WO2008059214A1 - Bisamlde derivatives and use thereof as fatty acid synthase inhibitors - Google Patents

Bisamlde derivatives and use thereof as fatty acid synthase inhibitors Download PDF

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Publication number
WO2008059214A1
WO2008059214A1 PCT/GB2007/004293 GB2007004293W WO2008059214A1 WO 2008059214 A1 WO2008059214 A1 WO 2008059214A1 GB 2007004293 W GB2007004293 W GB 2007004293W WO 2008059214 A1 WO2008059214 A1 WO 2008059214A1
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phenyl
methyl
carbonyl
piperidine
carboxamide
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PCT/GB2007/004293
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French (fr)
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Jonas BOSTRÖM
Kay Brickmann
Petra Johannesson
Laurent Daniel Knerr
Annika Petersson
Volker Schnecke
Christer Westerlund
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Astrazeneca Ab
Astrazeneca Uk Limited
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Publication of WO2008059214A1 publication Critical patent/WO2008059214A1/en

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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
    • C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D205/04—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • 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
    • A61P3/04—Anorexiants; Antiobesity agents
    • 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
    • A61P3/06—Antihyperlipidemics
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom 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
    • C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom 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 radicals, substituted by hetero atoms, attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
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    • 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
    • C07D211/10—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 radicals containing only carbon and hydrogen atoms attached to ring carbon atoms
    • C07D211/16—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 radicals containing only carbon and hydrogen atoms attached to ring carbon atoms with acylated ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
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    • 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
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    • 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
    • C07D211/20—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 singly bound oxygen or sulphur atoms
    • C07D211/22—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 singly bound oxygen or sulphur atoms by oxygen atoms
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    • 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
    • C07D211/20—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 singly bound oxygen or sulphur atoms
    • C07D211/24—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 singly bound oxygen or sulphur atoms by sulfur atoms to which a second hetero atom is attached
    • C—CHEMISTRY; METALLURGY
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    • 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
    • C07D211/28—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 to which a second hetero atom is attached
    • 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
    • C07D211/34—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 carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • 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
    • C07D211/36—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 hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/40—Oxygen atoms
    • C07D211/44—Oxygen atoms attached in position 4
    • C07D211/46—Oxygen atoms attached in position 4 having a hydrogen atom as the second substituent in position 4
    • 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
    • C07D211/36—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 hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D211/62—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals attached in position 4
    • 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
    • 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
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • 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
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
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    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention relates to novel benzamides, particularly to bisamides that are substituted N-[3-(4-phenylpiperidine-l-carbonyl)phenyl]carboxamides, to processes for preparing such compounds, to their use as Fatty Acid Synthase inhibitors, to methods for their therapeutic use, particularly in the treatment of obesity and diabetes mellitus, and to pharmaceutical compositions containing them.
  • Obesity and diabetes are reaching epidemic proportions in the USA, EU, Japan and developing countries.
  • Obesity is the major driver of the co-morbidities of the metabolic syndrome, particularly type 2 diabetes. Since no effective pharmacotherapies for obesity are available to date and current diabetes therapies do not stop the progression of the disease, there is a huge unmet medical need.
  • Fatty Acid Synthase is a critical enzyme for endogenous lipogenesis and plays an important role in the modulation of key intermediates of lipid and carbohydrate cellular metabolism.
  • FAS is highly expressed in the tissues with high metabolic activity (for example liver, adipose tissue and brain) and there are good reasons to believe that a FAS inhibitor would cause beneficial metabolic effects in peripheral tissues.
  • inhibition of FAS in the hypothalamus may result in reduced food intake.
  • the non-specific irreversible FAS inhibitors cerulenin and C-75 have been reported in the literature to decrease brain levels of orexigenic neuropeptides and to decrease food intake.
  • the present invention provides a compound of formula I
  • R 1 represents
  • Ci- 6 alkyl group a C 2-6 alkenyl group or a C 2-6 alkynyl group each of which is optionally substituted
  • optionally substituted means that any available carbon in R 1 is optionally substituted by one or more of the following 1) hydroxy 2) halo, 3) a Ci -6 alkoxy group optionally substituted by one or more of the following: halo, OH , C ⁇ alkoxy, phenyl or by a group of formula NR c R d in which R c and R d are as defined below 4) carboxy 5) C 1-6 alkoxycarbonyl 6) carbamoyl 7) N-Q- ⁇ alkylcarbamoyl 8) N, N-diCi- 6 alkylcarbamoyl 9) sulphamoyl 10) N-Ci.
  • ⁇ alkylsulphonyl group a Ci -6 alkoxycarbonyl group; a Ci -6 alkyl group optionally substituted by one or more hydroxy or , or R c and R d together with the nitrogen atom to which they are attached represent a saturated or partially unsaturated 3 to 8 membered heterocyclic ring optionally containing an additional sulphur including oxidised as SO or SO 2 , oxygen or nitrogen and/or optionally fused to a benz ring and/or optionally substituted by one or more of the following: a Ci- ⁇ alkoxy group; hydroxy; oxo; or a Ci- ⁇ alkyl group optionally substituted by one or more hydroxy or C 1-6 alkoxy; v) a C 3-1 ocycloalkyl group which may be monocyclic, bicyclic or tricyclic and optionally may be bridged ; vi) phenyl optionally substituted by one or more of the following: halo; C 1-3 alkyl; Ci
  • a Ci- ⁇ alkoxy group a Ci- ⁇ alkano
  • any cycloalkyl, phenyl, heteroaryl ring or carbon linked saturated or partiallys saturated 3 to 8 membered heterocyclic group in this list of optional substituents in 1 to 27 above is optionally substituted by one or more of the following: i) a Ci -3 alkyl group optionally substituted by one or more halo ii) a Ci -3 alkoxy group optionally substituted by one or more halo iii) halo, iv) nitro, v) cyano vi) hydroxy vii) a group of formula NR Q R d in which R c and R d are as defined above viii) carboxy ix) a group Q optionally substituted by one or more halo; x) a C ⁇ alkylsulphonyloxy group optionally substituted by one or more halo xi) carbamoyl xii) N-Ci ⁇
  • 3alkylcarbamoyl xiv) sulphamoyl xv) N-Ci-oalkylsulphamoyl xvi) N, N-diCi- 3alkylsulphamoyl and any alkyl, alkenyl or alkynyl chain in this list of optional substituents 1 to 29 above is optionally substituted by one or more of the following: i) a C 1- 5 3 alkyl group optionally substituted by one or more halo ii) a C 1-3 alkoxy group optionally substituted by one or more halo iii) halo, iv) nitro v) cyano vi) hydroxy vii) a group of formula ⁇ R c R d in which R c and R d are as defined above; and wherein an optionally substituted carbon linked saturated or partially saturated 3 to 8 membered heterocyclic group containing one or more N, S, SO, SO 2 or O described in c)
  • R 3 represents H; halo; hydroxy; a C ⁇ alkyl group optionally substituted by one or more halo; a Ci ⁇ alkoxy group optionally substituted by one or more halo; or cyano;
  • R 4 represents i) H, ii) a Ci ⁇ alkyl group optionally substituted by one or more halo iii) a C 1- 3 alkoxy group optionally substituted by one or more halo iv) halo, v) nitro, vi) cyano, vii) a Ci -6 alkylS(O)y(O)z- wherein y is 0,1 or 2 and z is 0 except when y is 2 when z is 0 or 1 viii) a group CH 2 NR U R V in which R u and R v independently represent H, a Ci_ 6 alkylsulphonyl group, a Ci- ⁇ alkanoyl group or a Ci ⁇ alkyl group optionally substituted by one or more of the following: hydroxy, a C 1-6 alkoxy group or a group of formula NR c R d in which R c and R d are as defined above or R u and R v together with the nitrogen atom to which
  • R 5 and R 5 independently represent H, halo, cyano, Ci- 3 alkyl optionally substituted by one or more halo or Ci- 3 alkoxy optionally substituted by one or more halo;
  • R 6 and R 6 independently represent H, halo, cyano, optionally substituted by one or more halo or Ci ⁇ alkoxy optionally substituted by one or more halo;
  • L represents a bond or CH 2 ;
  • m and n independently represent 0 or 1; with the proviso that when R 1 is CH 3 , R 2 is CH 3 , and R 3 , R 4 , R 5 , R 5' , R 6 , R 6' are each H, m is 1 and n is 1 then L is not CH 2 .
  • R 1 represents an optionally substituted Ci- ⁇ alkyl group.
  • R 1 represents an optionally substituted C 3- iocycloalkyl group which may be monocyclic, bicyclic or tricyclic and optionally may be bridged.
  • R 1 represents an optionally substituted carbon linked saturated or partially saturated 3 to 8 membered heterocyclic group containing one or more N, S, SO, SO 2 or O.
  • R 1 represents an optionally substituted heteroaryl including N-oxides thereof.
  • R 1 represents an optionally substituted phenyl.
  • R 1 represents an optionally substituted pyridyl.
  • n are each 1.
  • L represents a bond
  • R 2 represents halo; hydroxy; a C 1 - 3 alkyl group optionally substituted by one or more halo; a Ci -3 alkoxy group optionally substituted by one or more halo; or cyano and R 3 represents halo; hydroxy; a C ⁇ alkyl group optionally substituted by one or more halo; a Ci -3 alkoxy group optionally substituted by one or more halo; or cyano.
  • R 2 represents a C 1-3 alkyl group, particularly methyl.
  • R 3 represents H or a C ⁇ alkyl group, particularly methyl.
  • R 4 represents methyl, methoxy, chloro, nitro, CF 3 or cyano.
  • R 5 , R 5' , R 6 , R 6 are each H.
  • the term optionally substituted has the meaning as initially defined and the other unmentioned substituents in a group are selected from R 1 , R 2 , R 3 , R 4 , R 5 , R 5 R 6 , R 6 , L, m and n are as initially defined or as defined in any of groups one to thirteen or in any of the compound groups, claims or embodiments defined hereinbefore or hereinafter.
  • “Pharmaceutically acceptable salt”, where such salts are possible, includes both pharmaceutically acceptable acid and base addition salts.
  • a suitable pharmaceutically acceptable salt of a compound of formula I is, for example, an acid-addition salt of a compound of formula I which is sufficiently basic, for example an acid-addition salt with an inorganic or organic acid such as hydrochloric, hydrobromic, sulphuric, trifluoroacetic, citric or maleic acid; or, for example a base-addition salt of a compound of formula I which is sufficiently acidic, for example an alkali or alkaline earth metal salt such as a sodium, calcium or magnesium salt, or an ammonium salt, or a salt with an organic base such as methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine.
  • a given chemical formula or name shall encompass all stereo and optical isomers and racemates thereof as well as mixtures in different proportions of the separate enantiomers, where such isomers and enantiomers exist, as well as pharmaceutically acceptable salts thereof and solvates thereof such as for instance hydrates including solvates of the free compounds or solvates of a salt of the compound.
  • Isomers may be separated using conventional techniques, e.g. chromatography or fractional crystallisation.
  • the enantiomers may be isolated by separation of racemate for example by fractional crystallisation, resolution or HPLC.
  • the diastereomers may be isolated by separation of isomer mixtures for instance by fractional crystallisation, HPLC or flash chromatography.
  • stereoisomers may be made by chiral synthesis from chiral starting materials under conditions that will not cause racemisation or epimerisation, or by derivatisation, with a chiral reagent. All stereoisomers are included within the scope of the invention. All tautomers, where possible, are included within the scope of the invention.
  • the present invention also encompasses compounds containing one or more isotopes for example 14 C, 11 C or 19 F and their use as isotopically labelled compounds for pharmacological and metabolic studies.
  • the present invention also encompasses prodrugs of a compound of formula I that is compounds which are converted into a compound of formula I in vivo.
  • prodrugs of a compound of formula I that is compounds which are converted into a compound of formula I in vivo.
  • C 3- iocycloalkyl group which may be monocyclic, bicyclic or tricyclic and optionally may be bridged” includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, bicyclo(2.2.1)heptyl, bicyclo(2.2.2)octyl, perhydroindanyl and adamantyl.
  • heteroaryl includes pyrrolyl, thienyl, furyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, 1,3,4-oxadiazolyl, 1,2,4- oxadiazolyl, triazolyl, furazanyl, tetrazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, 1,3,5-triazinyl quinolyl, isoquinolyl, benzthienyl, benzofuranyl, benzofurazanyl, benzoxazolyl, benzimidazolyl, indolyl, benzthiazolyl, indazolyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, 1,5-naphth
  • heteroaryl including N-oxides includes heteroaryls as described immediately above and in addition N-oxides of such heteroaryls where such N-oxides are known to those skilled in the art to exist and are known to be stable at ambient conditions for example pyridine-N-oxides.
  • a carbon linked saturated or partially saturated 3 to 8 membered heterocyclic group containing one or more ⁇ , S, SO, SO 2 or O includes oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, 2,3-dihydro-l,3-thiazolyl, 1,3-thiazolidinyl, 1,3-oxazolidinyl, oxepanyl, aziridinyl, azetidinyl, pyrrolinyl, pyrrolidinyl, morpholinyl, thiamorpholinyl (perhydro-l,4-thiazinyl), (8-oxa-3-azabicyclo[3.2.1]octyl), (7-oxa-3- azabicyclo[3.1.1]heptyl), perhydroazepinyl, perhydrooxazepinyl, tetrahydro-l,4-thiazinyl,
  • alkyl denotes either a straight or branched alkyl group.
  • alkyl examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, sec-butyl , t-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, hexyl and isohexyl.
  • Preferred alkyl groups are methyl, ethyl, propyl, isopropyl, butyl and tertiary butyl.
  • alkoxy denotes a group O-alkyl, wherein alkyl is as defined above.
  • halogen shall mean fluorine, chlorine, bromine or iodine.
  • C 1-6 alkanoyloxy is acetoxy.
  • C 1-6 alkoxycarbonyl examples include Examples of “Ci-ealkoxycarbonylamino” include methoxycarbonylamino, ethoxycarbonylamino, n- and /-butoxycarbonylamino.
  • Examples of "Ci- ⁇ alkoxy” include methoxy, ethoxy and propoxy.
  • Examples of "Ci- ⁇ alkanoylamino” include formamido, acetamido and propionylamino.
  • Examples of “Ci- 6 alkylS(O) a wherein a is 0 to 2" include Ci -4 alkylsulphonyl, methylthio, ethylthio, methylsulphinyl, ethylsulphinyl, mesyl and ethylsulphonyl.
  • Examples of “Ci. 6 alkylsulphonylamino” include methylsulphonylamino, ethylsulphonylamino and propylsulphonylamino. Examples of "Ci.
  • 6 alkylsulphonyl-N-(C 1-6 alkyl)amino include methylsulphonyl-N-methylamino, ethylsulphonyl-N-methylamino and propylsulphonyl-iV-ethylamino.
