid salt
Figure imgf000031_0001
To (l-isopropylpiperidin-3-y]methyl)carbamic acid ieri-butyl ester (Preparation 7)
(96g, 375mmol) in DCM (350mL) at 0°C was gradually added TFA (150mL). After 16h TFA (50mL) was added and the mixture was stirred for an additional 2h. The solvent was removed in vacuo and the residue dissolved i DCM (200mL). The residue in DCM was added to a stirred biphasic mixture of NaOH (35g) in SOOmL of water and DCM (2Q0mL) before NaOH was added to reach pH~14 and the phases were separated. The aqueous phase was extracted with DCM and the combined organic phase dried (Na2S04) and the solvent was removed in vacuo. The residue was dissolved in water (SOrnL) and then propan-2-ol (60mL) was added followed by (25,3/S)-2,3-6/i-benzoyloxysuccinic aeid (58g, 154mmoi) in portions. Sonication was used to aid dissolution and then propan-2-ol (940mL) added. After stirring for 64h a precipitate was filtered off, washed with propan-2-ol then Et20 and dried to give the title compound: RT = 0.32min; m/z (ES+) = 157.2 \M+ H]+.
Preparation 9: 3-Fliioro~2~oxopiperidioe-3-carboxylic acid ethyl ester
Figure imgf000032_0001
To a solution of 2~oxopiperidine-3-carboxylic acid ethyl ester (ISg, 87.6mmol) in THF (200mL) at 0°C was added NaH (60% in mineral oil) (3.5g, 87.6mmol) in portions. The mixture was stirred at rt until effervescence ceased, cooled to 0°C and Λ- fluorobenzenesulfinimide (27.6g, 87,6niinol) was added. The reaction was stirred at rt for 16 h before water (80mL) was added and the THF removed in vacuo. The mixture was extracted with EtQAe, the combined organics were dried (MgSG4) and the solvent was removed in vacuo. The residue purified by column chromatography (EtOAc:hexane 60:40 to 80:20) to give, after removal of the solvent in vacuo, the title compound: RT = 1.90min; m z (ES r) 190.1 [M + H]+.
Preparation 10: 3~FIuoro~2~oxopiperidine-3-carbox Iic add dibeszylamide
Figure imgf000032_0002
To a solution of dibenzylamine (21.1mL, 109.5mmol) in toluene (150mL) at 0°C was added trimethylaluminiura (2M in hexanes, 54.8mL, 109.5mmol) over Ih. After stirring for 3h at rt the mixture was cooled to 0°C and 3-fluoro-2-oxopiperidine-3-carboxylic acid ethyl ester (Preparation 9) (10,4g, 54.8mmol) in PhMe (150mL) was added in portions. After the effervescence had ceased the mixture was heated under reflux for 16h. After cooling to 0"C, water (50mL) and IN HC1 (50mL) were added and the solvent was removed in vacuo. The mixture was extracted with EtOAc and solid material filtered off. The solid was dissolved in 1M HC1, extracted with EtOAc, the combined organics were dried (MgS04) and the solvent removed in vacuo, The residue was triturated with Et20, filtered and the solid purified by column chromatography (EtQAc:hexane 60:40 to EtOAc:DCM 50:50) to give, after removal of the solvent in vacuo, the title compound: RT = 3.30min; m/z (ES+) = 341.2 [M+ H]+.
Preparation 11 : Dibeazyl(3~fl oropiperidis-3-ylmethyl)amme
Figure imgf000033_0001
To 3~fluoro-2-oxopiperidine~3-carboxylic acid dihenzylamids (Preparation 10) (i0,5g; 30.7mmol) in THF (1 50mL) at 0°C under Ar was added dropwise BH3.THF (1M solution. 307raL, 307mmol). The mixture was heated at reflux for 64h, cooled to 0°C and MeOH (150mL) added slowly. After stirring for Ih at rt the solvent was removed in vacuo, The residue was purified by column chromatography (6:94 MeOH:DCM to 15:85 (2% N¾ in MeOH):DCM) to give, after removal of the solvent in vacuo, the title compound: RT = 2.59mm; m/z (ES÷) = 313.2 [M + H]+. Preparation 12: Bihe¾zyl(3-fliioro-l-iso ropyipiperldiii-3-ylmei¾yi)ainine
Figure imgf000033_0002
To a solution of dibenzyl(3-fluoropiperidin-3-ylmethyl)amme (Preparation 11) (5.8g, 1 8.6mmol) in THF (lOOmL) and Me2CO (50mL) under Ar was added NaBH(OAc)3. After 2h at rt IM NaOH was added until effervescence ceased and the solvent was removed in vacuo. The mixture was basified to pH ~10 using 2M NaOH and extracted with 9: 1
DCM:MeOH. The combined organic phase was dried (MgS04) and the solvent removed in vacuo to give the title compound which was used without further purification: RT ==: 2.75min; m/z (ES*) = 355.1 [ + Hf. Preparation 13; C-(3-FlMoro~l~isopro lpiperidin-3-yl)metliylamiHe
Figure imgf000033_0003
A solution of dibenzyl(3-fluoro-l-isopropylpiperidm-3-ylmemyl)amine (Preparation 12) (5.6 l g, 15.8mmol) in MeOH (317mL) was passed through a 10%Pd/C Cat Cart70 at 100°C on a Thales H-Cube with a flow rate of 2mL/rnin and full hydrogen mode. The solvent was removed in vacuo to give the title compound which was used without further purification: RT = 0.31 mm; m/z (ES+) = 175.1 [M + H]+.
Preparation 14; 2-(l-lsopropyl-4-oxopiperidiii-3~ylmethyi)isomdole-l,3~dioj5e
Figure imgf000034_0001
To a solution of diisopropylamine (3mL, 21.2mmol) in THF (15mL) at -78°C under Ar was added w-butyl lithium (2.5M in hexanes, 8.5mL, 21.2mmol) before 0,25h later 1- isopropylpiperidin-4-one (2.5g, 17.7mmol) in THF (15mL) was added dropwise to the mixture. After stirring for a further Ih at -78°C 2-chloromethylisoindole-l,3-dione (5.2g, 26.6mmol) in THF (30mL) was added dropwise. After Ih at -78ύ€ the mixture was warmed to ri, stirred for 16h before sat. NFLjCl solution (50mL) was added and the mixture extracted with EtOAc. The combined organic phase was washed with brine, dried (MgS04) and the solvent was removed in vacuo. The residue was purified by column chromatography (1 :199 NEt3:DCM to 1 :20: 179 NEt3:MeOH:DCM) to give, after removal of the solvent in vacuo, the title compound: RT=== 2.00mm; m/z (ES+) = 301.1 [M ÷ H]+.
Preparation 15: 2-(4,4-Dif1 oro~1 sopropy!plperidin-3-yImethyl)isoiiidole-l,3-dioiie
Figure imgf000034_0002
To 2-(l-isopropyl-4-oxopiperidin-3-ylmethyl)isoindole-l,3-dione (Preparation 14) (314mg, .05mmol) in DCM (5mL) at 0°C was added DAST (0.34mL, 2.61mmol). The mixture was allowed to warm to rt over 16h before sat. Na C03 (lOmL) was carefully added and the mixture extracted with DCM. The combined organic phase was dried (MgS04) and the solvent was removed in vacuo. The residue purified by column chromatography (1 :60:40 NEt3:Et20:hex ne to 1 : 199 NEt3:Et20) to give, after removal of the solvent in vacuo, the title compound: RT= 2.12min; m/z (ES+) = 323.1 [M + H]+.
Preparation 16: C-(4,4-DifIuoro~l-isopropylpipcridin-3-yl)meth lamine
pbtliaiaziaedioBe salt
Figure imgf000035_0001
To 2-(4,4-difluoro- 1 -isopropylpiperidin-3 -ylmethyl)iso indole- 1 ,3-dione ( 155mg, Q.Smmol) (Preparation 15) in EtOH (5mL) was added hydrazine monohydrate (35μΕ, 0.7nimol). The mixture was heated under reflux for 16h before the solvent was removed in vacuo to give the title compound: RT= 0.21mm; m/z (ES÷) = 193.1 [M+ H]+. RT= 2.02min; m z (ES ) - 163.0 [M + H]+ (Phthalazinedione).
Preparation 17: (J)-3-(Methoxymetliykarbamoyl)pip£ridiBe-l-carboxyIic add tert- butyl ester
Figure imgf000035_0002
To (53-piperidine-l,3-diearboxylic acid 1-fcrt-butyl ester (5g, 21.8mmol) in DMF (25mL) was added EDCI (4.2g, 22.1mmol) and dimeftylpyridin-4-ylamine (6.7g,
54.9nimoi). After lOmin 0,N~dimethylhydroxylamine hydrochloride (2.15g, 22.1nimol) was added and the mixture stirred for 16h. Water was added, the mixture extracted with DCM and the organic phase washed with sat. NaHC(¼. The solvent was removed in vacuo to give the title compound: RT=== 3.13mm; m/z (ES+) = 273.2 [M+ H]+.
Preparation 18: 3-Acetylpiperidine-l-carboxylic add tert-butyl ester
Figure imgf000035_0003
To (S)-piperidine- 1 ,.3-dicarboxylic acid 1-ieri-butyl ester (Preparation 17) (0.6g,
2.2nimol) in THF (15mL) at 0°C was added methyl magnesimn bromide (3M in Et20, 2.2mL, 0.0mmol). After 2h aqueous NH4CI (5mL) was added, the mixture was extracted with EtOAc, the organic phase was washed with brine, dried (MgSG4) and the solvent removed in vacuo to give the title compound: RT= 3.23mm; m/z (ES+) = 172.1 [M + H- C(CH3)3 +H]+.
Preparation 19: 3~(l-AmiMoethyI)piperidiBe~l~earboxy c. ¾dd tert-but l ester
Figure imgf000036_0001
To 3-acelylpiperidme-l-earboxylic acid fert-butyl ester (Preparation 18) (652mg, 2.2mmol) in MeOH (20mL) was added ammonium acetate (830mg, l l.Ommol) and sodium cyanoborohydride (488mg, S.Ommol). After 18h the solvent was removed in vacuo, the residue was partitioned between DCM and NaHCi¾ and the solvent removed in vacuo. The residue was purified using an SCX column (washing with MeOH and elution with
NHj/MeOH) to give, after removal of the solvent in vacuo, the title compound: RT=
1.90min; m z (ES+) - 229.2 [M÷ H]+. Preparation 20: ((i?)-l~IsopropyIpiperMij¾~3~yImetl5yl)(2-met!iylbeozyI)amiHe
Figure imgf000036_0002
To C-((ii)-l-isopropylpiperidin-3-yl)methylamine phthalazinedione salt (Preparation 5) (611mg, 1.92mmol) in MeOH (lOmL) was added Et3 (0.54mL, 3.84mmol). After lOmin 2-methylbenzaldehyde (254mg, 2, l lmmol) and 4A molecular sieves (500mg) were added before the mixture was heated at 70°C for 4h. After cooling to rt, NaB¾ (219mg, 5.8mmol) was added and the mixture stirred for 16h at rt. Water (ImL) was added, the mixture filtered and the solvent removed in vacuo. The residue was partitioned between 2M K2C03 and EiOAe and the aqueous phase was extracted with EtOAc. The combined organic phase was washed with brine, dried (MgS04) and the solvent removed in vacuo. The residue was purified using SCX (washing with MeOH and elution with NH^H/MeOH) to give, after removal of solvent in vacuo, the title compound: RT= 1.97min; m z (E8 = 261.2 [M + H]+.
Using the method outlined in Preparation 20, Preparations 21-25 were prepared from C-((i?)-l-isopropylpiperidin-3-yl)meth.ylamine phthalazmedione salt (Preparation 5) and the corresponding aldehyde (Table 1).
Table 1
Figure imgf000037_0001
Preparation 26; i"Isopropyipi eridiii-3- l0ieihyI)(2~plieBOxyetisyi)amiiie
Figure imgf000037_0002
To C-(l-isopropylpiperidin-3-yi)methylarnme (250mg, l„6mmol) in DCM (6mL) was added DIPEA (0.84mL, 4.8mmol) followed by phenoxyaeetyl el loride (328mg, .9mrnol). After 64h polyrner supported isocyanate (667mg) was added followed by 0.5h later 1M NaOH (l OmL). The mixture was placed in a hydrophobic phase separator, washed with DCM and the solvent was removed in vacuo from the organic phase to give N-(l- isopropylpiperidm-3-y3methyl)-3-phenoxypropionattiide. To AL(l-isopropyipiperidm-3- ylmethyi)-3~phenoxypropionamide (392mg, 1.3mniol) in Et20 (15mL) was added LiAlH,-. (154mg. 4mmol) in Et?Q (20mL). The mixture was heated under reflux for 16h before cooling to rt. The mixture was filtered, the residue washed with Et20 and the solvent was removed in vacuo. The residue was purified by column chromatography (1 :20:380
N¾OH:MeOH:DCM) to give, after removal of the solvent in vacuo, the title compound: RT= 0,67min; m/z (ES+) = 277.3 [ + Hf. Preparation 27: 4-Cliloropyridiee~2~earboxylic acid (l-isopropylpiperMIn-3-y!niethy!) amide
Figure imgf000038_0001
To 4-ehloropyridine"2-carboxylic acid (0.5g, 2.3mmol) in DCM (5mL) was added oxalylchloride (0.25mL, 2.8mmol) and DMF (O.l mL). After h NEt3 (0.65mL, 4.7mmol) and C-(l-isopropylpiperidin-3-yI)methylamine (0.44g, 2.8mmol) were added at 0°C. After 18h at rt EtOAc was added and the organic phase was washed with sat. Na2C03. The aqueous phase was extracted with EtOAc and the combined organic phase washed with brine, dried (MgS04) and the solvent was removed in vacuo. The residue was purified by column chromatography (0:4:96 to 1 :8:192 NEt :MeOH:DCM) to give, after removal of the solvent in vacuo, the title compound: RT = 1.97min; m z (ES+) === 296.2 [M+ H]+. acid (( ?)-!-
Figure imgf000038_0002
Using the method outlined in Preparation 27, 4-chloro-5-methy3pyridine~2-carboxylic acid and C-((i?)-l -isopropylpiperidin-3-yl)methylamine phthalazinedione salt (Preparation 5) were converted to the title compound: RT = 2.18min; m/z (ES†) = 310.1 [M + H]T.
Preparation 29: 4-CMoFO-3-inethylpyridme~2~carboxylk acid (( ?)-!- lsopropyipIperidin-3-ylmetMyl)amide
Figure imgf000038_0003
Using the method outlined in Preparation 27, 4-chloro-3-methylpyridme-2-carboxylic acid and C-((i?)-l-isopropylpiperidm-3-yl)methylamine phthalazinedione salt (Preparation 5) were converted to the title compound: RT = 1 ,88mm; m/z (ES+) = 310.1 [M -f H]+. Preparation 3i 4-ChIoropyridiMe~2~earbosylic acid ((«S)-l-pipendin~3~ylmethyI)amide
Figure imgf000039_0001
Using the method outlined in Preparation 27, (i?)-3-aminomethylpiperidine~l~ carboxylic acid feri-butyl ester (3.26g, 15.2mmol) and 4-ehloropvridine-2-carboxylic acid (2,0g, 12.7mmol) were converted to
Figure imgf000039_0002
carbonyl)amino]methyl}piperidine-l -carboxylic acid tert-butyl ester. To (Λ)-3-{[(4- chloropyridine-2-earbonyl)amiiio]methyl}-piperidine-l -carboxylic acid teri-butyl ester (crude) in DCM (50mL) was added TFA (5mL). After 3h TFA (2mL) was added and 16h later the solvent was removed in vacuo to give the title compound; RT = 1.77min; m/z (ESr) = 254.2 [Af- H]+.
Preparation 31: 4-CMorepyridme-2--carboxylk aeid ((^)-l-isopropylpiperidia-3- ylmethyj)-amide
Figure imgf000039_0003
Method A: To 4-ehloropyridine-2-carboxylic acid ((S)-l-piperidin-3-ylmethyl)amide
(Preparation 30) (9.3g, 25.3mmol) in DCE (50mL) was added Me2CO (5.6mL) and
NaBH(OAc)3 (21.4g, 101.2mmol). After 16h DCM and sat. NaHC03 were added, the organic phase was washed with NaHC03, dried (MgS04) and the solvent was removed in vacuo. The residue was purified by column chromatography (0.1 :5:95 NEi3 : eO H : DC M) to
;ive, after removal of the solvent in vacuo, the title compound: RT = 1.86min; m/z (ES ")
Figure imgf000039_0004
Method B: Using the method outlined in Preparation 27, C-(i?)-l-piperidin~3~ ylrnethylamine phtha lazinedione salt (Preparation 5) and 4-chloropyridine-2-carboxylic acid were converted to the title compound: RT = l ,95min; m/z (ES+) = 296.1 [M + H]÷. Preparation 32: 3-Bromo-iV-(l-is propy!piperidm~3"yImethyl)-4~met ylbe!izairiide
Figure imgf000040_0001
To a solution of 3-bromo-4-methylbenzoic acid (500mg, 2.33mmol) in DMF (l OmL) was added NEt3 (0.97niL, 6.98mmol), EDCI (535mg, 2.79mmol) and HOBt (377mg, 2.79mmol). After 20min C-(l-isopropylpiperidin-3-yl)methylamine (436mg, 2.79mmol) was added and 16h later the solvent was removed in vacuo. EtOAc (50mL) was added, the organic phase was washed with water, sat. a2CQ3, dried (MgS04) and the solvent was removed in vacuo. The residue was purified by column chromatography (4:96 to 6:94 MeOH:DCM) to give, after removal of the solvent in vacuo, the title compound: RT = 2.37min; m/z (ES ) = 353.2 [M + H]+.
Preparation 33: 4-Chloro-6-methyIpy]
isopropylpiperidiB~3~ylmetfeyl)a
Figure imgf000040_0002
Using the method outlined in Preparation 32, 4-chloro-6-methylpyridine-2-carboxyl acid and C-((R)- 1 -isopropylpiperidin-3-yl)meuiylamine phthalazinedione salt (Preparation 5), were converted to the title compound: RT = 2.00min; m/z (ES+) = 310.1 [M + H]+.
Preparation 34: 5-Iodo-iV-(l -isopropy!p!peridin-3-ylmethyI)~2~metlioxybenzamide
Figure imgf000040_0003
Using the method outlined in Preparation 32, 5-iodo~2~methoxybenzoic acid and (l -isopropylpiperidin-3-yl)methylamme were converted to the title compound: RT =-:
2.53min; m z (ES4) = 417.2 [M + H]+.
Preparation 35: 2-Cfaloro-5-fluoro-iV-((R)-l-isopropyIpiperidin-3- ylmcihyi)nicotinamide
Figure imgf000040_0004
To 2-chloro-5~fluofonicotinic acid (500mg, 2.8mmol) in DCE (20mL) was added 2- (l-cUoro-N^,2-trimethyl-l-propenylamine) (0.43mL, 3.2mmol). After 10 min C-((i?)-l- isopropylpiperidin-3-yl)memylamine phthalazinedione salt (Preparation 5) (l. lg, 3.4mmol) and NEt3 (1 ,27mL, 9.1mniol) in DCE (lOn L) were added. After lh a precipitate was filtered off and the filtrate partitioned between DCM and sat. Na C0 solution. The combined organic phase was washed with water, brine, dried (MgS{¾) and the solvent was removed in vacuo. The residue was purified by SCX (washing with MeOH and elution with NH3/MeOH) to give, after removal of solvent in vacuo, the title compound: RT = 1.67min; ni/z (ES+) = 314.1 [Af+ H]+.
Preparation 36; 3,6-Dichloropyridazine-4-carboxyiic acid ((J?)-1 soprapyIpIperidm~3~ yhnethyl)amide
Figure imgf000041_0001
To 3,6-dichloropyridazine-4-carboxylic acid (Ig, 5.2mmol) in DCE (20mL) at 0°C was added oxalyl chloride (1.36mL, 15.6mmoi) and DMF (2 drops). After 0.5h the solvent was removed in vacuo. The residue in DCE (lOmL) was added to C-((i?)-l- isopropylpiperidin-3-yl)methylamine phthalazinedione salt (Preparation 5) (1.5g, 4.7inmol) and NEt3 (0.66mL, 4.7mmol) in DCE (lOmL). After 0,5h the mixture was filtered and the solvent removed from the filtrate in vacuo. The residue was added to an MP-TsOH column, washed with MeOH and then crude product eluted with 2M NH3 in MeOH and the solvent was removed in vacuo. The residue was purified on a Biotage Isoiera (KP:NH column, Hexane to 100% EtOAc) to give, after removal of the solvent in vacuo, the title compound: RT- 1.70min; m/z (ES+) = 331.0 [M + llf. Preparation 37: 6~CSi!orQ~3-isopropoxypyriclaziMe-4-earboxy c acid ((^)-l~isopropyI- plperidin~3~ylmetliyl)amlde
Figure imgf000041_0002
Nail (60% dispersion in mineral oil, 27mg, 0.66mmol) was added to isopropanol (2mL) and the mixture heated at 50°C for 30min. The mixture was cooled to rt, 3,6- dichloropyridazine-4-carboxylie acid ((i?)-l-isopropylpiperidin-3-ylmethyl)amide
(Preparation 36) (200mg, 0.60mmol) in isopopanol (lmL) added and then heated at 50°C for 40min. The mixture was cooled and partitioned between chloroform and 2M K2CO3. The organic phase was dried (MgS04) and the solvent removed in vacuo to give the title compound: RT= 2.13min; m/z (ES+) = 355.2 [M+ H]+.
Preparation 38: 6-ChIoro-3-(tetrahydrop ran~4~yloxy)pyrida¾iEe~4~carboxyiie acid ((^-l-isopropylpiperidiii-S-ylraethy^ainMe
Figure imgf000042_0001
To 3,6-dichlorop>Tidazine-4-carboxylic acid ((i?)~1 -isopropylpiperidin-3
ylmethyl)amide (Preparation 36) (370mg, 1.12mmol) in DMF (8mL) was added K2C03 (232mg, 1.68mmol) and tetrahydropyran-4-ol (228mg, 2.24mmol). The mixture was stirred at rt for 0.5h then heated to 90°C for 18h before the solvent was removed in vacuo. DCM and water were added, the aqueous phase was extracted with DCM and the solvent was removed in vacuo from the combined organic phase, The residue purified by prep HPLC followed by SCX (washing with MeOH and emtion with NHi/MeOH) to give, after removal of the solvent in vacuo, the title compound: RT= 2,10min; m z (ES+) = 397,2 [M+ Hf .
Preparation 39: 6-Chloro-3-cydopentyIoxypyridazine-'4-carboxylic acid ((R)-l- isopropyl-pIperidiK-3-ylmeihyI)
Figure imgf000042_0002
Using the method outlined in Preparation 38, 3,6-dicUoropyridazine-4-carboxylic acid ((/?)-! -isopropylpiperidin-3-ylmethyl)amide (Preparation 36) and cyclopentanol were converted to the title compound: RT- 2.37min; m/z (ES'*') = 381.2 [M+ Hj+, Preparation 40: 6-Cliloro-3-!Sobiitoxypyr azine~4-ear oxylic acid ((i¾)-l-isopropyI-
Figure imgf000043_0001
Using the method outlined in Preparation 38, 3,6-dic oropyridazine-4-carboxylic acid ((R)- 1 -isopropylpiperidin-3 -ylmethyl)ainide (Preparation 36) and 2-methylpropan- 1 -ol were converted to the title compound: RT= 2.32mm; m/z (ES+) = 369,2 [M+ H]+. ion 41: 4-[2-(4-F oropheE l)[li3]dithioIan~2~yl]pyridme
Figure imgf000043_0002
To (4-fluorophenyl)pyridin-4~yhnethanone (5g, 24,8mmol) and ethan-l,2-dithiol
(4.17mL, 49,7mmol) was added boron trifluoride bis-acetie acid (6.9mL, 49.7mmol). The mixture was stirred at rt for 20h before EtOAc was added. The organic phase was washed with NaHC03, 1 M NaOH, brine, dried (MgS04) and the solvent was removed in vacuo. The residue was purified by column chromatography (30:70 to 40:60 ElOAe:Hexane) to give, after removal of the solvent in vacuo, the title compound: RT = 2.75min; m/z (ES ) = 278.2 t i n ' .
Preparation 42: 4-[Bifluoro(4-fluo pyridiHe
Figure imgf000043_0003
To a solution of 4-[2-(4-fluorophenyl)[l ,3]dithiolan-2-yl]pyridme (Preparation 41)
(6,27g, 22.6mmol) in DCM (120mL) was added N-bromosuccinimide (10.46g, 5.88mmol). After 5m in DAST (8.89ml.., 67.8mmol) was added and the mixture stirred for 16h. DCM was added and the combined organics washed with sat. NaHC03, dried (MgS04) and the solvent was removed in vacuo. The residue was purified by column chromatography (20:80 to 30:70 EtOAc:Hexane) to give, after removal of the solvent in vacuo, the title compound: RT = 3.27min; m/z (ES+) = 224.1 [M + H]+. Preparation 43: 4-[Difluoro(4"flisoropheiiyi)methyl]pyr!iline 1-oxide
Figure imgf000044_0001
To a solution of 4-[difluoro-(4-fluorophenyl)methyl]pyridine (Preparation 42) (2.22g, 9.95nimol) in DCM (35mL) at rt under Ar was added m-CPBA (70%, 2.94g, 1 1 .93mmol) and after 2h solvent was removed in vacuo. The residue was purified by column
chromatography (60:40 EtOAc:Hexane and then 8:92 MeOILDCM) to give, after removal of the solvent in vacuo, the title compound: RT = 2.80min; m/z (ES+) = 240.1 [M + H]+.
Preparation 44°. 4~(4-C orobeiizyl)pyridiiie 1-oxide
Figure imgf000044_0002
Using the method outlined in Preparation 43, 4-(4-c orcberi2yl)pyridine was converted to the title compound: RT - 2.87min; m z (ES!) - 220.1 [M+ H]+.
Figure imgf000044_0003
To 4-[difluoro(4-fluoiOphenyl)methyl]pyridine 1-oxide (Preparation 43) (800mg, 3.34mmol) in DCM (30mL) was added TMSCN (0.58mL, 4,35mmol) followed by dropwise addition of DMCC (0.4mL, 4.35mmol). After 64h TMSCN (0.58mL, 4.35mmol) and DMCC (0.4mL, 4.35mmol) were added. After a further 24h, TMSCN (1.16mL. 8,70mmol) and DMCC (0.8mL, 8.70mmol) were added and 24h later water (5()mL) was added. The mixture was extracted with DCM, tlie combined organic phase dried (MgS04) and the solvent was removed in vacuo. The residue was purified by column chromatography (10:90
EtOAc:Hexane) to give, after removal of the solvent in vacuo, the title compound: RT = 3.59min; m/z (ES+) = 249.1 [M + H]+.
Preparation 46; 4-(4-CMorobeiizyl)pyridiBe-2-earbomtFi!e
Figure imgf000044_0004
Using the method outlined in Preparation 45, 4-(4-ehlorobenz l)pyridine 1 -oxide (Preparation 44) was converted to the title compound: RT = 3.59min; m/z (ES+) = 2290.1 [M + H]+. Preparation 47: 4~{4~FI¾ior bei5zoyi)pyridise-2-carboxyIk add
Figure imgf000045_0001
To 4-[difluoro(4-fluorophenyl)inethyl]pyridine-2.-carboriitrile (Preparation 45) (829mg, 3.34mmol) was added cone sulfuric acid (70mL) and the mixture was heated at 70°C for 16h, The mixture was cooled to ~-40°C, water (5mL) was added and the mixture was heated at 70°C for further 24h. After cooling the was taken to pH6 by addition of NaOH and the mixture was extracted with 1: 1 EtOAc:THF and the combined organic phase dried (MgS0 ). The solvent was removed in vacuo to give the title compound: RT ~ 2.63mm; m/z (ES+) = 246.1 [ + H]+. Preparation 48: 4-(4-CMorob k add
Figure imgf000045_0002
Using the method outlined in Preparation 47, 4-(4-c orobenzyl)pyridine-2- carbonitrile (Preparation 46) was converted to the title compound: RT = 2.55min; m z (ES+) = 248.0 [ + H]+.
Preparation 49: iV-Methoxy-V~methyIisophthaiamic acid methyl ester
Figure imgf000045_0003
To isophthalic acid monomethyl ester (5g, 27.7mmol) in DCM (50mL) at 0°C was added oxalyl chloride (2.96mL, 33,3mmol) followed by DMF (0.5mL) dropwise. The mixture was wanned to rt and when effervescence ceased NEt3 (11.6mL, 83.2mmol) and then O, iV-dimethylhydroxylamine hydrochloride (4.06g, 41.6mmol) were added. After 2h DCM was added, the organic phase was washed with sat Na2C03, 1 M HCl, dried (MgS0 ) and the sol vent was removed in vacuo. The residue was purified by column chromatography (35:65 EtOAc :Hexane) to give, after removal of the solvent in vacuo, the title compound: RT = 2.62min; m/z (E8") - 224.2 [ + H]+,
Figure imgf000046_0001
To N-methoxy-N-methylisophthalamic acid methyl ester (Preparation 49) (5g, 22,4mmol) in THF (50mL) at -78°C was added 4-fluorophenyl magnesium bromide (1M TH , 33.6mL, 33,6mmoI) dropwise. After lh at rt the mixture was poured into EtOAc, washed with sat. NH4CI, brine and dried (MgS0 ). The solvent was removed in vacuo to give the title compound: RT = 3.65min; m z (ES+) = 259.2 [M + Ή. .
Figure imgf000046_0002
To 3-(4-fluorobenzoyi)benzoic acid methyl ester (Preparation 50) (500mg,
1.94mmol) in TFA (lOmL) was added triethylsilane (1.55mL, 9.68mmol). After 16h EtOAc was added, the mixture was washed with water, brine, dried (MgS04) and the solvent was removed in vacuo. The residue purified by column chromatography (35:65 EtOAc:Hexane) to give, after removal of the solvent in vacuo, the title compound: RT = 3.97min; m/z (ES+) " 245.2 \M H ]'\
Preparation 52: 3~[(4-FlHoroplsessyI)liydroxyi¾ethyl]b85Szok add methyl ester
Figure imgf000046_0003
To 3-(4-fluorobenzoyl)benzoic acid methyl ester (Preparation 51) (500mg,
1.94mmol) in MeOH (lOmL) was added NaBH4 (73mg, 1.94mmol). After 1.5h water (lOmL) was added and the mixture extracted with EtOAc, The organic phase was washed with water and the combined aqueous phase extracted with EtOAc. The combined organic phase was dried (MgS04) and the solvent was removed in vacuo. The residue was purified by column chromatography (20:80 EtOAc;Hexane) to give, after removal of the solvent in vacuo, the title compound: RT = 3.32min; m/z (ES+) ::: 243.2 [M- H20] +.
Preparation 53; 3~[2-(4-FiMoroplies !)il,31ditliiolan-2-yl]beMzoic acid methyl ester
Figure imgf000047_0001
Using the method outlined in Preparation 41, 3 -(4-fluorobenzoyl) benzoic acid methyl ester (Preparation 50) was converted to the title compound: RT = 4.24min: m/z (ES+) :::: 335.2 [M+ Preparation 54: 3- f Difl u or o(4-flu o ropheny l)raethyl] benzoic acid methyl ester
Figure imgf000047_0002
Using the method outlined in Preparation 42, 3~[2-(4-fluorophenyi)[l,3]dithiolan- yljbenzoic acid methyl ester (Preparation 53) was converted to to the title compound: RT 3.95min; m/z (ES+) = no ionization.
Preparation 55: 3-(4-FluQrobeHzoyi}beiizGic acid
Figure imgf000047_0003
To 3-(4-fluorobenzoyl)benzoic acid methyl ester (Preparation 50) (400mg,
1.55mmol) in THF (5mL) was added 1M NaOH (3mL). After 16h at rt, Et20 was added, the mixture was extracted with 2M NaOH and the organics discarded. The combtned aqueous phase was acidified with cone HCl, extracted with EtOAc and the organic phase dried
(MgS04). The solvent was removed in vacuo to give the title compound: RT = 3.15min; m/z (ES+) = 245.1 [M ' H] ' . Preparation 56: 3-[(4-F!uoFop¾eHyl)hydroxymethyljfoe ¾oie acid
Figure imgf000047_0004
To 3-[(4-fluoiOphenyl)hydroxymethyl]benzoic acid methyl ester (Preparation 52) (444mg, 1.71mmol) in MeOH (5mL) was added IM NaOH (3mL). The mixture was heated at 70°C for 2fa and then cooled to rt. The mixture was acidified with 2M HCl, extracted with EtOAc and the organic phase was washed with water. The combined aqueous phase was extracted with EtOAc before the combined organic phase was dried (MgS04) and the solvent was removed in vacuo to give the title compound: RT = 2.90min; m/z (ES+) = 229.2 [M—
-(4-Fluorohenzyl)henzoic acid
Figure imgf000048_0001
Using the method outlined in Preparation 55, 3-(4-fluorob£snzyl)benzoic acid methyl ester (Preparation 51) was converted to the title compound: RT = 3.50min; m/z (ESr) === no ionization. Preparation 58:
Figure imgf000048_0002
Using the method outlined in Preparation 55, 3-[difiuoro(4-fluorophenyl)methyl]- benzoic acid methyl ester (Preparation 54) was converted to the title compound: RT = 3.57mm; m/z (ES+) = no ionization.
Preparation 59: 3-(4-Fluorophenylamino)benzoic add methyl ester
Figure imgf000048_0003
To 3-bromobenzoic acid methyl ester (Ig, 4.65mmol) in PhMe (20mL) was added 4 fluorophenylamine (0.44mL, 4.65mmol), BINAP (217mg, 0.35mmol), CS2CO3 (1.52g, 4.65mmol) and Pd(OAc)2 (52mg, 0.23mmol). The mixture was degassed, placed under Ar and heated under reflux for 16h. EtOAc and water were added, the mixture was filtered through celite and the residue washed with EtOAc. The organic phase was washed with water and the combined aqueous phase extracted with EtOAc. The combined organic phase was dried (MgS04) and the solvent was removed in vacuo to give the title compound: RT : 3.75min; m/z (ES+) - 246.2 [M+ H] ' .