  • Examples of "Ci -6 aUcanoyl” include Ci -4 alkanoyl, propionyl and acetyl.
  • Examples of "N-(Ci -6 alkyl)amino” include methylamino and ethylamino.
  • N,N-(Ci-6alkyl) 2 amino examples include di-iV-methylamino, di-(N-ethyl)amino and N-ethyl-N-methylamino.
  • C 2-6 alkenyl examples are vinyl, allyl and 1-propenyl.
  • C 2 . 6 alkynyl examples are ethynyl, 1-propynyl and 2-propynyl.
  • Examples of " ⁇ (Ci.ealky ⁇ sulphamoyl” are N-(methyl)sulphamoyl and N-(ethyl)sulphamoyl.
  • N-(C 1 - 6 alkyl) 2 sulphamoyl are N,N-(dimethyl)sulphamoyl and N-(methyl)-N-(ethyl)sulphamoyl.
  • N-(C 1 . 6 alkyl)carbamoyl are N-(Ci- 4 alkyl)carbamoyl, methylaminocarbonyl and ethylaminocarbonyl.
  • Examples of "NN-(Ci. 6 alkyl) 2 carbamoyl” are N,N-(C 1-4 alkyl)carbamoyl, dimethylaminocarbonyl and methylethylaminocarbonyl.
  • Examples of “C 3-8 cycloalkyl ring” are cyclopropyl and cyclohexyl.
  • Examples of “(heterocyclic group)C 1-6 alkyl” include pyridylmethyl, 3-mo ⁇ holinopropyl and 2-pyrimid-2-ylethyl.
  • Examples of “Cs-scycloalkylCi-gcycloalkyl” include cyclopropylmethyl and 2-cyclohexylpropyl.
  • 'W-(Ci- 6 alkyl)sulphamoylamino are N-(methyl)sulphamoylamino and N-(ethyl)sulphamoylamino.
  • N-(C 1-6 alkyl) 2 sulphamoylamino are N,N-(dimethyl)sulphamoylamino and N-(methyl)-N-(ethyl)sulphamoylamino.
  • Examples of "Ci-ealkylsulphonylaminocarbonyl” include methylsulphonylaminocarbonyl, ethylsulphonylaminocarbonyl and propylsulphonylaminocarbonyl.
  • R 1 represents
  • an optionally substituted heteroaryl selected from: 3-pyridyl, 3-pyridyl-N-oxide, 4- pyridyl, 4-pyridyl-N-oxide, quinolyl, isoquinolyl, pyrazinyl, benzthiazolyl, pyrimidyl, cinnolyl, pyridazinyl, imidazopyridinyl, thiazolyl, pyrazolopyridinyl, or oxadiazinyl; or e) optionally substituted phenyl; wherein optionally substituted means that any available carbon in R 1 is optionally substituted by one or more of the followingl) hydroxy 2) halo, 3) a C 1-6 alkoxy group optionally substituted by one or more of the following: halo, OH , Ci -6 alkoxy, phenyl or by a group of formula ⁇ R c R d in which
  • alkyl is optionally substituted by one or more fluoro 19) cyano 20) phenyl 21) heteroaryl 22) substituted phenoxy 23) oxo or 24) a group ⁇ R a R b in which R a and R b independently represent i) H ii) Ci_ 6 alkanoyl iii) a carbon linked saturated or partially unsaturated 3 to 8 membered heterocyclic group containing one or more N, S, SO, SO 2 or O which is optionally fused to a benz ring and/or is optionally substituted by one
  • ⁇ alkylsulphonyl group; a d- ⁇ alkoxycarbonyl group; a Q-ealkyl group optionally substituted by one or more hydroxy or C 1-6 alkoxy , or R c and R d together with the nitrogen atom to which they are attached represent a saturated or partially unsaturated 3 to 8 membered heterocyclic ring optionally containing an additional sulphur including oxidised as SO or SO 2 , oxygen or nitrogen and/or optionally fused to a benz ring and/or optionally substituted by one or more of the following: a C 1-6 alkoxy group; hydroxy; oxo; or a C 1- ealkyl group optionally substituted by one or more hydroxy or Ci- ⁇ alkoxy; v) a Cs-iocycloalkyl group which may be monocyclic, bicyclic or tricyclic and optionally may be bridged ; vi) phenyl optionally substituted by one or more of the following: halo;
  • a Ci. 6 acylamino group carbamoyl; N-Ci- 6 alkylcarbamoyl; N,N-diC ⁇ . 5 ⁇ alkylcarbamoyl; vii) heteroaryl; viii) a Ci- ⁇ alkoxycarbonyl group; ix) R a and R b together with the nitrogen atom to which they are attached represent a saturated or partially unsaturated 3 to 8 membered heterocyclic ring optionally containingo an additional oxygen, sulphur, SO, SO 2 or nitrogen and/or optionally fused to a benz ring and/or optionally substituted by one or more of the following: a Ci- 6 alkoxy group; a Ci- ⁇ acyl group; a Ci ⁇ aUcoxycarbonyl group; carbamoyl; N-Ci- ⁇ alkylcarbamoyl; N, N-diCi.
  • a C 3- iocycloalkyl group which may be monocyclic, bicyclic or tricyclic and optionally may be bridged; o 26) a carbon linked saturated or partially saturated 3 to 8 membered heterocyclic group containing one or more N, S, SO, SO 2 or O which is optionally substituted by one or more of the following: a Ci -6 alkoxy group; a C 1-6 alkanoyl group; a Ci- ⁇ alkoxycarbonyl group; carbamoyl; iV-C L ⁇ alkylcarbamoyl; N, N-diCi- 6 alkylcarbamoyl; hydroxy; oxo; a Ci- ⁇ alkyl group (which is optionally substituted by one or more of the following: a Ci_ 6 alkoxy group,5 hydroxy or a group of formula ⁇ R c R d in which R c and R d are as defined above) or 27) by a Ci-6alkyl group optionally substituted
  • any cycloalkyl, phenyl, heteroaryl ring or carbon linked saturated or partially saturated 3 to 8 membered heterocyclic group in this list of optional substituents in 1 to 27o above is optionally substituted by one or more of the following: i) a Ci -3 alkyl group optionally substituted by one or more halo ii) a Ci -3 alkoxy group optionally substituted by one or more halo iii) halo, iv) nitro, v) cyano vi) hydroxy vii) a group of formula NR c R d in which R 0 and R d are as defined above viii) carboxy ix) a Ci- ⁇ alkylsulphonyl group optionally substituted by one or more halo; x) a Ci_ 6 alkylsulphonyloxy group optionally substituted by one or
  • 3alkylsulphamoyl and any alkyl, alkenyl or alkynyl chain in this list of optional substituents 1 to 29 above is optionally substituted by one or more of the following: i) a Ci- 3 alkyl group optionally substituted by one or more halo ii) a Ci_ 3 alkoxy group optionally substituted by one or more halo iii) halo, iv) nitro v) cyano vi) hydroxy vii) a group of formula ⁇ R c R d in which R° and R d are as defined above;
  • R 2 represents halo; a Ci ⁇ alkyl group optionally substituted by one or more halo;or a C 1 . 3 alkoxy group optionally substituted by one or more halo;
  • R 3 represents H; a C 1-3 alkyl group optionally substituted by one or more halo; or a Ci- 3 alkoxy group optionally substituted by one or more halo;
  • R 4 represents i) H, ii) a Ci ⁇ alkyl group optionally substituted by one or more halo iii) a Ci- 3 alkoxy group optionally substituted by one or more halo iv) halo, v) nitro, vi) cyano, vii) a C 1-6 alkylS(O) y (O)z- wherein y is 0,1 or 2 and z is 0 except when y is 2 when z is 0 or 1 viii) a group CH 2 NR U R V in which R u and R v independently represent H or a Ci ⁇ alkyl group optionally substituted by one or more of the following: hydroxy, a C ⁇ alkoxy group or a group of formula NR c R d in which R c and R d are as defined above or R u and R v together with the nitrogen atom to which they are attached represent a saturated or partially unsaturated 3 to 8 membered heterocyclic ring optionally containing
  • R x and R y independently represent H; or a Ci ⁇ alkyl group optionally substituted by phenyl wherein the phenyl is optionally substituted by one or more C 1 . 3 alkyl, halo or Ci ⁇ alkoxy; or R x and R y together with the nitrogen atom to which they are attached represent a saturated or partially unsaturated 3 to 8 membered heterocyclic ring optionally containing an additional sulphur, oxygen or nitrogen optionally substituted by one or more of the following: a Ci ⁇ alkyl group optionally substituted by one or more hydroxy or Ci- ⁇ alkoxy; a Ci -6 alkoxy group; hydroxy; Q ⁇ acy!
  • R 5 represents H, C 1-3 alkyl or halo
  • R 6 represents H, C 1-3 alkyl or halo
  • L represents a bond or CH 2
  • m and n independently represent 0 or 1 provided that m and n do not simultaneously represent 0.
  • R a represents a substituent from 1 to 29 as described above
  • R b represents represents halo; a C ⁇ alkyl group optionally substituted by one or more halo; a group optionally substituted by one or more halo;
  • R 2 represents a Ci -3 alkyl group, a C 1-3 alkoxy group, hydroxy, CF 3 or halo;
  • R 4 represents H, a C 1-6 alkyl group, a Ci- ⁇ alkoxy group, halo, nitro, CF 3 , SO 2 Me, CH 2 NR x R y , CO NR x R y or cyano;
  • R c represents H, a C ⁇ alkyl group or halo; and m and n independently represent 0 or 1.
  • R a represents trifluoromethoxy, tert-butyl or phenyl
  • R 2 represents methyl
  • R 4 represents methoxy
  • R a represents 1) hydroxy 2) halo, 3) a C ⁇ alkoxy group optionally substituted by one or more of the following: halo, OH , Ci_ 6 alkoxy, phenyl or by a group of formula
  • R a and R b independently represent i) H ii) Ci- ⁇ alkanoyl iii) a carbon linked saturated or partially unsaturated 3 to 8 membered heterocyclic group containing one or more N, S, SO, SO 2 or O which is optionally fused to a benz ring and/or is optionally substituted by one or more of the following: hydroxy, oxo, a Ci- ⁇ alkoxy group hydroxy, Ci -4 acyl, amino, C 1-3 alky lamino, di(Ci -3 alkyl)amino or a Ci- ⁇ alkyl optionally substituted by one or more hydroxy or Q- ⁇ alkoxy iv) a Ci. ⁇ alkyl group optionally substituted by one or more of the following: hydroxy; carboxy; a Ci.6alkoxycarbonyl group; a Ci- ⁇ alkoxy group; heteroaryl; a group of formula NR c R
  • ⁇ alkylsulphonyl group a Ci- ⁇ alkoxycarbonyl group; a Ci ⁇ alkyl group optionally substituted by one or more hydroxy , or C ⁇ 6 alkoxy , or R c and R d together with the nitrogen atom to which they are attached represent a saturated or partially unsaturated 3 to 8 membered heterocyclic ring optionally containing an additional sulphur including oxidised as SO or SO 2 , oxygen or nitrogen and/or optionally fused to a benz ring and/or optionally substituted by one or more of the following: a Ci- ⁇ alkoxy group; hydroxy; oxo; or a C 1 , 6alkyl group optionally substituted by one or more hydroxy or v) a C 3 -iocycloalkyl group which may be monocyclic, bicyclic or tricyclic and optionally may be bridged ; vi) phenyl optionally substituted by one or more of the following: halo; C ⁇ alkyl
  • a Cs-iocycloalkyl group which may be monocyclic, bicyclic or tricyclic and optionally may be bridged; o 26) a carbon linked saturated or partially saturated 3 to 8 membered heterocyclic group containing one or more N, S, SO, SO 2 or O which is optionally substituted by one or more of the following: a Ci ⁇ alkoxy group; a Ci- ⁇ alkanoyl group; a C ⁇ alkoxycarbonyl group; carbamoyl; N-Ci- ⁇ alkylcarbamoyl; N, N-diCi.
  • alkylsulphonyloxy group optionally substituted by one or more halo xi) carbamoyl xii) JV-C 1-3 alkylcarbamoyl xiii) N, N-diCi. 3alkylcarbamoyl xiv) sulphamoyl xv) N-Ci -3 alkylsulphamoyl xvi) N, N-diCi.
  • 3alkylsulphamoyl and any alkyl, alkenyl or alkynyl chain in this list of optional substituents 1 to 29 above is optionally substituted by one or more of the following: i) a Ci- 3 alkyl group optionally substituted by one or more halo ii) a Ci -3 alkoxy group optionally substituted by one or more halo iii) halo, iv) nitro v) cyano vi) hydroxy vii) a group of formula ⁇ R c R d in which R c and R d are as defined above;
  • R b represents halo; a C ⁇ alkyl group optionally substituted by one or more halo; a Ci- 3 alkoxy group optionally substituted by one or more halo;
  • R 2 represents halo; a Ci -3 alkyl group optionally substituted by one or more halo; a C 1 . 3 alkoxy group optionally substituted by one or more halo; or cyano;
  • R 4 represents i) H, ii) a Ci -3 alkyl group optionally substituted by one or more halo iii) a Ci- 3 alkoxy group optionally substituted by one or more halo iv) halo, v) nitro, vi) cyano, vii) a Ci -6 alkylS(O) y (O) z - wherein y is 0,1 or 2 and z is 0 except when y is 2 when z is 0 or 1 viii) a group CH 2 NR U R V in which R u and R v independently represent H or a Ci ⁇ alkyl group optionally substituted by one or more of the following: hydroxy, a Ci ⁇ alkoxy group or a group of formula NR c R d in which R c and R d are as defined above or R u and R v together with the nitrogen atom to which they are attached represent a saturated or partially unsaturated 3 to 8 membered heterocyclic ring optional
  • R x and R y together with the nitrogen atom to which they are attached represent a saturated or partially unsaturated 3 to 8 membered heterocyclic ring optionally containing an additional sulphur, oxygen or nitrogen optionally substituted by one or more of the following: a Ci- 6 alkyl group optionally substituted by one or more hydroxy or Ci -6 alkoxy; a C 1-6 alkoxy group; hydroxy; Ci ⁇ acyl or oxo; R° represents H, Ci -3 alkyl or halo; and m and n independently represent 0 or 1.