Preparation 60: 3 (4~FluGFoph rayl)metfeyIamIi8o] benzoic acid methyl ester
Figure imgf000049_0001
Using the method outlined in Preparation 59, 3-bromobenzoic acid methyl ester and (4-fluorophenyl)methylamme were converted to the title compound: RT = 4.05mm: m/z (ES+) = 260.2 [M+ H]+. Preparation 61: 3~(4 ¾orophesryiamisiG)beHZi>ie acid
Figure imgf000049_0002
To 3-(4-fluorophenylatnmo)benzoic acid methyl ester (Preparation 59) (986mg, 4.02mmol) in MeOH (40mL) was added 1M NaOH (8mL, Smmol). The mixture was heated for Ih at 60°C before the solvent was removed in vacuo. The residue was diluted with EtOAc, acidified to pH 5-6 with 1 M HCl, extracted with EtOAc and the combined organic phase dried (MgS04). The solvent was removed in vacuo to give the title compound: RT = 3.34mm; m z (E8+) = 232.1 [M+
Figure imgf000049_0003
Figure imgf000049_0004
Using the method outlined in Preparation 61, 3~[(4~
fluorophenyl)methylamino] benzoic acid methyl ester (Preparation 60) was converted to the title compound: RT = 3.52min; m z (ES+) === 246.2 [M + H]+. FreparatioH 63: 6-(4-F oroplieMoxy)pyridiMe-2-earboiiItrik
Figure imgf000049_0005
To 6-chloropyridine-2-carbonitrile (LOg, 7.22mmol) in DMF (40rnL) was added K2CO3 (1.50g, lO.Smmol) and 4-fluorophenol (0.81g, 7.22mmol). The mixture was heated at 100°C for 16h before the solvent was removed in vacuo. The mixture was partitioned between EtOAc and water, the aqueous phase re-extracted with EtOAc, the combined organic phase was dried (MgS04) and the solvent removed in vacuo. The residue was purified by column chromatography (25:75 EtOAc :Hexa.ne) to give, after removal of the solvent in vacuo, the title compound: RT = 3.52min; m/z (ES+) ==: 215.1 [M+ H]+.
Figure imgf000050_0001
Using the method outlined in Preparation 63, 2~ehloroisonicotinonitrile and 4- fluorophenol were converted to the title compound: RT = 3.44min; m z (ESr) = 215.1 [M + H]+,
Preparation 65; 2-(4-FfeorepheB add
Figure imgf000050_0002
To 2-(4-fluorophenoxy)isonicotinonitrile (Preparation 64) (1.68g, 7.85mmol) in water (25mL) and EtOH (5mL) was added NaOH (1.57g, 39.2rnrnol). The mixture was heated under reflux for 16h before the EtOH was removed in vacuo. DCM was added, the organic phase discarded and the aqueous phase was acidified with cone HQ. The precipitate was filtered off to give, after air drying, the title compound: RT ;;; 2.95rnin; m/z (ES+) =
Preparation 66: 6-(4-FIuorophesioxy)pyridii5e-2-carboxy!ic acid
Figure imgf000050_0003
Using the procedure outlined in Preparation 65, 6-(4-fluorophenoxy)pyridine-2 carbonitrile (Preparation 63) was converted to the title compound: RT ~ 2„97mm; m/z - 234.1 [ + H]+. Preparation 67: 5-(4-Fluorophenoxy)nicotinic acid
Figure imgf000051_0001
To 5-bromonicotinonitrile (1.83g, lO.Ommol) in DMSO (lOmL) under Ar was added 4-fluorophenol (1.5g, 13.3mmol) and NaH (60% in mineral oil, 0,57g, 14.3mmol) before the mixture was heated at 120°C for 16h. After cooling EtOAc was added, the organic phase was washed with brine and dried (MgS04). The solvent was removed in vacuo to give 5-(4- fluorophenoxy)nicotinonitrile. To 5~(4-fiiiorophenoxy)nicotinonitrile in EtOH (5mL) and water (25mL) was added NaOH (2.0g, SO.Qmmol). The mixture was heated under reflux for 16h before the EtOH was removed in vacuo. DCM was added, the organic phase discarded and the aqueous phase was acidified with cone HC1. The precipitate was filtered off to give after air drying the title compound: RT = 2.80min; m z (ES+) = 234,1 [M+ H]' .
Preparation 68; 5~(4-Flsioropheeoxy)~l~oxyiiicotmoi8itrlle
Figure imgf000051_0002
To 5-(4-fluorophenoxy)nicotinonitrile (Preparation 67) (2g, 9.3mmol) in DCM
(50mL) was added ra-CPBA (2,74g, 1 l .lmmoL). After 2h at rt ?n-CPBA (2.74g, 1 l .lmmoL) was added, the mixture heated under reflux for 3h, then cooled and the solvent was removed in vacuo. The residue was purified by column chromatography (3:7 EtOAc:Hexane) to give, after removal of the solvent in vacuo, the title compound: RT = 2.63min; m/z (ES+) = 231.0 [ + H]+.
Preparation 69s 2-C ore~5~(4~H;aoropheBoxy)sketinemtrile and 6-CM(iro-5~(4~ fluorophenoxy)nicotinoiiitrile
Figure imgf000051_0003
A mixture of 5-(4-fluorophenoxy)-l-oxynicotinonitrile (Preparation 68) (2.0g, 9.6mmol) and phosphorous oxychloride (15mL) was heated at 120°C for 3h. The mixture was cooled, added slowly to water before being basified with 2N NaOH, extracted with EtOAc and then the solvent was removed in vacuo from the organic phase. The residue was purified by column chromatography (1:9 EtOAc:Hexane) to give, after removal of the solvent in vacuo, the title compounds: RT = 3.52min; ro/z (ES+) =:: 249.0 [M+ H]+.
Figure imgf000052_0001
Using the method outlined in Preparation 63, 4-chloropyridine-2-carbonitrile and - fluorophenol were converted to the title compound: RT= 3.30min; m/z (E8+) = 215.1 [M- H]+. ion 71°, 4~(4~Fluor xylic add
Figure imgf000052_0002
Using the method outlined in Preparation 65, 4-(4-fluorophenoxy)pyridine-2- carbonitrile (Preparation 70) was converted to the title compound: RT= 2.15min; m/z (ES4) :
Figure imgf000052_0003
Preparation 72; 2-ABiino-S-(4-fliioroplieHOxy)beiizoic add methyl ester hydrochloride
Figure imgf000052_0004
To 5-hydroxy-2-mtrobenzoic acid methyl ester (2.0g, lOmmol) and 4-lluorophenol (1.14g, lOmmol) in DMSO (20mL) was added powdered NaOH (0.4 lg, lOmmol). After 1.5h AcOH (1.3mL), DCM and water were added, the layers were separated and the aqueous phase was extracted with DCM. The combined organic phase was washed with water, brine, dried (MgS0 ) and the solvent was removed in vacuo. The residue was purfied by column chromatography (DCM) to give, after removal of the solvent in vacuo, 5-(4-fluorophenoxy)- 2-nitro benzoic acid methyl ester. A solution of 5-(4-fluorophenoxy)-2-nitrobenzoic acid methyl ester (5g. 17.2mmol) in MeOH (221mL) was passed through an H-Cube (lmL min) fitted with a Pd C Cat-Cart using full hydrogen mode at ambient pressure and temperature. The solvent was removed in vacuo before the residue was dissolved in EtOAc (200mL) and washed with IN HCl. 4N HCl in dioxane was added to the organic phase to give a precipitate which was filtered off, washed with EtOAc and air dried to give the title compound: RT~ 3.79min; m/z (Ε8+) = 262.1 [M + H]+. Preparation 73; 2~Ami¾o~5~(4-fls add
Figure imgf000053_0001
To 2~amino-5-(4-fluorophenoxy)henzoic acid methyl ester hydrochloride
(Preparation 72) (298mg, l .Ommol) in MeOH (15mL) and water (lOmL) was added NaOH (240mg, β.θηΐίηοΐ). The mixture was heated to 80°C for Ih then cooled to rt, AcOH (lmL) added and the solvent was removed in vacuo. The residue was partitioned between H20 and EtOAc and the aqueous phase was extracted with EtOAc. The combined organic phase was washed with brine, dried (MgS04) and the solvent was removed in vacuo to give the title compound: RT- 3.21min; m z (ES+) = 248.0 [M + lif . Preparation 74; 5-(4-Fhs©repMeeoxy)-2-me£lhyIaminob6&iZQie acid methyl ester
Figure imgf000053_0002
To 2-ammo-5-(4-fluorophenoxy)benzoic acid methyl ester hydrochloride
(Preparation 72) (512mg, 1.7mmol) in DCE (5mL) was added DIPEA (360μΕ, 2.1mmol), formaldehyde (37% in water, 210μΕ, 2.6mmol) and after 5 min NaBH(OAc)s (51 lmg, 2.4mmol) was added. After 16h formaldehyde (37% in water, 210,uL, 2.6mmol) and
NaBH(OAc)3 (51 lmg, 2.4mmol) were added. After a further 24h water (lOmL) was added and the organic solvent removed in vacuo, EtOAc was added, the phases were separated and the solvent was removed in vacuo from the organic phase. The residue was purified by column chromatography (1 :9 EtOAc:Hexane) to give, after removal of the solvent in vacuo, the title compound: RT= 4.09mm; m/z (ES+) - 276.2 [M + iff.
Preparation 75: 5-(4-FlEor©pheH0xy)-2-methyIamisofoeezcHe acid
Figure imgf000054_0001
A mixture of 5-(4-fluorophenoxy)-2-metliylaminobenzoic acid methyl ester (Preparation 74) (163mg, 0.59mmol), MeOH (lOmL), water (6mL) and NaOH (474mg, 1 .9mmol) was heated at 80°C for 2h. After cooling the organic solvent was removed in vacuo, 1M HC1 was added to achieve pH-6 and a precipitate was filtered off. The residue was dissolved in EtO EtOAe, dried (MgS04) and the solvent was removed in vacuo to give the title compound: T= 3.59min; ni/z (ES÷) = 262.2 [M+ H]+.
Preparation 76: 2-Amino-5-(4-fluorophenoxy)nicotinic add methyl ester
Figure imgf000054_0002
To 2-aminonicotimc acid methyl eater (5.5g, 36.2mmol) in DMF (70mL) was added N-iodosuccinimide (9.8g, 43.7rmnol). After 16h the mixture was poured into sat. sodium thiosulfite solution and then extracted with Et20. The organic phase was washed with water, brine, dried (MgS04) and the solvent was removed in vacuo to give 2-amino-5-iodonicotinic acid methyl ester. To 4-fluorophenol (2.4g, 21.6mmol) in dioxane (50mL) was added
CS2CO3 (6g, 25.2mmol) and the mixture was heated to 50°C. After 20min Cul (0.56g, 3.0mmol) and 2-ammo-5-iodonicotrriic acid methyl ester (2g, 7.2mmol) were added and the mixture heated under reflux for 16h. After cooling the solvent removed in vacuo, the residue was partitioned between EtOAc and 4N HQ, the organic phase was extracted with 6N HC1 and the organic phase discarded. The combined aqueous phase was basified with NH4OH and re-extracted with EtOAc. The organic phase was dried (MgS04) and the solvent was removed in vacuo. The residue was purified by column chromatography (1 :3
EtOAcrHexane) to give, after removal of the solvent in vacuo, the title compound: RT= 3.30min; m/z (ES+) = 263.2 [M+ Iff".
Preparation! 77: 2-Amiso-5-(4-f!aoropheiioxy)siic0tii-Ic add
Figure imgf000054_0003
To 2-ammo-5-(4-fluorophenoxy)fiicoiinie acid methyl ester (Preparation 76) (125mg, 0,48irmiol) in MeOH (lOmL) and water (5mL) was added LiOH (87mg, 3.8mmol). After 6h the solvent was removed in vacuo and the residue was partitioned between EtOAc and water.. The organic phase was discarded, the aqueous phase was neutralised and extracted with EtOAc, The organic phase was dried (MgS04) and the solvent was removed in vacuo to give the title compound: RT= 2,47min; m/z (ES+) == 249.1 [M+ H]+,
Preparation 78: (^)~3-({[4-(4-FliioropheHoxy)pyridme-2-carbonyl]ami!io}methyl)- plperidlne-l-earboxy!ie ac
Figure imgf000055_0001
Using the method outlined in Preparation 27, ( ?)-3-ammomethylpiperidine-l- carboxylic acid iert-butyl ester and 4-(4-fluorophenoxy)pyridine-2-carboxylic acid
(Preparation 71) were converted to the title compound: RT ===: 3.89min; m z (ES+) = 430.4
Preparation 79: 4-(4~F!5i roplieEoxy)pyridiEe-2-earboxylIe acid ((S)-l-piperidin-3- ylmethyi)amide trifluoroacetate
Figure imgf000055_0002
To (R)-3 -( { [4-(4-fluorophenoxy)p Tidine-2-carbonyl]amino } methyl)piperidine- 1 - carboxylic acid tert-butyl ester (Preparation 78) (1.3g, 3.3mmol) in DCM (40mL) was added TFA (1 OmL). The mixture was stirred for 16h before PhMe (SOmL) was added and the solvent was removed in vacuo, PhMe (50mL) was added and the solvent was removed in vacuo to give the title compound: RT = 2.50min; m/z (ESr) = 330.3 [M+ H]+, Preparation 80: 2-({[4-(4~F!Moropheiioxy)pyridiHe-2- carboByl]ami¾o}methyl)morplioHne-4-carboxylic acid fert-butyl ester
Figure imgf000055_0003
Using the method outlined in Preparation 32, 4~(4-fluorophenoxy)pyridirie-2- carboxyiie acid (Preparation 71) and 2-aminomethylmorpholine-4-carboxylic acid tert-butyl ester were converted to the title compound: RT = 3,79min; m/z (ES+) = 432.4 [M + H]"\ Preparation 81: 4-(4-FIu0r©phenexy)pyridliie~2~earboxylie acid (morphoiin-2- ylniethyl)-amide
Figure imgf000056_0001
Using the method outlined in Preparation 79, 2-( {[4-(4-tluorophenoxy)pyridine-2- c.arbo yl]amino}rttethyl)moφhoίine-4-car oxylic acid tert-hutyl ester (Preparation 80) was converted to the title compound: RT = 2.40xnin; m/z (ES+) = 332,3 [M + H]+.
Preparation 82: 3-(l -{ [4-(4-Fiuorophenoxy)pyridme-2- carbo5syi|amino}etliyl)pip ster
Figure imgf000056_0002
Using the method described in Preparation 32, 3-(l-aminoethyl)piperidme~l - carboxylic acid tert-hutyl ester (Preparation 19) and 4-(4-fluorophenoxy)pyridine-2~ carboxylic acid (Preparation 71) were converted to the title compound: RT::: 4.32min; m/z
Figure imgf000056_0003
Preparation 83: 4-(4-F!iiorophtieioxy)pyridiiie-2-carboxy c acid (l-piperldin-3~ykihyl)~ amide
Figure imgf000056_0004
Using the method outlined in Preparation 79, 3-(l-{[4-(4-fluorophenoxy)pyridine- carbonyl]ainino}ethyl)piperidine-l -carboxylic acid tert-butyl ester (Preparation 82) was converted to the title compound: RT= 2.43min; m/z (ES+) = 344.2 [M+ H] r.
Preparation 84 : 3-(4-F oropbenoxy)- V-pheKyl-A'~piperidin-3-ylmethylbeiizamide
Figure imgf000057_0001
To 3-formylpiperidine-l-carboxylic acid iert-butyl ester (1.Og, 4.7mmol) in MeOH (20mL) was added phenylamine (416mg, 4,5ramol) and 4A molecular sieves. The mixture was heated under reflux for 16h, cooled to rt and NaBH4 (537mg, H.lmmol) was added. After 3h at rt the mixture was filtered, the residue washed with MeOH and the solvent was removed in vacuo. The residue was purified by column chromatography (1 :9
EtOAc:Hexane) to gi e, after removal of the solvent in vacuo, 3- phenylaminomethylpiperidme-I -carboxylic acid iert-butyl ester. Using the method outlined in Preparation 27, 3-ph.enylaminomethylpiperidine-l-carboxylic acid teri-butyl ester and 3- (4-fluorophe.noxy)benzoic acid were converted to give 3-({[3-(4- fluorophenoxy)benzoyl]phenylamino}methyl)piperidine-l-carboxyiic acid tert-buiy) ester. To 3 -( { [3 -(4-fluorophenoxy)benzoyl]phenylamino } methyl)piperidine- 1 -carboxyl ic acid tert- butyl ester (215mg, 0.43mmol) in DCM (20mL) was added TFA (!OmL) and after 15min solvent was removed in vacuo. The residue was purified by prep HPLC and then an SCX column (washing with MeOH and elution with NH3.MeOH) to gi ve, after removal of the solvent in vacuo, the title compound: RT=== 2.82min; m/z (ES+) = 405.2 [M+ H]+. (3-fluoro~l~
Figure imgf000057_0002
To a solution of 4-(4-fluorophenoxy)pyridine-2-carboxyIic acid (Preparation 71) (155mg, 0.57mmol) in DMF (5mL) was added EDCI (136mg, 0.72rnmol), HOBt (97mg, 0.72mmol) and NEt? (G,2mL, 1.43mmol). After 0.5h C-(3-fluoro-l -isopropylpiperidin-3-yl)- methylamine (Preparation 13) (50mg, 0.29mrraol) was added and the mixture was stirred at 50"C for 16h. The solvent was removed in vacuo and the residue dissolved in EtOAc. The organic phase was washed with water, sat. Na2CC«3, dried (MgS04) and the solvent was removed in vacuo. The residue was purified by prep HPLC to give, after neuraiisation with MP-carbonate in DCM and removal of the solvent in vacuo, the title compound: RT = 2.50min: m/z (ES4) = 390,4 [M+ H]+. Example 2: 4-(4~FI¾iorophenoxy)pyridine~2~earboxyIic acid ((S)~3-fiuoro-l-isopropyl- piperidin-3-ylmeihyl)amide
Figure imgf000058_0001
Purification by chiral prep HPLC (100:0.1 MTBE:DEA, ! 5mL/min) (RT on ehiral columnl 6.3mm) of Example 1 gave, after removal of the solvent in vacuo, the title compound: RT = 2.50min m/z (ES+) = 390.4 \M+ H]+.