  • R a represents: methyl; chloro; CF 3 ; morpholino; methoxycarbonyl; N,N- dimethylcarbamoyl; oxo; a C 1-3 alkoxy group optionally substituted by methoxy; pyrrolidino optionally substituted in the 2-position by oxo; piperidino optionally substituted in the 4-position by hydroxy, amino, methylamino or dimethylamino; 1-piperazinyl optionally substituted in the 4-position by amino or methyl or optionally substituted in the 3 -position by oxo; l,4-oxaze ⁇ an-4-yl; l,l-dioxo-l,4-thiazinan-4-yl; cyclohexyl substituted in the 4-position by methoxy; a group ⁇ R p R q in which R p and R q independently represent H, acetyl, or a C 1-3 alkyl group, or R p represents
  • R represents methyl
  • RR 44 rreepprreesseennttss mmeetthhyyll,, i methoxy, chloro, nitro, CF 3 or cyano;
  • R 5 represents H or alternatively represents chloro when R 4 also represents chloro.
  • R a represents a substituent from 1 to 29 as described above;
  • R b represents H, a C ⁇ aUcyl group or halo;
  • R 2 represents a Ci -3 alkyl group, a Ci -3 alkoxy group, hydroxy, oxo, CF 3 or halo;
  • R 4 represents H, a C ⁇ alkyl group, a Ci- ⁇ alkoxy group, halo, nitro, CF 3 , SO 2 Me, CH 2 NR x R y , CO NR x R y or cyano;
  • R c represents H, a d ⁇ alkyl group or halo; and m and n independently represent 0 or 1.
  • a particular embodiment of the invention is represented by a compound of formula IVA or a pharmaceutically acceptable salt thereof, in which x is 0 or 1 ;
  • R a represents H when x is 1 or when x is 1
  • R a represents 2-amino, 2-(2- hydroxyethyl)amino, 2-(2-oxopiperidino), 3-chloro, or 2-(3-carbamoylanilino);
  • R 2 represents methyl
  • R 4 represents Cl, CF 3 , CH 3 or cyano.
  • R 1 represents 3-quinolyl, 5-thiazolyl, 6-chloro-2-cinnolyl or 4-aza benzimidazol-6-yl
  • R 2 represents methyl
  • R 4 represents cyano
  • Specific compounds of the invention include one or more including any combination of the following compounds below, that is any number of compounds from 1 to 240 inclusive, labelled as List 1 :
  • 6-[(l-ethyl-3-piperidyl)amino]-N-[5-[4-(4-methoxyphenyl)piperidine-l-carbonyl]-2- methyl-phenyl]pyridine-3-carboxamide is 6-(3 -methoxyazetidin- 1 -y I)-N- [5 - [4-(4-methoxyphenyl)piperidine- 1 -carbonyl] -2-methyl- phenyl]pyridine-3-carboxamide
  • a compound of the Formula I, or a pharmaceutically-acceptable salt thereof may be prepared by any process known to be applicable to the preparation of chemically-related compounds. Such processes, when used to prepare a compound of the formula I are provided as a further feature of the invention and are illustrated by the following representative process variants. Necessary starting materials may be obtained by standard procedures of organic chemistiy. The preparation of such starting materials is described in conjunction with the following representative process variants and within the accompanying Examples. Alternatively necessary starting materials are obtainable by analogous procedures to those illustrated that are within the ordinary skill of an organic chemist.
  • a process for preparing a compound of formula I or a pharmaceutically acceptable salt thereof which process comprises of: (a) reacting a compound of formula VI
  • Xl in which X represents a leaving group for example halo, e.g. chloro, in the presence of a diluent for example a solvent e.g. dichloromethane and optionally in the presence of a base, for example an organic amine e.g DIPEA, at a temperature in the range of 0-150 0 C; e) reacting a compound of formula XII
  • X represents a replaceable group, eg. F, Cl, Br , I, OMesyl, or OTrifiyl with a compound of formula XIII
  • XV in the presence of carbon monoxide and in the presence of a metal catalyst, eg. Pd or derivatives thereof, and in a solvent such as an alcohol, THF, toluene, or DMF, and in the temperature range 0 - 15O 0 C.
  • the carbon monoxide may be gaseous or in the form of a metal carbonyl, eg. Molybdenum hexacarbonyl.
  • steps b and c above may be carried out with the use of different coupling agents, with or without additives, in various suitable diluents or solvents, and over a range of temperatures.
  • Examples of coupling agents are Dichlorotriphenyl phosphorane (DCTPP), 1-ethyl- 3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDAC), O-benzotriazol-1-yl- N,N,N',N'-tetramethyluronium hexafluorophosphate (HTBU), O-(7-azabenzotriazol-l-yl)- N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) and 4-(4,6-dimethoxy-l,3,5- triazin-2-yl)-4-methylmorpholinium chloride (DMTMM).
  • DCTPP Dichlorotriphenyl phosphorane
  • EDAC 1-ethyl- 3-(3-dimethylaminopropyl) carbodiimide hydrochloride
  • HTBU O-benzotriazol-1-yl- N,N,N
  • optional additives are: 1 -hydroxy benzotriazole (HOBt), 4- dimethylamino pyridine (DMAP), di- ⁇ o-propylethylamine (DIPEA), and triethylamine (TEA).
  • suitable solvents are: dimethyl formamide (DMF), chloroform, dichloromethane (DCM), and tetrahydrofuran (THF).
  • R 1 represents a 6-amino-3-pyridyl or a 6-(substituted-amino)-3-pyridyl group
  • R 1 represents a 6-amino-3-pyridyl or a 6-(substituted-amino)-3-pyridyl group
  • R 1 represents a 6-chloro (or 6-bromo)-3-pyridyl group
  • an compound of ammonia or a salt thereof or a substituted amine or a salt thereof in the presence of a diluent and optionally in the presence of abase, for example an organic base, e.g. triethylamine, at a temperature in the range of 0-200 0 C.
  • abase for example an organic base, e.g. triethylamine
  • Compounds of formula I in which R 1 represents an optionally substituted pyridyl- N-oxide may be prepared by reacting a compound of formula I in which R 1 represents an optionally substituted pyridyl with an oxidising agent for example urea hydrogen peroxide or 3-chloroperbenzoic acid, in the presence of a diluent for example dichloromethane or acetonitrile at a temperature in the range of 0-150 0 C.
  • an oxidising agent for example urea hydrogen peroxide or 3-chloroperbenzoic acid
  • compounds of formula I containing a sulphide group may be oxidised to SO or SO 2 for example by use of potassium peroxymonosulfate, nitriles may be reduce to aminomethyl compounds, amines may be acylated or sulphonated to to give amides or sulphonamides, respectively, activated heteroaryl halides may be hydrolysed to hydroxy groups, and esters may be hydrolysed to acids,
  • the compounds of the invention will normally be administered via the oral, parenteral, intravenous, intramuscular, subcutaneous or in other injectable ways, buccal, rectal, vaginal, transdermal and/or nasal route and/or via inhalation, in the form of pharmaceutical preparations comprising the active ingredient or a pharmaceutically acceptable addition salt, in a pharmaceutically acceptable dosage form.
  • the compositions may be administered at varying doses.
  • Suitable daily doses of the compounds of the invention in the therapeutic treatment of humans are about 0.001 - 10 mg/kg body weight, preferably 0.01-1 mg/kg body weight.
  • Oral formulations are preferred particularly tablets or capsules which may be formulated by methods known to those skilled in the art to provide doses of the active compound in the range of 0.5mg to 500mg for example 1 mg, 3 mg, 5 mg, 10 mg, 25mg, 50mg, lOOmg and 250mg.
  • a pharmaceutical formulation comprising a compound of formula I, or pharmaceutically acceptable salt thereof, including the compound of the proviso, in admixture with pharmaceutically acceptable adjuvants, diluents and/or carriers.
  • the compounds of formula (I) are useful for the treatment of obesity or being overweight, (e.g., promotion of weight loss and maintenance of weight loss), prevention of weight gain (e.g., medication-induced or subsequent to cessation of smoking), for modulation of appetite and/or satiety, eating disorders (e.g. binge eating, bulimia and compulsive eating), dyslipidaemia and the treatment of type 2 diabetes mellitus.
  • the present compounds of formula (I) are useful for the prophylaxis and/or treatment of clinical conditions associated with inherent or induced reduced sensitivity to insulin (insulin resistance) and associated metabolic disorders (also known as the metabolic syndrome). These clinical conditions will include, but will not be limited to, general obesity, abdominal obesity, arterial hypertension, hyperinsulinaemia, hyperglycaemia, type 2 diabetes and the dyslipidaemia characteristically appearing with insulin resistance.
  • This dyslipidaemia also known as the atherogenic lipoprotein profile, is characterised by moderately elevated non-esterified fatty acids, elevated very low density lipoprotein (VLDL) triglyceride rich particles, high Apo B levels, low high density lipoprotein (HDL) levels associated with low apoAI particle levels and high Apo B levels in the presence of small, dense, low density lipoproteins (LDL) particles, phenotype B.
  • VLDL very low density lipoprotein
  • HDL low high density lipoprotein
  • LDL low density lipoprotein
  • the compounds of the present invention are expected to be useful in treating patients with combined or mixed hyperlipidemias or various degrees of hypertriglyceridemias and postprandial dyslipidemia with or without other manifestations of the metabolic syndrome.
  • the cardiovascular disease conditions include macro- angiopathies of various internal organs causing myocardial infarction, congestive heart failure, cerebrovascular disease and peripheral arterial insufficiency of the lower extremities. Because of their insulin sensitizing effect the compounds of formula I are also expected to prevent or delay the development of type 2 diabetes from the metabolic syndrome and diabetes of pregnancy. Therefore the development of long-term complications associated with chronic hyperglycaemia in diabetes mellitus, such as the micro-angiopathies causing renal disease, retinal damage and peripheral vascular disease of the lower limbs, is expected to be delayed.
  • the compounds may be useful in treatment of various conditions outside the cardiovascular system whether or not associated with insulin resistance, like polycystic ovarian syndrome, obesity, cancer and states of inflammatory disease including neurodegenerative disorders such as mild cognitive impairment, Alzheimer's disease, Parkinson's disease and multiple sclerosis.
  • the compounds of formula I may also be useful in the treatment of metabolic syndrome and Prader-Willi syndrome.
  • the present invention provides a compound of formula I as previously defined for use as a medicament.
  • the present invention provides the use of a compound of formula I in the preparation of a medicament for the treatment or prophylaxis of obesity or being overweight, (e.g., promotion of weight loss and maintenance of weight loss), prevention of weight gain (e.g., medication-induced or subsequent to cessation of smoking), for modulation of appetite and/or satiety, eating disorders (e.g. binge eating, bulimia and compulsive eating) and for the treatment or prophylaxis of dyslipidaemia and for the treatment or prophylaxis of type 2 diabetes mellitus.
  • obesity disorders e.g. binge eating, bulimia and compulsive eating
  • the present invention provides a method of treating obesity or being overweight, (e.g., promotion of weight loss and maintenance of weight loss), 5 prevention of weight gain (e.g., medication-induced or subsequent to cessation of smoking), for modulation of appetite and/or satiety, eating disorders (e.g. binge eating, bulimia and compulsive eating) dyslipidaemia and type 2 diabetes mellitus comprising administering a pharmacologically effective amount of a compound of formula I, including the compound of the proviso, to a patient in need thereof.
  • the compounds of the invention may be combined with another therapeutic agent that is useful in the treatment of obesity such as other anti-obesity drugs, that affect energy expenditure, glycolysis, gluconeogenesis, glucogenolysis, lipolysis, lipogenesis, fats absorption, fat storage, fat excretion, hunger and/or satiety and/or craving mechanisms, appetite/motivation, food intake, or G-I motility.
  • another therapeutic agent that is useful in the treatment of obesity
  • anti-obesity drugs that affect energy expenditure, glycolysis, gluconeogenesis, glucogenolysis, lipolysis, lipogenesis, fats absorption, fat storage, fat excretion, hunger and/or satiety and/or craving mechanisms, appetite/motivation, food intake, or G-I motility.
  • the compounds of the invention may further be combined with another therapeutic agent that is useful in the treatment of disorders associated with obesity such as hypertension, hyperlipidaemias, dyslipidaemias, diabetes, sleep apnea, asthma, heartQ disorders, atherosclerosis, macro and micro vascular diseases, liver steatosis, cancer, joint disorders, and gallbladder disorders.
  • a compound of the present invention may be used in combination with a another therapeutic agent that lowers blood pressure or that decreases the ratio of LDL:HDL or an agent that causes a decrease in circulating levels of LDL-cholesterol.
  • the compounds of the invention may5 also be combined with therapeutic agents used to treat complications related to microangiopathies.
  • the compounds of the invention may be used alongside other therapies for the treatment of obesity and its associated complications the metabolic syndrome and type 2 diabetes, these include biguanide drugs, insulin (synthetic insulin analogues) and oralo antihyperglycemics (these are divided into prandial glucose regulators and alpha- glucosidase inhibitors).
  • the compound of formula I, or a pharmaceutically acceptable salt thereof may be administered in association with a PPAR modulating agent.
  • PPAR modulating agents include but are not limited to a PPAR alpha and/or gamma agonist, or pharmaceutically acceptable salts, solvates, solvates of such salts or prodrugs thereof.
  • Suitable PPAR alpha and/or gamma agonists, pharmaceutically acceptable salts, solvates, solvates of such salts or prodrugs thereof are well known in the art.
  • the combination of the invention may be used in conjunction with a sulfonylurea.
  • the present invention also includes a compound of the present invention in combination with a cholesterol-lowering agent.
  • the cholesterol-lowering agents referred to in this application include but are not limited to inhibitors of HMG-CoA reductase (3- hydroxy-3-methylglutaryl coenzyme A reductase).
  • HMG-CoA reductase inhibitor is a statin.
  • cholesterol-lowering agent also includes chemical modifications of the HMG-CoA reductase inhibitors, such as esters, prodrugs and metabolites, whether active or inactive.
  • the present invention also includes a compound of the present invention in combination with an inhibitor of the ileal bile acid transport system (IBAT inhibitor).
  • IBAT inhibitor an inhibitor of the ileal bile acid transport system
  • the present invention also includes a compound of the present invention in combination with a bile acid binding resin.
  • the present invention also includes a compound of the present invention in combination with a bile acid sequestering agent, for example colestipol or cholestyramine or cholestagel.
  • a combination treatment comprising the administration of an effective amount of a compound of the formula I, or a pharmaceutically acceptable salt thereof, optionally together with a pharmaceutically acceptable diluent or carrier, with the simultaneous, sequential or separate administration one or more of the following agents selected from: a CETP (cholesteryl ester transfer protein) inhibitor; a cholesterol absorption antagonist; a MTP (microsomal transfer protein) inhibitor ; a nicotinic acid derivative, including slow release and combination products; a phytosterol compound ; probucol; an anti-coagulant; an omega-3 fatty acid ; another anti-obesity compound for example sibutramine, phentermine, orlistat, bupropion, ephedrine, thyroxine; an aldose reductase inhibitor; a glycogen phosphorylase inhibitor; a glycogen synthase kinase inhibitors; a glucokinase activator; a haemostasis
  • a CETP cholesterol ester transfer protein
  • a combination treatment comprising the administration of an effective amount of a compound of the formula I, or a pharmaceutically acceptable salt thereof, optionally together with a pharmaceutically acceptable diluent or carrier, with the simultaneous, sequential or separate administration of very low calorie diets (VLCD) or low-calorie diets (LCD).
  • VLCD very low calorie diets
  • LCD low-calorie diets
  • a method for the treatment of obesity and its associated complications in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof in simultaneous, sequential or separate administration with an effective amount of a compound from one of the other classes of compounds described in this combination section, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof.
  • a method of treating hyperlipidemic conditions in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof in simultaneous, sequential or separate administration with an effective amount of a compound from one of the other classes of compounds described in this combination section or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof.
  • a pharmaceutical composition which comprises a compound of formula I, or a pharmaceutically acceptable salt thereof, and a compound from one of the other classes of compounds described in this combination section or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, in association with a pharmaceutically acceptable diluent or carrier.
  • kits comprising a compound of formula I, or a pharmaceutically acceptable salt thereof, and a compound from one of the other classes of compounds described in this combination section or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof.
  • kits comprising: a) a compound of formula I, or a pharmaceutically acceptable salt thereof, in a first unit dosage form; b) a compound from one of the other classes of compounds described in this combination section or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof; in a second unit dosage form; and c) container means for containing said first and second dosage forms.
  • kits comprising: a) a compound of formula I, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable diluent or carrier, in a first unit dosage form; b) a compound from one of the other classes of compounds described in this combination section or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, in a second unit dosage form; and c) container means for containing said first and second dosage forms.
  • a compound of the formula I or a pharmaceutically acceptable salt thereof, and one of the other compounds described in this combination section, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, in the manufacture of a medicament for use in the treatment of hyperlipidaemic conditions in a warm-blooded animal, such as man.
  • a combination treatment comprising the administration of an effective amount of a compound of the formula I, or a pharmaceutically acceptable salt thereof, optionally together with a pharmaceutically acceptable diluent or carrier, with the simultaneous, sequential or separate administration of an effective amount of one of the other compounds described in this combination section, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, optionally together with a pharmaceutically acceptable diluent or carrier to a warm-blooded animal, such as man in need of such therapeutic treatment.
  • a compound of the invention may also be combined with therapeutic agents that are useful in the treatment of disorders or conditions associated with obesity (such as type II diabetes, metabolic syndrome, dyslipidemia, impaired glucose tolerance, hypertension, coronary heart disease, non-alcoholic steatohepatitis, osteoarthritis and some cancers) and psychiatric and neurological conditions.
  • obesity such as type II diabetes, metabolic syndrome, dyslipidemia, impaired glucose tolerance, hypertension, coronary heart disease, non-alcoholic steatohepatitis, osteoarthritis and some cancers
  • psychiatric and neurological conditions psychiatric and neurological conditions.
  • a patient may be identified by, for example, measuring body mass index (BMI), which is calculated by dividing weight in kilograms by height'in metres squared, and comparing the result with the definitions.
  • BMI body mass index
  • the compounds of the invention may also be useful as anti-cell-proliferation (such as anti-cancer) agents and are therefore useful in methods of treatment of the human or animal body.
  • Such properties are expected to be of value in the treatment of disease states associated with cell cycle and cell proliferation such as cancers (solid tumors and leukemias), fibroproliferative and differentiative disorders, psoriasis, rheumatoid arthritis, Kaposi's sarcoma, haemangioma, acute and chronic nephropathies, atheroma, atherosclerosis, arterial restenosis, autoimmune diseases, acute and chronic inflammation, bone diseases and ocular diseases with retinal vessel proliferation.
  • cancers solid tumors and leukemias
  • fibroproliferative and differentiative disorders psoriasis, rheumatoid arthritis, Kaposi's sarcoma, haemangioma, acute and chronic nephropathies, atheroma, atherosclerosis, arterial restenosis, autoimmune diseases, acute and chronic inflammation, bone diseases and ocular diseases with retinal vessel proliferation.
  • anti-cancer treatment may be applied as a sole therapy or may involve, in addition to the compound of the invention, conventional surgery or radiotherapy or chemotherapy.
  • chemotherapy may include one or more of the following categories of anti-tumour agents:
  • antiproliferative/antineoplastic drugs and combinations thereof, as used in medical oncology such as alkylating agents (for example cis-platin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulphan and nitrosoureas); antimetabolites (for example antifolates such as fluoropyrimidines like 5-fluorouracil and tegafur, raltitrexed, methotrexate, cytosine arabinoside and hydroxyurea); antitumour antibiotics (for example anthracyclines like adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin and mithramycin); antimitotic agents (for example vinca alkaloids like vincristine, vinblastine, vindesine and vinorelbine and taxoids like taxol and
  • antiangiogenic agents such as those which inhibit the effects of vascular endothelial growth factor, (for example the anti-vascular endothelial cell growth factor antibody bevacizumab [AvastinTM], compounds such as those disclosed in International Patent Applications WO 97/22596, WO 97/30035, WO 97/32856 and WO 98/13354) and compounds that work by other mechanisms (for example linomide, inhibitors of integrin ⁇ v ⁇ 3 function and angiostatin);
  • vascular endothelial growth factor for example the anti-vascular endothelial cell growth factor antibody bevacizumab [AvastinTM]
  • vastinTM anti-vascular endothelial cell growth factor antibody bevacizumab
  • compounds that work by other mechanisms for example linomide, inhibitors of integrin ⁇ v ⁇ 3 function and angiostatin
  • vascular damaging agents such as Combretastatin A4 and compounds disclosed in International Patent Applications WO 99/02166, WO 00/40529, WO 00/41669, WO 01/92224, WO 02/04434 and WO 02/08213;
  • antisense therapies for example those which are directed to the targets listed above, such as ISIS 2503, an anti-ras antisense;
  • gene therapy approaches including for example approaches to replace aberrant genes such as aberrant p53 or aberrant BRCAl or BRC A2, GDEPT (gene-directed enzyme pro-drug therapy) approaches such as those using cytosine deaminase, thymidine kinase or a bacterial nitroreductase enzyme and approaches to increase patient tolerance to chemotherapy or radiotherapy such as multi-drug resistance gene therapy; and
  • immunotherapy approaches including for example ex- vivo and in- vivo approaches to increase the immunogenicity of patient tumour cells, such as transfection with cytokines such as interleukin 2, interleukin 4 or granulocyte-macrophage colony stimulating factor, approaches to decrease T-cell anergy, approaches using transfected immune cells such as cytokine-transfected dendritic cells, approaches using cytokine-transfected tumour cell lines and approaches -using anti-idiotypic antibodies.
  • cytokines such as interleukin 2, interleukin 4 or gran
  • Such conjoint treatment may be achieved by way of the simultaneous, sequential or separate dosing of the individual components of the treatment.
  • Such combination products employ the compounds of this invention within the dosage range described hereinbefore and the other pharmaceutically-active agent within its approved dosage range.
  • the compounds of the present invention may also be useful as anti-infective agents or as anti-bacterial agents.
  • the compounds of the present invention may also be useful as in decreasing sebum production following topical application.
  • the compounds of the present invention are Fatty Acid Synthase inhibitors.
  • the activity of the compounds of the invention was demonstrated using the following assay. Human and Rat FAS Enzyme Assay.
  • Fatty acid synthase is an enzyme complex that harbours seven enzymatic activities catalysing the reductive synthesis of long chain fatty acids from acetyl CoA and malonyl CoA to palmitate.
  • NADPH is consumed forming NADP. Since NADPH is fluorescent but not NADP the reaction can be measured by analysing the decrease in fluorescence.
  • Fatty acid synthase Human or rat enzyme (0.4 ⁇ g, produced in house), dissolved in 2OmM Tris/HCl pH 7.5, 5mM BOG 5 ImM TCEP,10% glycerol,lmM EDTA,150mM NaCl, was then added to the plate in a volume of lO ⁇ l. Enzyme was added to all but the last two columns of the plate, to which, lO ⁇ l of assay buffer was added (0.1M Tris ph7.5, O.lmM EDTA, ImM glutathion, 0.05%BSA) to provide a no enzyme assay control.
  • assay buffer 0.1M Tris ph7.5, O.lmM EDTA, ImM glutathion, 0.05%BSA
  • the compounds of the present invention were found to inhibit the activation of Fatty Acid Synthase with IC 5 oS in a range of about 0.001 ⁇ M to about 30 ⁇ M in the above assay.
  • the examples of the present invention inhibited the activition of Fatty Acid Synthase with IC 5 oS in a range of about O.OOl ⁇ M to about 5.0 ⁇ M.
  • the compounds inhibit the activition of Fatty Acid Synthase with ICso s in a range of about O.OOl ⁇ M to about 0.1 ⁇ M.
  • temperatures are given in degrees Celsius ( 0 C); operations were carried out at room or 15 ambient temperature, that is, at a temperature in the range of 18-25 0 C, unless otherwise stated;
  • yields are given for illustration only and are not necessarily those which can be obtained by diligent process development; preparations were repeated if more material was required;
  • NMR data when given, NMR data is in the form of delta values for major diagnostic protons, 30 given in parts per million (ppm) relative to tetramethylsilane (TMS) as an internal standard when the solvent is CDCl 3 (when the solvent is d 6- -DMSO, it locks on to the 2.49 DMSO peak), determined at 300 MHz unless otherwise indicated; the following abbreviations have been used: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; b, broad;
  • the m/z value for the (M+H) + and / or (M-H) " molecular ions may be based either on the 79 Br isotope or the 81 Br isotope. As the isotopes are of approximately equal abundance, in many cases both isotopes are seen in the spectrum, but only one is reported.
  • Example 50 25 N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]-2-(3-oxopiperazin-l- yl)acetamide Method Ib from Intermediate A 1 H NMR (400.132 MHz, DMSO) ⁇ l.43 - 1.83 (4H, m),2.17 (3H, s),2.63 - 2.89 (2H, m),2.96 - 3.02 (2H, m),3.13 - 3.30 (2H, m),3.30 - 3.40 (2H, m),3.55 - 3.65 (2H, m),4.45 - 4.54 (2H, m),4.66 (IH, s),7.06 - 7.11 (IH, m),7.20 - 7.24 (IH, m),7.43 (2H, d),7.56 (IH, s),7.70 (2H, d),8.09 (IH, s),9.59 (IH, s
  • Example 72 N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]-2-fluoro-pyridine-3- carboxamide Method Ib from Intermediate A 1H NMR (300.072 MHz, cdcl3) ⁇ 1.62 - 2.00 (4H, m),2.41 (3H, s), 2.77 - 2.91 (2H, m),3.00 - 3.26 (IH, m),4.04 - 4.11 (IH m),4.78 - 4.98 (IH, m), 7.21 - 7.31 (2H, m), 7.35 (2H, d), 7.41 - 7.48 (IH, m), 7.61 (2H, d),8.25 (IH, s),8.40 (IH, m),8.58 (IH, d),8.63-8.71 (IH, m). M/z (M+H) + 443.
  • Example 73 N-[5-[4-(4-
  • Example 189-203 were prepared from Intermediate NN in a similar manner to that described in Example 188 above:
  • Example 189-203 were prepared from Intermediate NN in a similar manner to that described in Example 188 above:
  • Example 212 N-[5-[4-[4-(benzyl-methyl-carbamoyl)phenyl]piperidine- 1 -carbonyl]-2-methyl- phenyl]pyridine-4-carboxamide

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Abstract

A compound of formula I, or a pharmaceutically acceptable salt thereof, processes for preparing such compounds, their use as Fatty Acid Synthase inhibitors, methods for their therapeutic use, particularly in the treatment of obesity and diabetes mellitus, and pharmaceutical compositions containing them.

Description

BISAMIDE DERIVATIVES AND USE THEREOF AS FATTY ACID SYNTHASE INHIBITORS
Field of invention
The present invention relates to novel benzamides, particularly to bisamides that are substituted N-[3-(4-phenylpiperidine-l-carbonyl)phenyl]carboxamides, to processes for preparing such compounds, to their use as Fatty Acid Synthase inhibitors, to methods for their therapeutic use, particularly in the treatment of obesity and diabetes mellitus, and to pharmaceutical compositions containing them.
Background of the invention
Obesity and diabetes are reaching epidemic proportions in the USA, EU, Japan and developing countries. Obesity is the major driver of the co-morbidities of the metabolic syndrome, particularly type 2 diabetes. Since no effective pharmacotherapies for obesity are available to date and current diabetes therapies do not stop the progression of the disease, there is a huge unmet medical need.
Fatty Acid Synthase (FAS) is a critical enzyme for endogenous lipogenesis and plays an important role in the modulation of key intermediates of lipid and carbohydrate cellular metabolism. FAS is highly expressed in the tissues with high metabolic activity (for example liver, adipose tissue and brain) and there are good reasons to believe that a FAS inhibitor would cause beneficial metabolic effects in peripheral tissues. In addition, inhibition of FAS in the hypothalamus may result in reduced food intake. The non-specific irreversible FAS inhibitors cerulenin and C-75 have been reported in the literature to decrease brain levels of orexigenic neuropeptides and to decrease food intake.
Therefore there is a need for an effective FAS inhibitor to treat obesity and diabetes.