Using the method outlined in Example 1, Examples 3-16 were prepared from the corresponding acid (Preparation X in Table 2) and the appropriate amine:
Table 2
Figure imgf000058_0002
Figure imgf000059_0001
acid (1-
Figure imgf000060_0001
Commercial
Example 17: 4-(4-FIuoroph¾n xy)pyridine-2-earboxylic add ( 1 -isopr op lpiperi di n-3- ylnieilsy!)amide
Figure imgf000060_0002
To a solution oi' 4-(4-il orophenoxy)pyridine-2-earboxylic acid (Preparation 71) (250nig, 1.07mmol) in DMF (5mL) was added HATU (812mg, 2.14mmol) and DIPEA (0.52mL). After 0.5b C-(l-isopropylpiperidin-3-yl)methylainine (175mg, 1.12mmol) was added and the mixture stirred at rt for 16h. The solvent was removed in vacuo and the residue dissolved in EtOAc. The organic phase was washed with water, sat. Na2CC>3, brine, dried (MgS04) and the solvent was removed in vacuo. The residue purified by column chromatography (1 :8: 1 NH3:MeQH:DCM) followed by SCX to give, after removal of the solvent in vacuo, the title compound: RT :== 2.53min; m/z (ES+) = 372.3 [M + H]+. Further purification of Example 17 using chiral prep HPLC (100:0,1 MTBE:DEA, 15mL/min) gave Examples 18 (RT on chiral column 25.6min) and 19 (RT on chiral column 29.5min): Example 18: 4-(4-Fluorop!ieiioxy)pyridiiie~2~€arboxylie acid ((sS)-l-isopropylpiperidm- 3-ylmethy!)amide
Figure imgf000061_0001
RT = 2.49mm; m/z (ES+) = 372.3 [M + H]+. Example 19: 4-(4-FIuoropheHoxy)pyridme~2~earboxylk acid ((^)-l-isopropylpiperidia- 3-yimeihyI)amide
Figure imgf000061_0002
RT === 2.48mm; m/z (ES ) = 372.3 [ + H]+,
Alternatively using the method outlined in Example 35, 4~chloropyridine-2- carboxylic acid ((i?)-l -iaopropylpiperidsn-3-ylinethyl)arnide (Preparation 31) and 4- fluorophenol were converted to the title compound: RT - 2,61min; m/z (ES*) ~ 372.3 [M+
Example 2Θ: 4-(4~Fiuorophenoxy)pyridiiie-2-carboxylic acid (l-isopropylpiperidi¾~3~ ylmcthyl)(2-phenoxyethyl)amide
Figure imgf000061_0003
Using the method outlined in Example 17, (l-isopropylpiperidin-3-ylmethyl) (2-phenoxyethyl)amine (Preparation 26) and 4-(4-fluorophenoxy)pyridine-2~carboxylic acid (Preparation 71) were converted to the title compound: RT = 3,09min; m/z (ES+) = 472,2 [M
+ H]T. Example 21: 4~Benzyloxypyridine-2-carboxylic add (l-isopropyipIperidta-3-ylmethyl)~ amide
Figure imgf000062_0001
To a solution of phenylmethanol (37mg, Q.34mmol) and 4-chloropyridine-2- carboxylie acid ( 1 -isopropylpiperidin-3 -ylmethyl)amide (Preparation 27) (lOQmg,
0.34mmol) in DMSO (2mL) were added NaH (60% suspension in mineral oil, 34mg,
0.85mmol) and potassium acetate (83mg, 0.85minol) at rt. The mixture was heated at 65°C for 16h before cooling to rt. Water (lOmL) was added, the mixture was extracted with EtOAc before the combined organic phase was dried (MgSQ4) and the solvent was removed in vacuo. The residue was purified by prep HPLC to give, after neutralising with MP- carbonate in DCM and removal of the solvent in vacuo, the title compound: RT = 2.45min; m/z (ES÷) = 368.4 [M+ H]+.
Example 22: 4~(4.4-DimethyIcycioliexyloxy)pyridiBe-2-£arboxyiic acid (l-lsopropyl plper i -3~ylmethyl)amide
Figure imgf000062_0002
Using the method outlined in Example 21, 4-chloropyridine-2-carboxylic acid (1- isopropylpiperidin-3-ylmethy].)amide (Preparation 27) and 4,4-dimethylcyclohexanol were converted to the title compound: RT = 2.70min; m/z (ES+) - 388.4 [M ÷ H]+. Example 23: 4-Phenoxypyridine~2~carboxy]ic add (l-isopropylpiperidin-3- ylmethyl)aimde
Figure imgf000062_0003
To a solution of phenol (30μΙ„, G,34mmol) and 4-chloropyridine-2-carboxylic acid (1- isopropyipiperidin-3~ylmethyl)amide (Preparation 27) (lOOmg, 0.34mmol) in DMSO (2mL) were added NaO'Bu (65mg, 0.68mmol) and potassium benzoate (108mg, 0.68mmol). The mixture was heated at 65°C for 16h before cooling to rt and adding water (5mL). The mixture was exti'acted with EtOAc before the combined organic phase was washed with brine, dried (MgS04) and the solvent was removed in vacuo. The residue was purified by prep HPLC to give, after neutralising with MP-carbonate in DCM and removal of the solvent in vacuo, the title compound: RT = 2.43min; m/z (ES') = 354,3 [M + H]+.
Example 24: 4-Cyclohexyloxypyridine-2-carboxylic acid (l-isopropylpipersdin-:
Diethylamide
Figure imgf000063_0001
Using the method outlined in Example 23, 4-chloropyridine-2-carboxylic acid (1 - isopropylpiperidin-3-ylmethyl)amide (Preparation 27) and cyclohexanol were converted to the title compound: RT = 2.47min; m/z (ES4) = 360.4 [M + H]+.
Example 25: 4-(3-Fluorophenoxy)pyridine-2-carboxylic add (l-isopropylpiperidiii~3-yi- methyl)amide
Figure imgf000063_0002
To a solution of 3-fluorophenol (57mg, O.Slmmol) in DMF (1.5mL) at rt was added
K2C03 (23mg, 0.17mmol) and KO'Bu (114mg, 1.Olmmol). After 2h 4-chloropyridine-2- carboxylic acid (l-isopropylpiperidin-3-ylmethyl)amide (Preparation 27) (lOOmg,
0.34mmol) in DMF (Iml.) was added and the mixture was heated at 80°C. After 16h KO'Bu (i 14mg, l.Ommol) was added and the mixture heated for a further 24h. The mixture was cooled to rt, water (8mL) added and the mixture was extracted with EtOAc, The organic phase was dried (MgS04) and the solvent was removed in vacuo. The residue was purified by prep HPLC to give, after neutralising with MP-carbonate in DCM and removal of the solvent in vacuo, the title compound: RT :::: 2,48mm; m/z (ES*) = 372,3 [M + K . Using the method outlined in Example 25, Examples 26-33 were prepared from the corresponding chloropyridineamide (Preparation X in Table 3) and the appropriate alcohol:
Table 3
Figure imgf000064_0001
Figure imgf000065_0001
Exam pie 34: 3-(4~F!iioropheno¾ y)~A~(l~isopropyIpiperl diii-3 -ylmethy [)-4-mef¾yl- beiszamide
Figure imgf000065_0002
To 3-bromo-N-(l-isopropylpiperidin-3-ylmethyl)-4-methylbenzamide (Preparation
32) (175mg, 0.50mmol) in dioxane (2mL) was added 4-fluorophenol (83mg, 0.70mmol), Cul (l Omg, O.OSmmol), dimethylaminoacetic acid hydrochloride (15mg, O. lSmmol) and CS2CO3 (323mg, LOinmol). The mixture was heated in a sealed tube under Ar at 1 10°C for 16h. After cooling water (lOmL) was added and the mixture extracted with EtOAc. The combined organic phase was washed with brine, dried (MgS04) and the solvent was removed in vacuo. The residue was purified by prep HPLC to give, after neutralising with MP-carbonate in DCM and removal of the solvent in vacuo, the title compound: RT = 2.59min; m/z (ES+) =
Figure imgf000065_0003
Example 35: 4-(4~FIuoroplie8ioxy)~6-iiiethy!pyridise~2~carboxylic add ((JQ-l-isopropyl- piper iB-3-ylmetliyI)amide
Figure imgf000066_0001
To 4-chloro-6-metliylpyridine-2-carboxylic acid ((R)- 1 -isopropylpiperidin-3 - ylmethyl)-amide (Preparation 33) (43mg, 0.14mmol) in DMF (2ml.) was added CS2CO3 (137mg, 0.42mmol) and 4-fluorophenol (47mg, 0.42mmol), The mixture was heated at 100°C for 16h before CS2CO3 (137mg, 0.42mmol) and 4-fluorophenol (47mg, 0.42mmol) were added and the mixture heated at 120°C for 64h. CS7.CO3 (137mg, 0.42mmol) and 4- fluorophenol (47mg, 0.42mmol) were added and the mixture heated at 120°C for a further 24h. The mixture was cooled, EtOAc added and the organic phase washed with water and sat, Na2C03. The combined aqueous phase was extracted with EtOAc, the combined organic phase was dried (MgS04) and the solvent was removed in vacuo. The residue was purified by prep HPLC to give, after neutralising with MP-carbonate in DCM and removal of the solvent in vacuo, the title compound: RT = 2.65min; m z (ES+) = 386.2 [M+ H .
Using the method outlined in Example 35, Examples 36-41 were prepared from the corresponding chloropyridine amide (Preparation X in Table 4) and the appropriate phenol: Table 4
Figure imgf000066_0002
Figure imgf000067_0001
ylmethyl)amide
Figure imgf000067_0002
o 5-(4-fluorophenoxy)nicotinic acid (0.18g, 0.65mmol) in DCM (2,5mL) and THF were added oxalyl chloride (0.16mL, 1.3mmol) and DMF (1 drop). The mixture was heated at 40°C for 5h before the solvent was removed in vacuo. The residue was dissolved in THF (2,5mL) and added to C-(l -isopropylpiperidin-3-yl)methylamme (78mg, O.Smmol) in TfiF (2mL). After 16h DCM was added and the organic phase washed with 1M NaOH. The aqueous phase was extracted with DCM and the combine organic phase was washed with brine, dried (MgS04) and the solvent was removed in vacuo. The residue was purified by prep HPLC to give, after removal of the solvent in vacuo, the title compound; RT = 2.38rnin; m/z (ES+) = 372.3 [M+ H]+.
Example 43: 5-(4-Fliioroph eihyl)isicotiBamide
Figure imgf000068_0001
Using the method outlined in Example 42, 5-(4-fluorophenoxy)nicotimc acid and C- (l-propylpiperidin-3-yl)methylamine were converted to the title compound: RT = 2.45min; m/z (ES+) = 372.3 [ + H]+. Using the method outlined in Example 42, with the exception that purification was achieved using SCX (washing with MeOH and elution with NHj MeOH), Examples 44-47 were prepared from 3-(4-fluorophenoxy)benzoic acid and the corresponding amine (Table 5):
Figure imgf000068_0002
Figure imgf000069_0001
-(4-FlHoropheBoxy)-iV-(l-isopropyIpiperIdin~3~ylmethyI)~2-inei oxy~
Figure imgf000069_0002
To 5-iodo-iV-(l-isopropylpiperidin-3-ylmethyl)-2-methoxybenzamide (Preparation
34) (200mg, 2,0mmol) in dioxane (2mL) was added Cul (22mg, 0.2mmol), 3,4,7,8- tetramethyl-l ,10-phenanthroline (94mg, 0.4mmol), CS2CO3 (975mg, 3.0mmol) and 4- fluorophenol (336mg, 3.0mmol). The mixture was degassed with Ar and heated at 110°C in a microwave for O.Sh. The solvent was removed in vacuo and the residue was purified by prep HPLC. The residue was treated with MP-carbonate and then HCl in dioxane. Precipitation of an impurity using DCM/Et20 gave, after removal of the solvent in vacuo, the title
compound: RT - 2.86min; m/z (ES+) = 401.4 [M + H]+.
Example 49; 4-(4-Fli_orophesoxy)pyri iiBe-2-earboxylic acid ((i?)-l- €yelope tylpiperidin-3-yls¾etli l)am de
Figure imgf000069_0003
To 4-(4-fluorophenoxy)pyridine-2-carbox lic acid ((5 -l-piperidin-3-ylmethyl)amide trifluoroacetate (Preparation 79) (70mg, 0.16mmol) in MeCN (3ml.) were added
bromocyclopentane (47μΕ, 0.47mmol) and .2CO3 (65mg, 0.47mmol). The mixture was heated at 60°C for 16h and then cooled to it. The mixture was partitioned between EtOAc and water, the organic phase was dried (MgS04) and the solvent was removed in vacuo. The residue was purified by prep HPLC to give, after removal of the solvent in vacuo, the title compound: T ~ 2.20min; m/z (ES+) = 398.3 [M+ H]+.
Using the method outlined in Example 49, Examples 50-58 were prepared from the appropriate amine (Preparation X in Table 6) and the corresponding alkylating agents:
Table 6
Figure imgf000070_0001
Figure imgf000071_0001
ylmethyl)amide
Figure imgf000071_0002
To qumolin-5~ol (85mg, 0.58mmol) in NMP (2mL) was added KO¾u (1M in THF) (0.4mL, 0,4mmol) and 4-chioropyridine-2-carboxylic acid ((iQ-l~isopropylpiperidm-3- ylmethyl)amide (Preparation 31 ) (58mg, G.20mmol). The mixture was heated in a microwave at 120°C for 2h before cooling to rt. DCM and water were added, the organic phase was then purified by SCX (washing with MeOH and elation with NHyMeQH) and the solvent was removed in vacuo. The residue was purified by prep HPLC to give, after neutralising with MP-carbonate in DCM and removal of the solvent in vacuo, the title compound: RT = 2.32min; m/z (ES+) = 405.2 [M + U]
Using the method outlined in Example 59, Examples 60-72 were prepared from 4- chloropyridme-2-carboxylic acid ((/?)- l-isopropylpiperidin-3-ylmethyl)amide (Preparation 31) and the corresponding phenol (Table 7):
Table 7
Figure imgf000072_0001
.
I Ex 1 Structure | Name m/z (ES+)
(min)
i80propylpiperidin-3- ylmethyl)aniide
4~(Quinolin-7- i yloxy)pyridine~2"Carboxylic
405.2 [M +
64 acid ((R)-l- 2.17
ιιγ isopropylpiperidm-3 - ylmethyl) amide
4~(Quinolin-8- yloxy)pyridine-2-carboxylic
405.2 [M+
65 acid ((ϋ!)-1- 2.17
H]+ isopropyipiperidin-3 - ylmethyl) amide
4-(Quinolin-6- yloxy)pyridine-2-carboxylic
405.2 [M+
66 acid ((R)-l- 2.05
H]+ isopropylpiperidin-3- ylmethyl) amide
4-(Isoquinolin-5-yloxy)- pyridine~2-carboxylic acid 405.2 [M+
67 2.10
((R)~ 1 -isopropylpiperidin-3- H]+ yimethyl)amide
4-[4-(2-Methoxyethyl)
phenoxy]pyridine-2-
412.2 [M +
68 carboxylic acid ((R)-l- 2.50
H]+ isopropylpiperidin~3 - ylmetnyl)aniide
4-(4-Imidazol- 1 -ylphenoxy)- pyridine-2-carboxylic acid 420.2 [M +
69 1.95
((/?)- ί -isopropylpiperidin-3- H]+ ylmethyl)amide
Figure imgf000074_0001
ylrneihyl)amide
* 4~Chloro-5-methylpyridme-2~carboxylie acid ((i?)-l-isopropylpiperidin-3-ylmeihyl)amide (Preparation 28) was used in place of 4-chloropyridine-2-carboxylic acid ((i?)~l~ isopropylpiperidin-3-ylineihyl)amide
Using the method outlined in Example 59, with the exception that the reactions were heated to 120°C using a hot plate rather then a microwave, Examples 74-122 were prepared from 4-chloropyridine-2-carboxylic acid ((i?)-l -isopropylpiperidin-3 -ylme†hyl)arnide (Preparation 31) and the corresponding phenol (Table 8): Table 8
Figure imgf000075_0001
RT
tructure Name mix (ES )
(mm)
((R)~ I -isopropylpiperidin-3- ylmethyl)amide
4~(4-Bromo-2- fluorophenoxy) pyridine-2-
! I , 1 450.1 [ + carboxylic acid 2.70
H]+ isopropylpiperidin-3 - ylmethyl)amide
4-(3-
Bromophenoxy)pyridine-2-
432.1 [M + carboxylic acid ((/?)- 1- 2.72
H]+ isopropylpiper idin-3 - ylmetihyl) amide
4-(Biphenyl-4-
! f yIoxy)pyridine-2-carboxylic
430.2 [M+ acid ((R)-l- 2.90 H]+ isopropylpiperidin-3 - ylmethyl)-amide
4-{2-[((R)-l-Isopropyl
piperidin-3 -ylmethyl) 412.2 [M+
2.57
carbamoyljpyiidin-4-yloxy} H]+ benzoic acid methyl ester
4-(3 -Di ethylaminophenoxy)
• « f pyridine~2-earboxylic acid 425.3 [M+
2.23
((R)~ 1 -isopropylpiperidin-3 - ιιγ ylmethyl)amide
4-(2-Methylbenzothiazol-5- yloxy)pyridine-2-carboxylic
425.2 [M+ acid ((R)-l- 2.45
isopropylpiperidin-3 - ylmethyl)amide
Figure imgf000077_0001
isopropylpiperidin-3-
Figure imgf000078_0001
yloxy)pyridine-2-carboxylic H]
Figure imgf000079_0001
acid((R)-l-
Figure imgf000080_0001
acid ((R i-
Figure imgf000081_0001
ylmethyl)amide
Figure imgf000082_0001
Example 123: 4-(4-Mctis icy !ohexylox )pyridku>-2-carboxyIic acid ((JQ-l-isopropyi- piperidm-3-ylmethyl)amide formic acid salt
Figure imgf000082_0002
To 4-methylcyc3ohexanol (194mg, 1.7mmol) m NMP (2mL) was added 4- chlorop>Tidine-2-carboxylic acid -isopropylpiperidin-3 ~yimethyl)amide (Preparation 31) (50mg, O.lTmmol) followed by NaH (60% dispersion, 20mg. 0.50mmol). After effervescence ceased the mixture was heated in a microwave to 100°C for lh before cooling to rt. The mixture was partitioned between DCM and water before the organic phase was purified by SCX (washing with MeOH and elution with NH3 MeOH) and the solvent was removed in vacuo. The residue was purified by prep HPLC to give, after removal of the solvent in vacuo, the title compound: RT = 2.32min; m/z (ES+) = 405.2 [M + H]+.