The compound Ν-[5-(4-benzylpiperidine-l-carbonyl)-2-methylphenyl]acetamide is known in Chemical Abstracts but no reference is given. This compound is excluded from the compound claims of this application. Description of the invention
The present invention provides a compound of formula I
Figure imgf000003_0001
I or a pharmaceutically acceptable salt thereof, in which
R1 represents
a) a Ci-6alkyl group, a C2-6alkenyl group or a C2-6alkynyl group each of which is optionally substituted; b) an optionally substituted C3-iocycloalkyl group which may be monocyclic, bicyclic or tricyclic and optionally may be bridged; c) an optionally substituted carbon linked saturated or partially saturated 3 to 8 membered heterocyclic group containing one or more N, S, SO, SO2 or O; d) optionally substituted heteroaryl including N-oxides thereof; or e) optionally substituted phenyl;
wherein optionally substituted means that any available carbon in R1 is optionally substituted by one or more of the following 1) hydroxy 2) halo, 3) a Ci-6alkoxy group optionally substituted by one or more of the following: halo, OH , C^alkoxy, phenyl or by a group of formula NRcRd in which Rc and Rd are as defined below 4) carboxy 5) C1-6 alkoxycarbonyl 6) carbamoyl 7) N-Q-δalkylcarbamoyl 8) N, N-diCi-6alkylcarbamoyl 9) sulphamoyl 10) N-Ci.6alkylsulphamoyl H) N, N-diC]-6alkylsulphamoyl 12) Ci- 6alkanoylamino 13)
Figure imgf000003_0002
14) N-Ci-βalkylsulphonylamino 15) Ci-όalkylthio 16) Ci-όalkylsulfϊnyl 17) Ci-βalkylsulfonyl 18) Ci-βalkylsulfonyloxy wherein the alkyl is optionally substituted by one or more fluoro 19) cyano 20) phenyl 21) heteroaryl 22) substituted phenoxy 23) oxo or 24) a group ΝRaRb in which Ra and Rb independently represent i) H ii) Ci_6alkanoyl iii) a carbon linked saturated or partially unsaturated 3 to 8 membered heterocyclic group containing one or more N, S, SO, SO2 or O which is optionally fused to a benz ring and/or is optionally substituted by one or more of the following: hydroxy, oxo, a Ci-βalkoxy group hydroxy, Ci-4acyl, amino, Ci^alkylamino, di(Ci-3 alkyl)amino or a Ci-6alkyl optionally substituted by one or more hydroxy or Ci^alkoxy iv) a Ci-6alkyl group optionally substituted by one or more of the following: hydroxy; carboxy; a Ci-ealkoxycarbonyl group; a C1^aIkOXy group; heteroaryl; a group of formula NRcRd in which R° and Rd independently represent H; a Ci-βalkanoyl group; a C1. βalkylsulphonyl group; a Ci-6alkoxycarbonyl group; a Ci-6alkyl group optionally substituted by one or more hydroxy or
Figure imgf000004_0001
, or Rc and Rd together with the nitrogen atom to which they are attached represent a saturated or partially unsaturated 3 to 8 membered heterocyclic ring optionally containing an additional sulphur including oxidised as SO or SO2 , oxygen or nitrogen and/or optionally fused to a benz ring and/or optionally substituted by one or more of the following: a Ci-βalkoxy group; hydroxy; oxo; or a Ci- βalkyl group optionally substituted by one or more hydroxy or C1-6alkoxy; v) a C3-1ocycloalkyl group which may be monocyclic, bicyclic or tricyclic and optionally may be bridged ; vi) phenyl optionally substituted by one or more of the following: halo; C1-3alkyl; Ci- 3alkoxy; a Ci.6acylamino group; carbamoyl; iV-Q-βalkylcarbamoyl; N,N-diC\. δalkylcarbamoyl; vii) heteroaryl; viii) a Ci-βalkoxycarbonyl group; ix) Ra and Rb together with the nitrogen atom to which they are attached represent a saturated or partially unsaturated 3 to 8 membered heterocyclic ring optionally containing an additional oxygen, sulphur, SO, SO2 or nitrogen and/or optionally fused to a benz ring and/or optionally substituted by one or more of the following: a Ci^alkoxy group; a Q- 6acyl group; a Ci-βalkoxycarbonyl group; carbamoyl; N-C1-6alkylcarbamoyl; N, N-diCμ δalkylcarbamoyl; hydroxy; oxo; a Ci-βalkyl group (which is optionally substituted by one or more of the following: a Ci-6alkoxy group, hydroxy or a group of formula ΝRcRd in which Rc and Rd are as defined above) or a group of formula NR°Rd in which Rc and Rd are as defined above; x) a Ci_6alkylsulphonyl group;
25) a C3-10cycloalkyl group which may be monocyclic, bicyclic or tricyclic and optionally 5 may be bridged;
26) a carbon linked saturated or partially saturated 3 to 8 membered heterocyclic group containing one or more N, S, SO, SO2 or O which is optionally substituted by one or more of the following: a Ci-βalkoxy group; a Ci-όalkanoyl group; a d-βalkoxycarbonyl group; carbamoyl; N-Ci-δalkylcarbamoyl; N, N-diCuδalkylcarbamoyl; hydroxy; oxo; a CμδalkylQ group (which is optionally substituted by one or more of the following: a Ci^alkoxy group, hydroxy or a group of formula ΝRcRd in which Rc and Rd are as defined above) or 27) by a Ci^alkyl group optionally substituted by one or more groups as described in 1 -26 above; 28) a C2.4alkenyl or 29) a C2-4alkynyl; wherein any cycloalkyl, phenyl, heteroaryl ring or carbon linked saturated or partiallys saturated 3 to 8 membered heterocyclic group in this list of optional substituents in 1 to 27 above is optionally substituted by one or more of the following: i) a Ci-3alkyl group optionally substituted by one or more halo ii) a Ci-3alkoxy group optionally substituted by one or more halo iii) halo, iv) nitro, v) cyano vi) hydroxy vii) a group of formula NRQRd in which Rc and Rd are as defined above viii) carboxy ix) a
Figure imgf000005_0001
group Q optionally substituted by one or more halo; x) a Cμβalkylsulphonyloxy group optionally substituted by one or more halo xi) carbamoyl xii) N-Ci^alkylcarbamoyl xiii) N, iV-diC!. 3alkylcarbamoyl xiv) sulphamoyl xv) N-Ci-oalkylsulphamoyl xvi) N, N-diCi- 3alkylsulphamoyl and any alkyl, alkenyl or alkynyl chain in this list of optional substituents 1 to 29 above is optionally substituted by one or more of the following: i) a C1-5 3alkyl group optionally substituted by one or more halo ii) a C1-3alkoxy group optionally substituted by one or more halo iii) halo, iv) nitro v) cyano vi) hydroxy vii) a group of formula ΝRcRd in which Rc and Rd are as defined above; and wherein an optionally substituted carbon linked saturated or partially saturated 3 to 8 membered heterocyclic group containing one or more N, S, SO, SO2 or O described in c) above is optionally0 substituted on nitrogen by: a Ci-4alkyl group optionally substituted by one or more hydroxy or a group of formula NRcRd in which Rc and Rd are as defined above; or by Ci- δalkanoyl; R2 represents halo; hydroxy; a C1-3alkyl group optionally substituted by one or more halo; a Ci-3alkoxy group optionally substituted by one or more halo; or cyano;
R3 represents H; halo; hydroxy; a C^alkyl group optionally substituted by one or more halo; a Ci^alkoxy group optionally substituted by one or more halo; or cyano;
R4 represents i) H, ii) a Ci^alkyl group optionally substituted by one or more halo iii) a C1- 3alkoxy group optionally substituted by one or more halo iv) halo, v) nitro, vi) cyano, vii) a Ci-6alkylS(O)y(O)z- wherein y is 0,1 or 2 and z is 0 except when y is 2 when z is 0 or 1 viii) a group CH2NRURV in which Ru and Rv independently represent H, a Ci_6alkylsulphonyl group, a Ci-βalkanoyl group or a Ci^alkyl group optionally substituted by one or more of the following: hydroxy, a C1-6alkoxy group or a group of formula NRcRd in which Rc and Rd are as defined above or Ru and Rv together with the nitrogen atom to which they are attached represent a saturated or partially unsaturated 3 to 8 membered heterocyclic ring optionally containing an N, S, SO, SO2 or O; ix) a group CO2RW in which Rw is a Ci- 3alkyl group; or x) a group CONRxRy in which Rx and Ry independently represent H; or a Ci.6alkyl group optionally substituted by phenyl wherein the phenyl is optionally substituted by one or more
Figure imgf000006_0001
or Rx and Ry together with the nitrogen atom to which they are attached represent a saturated or partially unsaturated 3 to 8 membered heterocyclic ring optionally containing an additional sulphur, oxygen or nitrogen, wherein any ring carbon or is optionally substituted by one or more of the following: a Ci^alkyl group optionally substituted by one or more hydroxy or Ci-6alkoxy; a Ci-6alkoxy group; hydroxy; Ci-βacyl or oxo and any additional ring nitrogen is optionally substituted by a Ci^acyl or a Ci^alkyl group optionally substituted by one or more hydroxy or Ci-6alkoxy;
R5 and R5 independently represent H, halo, cyano, Ci-3alkyl optionally substituted by one or more halo or Ci-3alkoxy optionally substituted by one or more halo; R6 and R6 independently represent H, halo, cyano,
Figure imgf000006_0002
optionally substituted by one or more halo or Ci^alkoxy optionally substituted by one or more halo; L represents a bond or CH2; m and n independently represent 0 or 1; with the proviso that when R1 is CH3, R2 is CH3, and R3 , R4, R5, R5', R6, R6' are each H, m is 1 and n is 1 then L is not CH2.
Further sub-definitions of the meaning of R1, R2, R3, R4, R5, R5' R6, R6', L, m and n in compounds of formula I now follow. It will be understood that any combination of these sub-definitions may be used instead of the original definitions where appropriate in any of the compound groups, claims or embodiments defined hereinbefore or hereinafter.
In a first group of compounds of formula I, R1 represents an optionally substituted Ci-βalkyl group.
In a second group of compounds of formula I, R1 represents an optionally substituted C3-iocycloalkyl group which may be monocyclic, bicyclic or tricyclic and optionally may be bridged.
In a third group of compounds of formula I, R1 represents an optionally substituted carbon linked saturated or partially saturated 3 to 8 membered heterocyclic group containing one or more N, S, SO, SO2 or O.
In a fourth group of compounds of formula I, R1 represents an optionally substituted heteroaryl including N-oxides thereof.
In a fifth group of compounds of formula I, R1 represents an optionally substituted phenyl. In a sixth group of compounds of formula I, R1 represents an optionally substituted pyridyl.
In a seventh group of compounds of formula I, m and n are each 1.
In an eighth group of compounds of formula I, L represents a bond.
In a ninth group of compounds of formula I, R2 represents halo; hydroxy; a C1- 3alkyl group optionally substituted by one or more halo; a Ci-3alkoxy group optionally substituted by one or more halo; or cyano and R3 represents halo; hydroxy; a C^alkyl group optionally substituted by one or more halo; a Ci-3alkoxy group optionally substituted by one or more halo; or cyano.
In a tenth group of compounds of formula I, R2 represents a C1-3alkyl group, particularly methyl.
In an eleventh group of compounds of formula I, R3 represents H or a C^alkyl group, particularly methyl. In a twelfth group of compounds of formula I, R4 represents methyl, methoxy, chloro, nitro, CF3 or cyano.
In a thirteenth group of compounds of formula I, R5, R5', R6, R6 are each H. In the thirteen groups above the term optionally substituted has the meaning as initially defined and the other unmentioned substituents in a group are selected from R1, R2, R3, R4, R5, R5 R6, R6 , L, m and n are as initially defined or as defined in any of groups one to thirteen or in any of the compound groups, claims or embodiments defined hereinbefore or hereinafter.
"Pharmaceutically acceptable salt", where such salts are possible, includes both pharmaceutically acceptable acid and base addition salts. A suitable pharmaceutically acceptable salt of a compound of formula I is, for example, an acid-addition salt of a compound of formula I which is sufficiently basic, for example an acid-addition salt with an inorganic or organic acid such as hydrochloric, hydrobromic, sulphuric, trifluoroacetic, citric or maleic acid; or, for example a base-addition salt of a compound of formula I which is sufficiently acidic, for example an alkali or alkaline earth metal salt such as a sodium, calcium or magnesium salt, or an ammonium salt, or a salt with an organic base such as methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine.
Throughout the specification and the appended claims, a given chemical formula or name shall encompass all stereo and optical isomers and racemates thereof as well as mixtures in different proportions of the separate enantiomers, where such isomers and enantiomers exist, as well as pharmaceutically acceptable salts thereof and solvates thereof such as for instance hydrates including solvates of the free compounds or solvates of a salt of the compound. Isomers may be separated using conventional techniques, e.g. chromatography or fractional crystallisation. The enantiomers may be isolated by separation of racemate for example by fractional crystallisation, resolution or HPLC. The diastereomers may be isolated by separation of isomer mixtures for instance by fractional crystallisation, HPLC or flash chromatography. Alternatively the stereoisomers may be made by chiral synthesis from chiral starting materials under conditions that will not cause racemisation or epimerisation, or by derivatisation, with a chiral reagent. All stereoisomers are included within the scope of the invention. All tautomers, where possible, are included within the scope of the invention. The present invention also encompasses compounds containing one or more isotopes for example 14C, 11C or 19F and their use as isotopically labelled compounds for pharmacological and metabolic studies.
The present invention also encompasses prodrugs of a compound of formula I that is compounds which are converted into a compound of formula I in vivo. The following definitions shall apply throughout the specification and the appended claims.
The term "C3-iocycloalkyl group which may be monocyclic, bicyclic or tricyclic and optionally may be bridged" includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, bicyclo(2.2.1)heptyl, bicyclo(2.2.2)octyl, perhydroindanyl and adamantyl.
The term "heteroaryl" includes pyrrolyl, thienyl, furyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, 1,3,4-oxadiazolyl, 1,2,4- oxadiazolyl, triazolyl, furazanyl, tetrazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, 1,3,5-triazinyl quinolyl, isoquinolyl, benzthienyl, benzofuranyl, benzofurazanyl, benzoxazolyl, benzimidazolyl, indolyl, benzthiazolyl, indazolyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, 1,5-naphthyridinyl, 1,6-naphthyridinyl, 1,7-naphthyridinyl, 1,8- naphthyridinyl, pyrrolopyridinyl, pyrrolopyrazinyl, pyrazolopyridinyl or imidazopyridinyl.
The term "heteroaryl including N-oxides" includes heteroaryls as described immediately above and in addition N-oxides of such heteroaryls where such N-oxides are known to those skilled in the art to exist and are known to be stable at ambient conditions for example pyridine-N-oxides.
The term "a carbon linked saturated or partially saturated 3 to 8 membered heterocyclic group containing one or more Ν, S, SO, SO2 or O" includes oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, 2,3-dihydro-l,3-thiazolyl, 1,3-thiazolidinyl, 1,3-oxazolidinyl, oxepanyl, aziridinyl, azetidinyl, pyrrolinyl, pyrrolidinyl, morpholinyl, thiamorpholinyl (perhydro-l,4-thiazinyl), (8-oxa-3-azabicyclo[3.2.1]octyl), (7-oxa-3- azabicyclo[3.1.1]heptyl), perhydroazepinyl, perhydrooxazepinyl, tetrahydro-l,4-thiazinyl, 1-oxotetrahydrothienyl, l,l-dioxotetrahydro-l,4-thiazinyl, piperidinyl, homopiperidinyl, piperazinyl, homopiperazinyl, dihydropyridinyl, tetrahydropyridinyl, dihydropyrimidinyl or tetrahydropyrimidinyl each of which amy be optionally substituted as previously described. When two substituents on an amine together with the nitrogen atom to which they are attached represent a saturated or partially unsaturated 3 to 8 membered heterocyclic ring optionally containing an additional oxygen, sulphur, SO, SO2 or nitrogen O and/or optionally fused to a benz ring then such rings include aziridino, azetidino, pyrrolidino, morpholino, piperidino, imidazolidinyl, imidazolinyl, piperazino, thiamorpholino
(perhydro-l,4-thiazinyl), homopiperazino, perhydroazepino, perhydrooxazepino, (2,3- dihydro-l,3-thiazolyl, 1,3-thiazolidinyl, 1,3-oxazolidinyl, oxepanyl , oxazepanyl, dihydropyrimidinyl, tetrahydropyrimidinyl, and homopiperidinyl, each of which is optionally substituted as previously described. Unless otherwise stated or indicated, the term "alkyl" denotes either a straight or branched alkyl group. Examples of said alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, sec-butyl , t-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, hexyl and isohexyl. Preferred alkyl groups are methyl, ethyl, propyl, isopropyl, butyl and tertiary butyl. Unless otherwise stated or indicated, the term "alkoxy" denotes a group O-alkyl, wherein alkyl is as defined above.
Unless otherwise stated or indicated, the term "halogen" shall mean fluorine, chlorine, bromine or iodine.
An example of "C1-6alkanoyloxy" is acetoxy. Examples of "C1-6alkoxycarbonyl" include
Figure imgf000010_0001
Examples of "Ci-ealkoxycarbonylamino" include methoxycarbonylamino, ethoxycarbonylamino, n- and /-butoxycarbonylamino. Examples of "Ci-βalkoxy" include methoxy, ethoxy and propoxy. Examples of "Ci-βalkanoylamino" include formamido, acetamido and propionylamino. Examples of "Ci-6alkylS(O)a wherein a is 0 to 2" include Ci-4alkylsulphonyl, methylthio, ethylthio, methylsulphinyl, ethylsulphinyl, mesyl and ethylsulphonyl. Examples of "Ci.6alkylsulphonylamino" include methylsulphonylamino, ethylsulphonylamino and propylsulphonylamino. Examples of "Ci.6alkylsulphonyl-N-(C1-6alkyl)amino" include methylsulphonyl-N-methylamino, ethylsulphonyl-N-methylamino and propylsulphonyl-iV-ethylamino. Examples of "Ci-6aUcanoyl" include Ci-4alkanoyl, propionyl and acetyl. Examples of "N-(Ci-6alkyl)amino" include methylamino and ethylamino. Examples of "N,N-(Ci-6alkyl)2amino" include di-iV-methylamino, di-(N-ethyl)amino and N-ethyl-N-methylamino. Examples of "C2-6alkenyl" are vinyl, allyl and 1-propenyl. Examples of "C2.6alkynyl" are ethynyl, 1-propynyl and 2-propynyl. Examples of "^■(Ci.ealky^sulphamoyl" are N-(methyl)sulphamoyl and N-(ethyl)sulphamoyl. Examples of "N-(C1 -6alkyl)2sulphamoyl" are N,N-(dimethyl)sulphamoyl and N-(methyl)-N-(ethyl)sulphamoyl. Examples of "N-(C1.6alkyl)carbamoyl" are N-(Ci-4alkyl)carbamoyl, methylaminocarbonyl and ethylaminocarbonyl. Examples of "NN-(Ci.6alkyl)2carbamoyl" are N,N-(C1-4alkyl)carbamoyl, dimethylaminocarbonyl and methylethylaminocarbonyl. Examples of "C3-8cycloalkyl ring" are cyclopropyl and cyclohexyl. Examples of "(heterocyclic group)C1-6alkyl" include pyridylmethyl, 3-moφholinopropyl and 2-pyrimid-2-ylethyl. Examples of "Cs-scycloalkylCi-gcycloalkyl" include cyclopropylmethyl and 2-cyclohexylpropyl. 'W-(Ci-6alkyl)sulphamoylamino" are N-(methyl)sulphamoylamino and N-(ethyl)sulphamoylamino. Examples of "N-(C1-6alkyl)2sulphamoylamino" are N,N-(dimethyl)sulphamoylamino and N-(methyl)-N-(ethyl)sulphamoylamino. Examples of "Ci-ealkylsulphonylaminocarbonyl" include methylsulphonylaminocarbonyl, ethylsulphonylaminocarbonyl and propylsulphonylaminocarbonyl.
In a particular group of compounds of formula I
Figure imgf000011_0001
or a pharmaceutically acceptable salt thereof, R1 represents
a) an optionally substituted C^oalkyl group; b) an optionally substituted CMocycloalkyl group which may be monocyclic, bicyclic or tricyclic and optionally may be bridged; c) an optionally substituted C-linked piperidiny! or tetrahydrofuryl ring; d) an optionally substituted heteroaryl selected from: 3-pyridyl, 3-pyridyl-N-oxide, 4- pyridyl, 4-pyridyl-N-oxide, quinolyl, isoquinolyl, pyrazinyl, benzthiazolyl, pyrimidyl, cinnolyl, pyridazinyl, imidazopyridinyl, thiazolyl, pyrazolopyridinyl, or oxadiazinyl; or e) optionally substituted phenyl; wherein optionally substituted means that any available carbon in R1 is optionally substituted by one or more of the followingl) hydroxy 2) halo, 3) a C1-6alkoxy group optionally substituted by one or more of the following: halo, OH , Ci-6alkoxy, phenyl or by a group of formula ΝRcRd in which R° and Rd are as defined below 4) carboxy 5) C1-6 alkoxycarbonyl 6) carbamoyl 7) N-Ci-δalkylcarbamoyl 8) N, N-diCi-6alkylcarbamoyl 9) sulphamoyl 10) N-Ci-6alkylsulphamoyl H) N, N-diC^ealkylsulphamoyl 12) C1.
6alkanoylamino 13) (N-C1-6alkyl)C1-6alkanoylamino 14) N-Ct.ealkylsulphonylamino 15) Cj-βalkylthio 16) Q-oalkylsulfinyl 17) C1-6alkylsulfonyl 18) Q-βalkylsulfonyloxy wherein the alkyl is optionally substituted by one or more fluoro 19) cyano 20) phenyl 21) heteroaryl 22) substituted phenoxy 23) oxo or 24) a group ΝRaRb in which Ra and Rb independently represent i) H ii) Ci_6alkanoyl iii) a carbon linked saturated or partially unsaturated 3 to 8 membered heterocyclic group containing one or more N, S, SO, SO2 or O which is optionally fused to a benz ring and/or is optionally substituted by one or more of the following: hydroxy, oxo, a Ci-βalkoxy group hydroxy, C1-4acyl, amino, C^alkylamino, di(Ci_3 alkyl)amino or a Ci-6alkyl optionally substituted by one or more hydroxy or C^alkoxy iv) a C^alkyl group optionally substituted by one or more of the following: hydroxy; carboxy; a C^alkoxycarbonyl group; a Ci-6alkoxy group; heteroaryl; a group of formula NR°Rd in which Rc and Rd independently represent H; a Ci-βalkanoyl group; a C1. βalkylsulphonyl group; a d-βalkoxycarbonyl group; a Q-ealkyl group optionally substituted by one or more hydroxy or C1-6alkoxy , or Rc and Rd together with the nitrogen atom to which they are attached represent a saturated or partially unsaturated 3 to 8 membered heterocyclic ring optionally containing an additional sulphur including oxidised as SO or SO2 , oxygen or nitrogen and/or optionally fused to a benz ring and/or optionally substituted by one or more of the following: a C1-6alkoxy group; hydroxy; oxo; or a C1- ealkyl group optionally substituted by one or more hydroxy or Ci-βalkoxy; v) a Cs-iocycloalkyl group which may be monocyclic, bicyclic or tricyclic and optionally may be bridged ; vi) phenyl optionally substituted by one or more of the following: halo; C1-3alkyl; C1.
3alkoxy; a Ci.6acylamino group; carbamoyl; N-Ci-6alkylcarbamoyl; N,N-diC\. 5 δalkylcarbamoyl; vii) heteroaryl; viii) a Ci-βalkoxycarbonyl group; ix) Ra and Rb together with the nitrogen atom to which they are attached represent a saturated or partially unsaturated 3 to 8 membered heterocyclic ring optionally containingo an additional oxygen, sulphur, SO, SO2 or nitrogen and/or optionally fused to a benz ring and/or optionally substituted by one or more of the following: a Ci-6alkoxy group; a Ci- βacyl group; a Ci^aUcoxycarbonyl group; carbamoyl; N-Ci-όalkylcarbamoyl; N, N-diCi.
6alkylcarbamoyl; hydroxy; oxo; a C^alkyl group (which is optionally substituted by one or more of the following: a Ci-galkoxy group, hydroxy or a group of formula ΝR°Rd ins which R° and Rd are as defined above) or a group of formula NR°Rd in which Rc and Rd are as defined above; x) a Ci-βalkylsulphonyl group;
25) a C3-iocycloalkyl group which may be monocyclic, bicyclic or tricyclic and optionally may be bridged; o 26) a carbon linked saturated or partially saturated 3 to 8 membered heterocyclic group containing one or more N, S, SO, SO2 or O which is optionally substituted by one or more of the following: a Ci-6alkoxy group; a C1-6alkanoyl group; a Ci-βalkoxycarbonyl group; carbamoyl; iV-CLβalkylcarbamoyl; N, N-diCi-6alkylcarbamoyl; hydroxy; oxo; a Ci-βalkyl group (which is optionally substituted by one or more of the following: a Ci_6alkoxy group,5 hydroxy or a group of formula ΝRcRd in which Rc and Rd are as defined above) or 27) by a Ci-6alkyl group optionally substituted by one or more groups as described in 1
-26 above; 28) a C2-4alkenyl or 29) a C2-4alkynyl; wherein any cycloalkyl, phenyl, heteroaryl ring or carbon linked saturated or partially saturated 3 to 8 membered heterocyclic group in this list of optional substituents in 1 to 27o above is optionally substituted by one or more of the following: i) a Ci-3alkyl group optionally substituted by one or more halo ii) a Ci-3alkoxy group optionally substituted by one or more halo iii) halo, iv) nitro, v) cyano vi) hydroxy vii) a group of formula NRcRd in which R0 and Rd are as defined above viii) carboxy ix) a Ci-βalkylsulphonyl group optionally substituted by one or more halo; x) a Ci_6alkylsulphonyloxy group optionally substituted by one or more halo xi) carbamoyl xii) N-Ci^alkylcarbamoyl xiii) N, N-diCi. 3alkylcarbamoyl xiv) sulphamoyl xv) N-C1-3alkylsulphamoyl xvi) N, N-diCi. 3alkylsulphamoyl and any alkyl, alkenyl or alkynyl chain in this list of optional substituents 1 to 29 above is optionally substituted by one or more of the following: i) a Ci- 3alkyl group optionally substituted by one or more halo ii) a Ci_3alkoxy group optionally substituted by one or more halo iii) halo, iv) nitro v) cyano vi) hydroxy vii) a group of formula ΝRcRd in which R° and Rd are as defined above;
R2 represents halo; a Ci^alkyl group optionally substituted by one or more halo;or a C1. 3alkoxy group optionally substituted by one or more halo;
R3 represents H; a C1-3alkyl group optionally substituted by one or more halo; or a Ci- 3alkoxy group optionally substituted by one or more halo;
R4 represents i) H, ii) a Ci^alkyl group optionally substituted by one or more halo iii) a Ci- 3alkoxy group optionally substituted by one or more halo iv) halo, v) nitro, vi) cyano, vii) a C1-6alkylS(O)y(O)z- wherein y is 0,1 or 2 and z is 0 except when y is 2 when z is 0 or 1 viii) a group CH2NRURV in which Ru and Rv independently represent H or a Ci^alkyl group optionally substituted by one or more of the following: hydroxy, a Cμβalkoxy group or a group of formula NRcRd in which Rc and Rd are as defined above or Ru and Rv together with the nitrogen atom to which they are attached represent a saturated or partially unsaturated 3 to 8 membered heterocyclic ring optionally containing an additional N, S, SO, SO2 or O ix) a group CO2RW in which Rw is a Ci-3alkyl group; or x) a group
CONRxRy in which Rx and Ry independently represent H; or a Ci^alkyl group optionally substituted by phenyl wherein the phenyl is optionally substituted by one or more C1. 3alkyl, halo or Ci^alkoxy; or Rx and Ry together with the nitrogen atom to which they are attached represent a saturated or partially unsaturated 3 to 8 membered heterocyclic ring optionally containing an additional sulphur, oxygen or nitrogen optionally substituted by one or more of the following: a Ci^alkyl group optionally substituted by one or more hydroxy or Ci-βalkoxy; a Ci-6alkoxy group; hydroxy; Q^acy! or oxo; R5 represents H, C1-3alkyl or halo; R6 represents H, C1-3alkyl or halo; L represents a bond or CH2; m and n independently represent 0 or 1 provided that m and n do not simultaneously represent 0.
A particular embodiment of the invention is represented by a compound of formula II
Figure imgf000015_0001
or a pharmaceutically acceptable salt thereof, in which Ra represents a substituent from 1 to 29 as described above
Rb represents represents halo; a C^alkyl group optionally substituted by one or more halo; a group optionally substituted by one or more halo; R2 represents a Ci-3alkyl group, a C1-3alkoxy group, hydroxy, CF3 or halo; R4 represents H, a C1-6alkyl group, a Ci-βalkoxy group, halo, nitro, CF3, SO2Me, CH2NRxRy, CO NRxRy or cyano; Rc represents H, a C^alkyl group or halo; and m and n independently represent 0 or 1.
In a further particular embodiment there is provided a compound of formula HA in which
Figure imgf000015_0002
or a pharmaceutically acceptable salt thereof, in which Ra represents trifluoromethoxy, tert-butyl or phenyl; R2 represents methyl; R4 represents methoxy.
A particular embodiment of the invention is represented by a compound of formula III
Figure imgf000016_0001
or a pharmaceutically acceptable salt thereof, in which x is 0 or 1; wherein Ra represents 1) hydroxy 2) halo, 3) a C^alkoxy group optionally substituted by one or more of the following: halo, OH , Ci_6alkoxy, phenyl or by a group of formula
NRcRd in which Rc and Rd are as defined below 4) carboxy 5) Ci-6 alkoxycarbonyl 6) carbamoyl 7) N-Cμδalkylcarbamoyl 8) N, N-diQ-ήalkylcarbamoyl 9) sulphamoyl 10) N- d-ealkylsulphamoyl H) N, N-diCi.6alkylsulphamoyl 12) Q-ealkanoylamino 13) (N-C1. ealkytyCi-ealkanoylamino 14) N-Q-galkylsulphonylamino 15) C^alkylthio 16) C1.