Using the method outlined in Example 123, Examples 124 and 125 were prepared from 4-chloropyridine-2-carboxylic acid ((R)- 1 -isopropylpiperidin-3-ylmethyl)amide
(Preparation 31) and the corresponding alcohol (Table 9):
Table 9
Figure imgf000083_0002
Example 126: 4-(4-Methoxypheiiylarain )pyridlne-2-carboxylic acid ((It)-l-isopropyl piper m-3-ylmethyl)amIde bis formic add salt
Figure imgf000083_0001
To 4-methox phenyl amine (72mg, 0,58mmol) in NMP (2mL) was added 4- chloropyridine-2-carboxylic acid ((i?)-l -isopropylpiperidin-3-ylmethyl)amide (Preparation 31 ). The mixture was heated in a microwave at 160°C for 2h before cooling to rt. The mixture was partitioned between DCM and water before the organic phase was purified by SCX (washing with MeOH and elution with NH3 MeOH) and the solvent was removed in vacuo. The residue was purified by prep HPLC to give, after removal of the solvent in vacuo, the title compound: RT = l ,99min; m/z (ES+) = 383.2 [M + H]""". Example 127; 4-(Isdan-5-yIamiHo)pyridiMe-2-earfooxylic acid ((R)-l-isopropylpiperidin-
3-ylmethyl)amIde formic acid salt
Figure imgf000084_0001
Using the method outlined in Example 126, 4-e oropyridme~2-carboxylic acid (( ?)- l-isopropylpiperidm-3-ylmethyS)amide (Preparation 31) and indan-5-yl amine were converted to the title compound: RT = 2.10rnin; m z (ES+) = 393.3 [M + H]+.
Example 128: [3-(4-Fluorophenoxy)phenyl] [2-(l-isopropylplperidiii-3-yI)pyrr lidin-l- yljmethanone
Figure imgf000084_0002
To 2-piperidin-3-ylpyrrolidine-l-carboxyiic acid tert-bu yl ester (0,787 mmol) in Me2CO (4mL) was added NaBH(OAc)3 (2.361 mmol). After shaking for 16h at rt MeOH (4mL) was added and the mixture purified using an SCX-2 cartridge (washing with MeOH and elution with NH3 MeOH). The solvent was removed in vacuo to give 2-(l- isopropylpiperidm-3-yl)pviTolidine-l-carboxylic acid tert-butyl ester. The residue was dissolved in 1 : 1 DCM:MeOH (ImL) and 4M HCl in dioxane (ImL) was added. After 16h at rt the solvent was removed in vacuo to give l-isopropyl-3-pyrrolidin-2-ylpiperidine
dihydrocMoride. Using the method outlined in Example 42, l-isopropyl-3-pyrrolidin-2- ylpiperidine dihydrochlonde and 3-(4-fluorophenoxy)benzoic acid were converted to the title compound: RT= 2.72min; m/z (ES+) = 411.2 [M+ H]†.
Example 129: [3~(4-FIsjoropl e¾oxy)phenyl] [2~(l-propylpiperidta-3-y!)pyrroMdiB~l~ yljmethanoiie
Figure imgf000084_0003
Using the methods outlined in Example 128, 2~piperidm-3~ylpyrrolidine-l-ca;
acid tert -butyl ester and 3-(4-fluorophenoxy)benzoic acid were converted to the title compound: RT== 2.73min; m/z (ES+) = 41 1.2 [M + H]+.
Example 130 s 4~(4-FI¾i®ropheMoxy)pyridme~2~earboxylk add
isopropyIpiperidiE-3-yliaet ~fflethyIbe! ¾yl)amide
Figure imgf000085_0001
Using the method outlined in Example 1, ((i?)-l-isopropylpiperidin~3- ylmemyl)pyridin-2-ylmethylamine (Preparation 20) and 4-(4-fluorophenoxy)pyridine-2- carboxylic acid (Preparation 71) were converted to the title compound: R - 2,8Smm, ; m/z (ES+) = 476.2 [M+ H]+,
Example 131: 3~(4~Fluoropbe¾oxy)~ ~((¾-l"isopropyIplperIdiB~3~ylmethyI)-jY~(2~ iHethyl-benzyl)beiizamide
Figure imgf000085_0002
Using the method outlined in Example 1, ((i?)-l-isopropylpiperidin-3- ylmethyl)p iidin-2-ylmethylamme (Preparation 20) and 3-(4-fluorophenoxy)benzoic acid were converted to the title compound: RT= 3,0Gmin, ; m/z (ES*) = 475,2 [M + H]+.
Using the method outlined in Example 42, Examples 132-135 were prepared from 4-
(4-fluorophenoxy)pyridine-2-carboxylic acid (Preparation 71 ) and the corresponding amine (Preparation X in Table 10):
Table 10
RT
Ex Structure Name X m/z (ES+)
(mln)
4-(4-Fluorophenoxy)
1 § pyridine-2-carboxylic
132 acid benzyl ((S)-l- 25 2.75 462.2 [Μ+ Ή
G isopropylpiperidin-3 - ylmethyl)amide
4-(4-Fluorophenoxy)
pyridine-2-carboxylic
acid ((_5)-l-isopropyl
133 21 2.38 463.2 [Μ+ Ι-Ιγ piperidin-3 -ylmethyl)
pyridin-2- ylmethylamide
4-(4-Fluorophenoxy)
pyridme-2-carboxylic
acid ((iS)-l-isopropyl
134 22 2.18 463.2 [Αί τ Η Γ o piperidin-3 -ylmethyl)
pyridin-3- ylmethylamide
4-(4-Fluorophenoxy)
pyridine-2-carboxylic
acid ((_?)- 1-isopropyl
135 23 2.10 463.2 ( - Η ί ' piperidin-3-ylmethyl)
pyridin-4- ylmethylamide
Using the method outlined in Example 42, Examples 136-140 were prepared from 3- (4~fluorophenoxy)benzoic acid and the corresponding amine (Preparation X in Table 11): Table 11
Figure imgf000087_0001
Examples 141 asid 142: 4-(4-Fluorophenoxy)pyridine-2-carboxylic add ((^)-4,4~ difliioro-l-isopropylpiperidi!i-3-ylmetliyl)amide aed 4-(4-Fluorophenoxy)pyridiue-2- carboxylic acid (i.S)~4,4~difliioro-l-isopropylpiperidiii~3~ylmetliyI)am de
Figure imgf000088_0001
Using the method outlined in Example 1, 4-(4-fluorophenoxy)pyridine-2-carboxylic acid (Preparation 71) and C-(4,4-cUfluoro-l-isopropylpiperidin-3-yl)methylamine phthalazinedione salt (Preparation 16) were converted to give 4-(4-fluorophenoxy)pyridine- 2-carboxylie acid (4,4-difluoro-l-isopropylpiperidin-3-ylmethyl)amide. Preparative ehiral HPLC of 4-(4-fluorophenoxy)pyridine-2-carboxylic acid (4,4-difluoiO-l-isopropylpiperidin- 3-ylmethyl)amide (92:4:4:0.1 isohexane:EtOH:MeOH:DEA, 15mL/min) gave the title compounds: (4-(4-Fluorophenoxy)pyridine-2-carboxylic acid ((i?)-4,4-difluoro-l- isopropylpiperidin-3-ylmethyl)amide, (RT on chiral column 15.9min) RT:= 2.60min; m/z (ES+) = 408.2 [M + H]+, 4-(4-Fluorophenoxy)pyridine-2-carboxylic acid ((5)-4,4-difluoro-l- isopropylpiperidin-3-ylmethyl)amide, (RT on chiral column 16.8min) RT= 2.6Qmin; m/z (ES+) = 408.2 [AT+ H]+.
Example 143' 4-(4-Fl oropheMoxy)pyridiiie~2~earboxylk add ((i?)-l-pyridin-3- ylmethyl-piperidia~3~ylmethyl)amide
Figure imgf000088_0002
To pyridine-3-carbaldehyde (27mg, 0.25mmol) in DCE (4mL) was added 4-(4- fluorophenoxy)pyridine-2-carboxylic acid ((iS -l-piperidin-3-ylmethyl)amide (Preparation 79) (40mg, 0.12mmol) and NaBH(OAc)3 (53mg, 0.25mmol). After stirring at it for lh the mixture heated to 70UC for 2h before being cooled to rt. The mixture partitioned between DCM and Na2CC>3, the aqueous phase was extracted with DCM and the solvent was removed in vacuo from the combined organic phase. The residue was purified by prep HPLC (Basic Method) followed by SCX (washing with MeOH and elution with ¾ MeOH), to give, after removal of the solvent in vacuo, the title compound: RT= 2.43rain; m/z (ES÷) = 421.2 [M + H\+. Using the method outlined in Example 143, Examples 144-147 were prepared from 4-(4-fluorophenoxy)pyridine-2-carboxylic acid ((S)- 1 ~piperidm~3 ~ylmethyl)amide
(Preparation 79) and the corresponding aldehyde (Table 11):
Figure imgf000089_0001
Example 147: 4~(4-Flisorophenoxy)pyridme~2~earboxyIie add ((J?)-l-methyIpiperIdiB~3 vlmet
Figure imgf000089_0002
A mixture of 4-(4-fliiorophenoxy)pyridine-2-carboxylie acid ((5)-l-piperidin-3- ylmethyl)amide (Preparation 79) (40mg, 0.12mmol), formaldehyde (33%, 0.2mL,
0.66mmol), formic acid (0.2mL) and water (3mL) were heated at 100°C for 2h before the solvent was removed in vacuo. The residue was partitioned between DCM and 2M Na2CC¼, the organic phase was dried (MgS04) and the solvent removed in vacuo to give the title compound: RT= 2.32min: m z (ES÷) = 344.2 [M+ H]+,
Example 148: 4-(4-Fluorophenoxy)pyridine-2-carboxylic acid ((jR)-l-ethylpiperidin-3- ylHiethyI)amide
Figure imgf000090_0001
To 4-(4-fluorophenoxy)pyridine-2-carboxylic acid ((S)-l-piperidin-3-ylmethyl)amide
(Preparation 79) (40mg, 0.12mmol) i DCE (3mL) were added acetaldehyde (16rag,
0.37mmol) and NaBH(OAc)3 (53mg, 0,24mmol), The mixture was stirred at rt for 2h, then partitioned between DCM and Na2C03 and the solvent was removed in vacuo from the organic phase. The residue was purified by prep HPLC (Basic Method) and then SCX (washing with MeOH and elution with Hs/MeOH) to give, after removal of the solvent in vacuo, the title compound: RT= 2.45min; m/z (EST) = 358.2 [M + H'f.
Figure imgf000090_0002
To 4-(4-fluorophenoxy)pyridine-2-carboxylic acid ((5)-l-piperidin-3-ylmethyl)amide
(Preparation 79) (40mg, 0.12mmol) in THF (2mL) was added NEtg (50μΕ, 0.37mmol) and 3- bromopentane (39mg, 0.26mmol). The mixture was heated at 100°C for lh in a microwave then cooled to rt, partitioned between DCM and water and the solvent was removed in vacuo from the organic phase. The residue was purified by SCX (washing with MeOH and elution with NH-/MeOH) to give, after removal of the solvent in vacuo, the title compound: RT== 2.79min; m/z (ES+) = 400.2 [M+ H]+.
Example 150: 4-(4-Fluorophenoxy)pyridine-2-carboxylic add [(R)-l-(l-phenylethyl)- p!peridra-3-ylmetbyl] amide
Figure imgf000091_0001
Using the method outlined in Example 149, 4-(4-fluorophenoxy)pyridine-2- carboxylic acid ((iS)-l-piperidin-3-ylmethyl)amide (Preparation 79) and 1- bromoethylbenzene were converted to the title compound: RT~ 2.73min; m/z (ES!) = 434.2
Example 151 and Example 152: 4~(4-Ftaorophenoxy)pyridine~2-earboxy!ie add ((^)-l,2-dimefliyl-propyl)piperidta-3-ylmetayl]amide aad 4-(4-
Fl¾ioropliesiQxy)pyridiae-2-earboxylk add [(^)-l-((S)-l,2-dimetby!-propyl)piperidiE-3- ylmethyl] amide
Figure imgf000091_0002
To 4-(4-fluorophenoxy)pyridine-2-carboxylic acid ((S)-l-piperidin-3-ylmethyl)amide (Preparation 79) (40mg, 0.12mmol) in DCE (1.5mL) were added 3-methylbutan-2-one (0.5mL) and NaBH(OAc)3 (79mg, 0.37mmol). The mixture was stirred at rt for 1.5h then heated at 70°C for a fiirther Ih. The mixture was partitioned between DCM and a2C03, the organic phase was dried (MgS04) and the solvent removed in vacuo. The residue was initially purified by SCX (washing with MeOH and elution with NH3/MeOH), and prep HPLC (Basic Method) with the solvent being removed in vacuo. Purification of the residue by SCX (washing with MeOH and elution with NH3 MeOH) gave, after removal of the solvent in vacuo, the title compounds: 4-(4-Fluorophenoxy)pyridine-2-carboxylic acid [(i?)- l -(( ?)-l,2-dimethylpropyl)piperidin-3-ylmethyl]amide, RT= 2,70min; m/z (ES+) = 400.2 \M + H]+: 4-(4-Fluorophenoxy)pyridine-2-carboxylic acid [(R)-\-{(S)-\,2- dimethylpropyl)piperidin-3-ylmethyl]amide, RT= 2.88min; m/z (ES1") = 400.2 [M + H]+. Example 153: 4-(4-FInorophenoxy)pyrMme-2~carboxylk add [(¾~l~(l~pyridiH-3- ylethyI)-piperidiH~3~ylmeth ]]amide
Figure imgf000092_0001
Using the method outlined in Example 151, 4-(4-fluorophenoxy)pyridine~2- earboxylic acid ((5)-l-piperidiii-3-ylmethyl)amide (Preparation 79) and l-pyridin-3- ylethanone were converted to the title compound: RT=== 2,47min; m/z (ES+) === 435.2 \M+
Example 154; 2,5-AVbeiizylox -^-((ir)-1 sopropylpiperidin-3-ylmethyl)nicotinamide
Figure imgf000092_0002
To benzyl alcohol (105mg, 0.96mmol) in NMP (6mL) was added Nail (60% in mineral oil, 60mg, 1.44mmol). After 5min 2-cWoro-5-fluoro-N-((R)-l-isopropylpiperidin-3- ylmethyl)nicotinamide (Preperation 35) (150mg, 0.48mmol) was added and the mixture was heated at 80°C for 2h, The mixture was cooled, partitioned between DCM and water before the organic phase was washed with brine, dried (MgS04) and the solvent was removed in vacuo. The residue was initially purified by SCX (washing with MeOH and elution with NH3 MeOH) and the solvent was removed in vacuo. The residue was purified by prep liPLC followed by SCX (washing with MeOH and elution with NH3 MeOH) to give, after removal of the solvent in vacuo, the title compound: RT= 3.02min; m z (ES+) = 474,4 [M + H]+.
Example 15S: 6-(4-F!iioropliei oxy)-3-isopropoxypyrida¾tae~4-earboxyIie acid {(R}~\~ isopropyIpiperldiii-3-ylmethyI)amide
Figure imgf000092_0003
To 6-chloro-3-isopropoxypyridazine-4-carboxylie acid ((i?)-l-isopropylpiperidin-3- ylmethyl)amide (Preparation 37) (39mg, 0.1 1 mmol) and 4-fluorophenol (123rag, l . lmraol) in NMP (ImL) was added NaH (60% mineral dispersion in oil, 13mg, 0.33mmol). The mixture was heated at 150°C in a microwave for Ih and then cooled to rt. The mixture was partitioned between DCM and water before the organic phase was purified on an SCX-2 column (washing with MeOH and elution with M¾/MeOH) and the solvent was removed in vacuo. The residue was purified by prep HPLC to give, after removal of the solvent in vacuo, the title compound: RT= 2.62min; m/z (ES+) = 431.3 [M+ H]+.
Using the method outlined in Example 155, Examples 156-159 were obtained from the respective 6-chloropyridazin.e-4-carboxylic acid (( ?)- l -isopropylpiperidin-3- ylmethyl)amides (Preparation X in Table 13) and the corresponding phenol:
Table 13
Figure imgf000093_0001
Figure imgf000094_0001
Example 160; 6-(4-FI ioropheiiyIamii¾o)-3-isopropoxypyridaziae-4-earboxylk aeid ((M)~ l~isopropy!plperidta-3-ylmethyl)amide
Figure imgf000094_0002
To 6-chloro-3-isopropoxypyridaziiie-4-carboxylic acid ((i?)-l-isopropylpiperidin-3- ylmethyljamide (Preparation 37) (75mg, 0.21 mmol), biphenyl-2-yldi-tert-butylphosphane (5mg, 0.02mmoi) and 4-fluorophenylamine (47mg, 0.42mmol) in PhMe (1.5mL) was added NaO'Bu (61mg, 0.64inmol). The mixture was degassed with Ar, Pd2dba (5mg, 0.005mmol) added and the mixture was heated at 90°C in a microwave for 1.5h before cooling to rt. The mixture was partitioned between EtOAc and water with the aqueous phase being re-extracted with EtOAc. The combined organic phase was washed with brine, initially purfied on a Phosphonics STMAD cartridge (washing with MeOH and elution with N¾/MeQH) and the solvent was removed in vacuo. The residue was purified by prep HPLC to give, after removal of the sol vent in vacuo, the title compound: RT= 2,54mm; m z (ES+) = 430.2 [M+ H]+.
Using the method outlined in Example 160, Examples 61-164 were obtained from 6-chloro-3 -isopropoxypyridazine-4-carboxylic acid {(R)~ 1 -isopropylpiperidin-3 - ylmethyl)amide (Preparation 37) and the corresponding aniline (Table 14): 6-[(4-Fluorophenyl)
methylamino] -3 - isopropoxypyridazine-4- carboxylic acid
Figure imgf000095_0001
isopropylpiperidin~3-yl
methyl)amide
6-(Benzothiazoi-6- ylamino)~3~
isopropoxypyridazine-
Figure imgf000095_0002
carbox lic acid ((i?)-l- isopropylpiperidin-3-
6-(Indan-5-ylamino)-3 - iazine-^
v carboxylic acid ((i?)-l- 2.68 452.3 [M+H isopropylpiperidirt-3 - ylmethyl)amide
3-Isopropoxy-6-(quinolin- 8-ylamino)pyridazine-4- carboxylic acid ((i?)-l- 2.79 463.3 [ +H]+
Figure imgf000095_0003
isopropylpiperidin-3 - ylmethyl)amide
Figure imgf000095_0004
To 4-(4-fluorophenoxy)pyridine-2-carboxylic acid (morpholin-2-ylmethyl)amide (Preparation 81 ) (50mg, O.lSmmol) in DCE (3mL) was added Me?CO (26mg, 0.45mmol) and NaBH(OAc)3 (96mg, 0.45mmol). After 16h DCM was added and the organic phase was washed with NaHCO.3 . The solvent was removed in vacuo to give the title compound: RT= 2.52min; mlz (ES+) = 374.3 [M+ H]+. Example 166: 5-(4-Fl oropheBoxy)- V-(l- sopropy!piperidiis~3~ylmethyl)~2-methyl- braz&mlde
Figure imgf000096_0001
To 5-hydroxy-2-methylbenzoic acid (Ig, 6.6mmol.) in DCM (20mL) and MeOH (5mL) was added trimethylsilyldiazomethane (2M solution, 6.5mL), After 0.25h AeOH (ImL) was added and the solvent was removed in vacuo. The residue was dissolved in
EtOAc. washed with 1M NaOH, the organic phase was dried (MgS04) and the solvent was removed in vacuo to give S-hydroxy~2~methylhenzoie acid methyl ester, The residue and CS2CO3 (5.8g, 18.0mmol) in dioxane (50mL) was heated under reflux for 0.25h and then Cul (L26g, 6.6mmol) and i-fiuoro-4-iodoberizene (5.3g, 24.0mmol) were added. The mixture was heated under reflux for 16h before the solvent was removed in vacuo. The residue was treated with EtOAc and filtered through a pad of celite. The filtrate was washed with water, 1M HQ, 1M NaOH, brine and then dried (MgS04), The solvent was removed in vacuo to give 5-(4-fluorophenoxy)-2-methyl-benzoic acid methyl ester. To 250mg of the residue in MeOH (lOmL) and water (l OmL) was added LiOH (50mg). The mixture was heated at 80°C for 16h and then the solvent was removed in vacuo. The residue was partitioned between water and DCM, the aqueous phase was separated, acidified and extracted with EtOAc. The combined organic phase was dried (MgSQ4) and the solvent removed in vacuo to give 5-(4- fiuorophenoxy)-2-methylbenzoic acid. To the residue in DMF (30mL) was added NEt3 (0.5mL) and HATU (1.02g, 2.7mmol) and after 0.5h C-(l-isopropylpiperidin-3- yl)methylamine (153mg, LOmmoI) was added. After 64h the solvent was removed in vacuo and the residue was partitioned between EtOAc and water. The organic phase was washed with NaHC03, brine, dried (MgS04) and the solvent was removed in vacuo. The residue was purified by column chromatography (1 :9 MeOH:DCM to 15:85 MeOH:EtOAc) to give, after removal of the solvent in vacuo, the title compound: RT= 2.70mm; m/z (ES+) = 385,4 [M+ H]+. Example 167: 4-(4-Chloro-2-fliioroplieHoxy)pyridine-2-£arbosyIic add ((5)-l-isopropyl- p!perfdiB~3~yImethyl)methy?amlde
To 4-(4-chloro-2-fluorophenoxy)p>Tidine-2-carboxylic acid ((i?)-l- isopropylpiperidin~3-ylmethyl)aniide (Example 32) (76mg, 0.19n mol) in DMF (2mL) was added NaH (60% dispersion in oil, 8mg, 0.21mmol). After ISrnin methyl iodide (ΙΟμΕ, 0.17mmol) was added and after a further 30 mm the solvent was removed in vacuo. The residue was purified by column chromatography (1 :5:94 NE MeOHiDCM) to give, after removal of the solvent in vacuo, the title compound: RT= 2,65min; m/z (ES+) = 420,2 [M · H]+.
Example 168: 2-Amino-5-(4-fliiorop eBoxy)-iV-(l-isopropylpiperidia-3-ylmettiyl)- benzamide
Figure imgf000097_0002
Using the method outlined in Example 1, C-(l-isopropylpiperidin-3-yl)methylamine and 2-amino-5-(4-fluorophenoxy)benzoic acid (Preparation 73) were converted to the title compound: RT= 2.48min; m/z (EST) = 386,4 [M+ ETf .
Example 16 : 5-(4-Fl uor ophenoxy)-Ar-(l -isopr opylpiperidin-3-ylmethyl)-2-
Figure imgf000097_0003
Using the method outlined in Example 1, C-(l-isopropylpiperidin-3-yl)methylamine and 5-(4-fluorophenoxy)-2-metJiylarninobenzoic acid (Preparation 75) were converted to the title compound: RT= 2,55min; m z (ES+) = 400.3 [M+ H]+. Example 170: 2-Ammo-5-(4-fluorophenoxy)-AL(l-isopropylpiperidin-3-ylmethyl)- nicotinamide
Figure imgf000098_0001
Using the method outlined in Example 17, 2-amino-5-(4-fluorophenoxy)nicotinic acid (Preparation 77) and C-(l-isopropylpiperidin-3-yl)methylamine were converted to the title compound: RT- 2.20min; m/z (ES+) === 387.3 [M+ Hj+.
Example 171: 4-(4-FIuoroptseHoxy)pyridiiie-2-carboxylic acid [l-(l-isopropylpiperidin- 3-yl)ethyl] amide
Figure imgf000098_0002
To 4-(4-fluorophenoxy)pyridine-2-carboxylic acid ( 1 -piperidin-3 - yiethyl)amide (Preparation 83) (299mg, 0.87mmol) in THF (lOmL) and Me2CO (l OmL) was added
NaBH(OAc)3 (426mg, 2.0mmol). After 40h solvent was removed in vacuo, the residue was partitioned between DCM and IM NaOH and the solvent was removed in vacuo from the organic phase, The residue was purified by an SCX column (washing with MeOH and elution with NEt3/MeOH) to give the title compound: RT= 2.52min; m/z (ES+) = 386,2 [ +
Example 172: 3-<4-F!uorophenoxy)-AHl-«sopropyJpipendin-3-yimethyl)-A-phenyl- beiizamide
Figure imgf000098_0003
Using the method outlined in Example 171, 3-(4-fluorophenoxy)-N~pheny1~N~ piperidin-3-ylmethylbenzamide (Preparation 84) was converted to the title compound: RT- 2.75mim m/z (ES4) = 447.3 [M+ H]+. Example 173: 5-(4-Fluorophenoxy)-2-isopropoxy-JV-((R)-l-isopropylpiperidin-3-yl- met yl)HicotisiaBiIde
Figure imgf000099_0001
To propan-2-ol (348mg, 5.8mmol) in THF (4mL) was added Nail (60% in mineral oil, 224mg, 5.6mmol) followed by a 1 : 1 mixture of 2-chloro-5-(4- fluoroph.enoxy)nicotinonitrile and 6-cUoro-5-(4-fluoiOphenoxy)nicotinonitrile (Preparation 69) (950mg, 3.8mmol). The mixture was heated to 50°C for 16h before cooling to rt. The mixture was partitioned between water and EtOAc, the organic phase was washed with 1M NaOH and the solvent was removed in vacuo. The residue purified by column
chromatography (DCM/MeOH) to give, after removal of the solvent in vacuo, 5-(4- fluorophenoxy)-2-isopropoxymcotinonitrile. To the residue in PhMe (5mL) at 0°C was added DIBAL (1.5M in PhMe, 0.7mL) and the mixture was allowed to warm to rt over 16h. To the mixture was added IM HC1 (2mL) followed by NaOH basify the mixture (pH~10). The mixture was extracted with DCM and the solvent removed in vacuo to give crude 5-(4- fluorophenoxy)-2-isopropoxypyridine-3-carbaldehyde. To the residue in 2-methylpropan-2- ol (16mL) and water (4mL) was added sodium dihydrogen phosphate (567mg, 4.0mmol) and NaC102 (80%, 108mg, l.Ommol). After 16h water and DCM were added and the solvent was removed in vacuo from the organic phase to give crude 5-(4-fluorophenoxy)-2- isopropoxynicotinic acid. Using the method outlined in Example 1, 5-(4~fluorophenoxy)-2- isopropoxynicotinic acid and C-((i?)- 1 -isopropylpiperidin-3 -yl)methylamine
phthalazinedione salt (Preparation 5) were converted to the title compound: RT = 2.88min; m/z (ES*) = 430.2 [M+ H] ' .
Example 174: 5-(4-Fluorophenoxy)-^-((J?)-l-isopropylpiperidin-3-ylmethyl)-6- phenoxyHnicotinamide
Figure imgf000099_0002
Using the method outlined in Example 173, 2-chloro-5-(4-fl orophenoxy)- nicotinonitrile, 6-chloro-5-(4-fluorophenoxy)nicotinoiiitrile (Preparation 69) and phenol were converted to the title compound: RT == 2.86min; m/z (ES+) :;; 464.2 [M+ H]+. Example 175: S-{4-FluoropJieBQxy)-A-((^)-i- sopropyIpiperIdIn~3~ylmet¾yI)-6- phe&ethy!-oxy nico t iisamide
Figure imgf000100_0001
Using the method outlined in Example 173, 2-chloro-5-(4-fluorophenoxy)- nicoiinonitrile, 6-chloro-5-(4-fluorophenoxy)mcotinonitrile (Preparation 69) and 2- phenylethanol were converted to the title compound: RT = 2.97min; m/z (ES+) = 492.2 [M+ H]+.
The biological activity of the compounds of the invention may be tested in the following assay systems:
GHSR Ghrelin competition assay
0.1 μ§ of human GHSR membranes (Millipore. prepared from Chem-1 cells stably overexpressing GHS-Rla), 0.025nM human i25i~Ghrelin (Perkin Elmer) and the compound of interest were incubated in 25 mM Hepes pH 7.4 containing 5 mM MgCl2, 1 mM Ca€l2, 2.5 mM EDTA and 0.2% BSA for 2h at room temperature. Radioligand bound to the membrane was trapped onto a 0.5% PEI presoaked filtermat B (Perkin Elmer) using a Filtermate harvester (Perkin Elmer). The effect of compound upon the specific binding of ! '5I-ghrelin was then measured using scintillation counting using Meltilex (Perkin Elmer) and a Trilux scintillation counter and IC50 values were determined by fitting the data to a hyperbolic binding model.. K; values were calculated according to Cheng-Prusoff, using the KD for the radioligand at the receptor as determined by saturation binding kinetics. rSJGTPyS Blading
The binding assay was initiated by the addition of [i3S]-GTPyS (Perkin Elmer) to a final concentration of 150 pM in a 100 μΕ assay solution containing 24 mM HEPES pH 7.1, 49 mM NaCL 10 mM MgCl?, 0.1% BSA, 0.5% DMSO, 10 μ§/ηι£ saponin, 1 μΜ GDP, 20 μ§/ηι1 membranes (Milltpore, prepared from Chem~l cells stably overexpressing GHS~Rl a), 10 nM human ghrelin (Peptides International) and the compound of interest. The assay was incubated at 30°C for 30 min. Prior to this incubation step, membranes, saponin and GDP were pre-incubated for 10 min, and a further 15 min after the addition of ghrelin. 10 μΜ unlabelled GTPyS was used instead of compound and ghrelin to determine non-specific binding. Membranes were captured on wheatgerm agglutinin SPA beads (4 mg/mL, GE Healthcare) in a 30 min incubation at room temperature. Th beads were pelleted by centrifugation at 1,300 g for 5 min at room temperature and bound [3SS]-GTPyS was measured by scintillation counting using a Wallac Microbeta® TriLux counter (Perldn Elmer), The effect of compound upon the specific binding of [j5S]-GTPyS was utilized to determine the IC50 by fitting the data to a hyperbolic model.
All the examples of the invention gave a K, of <lQQQGnM in the binding assay, for example, Example 1 gave a Kj of 16nM and GTPyS IC5Q 1120nM.
K and IC50 values determined respectively by the GHSR Ghrelin competition assay and the [35S]GTPgS binding assay described above are provided for compounds of the present invention in Table 15.
Figure imgf000101_0001
Figure imgf000102_0001
Figure imgf000103_0001
- 10 i ·
Figure imgf000104_0001
ect on o y we g t an postpran a g eose
The effects of the compounds of invention on body weight, food and water intake and postprandial glucose handling may be examined in diet induced obese (DIO) mouse. Tes compounds and reference compounds are dosed by appropriate routes of administration (e.g. intraperitonally or orally) for up to two weeks. During the baseline and treatment period body weight, food intake and water intake is measured daily and any significant differences between treatment groups and control group are analysed. All animals have free access to a high fat diet (45% kcal) and water and will be maintained on a normal phase 12h light-dark cycle. Animals will be exposed to the appropriate diet for at least 15 weeks before experiment. In the end of the experiment, the animals may be fasted over night and the next day an oral glucose tolerance test (OGTT) performed. On the day of the OGTT the compound or vehicle is administered and up to 60min later a bolus dose of glucose (eg 2g/kg) is given by oral gavage. The level of blood glucose and insulin are measured at predefined time intervals before and after the bolus glucose dose. Any significant difference in glucose excursion between treatment groups and control group are analysed.