6alkylsulfmyl 17) Q-βalkylsulfonyl 18) Cμβalkylsulfonyloxy wherein the alkyl is optionally substituted by one or more fluoro 19) cyano 20) phenyl 21) heteroaryl 22) substituted phenoxy 23) oxo or
24) a group ΝRaRb in which Ra and Rb independently represent i) H ii) Ci-βalkanoyl iii) a carbon linked saturated or partially unsaturated 3 to 8 membered heterocyclic group containing one or more N, S, SO, SO2 or O which is optionally fused to a benz ring and/or is optionally substituted by one or more of the following: hydroxy, oxo, a Ci-βalkoxy group hydroxy, Ci-4acyl, amino, C1-3 alky lamino, di(Ci-3 alkyl)amino or a Ci-βalkyl optionally substituted by one or more hydroxy or Q-βalkoxy iv) a Ci.βalkyl group optionally substituted by one or more of the following: hydroxy; carboxy; a Ci.6alkoxycarbonyl group; a Ci-βalkoxy group; heteroaryl; a group of formula NRcRd in which Rc and Rd independently represent H; a Ci^alkanoyl group; a C1. βalkylsulphonyl group; a Ci-δalkoxycarbonyl group; a Ci^alkyl group optionally substituted by one or more hydroxy, or Cμ6alkoxy , or Rc and Rd together with the nitrogen atom to which they are attached represent a saturated or partially unsaturated 3 to 8 membered heterocyclic ring optionally containing an additional sulphur including oxidised as SO or SO2 , oxygen or nitrogen and/or optionally fused to a benz ring and/or optionally substituted by one or more of the following: a Ci-βalkoxy group; hydroxy; oxo; or a C1, 6alkyl group optionally substituted by one or more hydroxy or
Figure imgf000017_0001
v) a C3-iocycloalkyl group which may be monocyclic, bicyclic or tricyclic and optionally may be bridged ; vi) phenyl optionally substituted by one or more of the following: halo; C^alkyl; Ci- 3alkoxy; a Ci^acylamino group; carbamoyl; N-Ci-βalkylcarbamoyl; AζN-diCi. 5 βalkylcarbamoyl; vii) heteroaryl; viii) a Ci_6alkoxycarbonyl group; ix) Ra and Rb together with the nitrogen atom to which they are attached represent a saturated or partially unsaturated 3 to 8 membered heterocyclic ring optionally containing0 an additional oxygen, sulphur, SO, SO2 or nitrogen and/or optionally fused to a benz ring and/or optionally substituted by one or more of the following: a Ci^alkoxy group; a Ci- βacyl group; a Ci.6alkoxycarbonyl group; carbamoyl; N-Ci-βalkylcarbamoyl; N, N-diCi. 6alkylcarbamoyl; hydroxy; oxo; a Ci-βalkyl group (which is optionally substituted by one or more of the following: a C1-6alkoxy group, hydroxy or a group of formula ΝRcRd in5 which Rc and Rd are as defined above) or a group of formula NRcRd in which Rc and Rd are as defined above; x) a C^alkylsulphonyl group;
25) a Cs-iocycloalkyl group which may be monocyclic, bicyclic or tricyclic and optionally may be bridged; o 26) a carbon linked saturated or partially saturated 3 to 8 membered heterocyclic group containing one or more N, S, SO, SO2 or O which is optionally substituted by one or more of the following: a Ci^alkoxy group; a Ci-βalkanoyl group; a C^alkoxycarbonyl group; carbamoyl; N-Ci-βalkylcarbamoyl; N, N-diCi.6alkylcarbam.oyl; hydroxy; oxo; a Ci_6alkyl group (which is optionally substituted by one or more of the following: a Ci^alkoxy group, hydroxy or a group of formula ΝRcRd in which R° and Rd are as defined above) or 27) by a Cμβalkyl group optionally substituted by one or more groups as described in 1 -26 above; 28) a C2-4alkenyl or 29) a C2-4alkynyl; wherein any cycloalkyl, phenyl, heteroaryl ring or carbon linked saturated or partially saturated 3 to 8 membered heterocyclic group in this list of optional substituents in 1 to 27 above is optionally substituted by one or more of the following: i) a Ci-3alkyl group optionally substituted by one or more halo ii) a Ci-3alkoxy group optionally substituted by one or more halo iii) halo, iv) nitro, v) cyano vi) hydroxy vii) a group of formula NRcRd in which Rc and Rd are as defined above viii) carboxy ix) a Ci-6alkylsulphonyl group optionally substituted by one or more halo; x) a Ci.6alkylsulphonyloxy group optionally substituted by one or more halo xi) carbamoyl xii) JV-C1-3alkylcarbamoyl xiii) N, N-diCi. 3alkylcarbamoyl xiv) sulphamoyl xv) N-Ci-3alkylsulphamoyl xvi) N, N-diCi. 3alkylsulphamoyl and any alkyl, alkenyl or alkynyl chain in this list of optional substituents 1 to 29 above is optionally substituted by one or more of the following: i) a Ci- 3alkyl group optionally substituted by one or more halo ii) a Ci-3alkoxy group optionally substituted by one or more halo iii) halo, iv) nitro v) cyano vi) hydroxy vii) a group of formula ΝRcRd in which Rc and Rd are as defined above;
Rb represents halo; a C^alkyl group optionally substituted by one or more halo; a Ci- 3alkoxy group optionally substituted by one or more halo;
R2 represents halo; a Ci-3alkyl group optionally substituted by one or more halo; a C1. 3alkoxy group optionally substituted by one or more halo; or cyano;
R4 represents i) H, ii) a Ci-3alkyl group optionally substituted by one or more halo iii) a Ci- 3alkoxy group optionally substituted by one or more halo iv) halo, v) nitro, vi) cyano, vii) a Ci-6alkylS(O)y(O)z- wherein y is 0,1 or 2 and z is 0 except when y is 2 when z is 0 or 1 viii) a group CH2NRURV in which Ru and Rv independently represent H or a Ci^alkyl group optionally substituted by one or more of the following: hydroxy, a Ci^alkoxy group or a group of formula NRcRd in which Rc and Rd are as defined above or Ru and Rv together with the nitrogen atom to which they are attached represent a saturated or partially unsaturated 3 to 8 membered heterocyclic ring optionally containing an additional N, S, SO, SO2 or O ix) a group CO2RW in which Rw is a Ci-3alkyl group; or x) a group C0NRxRy in which Rx and Ry independently represent H; or a
Figure imgf000019_0001
group optionally substituted by phenyl wherein the phenyl is optionally substituted by one or more C1. 3alkyl, halo or Ci-3alkoxy; or Rx and Ry together with the nitrogen atom to which they are attached represent a saturated or partially unsaturated 3 to 8 membered heterocyclic ring optionally containing an additional sulphur, oxygen or nitrogen optionally substituted by one or more of the following: a Ci-6alkyl group optionally substituted by one or more hydroxy or Ci-6alkoxy; a C1-6alkoxy group; hydroxy; Ci^acyl or oxo; R° represents H, Ci-3alkyl or halo; and m and n independently represent 0 or 1.
A further particular embodiment of the invention is represented by a compound of formula HIA
Figure imgf000019_0002
or a pharmaceutically acceptable salt thereof, in which
Ra represents: methyl; chloro; CF3; morpholino; methoxycarbonyl; N,N- dimethylcarbamoyl; oxo; a C1-3alkoxy group optionally substituted by methoxy; pyrrolidino optionally substituted in the 2-position by oxo; piperidino optionally substituted in the 4-position by hydroxy, amino, methylamino or dimethylamino; 1-piperazinyl optionally substituted in the 4-position by amino or methyl or optionally substituted in the 3 -position by oxo; l,4-oxazeρan-4-yl; l,l-dioxo-l,4-thiazinan-4-yl; cyclohexyl substituted in the 4-position by methoxy; a group ΝRpRq in which Rp and Rq independently represent H, acetyl, or a C1-3alkyl group, or Rp represents H or CH3 and Rq represents a group -CH2-(C(Rd)2)a-(CH2)b-Rk in which a is 0 or 1, Rd is H or CH3, b is 0 or 1 and R is -OH when a is 0 and b is 1 or R is NHCH3, N(CH3)2, piperidino or imidazol- 1-yl when a is 1, Rd is H or methyl and b is 1, or Rk is tert-butoxycarbonyl when a and b are 0;
R represents methyl;
RR44 rreepprreesseennttss mmeetthhyyll,, i methoxy, chloro, nitro, CF3 or cyano;
R5 represents H or alternatively represents chloro when R4 also represents chloro.
A particular embodiment of the invention is represented by a compound of formula IV
Figure imgf000020_0001
or a pharmaceutically acceptable salt thereof, in which x is 0 or 1
Ra represents a substituent from 1 to 29 as described above; Rb represents H, a C^aUcyl group or halo; R2 represents a Ci-3alkyl group, a Ci-3alkoxy group, hydroxy, oxo, CF3 or halo; R4 represents H, a C^alkyl group, a Ci-δalkoxy group, halo, nitro, CF3, SO2Me, CH2NRxRy, CO NRxRy or cyano; Rc represents H, a d^alkyl group or halo; and m and n independently represent 0 or 1.
A particular embodiment of the invention is represented by a compound of formula IVA
Figure imgf000021_0001
or a pharmaceutically acceptable salt thereof, in which x is 0 or 1 ;
Ra represents H when x is 1 or when x is 1 Ra represents 2-amino, 2-(2- hydroxyethyl)amino, 2-(2-oxopiperidino), 3-chloro, or 2-(3-carbamoylanilino);
R2 represents methyl; and
R4 represents Cl, CF3, CH3 or cyano.
A particular embodiment of the invention is represented by a compound of formula V
Figure imgf000021_0002
or a pharmaceutically acceptable salt thereof, in which
R1 represents 3-quinolyl, 5-thiazolyl, 6-chloro-2-cinnolyl or 4-aza benzimidazol-6-yl
R2 represents methyl; and
R4 represents cyano.
Specific compounds of the invention include one or more including any combination of the following compounds below, that is any number of compounds from 1 to 240 inclusive, labelled as List 1 :
N-[5-[4-(4-cyanophenyl)piperidine- 1 -carbonyl]-2-methyl-ρhenyl]- 1 -oxido-pyridine-4- carboxamide
6-acetamido-N-[2-methyl-5-(4-phenylpiperidine-l-carbonyl)phenyl]ρyridine-3- carboxamide 6-chloro-N-[2-methyl-5-(4-phenylpiperidine-l-carbonyl)phenyl]pyridine-3-carboxamide
N-[5-(4-benzylpiperidine-l-carbonyl)-2-tnethyl-phenyl]-6-chloro-pyridine-3-carboxamide
N-[5-(4-ben2ylpiperidine-l-carbonyl)-2-methyl-phenyl]-6-(trifluoromethyl)pyridine-3- carboxamide N-[5-(4-benzylpiperidine-l-carbonyl)-2-ethyl-phenyl]-6-chloro-pyridine-3-carboxamide
4-chloro-N-[2-methyl-5-(4-phenylpiperidine-l-carbonyl)phenyl]benzamide
N-[2-methyl-5-(4-phenylpiperidine-l-carbonyl)phenyl]-6-(trifluoromethyl)pyridine-3- carboxamide
6-dimethylamino-N-[2-methyl-5-(4-phenylpiperidine-l-carbonyl)phenyl]pyridine-3- carboxamide
N-[2-methyl-5-(4-phenylpiperidine-l-carbonyl)phenyl]-6-morpholin-4-yl-pyridine-3- carboxamide
6-chloro-N-[5-[4-(4-methoxyphenyl)piperidine-l-carbonyl]-2-methyl-phenyl]pyridine-3- carboxamide 2-bromo-5-methoxy-N-[5-[4-(4-methoxyρhenyl)piperidine- 1 -carbonyl]-2-methyl- phenyl]benzamide
N-[5-[4-(4-methoxyphenyl)piperidine-l-carbonyl]-2-methyl-phenyl]benzothiazole-2- carboxamide
6-acetamido-N-[5-[4-(4-methoxyphenyl)piperidine-l-carbonyl]-2-methyl-phenyl]pyridine- 3 -carboxamide
N-[5-[4-(4-methoxyphenyl)piperidine-l-carbonyl]-2-methyl-phenyl]benzamide
N-[5-[4-(4-methoxyρhenyl)piperidine-l-carbonyl]-2-methyl-ρhenyl]-4-phenyl-benzamide
2-chloro-N-[5-[4-(4-methoxyphenyl)piperidine-l-carbonyl]-2-methyl-phenyl]pyridine-3- carboxamide 2-methoxy-N-[5-[4-(4-methoxyρhenyl)piperidine-l-carbonyl]-2-methyl-phenyl]benzamide
N-[5-[4-(4-methoxyphenyl)piperidine-l-carbonyl]-2-methyl-phenyl]pyridine-3- carboxamide
N-[5-[4-(4-methoxyphenyl)piperidine-l-carbonyl]-2-methyl-phenyl]-3-methyl-benzamide
3-chloro-N-[5-[4-(4-methoxyphenyl)piperidine-l-carbonyl]-2-methyl-phenyl]benzamide N-[5-[4-(4-methoxyphenyl)piperidine-l-carbonyl]-2-methyl-plienyl]-4-tert-butyl- benzamide 2-chloro-6-methoxy-N-[5-[4-(4-methoxyphenyl)piperidine-l-carbonyl]-2-methyl- phenyl]pyridine-4-carboxamide
N-[5-[4-(4-methoxyphenyl)piperidine-l-carbonyl]-2-methyl-plienyl]-4-methyl-benzamide
2-chloro-N-[5-[4-(4-methoxyphenyl)piperidine-l-carbonyl]-2-methyl-phenyl]pyridine-4- carboxamide
N-[5-[4-(4-methoxyphenyl)piperidine-l-carbonyl]-2-methyl-phenyl]-4-
(trifluoromethoxy)benzamide
2-chloro-N-[5-[4-(4-methoxyphenyl)piperidine-l-carbonyl]-2-methyl-phenyi]-6-methyl- pyridine-4-carboxamide 2,4-dichloro-N-[5-[4-(4-methoxyphenyl)piperidine- 1 -carbonyl]-2~methyl- phenyl]benzamide
N-[5-[4-(4-methoxyphenyl)piperidine-l-carbonyl]-2-methyl-phenyl]-3-
(trifluoromethoxy)benzamide