Claims

1. A compound of formula (1) or a pharmaceutically acceptable salt thereof:
Figure imgf000105_0001
wherein:
R is C2-6 alkyl, C3.7 cycloalkyl, Cj-3 alkyl~C3.7 cycioaikyl, C1.3 alkyl-aryl or C1.3 alkyl- heteroaryl, any of which may be optionally substituted with one or more F, OH or Q.3 alkoxy groups;
Rl and R2 are independently selected from H, C e alkyl, C1.3 alkyl-aryl, aryl, C1.3 alkyl- heteroaryl and heteroaryl, or R1 and R2 taken together may fonn a 3~ to 7-membered carbocyclic ring; optionally substituted with halogen, .3 alkoxy or Q-3 aikyl;
R3 and R4 are independently selected from H, F, Q.3 alkyl, OH or Q.3 alkoxy;
R" to R14 are independently selected from H and CH3;
W is CH2, CHF, CF2, O, CH(OH), C(OH)C!-3 alkyl, CH(OQ_3 alkyl), C(OCi.3 alkyl)Ci.3 alkyl, -CH(Ci_3 alkyl) or -C(C! -3 alkyl)(Q.3 alkyi);
R99 is H, Ci-6 alkyl, -(CHa aryl, -(CH^-heteroaryl or -(CH2)p-0-ary] where aryl or heteroaryl groups may be optionally substituted with C1.3 aikyl, Q.3 alkoxy or halogen; or R¼ together with R! or R2 form a 5- to 6-membered nitrogen containing ring;
Y, Y!, Y2 and Y3 are independently N or CR20 such that the ring contains 0, 1 or 2 nitrogens;
R ' is independently selected from H, halogen, Q.g alkoxy, O-C3.6 cycloalkyl, Q-(4- to 7-membered heterocyclyi), C1-3 alkyl, NR96R97, 0-(CH.2)q-Q-6 alkoxy, 0-(CH2)q-aryl and 0-(CH2)q-heteroary1;
R96 and R97are independently selected from H, Q-3 aikyl and€3.6 cycloalkyl;
X is O, NR6, CR7R8, or C=0 and when Ring is aryl then X can b 0{CH2)r;
Rb is H, C1.3 alkyl, C3.7 cycloalkyl, C1.3 alkyl-C3-7 cycloalkyl Cj-3 alkyl-aryl or C1.3 alkyl- heteroaryl, any of which may be optionally substituted with one or more F, OH or Cj.3 alkoxy groups; K7 and Rs independently selected from H, OH, F, C5 -3 alkoxy or€ .3 alkyl, provided that when one of R' or R8 is OH the other cannot be F, OH, or€5.3 alkoxy;
Ring is a Ce-io carbocyclie, Ce-io aryl, 6- to 10-membered heteroaryl ring or a bicyclic structure comprising a 5- or 6- membered aryl or heteroaryl with a 5 or 6 membered earboeycle or heterocycle fused thereto wherein the bicyclic structure bonds to X via one of the atoms on the aryl or heteroaryl moiety, any of which may be optionally substituted by 1 to 3 groups selected from halogen, Ci_3 alkyl optionally substituted by hydroxy or 1 to 3 halogens, C1-3 alkoxy, CN, C02Ris, CON(R15)2, SO?OH, SO?N(R15)2, N(RIS)2,
N(R15)2(C0)N(R1S)2, 0(CH2)q-aryl, 0(CH2)q-heteroary!5 NH(CO)CM alkyl, OH, aryl, heteroaryl and COCi-salkyl; provided that Ring is not unsubstituted 4-pyridyl;
RiS is independently seletected from H and C1.3 alkyl;
n is 0, 1 , 2 or 3;
p is 2 or 3;
q is 0, 1 or 2; and
r is 1 or 2;
subject to the proviso that the compound is not N-((4-benzylmorpholin-2-yl)methyl)- 3-phenoxybenzamide or N-((4-benzylmorpholin-2-yl)rnethyl)-3-(benzyloxy)benzamide. 2. A compound of formula (I):
Figure imgf000106_0001
or a pharmaceutically acceptable salt thereof for use in a method of treatment of the human or animal body by therapy,
wherein:
R is C2-6 alkyl, C3.7 cycloalkyl, C1.3 aiky]-C3.7 cycloalky!, C1.3 alkyl-aryl or C1.3 alkyl- heteroaryl, any of which may be optionally substituted with one or more F, OH or .3 alkoxy groups; R! and are independently selected from H, -g alkyl, C1.3 alkyl-aryl, aryl, Cj.3 alkyl- heteroaryl and heteroaryl, or R1 and R2 taken together may form a 3- to 7-membered carbocyclic ring; optionally substituted with halogen,€5.3 aikoxy or C5.3 alkyl;
RJ and R4 are independently selected from H, F, C ¾ alkyl, OH or C1.3 aikoxy;
Rn to R* are independently selected from H and CH3;
W is CH2, CF1F, CF2, O, CH(OH), C(OH)Ci.3 alkyl, CH(OC1-3 alkyl), C(OC{-3 alkyi)Ci-3 alkyl, -CH(C|..3 alkyl) or ~C(C|.3 aIkyl)(CJ-3 alkyl);
R99 is H, Ci .6 alkyl, -(CHsVaryl, -(CHsiij-heteroaryl or -(CH2)P-0-aryl where aryl or heteroaryl groups may be optionally substituted with C1-3 alkyl, C-..3 aikoxy or halogen; or R99 together with R] or R^ form a 5- to 6-membered nitrogen containing ring;
Y, Y!, Y2 and Y3 are independently N or CR20 such that the ring contains 0, 1 or 2 nitrogens;
R20 is independently selected from H, halogen, Cj .6 aikoxy, O-C3-6 cycioalkyl, 0~(4- to 7-membered heterocyclyl), Cf.3 alkyl, NR96R97, 0-(CH2)q-Ci-6 aikoxy, 0-(CH2)q-aryl and 0-(CH2)q-heteroaryl;
R96 and R97are independently selected from H, C1.3 alkyl and C3.6 cycioalkyl:
X is O, NR6, CR7R8, or C=0 and when Ring is aryl then X can be 0(CH2)r;
R6 is H, Cj-3 alkyl, C3.7 cycioalkyl, C\.% alkyi~C3.7 cycioalkyl, C1.3 alkyl-aryl or C1.3 alkyl- heteroaryl, any of which may be optionally substituted with one or more F, OH or C 5.3 aikoxy groups;
R' and R8 independently selected from H, OH, F, C1.3 aikoxy or Cu alkyl, provided that when one of R7 or R8 is OH the other cannot be F, OH, or Ci-3 aikoxy;
Ring is a Ce-io carbocyclic, Ce-io aryl, 6- to 10-membered heteroaryl ring or a bieyclic structure comprising a 5- or 6- membered aryl or heteroaryl with a 5 or 6 membered carbocycle or heterocye!e fused thereto wherein the bieyclic structure bonds to X via one of the atoms on the aryl or heteroaryl moiety, any of which may be optionally substituted by 1 to 3 groups selected from halogen, Ci-3 alkyl optionally substituted by hydroxy or 1 to 3 halogens, C1.3 aikoxy, CN, C02R!5, CON(Ri5)2, S02OH, S02N(R1S)2, N(R1S)2,
N(R! 5)2(C0)N(R1S)2, 0(CH2)q-aryl, 0(CH2)q-heteroaryl, NH(CO)CY.6 alkyl, OH, aryl, heteroaryl and COCj.3alkyl; provided that Ring is not unsubstituted 4-pyridyl; is independently seletected from H and C1.3 alkyl; n is 0, I, 2 or 3;
p is 2 or 3;
q is 0, 1 or 2; and
r is 1 or 2.
3. A compound or pharmaceutically acceptable salt for use as claimed in claim 2, wherein said method of treatment comprises the treatment of diabetes, obesity, metabolic syndrome (syndrome X), impaired glucose tolerance, Prader-Willi syndrome,
hyperlipidaeniia, hypertriglyceridaemia, hyperchoiesterolaemia, low HDL levels, hypertension or abnormal sensitivity to ingested fats.
4. A compound according to claim 1, claim 2 or claim 3, or a pharmaceutically acceptable salt thereof, wherein R is C2-6 alkyl optionally substituted with one or more F, OH or Ci-3 aikoxy groups.
5. A compound according to any of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein R1 and I 2 are independently selected from H and C;. alkyl.
6. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein RJ and R4 are independently selected from H and F.
7. A compound according to any one of the preceding claims, or a phannaceuticallv acceptable salt thereof, wherein Ri ! to Ri4 are H. 8. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein W is CH2, CHF, CF2, CH(OH), C(OH)C|.3 alkyl, CH(OCi-3 alkyl), C(OC|.3 alkyl)Cl -3 alkyl, -CH(Ci -3 alkyl) or -C(Ci-3 alkyl)(C,-3 alkyl).
9. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R99 is H.
10. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein the ring containing Y, Y!, Y2 and Y3 contains 1 or 2 nitrogen atoms. 11. A compound according to claim 10, or a pharmaceutically acceptable salt thereof, wherein the ring contains 1 nitrogen atom and this is represented by Y or Y1,
12. A compound according to claim 10, or a pharmaceutically acceptable salt thereof, wherein the ring contains 2 nitrogen atoms and these are represented by Y1 and Y2.
13. A compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein Y is N or C(C}.6 alkoxy).
14. A compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein Y! is CH or N.
15. A compound according to any one of claims 1 to 10, or a pharmaceuticaily acceptable salt thereof, wherein Y~2 is CH, CMe or N. 16. A compound according to any one of claims 1 to 10, or a pharmaceuticaily acceptable salt thereof, wherein Y is CH.
17. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R20 is independently selected from H, Ci-e alkoxy, O-C3-6 cycloalkyl, 0-(CH2)q-Ci.6 alkoxy and 0-(CH2)q-aryl.
18. A compound according to any one of the preceding claims, or a pharmaceuticaily acceptable salt thereof, wherein X is O, NR", CR7R8, preferably CH2, C(Hal)2, or CHOH, or C=0. 19. A compound according to claim 18, or a pharmaceutically acceptable salt thereof, wherein X is O. 20, A compound according to claim 18 or 19 or a pharmaceutically acceptable salt thereof wherein Ring is phenyl, napthyi, pyridine or quinoline, optionally substituted with one or more groups selected from halogen atom and C-. to C3 alkyl. 21 , A compound according to claims 20 or a pharmaceutically acceptable salt thereof wherein the one or more halogen atom on Ring is selected from F and Ci, at least one of which is preferably ortho or para to the X~Ring bond.
22. A compound according to claim 19 to 21 wherein Ring is substituted with one or more d to C3 alkyl, d to C3 alkoxy, nitro, CN, CF3s C02R35 S CON(Ri5)2, S02OH,
S02N(R15)2, N(R! 5)2, N(R15)2(CO)N(RiS)2, ar l, G(CH2)q-aryl, heteroaryl, 0(CH2)q- heteroaryl.
23. A compound according to claim 39 or a pharmaceutically acceptable salt thereof wherem Ring is selected from pyridine, indole, benzol , 3dioxole, quinoline, benzothiazole, indazole, imidazole, benzoiniidazole, dihydrobenzooxazine, , dihydrobenzodioxine, adamantane, cyelohexane, 4,4-dimethylcyclohexane, 2,3 dihydroindene,
24. A compound according to claim 18, or a pharmaceutically acceptable salt thereof, wherein X is NR6 and Ring is phenyl, napthyi, pyridine or quinoline, optionally substituted with one or more groups selected from halogen atom and Q to C3 alkyl, or 2,3 dihydroindene.
25. A compound according to claim 24 or a pharmaceutically acceptable salt thereof, wherein the one or more halogen atom ors Ring is selected from F and CS, at least one of which is preferably ortho or para to the X-Ring bond.
26. A compound according to claim 18, or a pharmaceutically acceptable salt thereof, wherein X is CH2 and Ring is phenyl, napthyi, pyridine or quinoline, optionally substituted with one or more groups selected from halogen atom and Cj to C3 alkyl.
27. A compound according to claim 26 or a pharmaceutically acceptable salt thereof, wherein the one or more halogen atom on Ring is selected from F and CI, at least one of which is preferably ortho or para to the X-Rmg bond. 28, A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R6, R7 and Rs are I I.
29. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein Ring is an optionally substituted Cg-jo aryl or 6- to 10- membered heteroaryl ring.
30. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein Ring is optionally substituted by 1 to 3 groups selected from halogen, Cj.3 alkyl optionally substituted by OH,€1,3 alkoxy and aryl.
31. A compound as defined in any one of Examples 1 to 175 as the free base or a pharmaceutically acceptable salt thereof.
32. A pharmaceutical composition comprising a compound according to any one of claims 1 to 31, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
33. A method for the treatment of a disease or condition in which the ghrelin receptor plays a role comprising a step of administering to a subject in need thereof an effective amount of a compound according to any one of claims 1 to 31, or a pharmaceutically acceptable salt thereof.
34. A method for the treatment of diabetes comprising a step of administering to a subject in need thereof an effective amount of a compound according to any one of claims 1 to 31 , or a pharmaceutically acceptable salt thereof.
35. A method for the treatment of obesity comprising a step of administering to a patient in need thereof an effective amount of a compound according to any one of claims 1 to 31, or a pharmaceutically acceptable salt thereof. 36. A method for the treatment of metabolic syndrome (syndrome X), impaired glucose tolerance, Prader-Willi syndrome, hyperlipidemia, hypertriglyceridemia,
hypercholesterolemia, low HDL levels, hypertension, or abnormal sensitivity to ingested fats comprising a step of administering to a patient in need thereof an effective amount of a compound according to any one of claims 1 to 31 , or a pharmaceutically acceptable salt thereof.
A method of synthasising a compound of formula (I):
Figure imgf000112_0001
or a pharmaceutically acceptable salt thereof,
wherein:
R is C2-6 alky!, C3.7 cyc!oalkyl, Q.3 alkyl-C3.7 cycloalkyi, C1.3 alkyl-aryl or C1-3 alkyl- heteroaryl, any of which may be optionally substituted with one or more F, OH or C1.3 alkoxy groups;
R] and R2 are independently selected from H, -e alkyl, C1-3 alkyl-aryl, aryl, Ci-3 all l- heteroaryl and heteroaryl, or R! and R2 taken together may form a 3~ to 7-membered carbocyclic ring; optionally substituted with halogen, C1.3 alkoxy or C1.3 alkyl:
R3 and R4 are independently selected from H, F,€5.3 alkyl. OH or€5 ,3 alkoxy;
Rn to R! 4 are independently selected from H and Cl¾
W is CH2, CHF, CF2, O, CH(OH), C(OH)do alkyl, CH(OC|.3 alkyl), C(OC,.3 alkyl)Ci-3 alkyl, -CH(Ci_3 alkyl) or ~C(C;.3 alkyl)(Ci-3 alkyl);
R99 is H, C e alkyl, -(CH2)n-aryl, -(CH2)n-heteroaryl or -(CH2)P~Q~aryi where aryl or heteroaryl groups may be optionally substituted with C3.3 alkyl, C1.3 alkoxy or halogen; or R99 together with R! or R2 form a 5~ to 6-membered nitrogen containing ring;
- no - Y, Υ', Υ2 and Υ3 are independently Ν or CR20 such thai the ring contains 0, 1 or 2 nitrogens;
R 0 is independently selected from H, halogen, C], 6 alkoxy, 0-C3-6 cycloalkyl, 0-(4- to 7-membered heterocyclyl), C] -3 alkyl, NRS6R97, 0-(CH2). Ci.6 a]koxy, 0-(CH2)q-aryl and 0-(CH2)q-heteroaryl;
R96 and R9'are independently selected from H, Cj,3 alkyl and cycloalkyl;
X is O, NR6, CR7R8, or C=0 and when Ring is aryl then X can be 0(CH2)r;
11° is H, Ci-3 alkyl. C3.7 cycloalkyl, C<1-3 alky]-C3.7 cycloalkyl, Q.3 alkyl-aryl or alkyl- heieroaryl, any of which may be optionally substituted with one or more F, OH or C1 -3 alkoxy groups;
R7 and Rs independently selected from H, OH, F3 C1-3 alkoxy or C1-3 alkyl, provided that when one of R7 or R* is OH the other cannot be F, OH, or C alkoxy;
Ring is a Ce-io carbocyclic, Ce.io aryl, 6~ to 10-membered heteroaryl ring or a bicyclic structure comprising a 5- or 6- membered aryl or heteroaryl with a 5 or 6 membered carbocycle or heierocycle fused thereto wherein the bicyclic structure bonds to X via one of the atoms on the aryl or heteroaryl moiety, any of which may be optionally substituted by 1 to 3 groups selected from halogen, Cj.3 alkyl optionally substituted by hydroxy or 1 to 3 halogens, Cj.3 alkoxy, CN,
Figure imgf000113_0001
CO (R, s)¾ S02OH, SQ2N(R] 5)2, N(R]5)2,
N(Ri5)2(CO)N(Ri5)2, 0(CH2)q-aryl, 0(CH2)q-heteroaryl, NH(C0)Ci..6 alkyl, OH, aryl, heteroaryl and
Figure imgf000113_0002
provided that Ring is not unsubstituted 4-pyridyl;
R is independently seletected from H and C..3 alkyl;
n is 0, 1 , 2 or 3;
p is 2 or 3;
q is 0, 1 or 2; and
r is 1 or 2
comprising the step of reacting a compound of Formula ΪΪ
Figure imgf000113_0003
wherein Y, Y!, Y2 and Y3 are independently N or CR20 such that the ring contains 0, nitrogens;
- I l l - R2u is independently selected from H, halogen, Cj.6 alkoxy, O-C3.6 cycloalkyi, Q-(4~ to 7-membered heterocyel l), C 1 - aikyl, NR9¾9', O-iCHjJq-Ci-e alkoxy, 0~(Ci-l2)q~aryl and 0~(CH2)q-hetei'oaryl ;
R96 and R9 'are independently selected from H, C5.3 aikyl and C3.6 cycloalkyi;
X is O, NR.6, CR7R8, or C=0 and when Ring is aryl then X can be 0(CH2)r;
R6 is H, C| -3 alkyi. C3..7 cycloalkyi, C1-3 alkyl-C^.? cycloalkyi, Cj. aSkyS-aryl or C1.3 aikyl- heteroaryi, any of which may be optionally substituted with one or more F, OH or C1.3 alkoxy groups;
R7 and R8 independently selected from H, OH, F, Ci-3 alkoxy or C1.3 aikyl, provided that when one of R7 or e is OH the other cannot be F, OH, or C1.3 alkoxy;
Ring is a Ce-io carbocyclic, Ce- o aryl, 6~ to 10-membered heteroaryi ring or a bicyciic structure comprising a 5- or 6- membered aryl or heteroaryi with a 5 or 6 membered carbocyele or heterocycle fused thereto wherein the bicyciic structure bonds to X via one of the atoms on the aryl or heteroaryi moiety, any of which may be optionally substituted by 1 to 3 groups selected from halogen, C1.3 aikyl optionally substituted by hydroxy or 1 to 3 halogens, C M alkoxy, CN, C02R i 5, CON(Ri S)2, S02OH, S02N(R,5)2, N(R15)2,
N(Ri 5)2(CO)N(Ri 5)2s 0(CH2)q-aryl, 0(CH2XrlieteroaryL H(CO)Ci,6 aikyl, OH, aryl, heteroaryi and COCj,3alkyl; provided that Ring is not unsubstituted 4-pyridyl;
R15 is independently seletected from H and Cj.3 aikyl;
n is 0, 1 , 2 or 3;
p is 2 or 3;
q is 0, 1 or 2; and
r is 1 or 2
with a compound of Formula ill
Figure imgf000114_0001
wherein R is C2-6 aikyl, C3.7 cycloalkyi, C1.3 aikyi-C3-7 cycloalkyi, C1.3 alkyi -ary! or C1..3 alkyi- heteroaryi, any of which may be optionally substituted with one or more F, OH or Cj.3 alkoxy groups; R! and R2 are independently selected from H, Cj-6 alkyl, C1.3 alkyl-aryl, aryl, C1.3 alkyl- heteroaryl and heteroaryl, or R! and R taken together may form a 3- to 7-membered earboeyc!ic ring; optionally substituted with halogen, C1.3 alkoxy or C1.3 alkyi;
R3 and R4 are independently selected from H, F,€5.3 alkyl, OH or C]-3 alkoxy;
R1 1 to R14 are independently selected from H and CH3;
W is CH2, CHF, CF2, O, CH(OH), C(OH)C3-3 alkyl, CH(OCi.3 alkyl), C(OCi.3 aikyl)Ci -3 alkyl, -CH(CS..3 alkyl) or -C(Ci-3 alkyl)(C] -3 alkyi);
R¼ is H, C e alkyl, -(CH2)n-aryl, -(CH2)n-heteroaryl or -(CH2)p-0-aryl where aryl or heteroaryl groups may be optionally substituted with Q-3 alkyl, C1-3 alkoxy or halogen; or R99 together with R! or R2 form a 5~ to 6-membered nitrogen containing ring,
and optionally converting to a pharmaceutically acceptable salt.
38. The method of claim 37 wherein the step is carried out in the presence of one or more reagents selected from a base and an amide coupling agent,
39. The method of claim 37 or 38 wherein the compound of formula II is converted to the corresponding acid halide, preferably the acid chloride, prior to reaction with the compound of formula III. 40. A method of synthasising a compound of formula (I):
Figure imgf000115_0001
or a pharmaceutically acceptable salt thereof,
wherein:
R is C2-6 alkyl, C3-? cye-ioalkyl, C1-3 alkyl-C3.7 cycloalkyl, C1-3 alkyl-aryl or Cj-3 alkyl- heteroaryl, any of which may be optionally substituted with one or more F, OH or C 1.3 alkoxy groups; R1 and are independently selected from H, Ci-6 alkyi, C1-3 alkyl-aryl, aryi, Cj-3 alkyl- heteroaryl and heteroaryl, or R! and R* taken together may form a 3- to 7-membered carbocyclic ring; optionally substituted with halogen, Ci.3 alkoxy or Cj„3 alkyi;
R3 and R.4 are independently selected from H, F, Ci-3 alkyl, OH or C]-3 alkoxy;
R" to R14 are independently selected from H and CH3;
W is CH2, CHF, CF2, O, CH(OH), C(OH)C!-3 alkyl. CH(OCi.3 alkyl), C(OCj.3 alkyl)Ci-3 alkyl, -CH(Ci-3 alky!) or -C(C1-3 alkyS)(C!-3 alkyl);
R." is H, Ci-6 alkyl, ~(C¾)r,-aryl, -(CH2)n-heteroaryl or -(CH2)p-0-aryI where aryi or heteroaryl groups may be optionally substituted with C}.3 alkyl C1. alkoxy or halogen; or R99 together with R1 or R2 form a 5~ to 6-membered nitrogen containing ring;
Y, Υ', Y2 and YJ are independently N or CR20 such that the ring contains 0, 1 or 2 nitrogens;
R20 is independently selected from H, halogen, C 1.5 alkoxy, 0-C3_6 cycloalkyi, 0-(4- to 7-membered heteroeyclyl), Ci -3 alkyi, NR96R97, 0-(CH2)q-C]-6 alkoxy, 0-(CH2)q-aryl and 0-(CH2)q-heteroaryl;
R9b and R97are independently selected from H, C1-3 alkyl and C3-6 cycloalkyi;
X is O, NR.6. CR7R8, or C=0 and when Ring is aryi then X can be Q(CH2)r;
R6 is H, Ci-3 alkyl, C3.7 cycloalkyi, alkyl-C3.7 cycloalkyl, C1.3 alkyl-aryl or d.3 alkyl- heteroaryl. any of which may be optionally substituted with one or more F, OH or Ci .3 alkoxy groups;
R7 and independently selected from H, OH, F, C1-3 alkoxy or C1-3 alkyl, provided that when one of R7 or R8 is OH the other cannot be F, OH, or C-1.3 alkoxy;
Ring is a Ce-io carbocyclic, Ce-io aryi, 6- to 10-menibered heteroaryl ring or a bicyclie structure comprising a 5- or 6- membered aryi or heteroaryl with a 5 or 6 membered carbocycle or heterocyele fused thereto wherein the bicyclie structure bonds to X via one of the atoms on the aryi or heteroaryl moiety, any of which may be optionally substituted by 1 to 3 groups selected from halogen, C1.3 alkyl optionally substituted by hydroxy or 1 to 3 halogens, C1-3 alkoxy, CN, CQ2R! 5, CGN(R! 5)2, S02OH, S02N(R35)2; N(R1S)2,
N(Rl5)2(CO)N(RI5)2, 0(CH2)q-aryl, 0(CH2)q-heteroaryl, NH(CO)Cw alkyi, OH, aryi, heteroaryl and COCi.3aikyl; provided that Ring is not unsubstituied 4-pyridyl;
R15 is independently seletected from H and C1.3 alkyl;
n is 0, 1, 2 or 3;
p is 2 or 3: q is 0, 1 or 2; and
r is 1 or 2
comprising the step of reacting a compound of Formula V
Figure imgf000117_0001
R is C2.6 alkyl, C3.7 cycloalkyl, C1.3 alkyl-C3.7 cycloalkyl, -3 alkyl-aryl or C1.3 alkyl- heteroaryl, any of which may be optionally substituted with one or more F, Oil or C..3 alkoxy groups;
R! and R are independently selected from H, -e alkyl, d.3 alkyl-aryl, aryl, d-3 alkyl- heteroaryl and heteroaryl, or R' and R2 taken together may form a 3- to 7-membered carbocyciic ring; optionally substituted with halogen, C1-3 alkoxy or C1-3 alkyl;
R3 and R4 are independently selected from H, F, C1-3 alkyl, OH or d.3 alkoxy;
R' ! to R'4 are independently selected from H and CH3;
W is CH2, CHF, CF2, O, CH(OH), C(GH)d-3 alkyl, CH(Od-3 alkyl), C(OCi_3 alkyi)C] -3 alkyl, -CH(C1-3 alkyl) or -C(CM alkyl)(Ci.3 alkyl);
R99 is H, C 1-6 alkyl, -(CI-I2)n-aryl, -(CH2)n~heteroaryl or -(CH2)p-0-aryl where aryl or heteroaryl groups may be optionally substituted with -3 alkyl, .3 alkoxy or halogen; or R99 together with R! or form a 5- to 6-membered nitrogen containing ring;
Y, Y1, Y2 and Y3 are independently N or CR"40 such that the ring contains 0, 1 or 2 nitrogens;
R20 is independently selected from H, halogen, -6 alkoxy, O-C3-6 cycloalkyl, 0-(4- to 7-membered heterocyciyi), -3 alkyl, NR9bR97, 0-(CH2)q-C].6 alkoxy, 0-(CH2)q-aryl and 0-(CH2)q-heteroaryl;
R96 and R97 are independently selected from H, d-3 alkyl and C3.6 cycloalkyl;
with a compound of Formula XXXVII
H-X-Ring
XXXVII
or a boronic acid or boronic ester thereof,
wherein X is O, NR6, CR'R8, or C=0 and when Ring is aryl then X can be 0(C¾)r; 6 is H, Cj.3 alkyl, C3.7 cyeloalkyl, C1.3 alkyl-C3-7 cycioalkyl, C3.3 alkyl-aryl or C]-3 alkyl- heteroaryl, any of which may be optionally substituted with one or more F, OH or Cj-3 aikoxy groups;
R' and 8 independently selected from H, OH, F, C-._3 aikoxy or Ci„3 alkyl, provided that when one of R7 or R8 is OH the other cannot be F, OH, or Ci-3 aikoxy;
Ring is a C6-io carboeyciic, Ce-io aryl, 6~ to 10-membered heieroaryl ring or a bieyclic structure comprising a 5~ or 6- membered aryl or heteroaryl with a 5 or 6 membered carbocycle or heterocycie fused thereto wherein the bicyciic structure bonds to X via one of the atoms on the aryl or heteroaryl moiety, any of which may be optionally substituted by 1 to 3 groups selected from halogen, C-..3 alkyl optionally substituted by hydroxy or 1 to 3 halogens, Ci.3 aikoxy, CN, C02Ri s, C0N(R1S)2, S02OH, S021 (R15)2, N(R15)2,
N(R15)2(CO)N(R,s)2, 0(CH2)q-aryI. Q(C¾)q-heteroaryl, NH(CO)Cw alkyl, OH, aryl, heteroaryl and COCi-3aikyl; provided that Ring is not unsubstituted 4-pyridyl;
ίΙΐΛ is independently seletected from H and .3 alkyl;
n is 0, 1 , 2 or 3;
p is 2 or 3;
q is 0, 1 or 2; and
r is 1 or 2
and optionally converting to a pharmaceutically acceptable salt.
41. The method of claim 40 wherein the step is carried out in the presence of one or more reagents selected from a base and a catalyst, preferably a Pd or Cu based catalyst.
42. The method of claims 40 and 41 wherein the compound of formula V is prepared by reacting a compound of formula III
Figure imgf000118_0001
wherein R is C2-g aikyl, C3-7 cycloalkyl, C1.3 alkyl-C-,.? cycSoalkyl, C1.3 alkyi-aryS or Cj-3 aikyl- heteroaryl, any of which may be optionally substituted with one or more F, OH or Cj -3 aikoxy groups;
R! and Rz are independently selected from H, Ch alky!, C1.3 alkyi-ary!, aryl, CJ.J alkyl- heteroaryl and heteroaryl, or Rl and R2 taken together may form a 3- to 7-rnembered carhocyelie ring; optionally substituted with halogen, C1-3 aikoxy or Ci-s alkyl;
R3 and R4 are independently selected from H, F, C1-3 alkyl, OH or Cj-3 aikoxy;
Rn to ll'4 are independently selected from H and CH3;
W is C¾, CHF, CF2, O, CH(OH), C(OH)Ci.3 alkyl, CH(OCM alkyl), C(OC3-3 alky!)Ci..3 alkyl, ~CH(Ci..3 aikyl) or -C(Ci-3 aikyl)(Ci-3 alkyl);
R99 is H, Cj -6 alkyl, -(CEk ar l,
Figure imgf000119_0001
or -(CH2)p-0-aryl where aryl or heteroaryl groups may be optionally substituted with Cj-3 alkyl, C1-3 aikoxy or halogen; or R^ together with R1 or R2 form a 5- to 6-membered nitrogen containing ring,
with a compound of formula IV
Figure imgf000119_0002
iv
wherein Y, Y!, Y2 and Ys are independently N or CR20 such that the ring contains 0, 1 or 2 nitrogens;
R20 is independently selected from H, halogen, Ci_6 aikoxy, O-C3.6 cycloalkyl, 0-(4- to 7-membered heterocyclyl), C1.3 alkyl, NR96R97, 0-(CH2)q-Ci-6 aikoxy, 0-(CH2)q-aryl and 0-(CH2)q-heteroaryl;
R* and R* ' are independently selected from H, C1.3 alkyl and C3. cycloalkyl.
43. The method of claim 42 wherein the step of reacting a compound of Formula IV with a compound of Formula V is carried out in the presence of one or more reagents selected from a base and an amide coupling agent.
44. The method of claims 42 and 43 wherein the compound of formula IV is converted to the corresponding acid halide, preferably the acid chloride, prior to reaction with the compound of formula V.
45. A method of synthasising a compound of formula (I):
Figure imgf000120_0001
or a pharmaceutical !y acceptable salt thereof,
wherein:
R is C-2-6 alkyl, C3.7 cycI0a.lkyl, C1.3 alkyi-C3.7 cyeioa.kyl, C1-3 aikyl-aryl or C5.3 alkyl- heteroaryl, any of which may be optionally substituted with one or more F, OH or Cj.3 aikoxy groups;
R1 and R2 are independently selected from H, Cj-g alkyl, C1.3 alkyl-aryl, aryl, C1.3 alkyl- heteroaryl and heieroaryl, or R! and R2 taken together may form a 3- to 7-memhered carbocyclic ring; optionally substituted with halogen, C;-3 aikoxy or Q.3 alkyl;
R3 and R4 are independently selected from H, F, C1.3 alkyl, OH or C1..3 aikoxy;
R1 1 to Ri4 are independently selected from H and CH3;
W is CH2, CHF, CF2, O, CH(OH), C(OH)C 3 alkyl, CH(OC,.3 alkyl), C(QC3.3 alkyl)C].3 a!kyl, -CH(Cj.3 alkyl) or -C(C1 -3 alkyl)(Ci.3 alkyl);
R9 is H, Ci-6 alkyl, ~(CH2)n~aryis ~(CH2)n-heteroaryl or -(CH2)P~Q-aryl where aryl or heteroaryl groups may be optionally substituted with C1..3 alkyl, Cj-3 aikoxy or halogen; or R99 together with R5 or R2 form a 5- to 6-memhered nitrogen containing ring;
Y, Y1, Y2 and Y3 are independently N or CR2G such that the ring contains 0, 1 or 2 nitrogens;
ΚΛ' is independently selected from H, halogen, C1-6 aikoxy, O-C3.S cycloalkyl, 0-(4- to 7-membered heterocyclyl), C,-3 alkyl, NR96R97, 0-(CH2)q-Cw aikoxy, 0-(CH2)q-aryl and 0-(CH2)q-heteroaryl;
R 6 and R97 are independently selected from H, C1..3 alkyl and C3-6 cycloalkyl;
X is O, NR6;
Rb is H, Ci-3 alkyl, C3.7 cycloalkyl, C1.3 alkyl-C3.7 cycloalkyl, Cj.3 alkyl-aryl or C1.3 alkyl- heteroaryl, any of which may be optionally substituted with one or more F, OH or Cj .3 aikoxy groups; Ring is a C6-10 carbocyciic, C6-;o aryi, 6- to I G-membered heteroaryl ring or a bicyclic structure comprising a 5- or 6- membered aryi or heteroaryl with a 5 or 6 membered carbocycle or heteroeycle fused thereto wherein the bicyclic structure bonds to X via one of the atoms on the aryi or heteroaryl moiety, any of which may be optionally substituted by 1 to 3 groups selected from halogen, d-s alkyl optionally substituted by hydroxy or 1 to 3 halogens, Ci.3 alkoxy, CN, C02R15, CON(Rt5)2, S02OH, S02N(R!5)2, N(R!5)2,
N(R! 5)2(CO)N(R! 5)2, 0(C¾) -ary], 0(CH2)q-heteroaryi5 NH(CO)d-6 alkyl, OH, aryi, heteroaryl and COCi-3alkyl; provided that Ring is not unsubstituted 4-pyridyl;
R15 is independently seletected from H and d-3 alkyl;
n is 0, 1, 2 or 3;
p is 2 or 3 ;
q is 0, 1 or 2; and
r is 1 or 2
comprising the step of re
Figure imgf000121_0001
wherein:
R is C2_6 alkyl, C3..7 cycloalkyl, d.3 alkyl-Cs.? cycloaikyl, d-3 alkyl-aryl or C1.3 alkyl- heteroaryl, any of which may be optionally substituted with one or more F, OH or .3 alkoxy groups;
R' and R2 are independently selected from H, d-6 alkyl, -3 alkyl-aryl, aryi, Ci-3 alkyl- heteroaryl and heteroaryl, or R! and R2 taken together may form a 3- to 7-membered carbocyclic ring; optionally substituted with halogen, d-3 alkoxy or d-3 alkyl;
R' and R4 are independently selected from II, F,€3.3 alkyl, OH or C1.3 alkoxy;
R! ! to i are independently selected from H and CH3;
W is CH2, CHF, CF2, O, CH(OH), C(OH)C]-3 alkyl, CH(Od.3 alkyl), C(OCi.3 aIk l)Ci_3 alkyl -CH(C1-3 alkyl) or -C(d.3 aikyl)(d-3 alkyl);
R99 is H, d-6 alkyl, -(CH2)n-aryl, -(Cl¾)n-heteroaryl or -(CH2)p-0-aryl where aryi or heteroaryl groups may be optionally substituted with d-3 alkyl, -3 alkoxy or halogen; or R99 together with R1 or R2 form a 5- to ό-mernbered nitrogen containing ring: Y, Y\ and Υ3 are independently Ν or CR20 such that the ring contains 0, 1 or 2 nitrogens;
R20 is independently selected from H, halogen, Ci^ alkoxy, Q- s cycloalkyl, 0-(4- to 7-membered heteroeyclyi), C1-3 alkyl, NR96R97, 0-(CH2)q-C]-6 alkoxy, 0-(CH2)q-aryl and 0-(CH2)q-heteroaryl;
R96 and R.97are independently selected from H, C|.3 alkyl and C3-s cycloalkyl;
X is O, NR6;
R6 is H, Ci-3 alkyl, C3.7 cycloalkyl, C1-3 alkyl-C3-7 cycloalkyl, C1-3 alkyl-aryl or€-..3 alkyl- heteroaryl, any of which may be optionally substituted with one or more F, OH or Cj.3 alkoxy groups;
With a compound of Formula XXXVIII
X'-Ring
XXXVIII
Ring is a Ce-jo carbocyclic, C -io aryl, 6- to 10-membered heteroaryl ring or a bicyclic structure comprising a 5- or 6- membered aryl or heteroaryl with a 5 or 6 membered carbocycle or heierocycle fused thereto wherein the bicyclic structure bonds to XJ via one of the atoms on the aryl or heteroaryl moiety, any of which may be optionally substituted by I to 3 groups selected from halogen, Cj.3 alkyl optionally substituted by hydroxy or 1 to 3 halogens, C 1 -3 alkoxy, CN, C02R! 5, CON(RI 5)2, S02OH, S02N(RJS)2, N(Rls)2,
N(RS 5)2(CO)N(R! 5)2, 0(CH2)q-aryl, 0(C¾)q-heteroaiyl. NH(CO)Cw alkyl, OH, ary!, heteroaryl and COCi-3alkyl; provided that Ring is not unsubstituted 4-pyridyl;
R15 is independently seietected from H and Cj.3 alkyl;
n is 0, 1, 2 or 3;
p is 2 or 3;
q is 0, 1 or 2; and
r is 1 or 2 and
X: is a leaving group, preferably a boronic acid or boronic ester group; and optionally converting to a pharmaceutically acceptable salt,
46, The method of claim 45 wherein the reaction is carried out in the presence of one or more reagents selected from a base and a catalyst, preferably a Pd or Cu based catalyst.
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CN104496896A (en) * 2014-05-21 2015-04-08 江西科技师范大学 Preparation and application of sorafenib derivative containing sulfonylurea structure
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