N-[5-[4-(4-methoxyphenyl)piperidine-l-carbonyl]-2-metb.yl-phenyl]pyridine-4- carboxamide
N-[5-[4-(4-methoxyphenyl)piperidine-l-carbonyl]-2-methyl-phenyl]-2-methylsulfanyl- pyridine-3 -carboxamide
N-[5-[4-(4-methoxyphenyl)piperidine-l-carbonyl]-2-methyl-prienyl]qiiinoline-2- carboxamide 6-acetamido-N- [2-methyl-5- [4-(4-methylsulfonylpheny l)piperidine- 1 - carbonyl]phenyl]pyridine-3-carboxamide
N-[5-[4-(4-chlorophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]-6-methyl-pyridine-3- carboxamide
6-chloro-N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-plienyl]pyridine-3- carboxamide
N-[5-[4-(4-chlorophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]-6-
(trifluorometh.yl)pyridine-3-carboxamide
N-[2-metriyl-5-[4-[4-(trifluoromethyl)ρhenyl]piperidine-l-carbonyl]plienyl]pyridine-4- carboxamide N-[5-[4-(4-fluorophenyl)piperidine- 1 -carbonyl]-2-methyl-phenyl]pyridine-4-carboxamide
N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]pyridine-4-carboxamide N-[5-[4-(4-cyanophenyl)piperidine- 1 -carbonyl]-2-methyl- phenyl] cyclopropanecarboxamide
N- [5 - [4-(4-cyanopheny l)piperidine- 1 -carbonyl] -2-methyl-phenyl]-6-oxo- 1 H-pyridine-3 - carboxamide N-[5-[4-(4-cyanoρhenyl)piperidine-l-carbonyl]-2-methyl-phenyl]-6-morpholin-4-yl- pyridine-3 -carboxamide
6-acetamido-N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]pyridine-3- carboxamide
N-[5 -[4-(4-cyanophenyl)piperidine- 1 -carbonyl]-2-methyl-phenyl] cyclobutanecarboxamide N-[5-[4-(4-cyanophenyl)piperidine- 1 -carbonyl]-2-methyl-phenyl]butanamide
N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]-3,3-dimethyl- butanamide
N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]benzamide
N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]pyridine-3-carboxamide N-[5-[4-(4-cyanophenyl)piperidine- 1 -carbonyl]-2-methyl-phenyl]cyclohexanecarboxamide
N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]-2-(3-oxopiperazin-l- yl)acetamide l-acetyl-N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]piρeridine-4- carboxamide N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl- phenyl] cyclopentanecarboxamide
N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]-2-methyl-ρropanamide
N-[5 - [4-(4-cy anophenyl)piperidine- 1 -carbonyl] -2-methyl-phenyl] -6-oxo- 1 H-pyridazine-3 - carboxamide N-[2-chloro-5-[4-(4-cyanophenyl)piperidine- 1 -carbonyl]phenyl]pyridine-4-carboxamide
N-[5-[4-(4-cyanophenyl)piperidine- 1 -carbonyl]-2-methyl-phenyl]- 1 -hydroxy-cyclohexane-
1 -carboxamide
N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]-2-phenoxy-acetamide l-[[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl- phenyl]carbamoylmethyl]piperidine-4-carboxamide
N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]-3-hydroxy-butanamide
N-[5-[4-(4-cyanopb.enyl)piperidine-l-carbonyl]-2-methyl-phenyl]oxolane-3-carboxamide N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]-2-hydroxy-cyclohexane-
1-carboxamide
N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]-4-methoxy- cyclohexane- 1 -carboxamide N-[5-[4-(4-cyanoρhenyl)piperidine- 1 -carbonyl]-2-methyl-phenyl]-4-methoxy- cyclohexane- 1 -carboxamide
N-[5-[4-(4-cyanoρhenyl)piperidine-l-carbonyl]-2-methyl-phenyl]-3-methoxy- cyclohexane- 1 -carboxamide
6-chloro-N-[2-chloro-5-[4-(4-cyanophenyl)piperidine-l-carbonyl]phenyl]pyridine-3- carboxamide
N-[2-chloro-5-[4-(4-cyanophenyl)piperidine-l-carbonyl]phenyl]butanamide methyl 5-[[5-[4-(4-cyanophenyl)piperidine- 1 -carbonyl]-2-methyl- phenyl]carbamoyl]pyridine-2-carboxylate ethyl 5-[[5-[4-(4-cyanophenyl)piperidine-l -carbonyl]-2-methyl- phenyl] carbamoyl]pyridine-3 -carboxylate
N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]-2-(4-hydroxy-l- piperidyl)acetamide
6-cyano-N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]pyridine-3- carboxamide N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]-2-[(4- methoxyphenyl)amino]pyridine-4-carboxamide
N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-ρhenyl]-2-fluoro-pyridine-3- carboxamide
N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-ρhenyl]-6-(l-piperidyl)pyridine- 3 -carboxamide
N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-ρhenyl]-2-pyrrolidin-l-yl- pyridine-4-carboxamide
N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]-2-(l-piperidyl)pyridine-
4-carboxamide N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]-2-(l,2,4-triazol-l- yl)pyridine-4-carboxamide
N- [5- [4-(4-cy anophenyl)piperidine- 1 -carbonyl] -2-methyl-phenyl] quinoline-3 -carboxamide 6-amino-N- [5- [4-(4-cy anophenyl)piperidine- 1 -carbonyl] -2-methyl-phenyl]pyridine-3 - carboxamide
N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]-6-methyl-pyridine-3- carboxamide 2-chloro-N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]pyridine-4- carboxamide
N-[5 - [4-(4-cyanophenyl)piperidine- 1 -carbonyl] -2-methyl-phenyl] - 1 -oxido-pyridine-5- carboxamide
5-bromo-N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]pyridine-3- carboxamide
N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-plienyl]-6-methoxy- benzothiazole-2-carboxamide
N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]-2-methyl-6-oxo-lH- pyridine-4-carboxamide 6-[(4-acetamidophenyl)amino]-N-[5-[4-(4-cyanophenyl)piperidine- 1 -carbonyl]-2-methyl- phenyl]pyridine-3 -carboxamide
2- [(3 -carbamoylphenyl)amino] -N-[5 - [4-(4-cyanophenyl)piperidine- 1 -carbonyl] -2-metby 1- phenyl]pyridine-4-carboxamide
2,5-dichloro-N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]pyridine-4- carboxamide
N-[5-[4-(4-cyanophenyl)piperidine- 1 -carbonyl]-2-methyl-phenyl]-6-(2-pyrrolidin- 1 - ylethyl)pyridine-3 -carboxamide tert-butyl 4-[5-[[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl- phenyl]carbamoyl]pyridin-2-yl]piperazine- 1 -carboxylate N-[5-[4-(4-cyanophenyl)piperidine- 1 -carbonyl]-2-methyl-phenyl]-2-moφholin-4-yl- pyridine-4-carboxamide
N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-plienyl]-6-(2- methoxyethoxy)pyridine-3-carboxamide
2-amino-N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]pyridine-4- carboxamide
3-chloro-N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]pyridine-4- carboxamide N- [5 - [4-(4-cyanophenyl)piperidine- 1 -carbonyl] -2-methyl-phenyl] -6-ethoxy-pyridine-3 - carboxamide
N- [5 - [4-(4-cyanophenyl)piperidine- 1 -carbonyl] -2-methyl-phenyl] -6-propan-2-y loxy- pyridine-3 -carboxamide tert-butyl N-[[5-[[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl- phenyl]carbamoyl]pyridin-2-yl]methyl]carbamate
N-[5-[4-(4-cyanophenyl)piperidine- 1 -carbonyl]-2-methyl-phenyl]- 4-azabenzimidazol-6- carboxamide
N- [5 - [4-(4-cyanophenyl)piperidine- 1 -carbonyl] -2-methyl-phenyl]pyrimidine-5 - carboxamide
6-chloro-N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]cinnoline-3- carboxamide
N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]pyrimidine-4- carboxamide N-[5-[4-(4-cyanophenyl)piperidine- 1 -carbonyl]-2-methyl-phenyl]pyridazine-4- carboxamide
N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]l,3-thiazole-4- carboxamide
N-[5-[4-(4-cyanophenyl)piperidine- 1 -carbonyl]-2-methyl-phenyl] 1 ,3-thiazole-5- carboxamide
N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]-2-morpholin-4-yl-l,3- thiazole-4-carboxamide
N- [5 - [4-(4-cyanophenyl)piperidine- 1 -carbonyl] -2-methyl-phenyl] -2 ,4-dimethyl- 1,3- thiazole-5-carboxamide N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]pyrazine-2-carboxamide
N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]-5-methyl-pyrazine-2- carboxamide
2-acetamido-N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]-4-methyl-
1 ,3-thiazole-5-carboxamide N-[2-chloro-5-[4-(4-cyanophenyl)piperidine-l-carbonyl]phenyl]cyclopropanecarboxamide
3 , 5 -dichloro-N- [5 - [4-(4-cyanophenyl)piperidine- 1 -carbonyl] -2-methyl-phenyl]pyridine-4- carboxamide N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]-2,4-dimethyl-pyridine-
3-carboxamide
N-[5-(4-ben2ylpiperidine-l-carbonyl)-2-methyl-phenyl]-6-morpholin-4-yl-pyridine-3- carboxamide N-[5-(4-benzylpiperidine- 1 -carbonyl)-2-methyl-phenyl]-6-[(3-dimethylamino-2,2- dimethyl-propyl)amino]pyridine-3-carboxamide
6-[(3-dimethylamino-2,2-dimetliyl-propyl)ammo]-N-[2-methyl-5-(4-phenylpiperidine-l- carbony^phenylJpyridine-S-carboxamide
6-(3-dimethylaminopropylamino)-N-[2-methyl-5-(4-phenylpiperidine-l- carbonyl)phenyl]pyridine-3-carboxamide
6-(3-methylbutylamino)-N-[2-methyl-5-(4-phenylpiperidine-l-carbonyl)phenyl]pyridine-
3-carboxamide
6-(4-diniethylamino- 1 -piperidyl)-N-[2-methyl-5-(4-phenylpiperidine- 1 - carbonyl)phenyl]pyridine-3-carboxamide N-[2-methyl-5-(4-phenylpiperidine- 1 -carbonyl)phenyl]-6-piperazin- 1 -yl-pyridine-3- carboxamide
6-(4-amino- 1 -piperidyl)-N-[2-methyl-5-(4-phenylpiperidine- 1 -carbonyl)phenyl]pyridine-3 - carboxamide
N-[5-[4-(4-methoxyphenyl)piperidine-l-carbonyl]-2-methyl-phenyl]-6-morpholin-4-yl- pyridine-3 -carboxamide
6-dimethylamino-N-[5-[4-(4-methoxyphenyl)piperidine-l-carbonyl]-2-methyl- phenyl]pyridine-3 -carboxamide
N-[2-methyl-5-[4-(4-methylphenyl)piperidine-l-carbonyl]phenyl]-6-morpholin-4-yl- pyridine-3 -carboxamide 6-dimethylamino-N-[5-[3-(4-methoxyphenyl)pyrrolidine- 1 -carbonyl]-2-methyl- phenyl]pyridine-3 -carboxamide
6-dimethylamino-N-[5-[4-(4-methoxyphenyl)piperidine-l-carbonyl]-2-
(trifluoromethyl)phenyl]pyridine-3-carboxamide
N-[5-[4-(4-methoxyphenyl)piperidine-l-carbonyl]-2-(trifluoromethyl)phenyl]-6- morpholin-4-yl-pyridine-3 -carboxamide
N-[2-methyl-5-[4-[4-(trifluoromethyl)phenyl]piperidine-l-carbonyl]phenyl]-6-moφholin-
4-yl-pyridine-3 -carboxamide N-[5-[4-(4-chlorophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]-6-morpholin-4-yl- pyridine-3 -carboxamide
N-[2-methyl-5-[4-(4-methylsulfonylphenyl)piperidine-l-carbonyl]phenyl]-6-moφholin-4- yl-pyridine-3-carboxamide 5 N-[5-[4-(4-methoxyphenyl)piperidine- l-carbonyl]-2-methyl-phenyl]-6-(l - piperidyl)pyridine-3-carboxamide
6-(2-methoxyethylamino)-N-[5-[4-(4-methoxyphenyl)piperidine-l-carbonyl]-2-methyl- phenyl]pyridine-3 -carboxamide
N-[5-[4-(4-methoxyphenyl)piperidine-l-carbonyl]-2-niethyl-phenyl]-6-[2-(2- i o oxoimidazolidin- 1 -yl)ethy lamino]pyridine-3 -carboxamide
N-[5-[4-(4-methoxyphenyl)piperidine- 1 -carbonyl]-2-methyl-phenyl]-6-(3-oxopiperazin- 1 - yl)pyridine-3 -carboxamide
6-[(l-ethyl-3-piperidyl)amino]-N-[5-[4-(4-methoxyphenyl)piperidine-l-carbonyl]-2- methyl-phenyl]pyridine-3-carboxamide is 6-(3 -methoxyazetidin- 1 -y I)-N- [5 - [4-(4-methoxyphenyl)piperidine- 1 -carbonyl] -2-methyl- phenyl]pyridine-3-carboxamide
N-[5-[4-(4-methoxyphenyl)piperidine-l-carbonyl]-2-methyl-phenyl]-6-pyrrolidm-l-yl- pyridine-3 -carboxamide
6-(2-hydroxyethyl-methyl-amino)-N-[5-[4-(4-methoxyphenyl)piperidine-l-carbonyl]-2- 20 methy 1-pheny l]pyridine-3 -carboxamide
N-[5-[4-(4-methoxyphenyl)piperidine-l-carbonyl]-2-methyl-phenyl]-6-[(l-methyl-4- piperidyl)amino]pyridine-3-carboxamide
6-(3-imidazol-l-ylpropylamino)-N-[5-[4-(4-methoxyphenyl)piperidine-l-carbonyl]-2- methyl-phenyl]pyridine-3-carboxamide 25 6-(azetidin-l-yl)-N-[5-[4-(4-methoxyphenyl)piperidine-l-carbonyl]-2-methyl- phenyl]pyridine-3-carboxamide
N- [5 - [4-(4-methoxyphenyl)piperidine- 1 -carbonyl] -2-methy 1-pheny 1] -6-( 1 ,4-oxazepan-4- yl)pyridine-3-carboxamide
N-[5-[4-(4-methoxyphenyl)piperidine-l-carbonyl]-2-metliyl-phenyl]-6-[3-(2- 30 oxopyrrolidin-l-yl)propylamino]pyridine-3-carboxamide
N-[5-[4-(4-methoxyphenyl)piperidine-l-carbonyl]-2-methyl-phenyl]-6-(propan-2- ylamino)pyridine-3-carboxamide 6-(2-hydroxyethylamino)-N-[5-[4-(4-methoxyphenyl)piperidine-l-carbonyl]-2-methyl- phenyl]pyridme-3-carboxamide
N-[5-[4-(4-methoxyphenyl)piperidine- 1 -carbonyl]-2-methyl-phenyl]-6-[3-(l - piperidyl)propylamino]pyridine-3-carboxamide N-[5-[4-(4-methoxyphenyl)piperidine-l-carbonyl]-2-methyl-phenyl]-6-(3-morpholin-4- ylpropylamino)pyridine-3-carboxamide
6-[4-(2-methoxyethyl)piperazin-l-yl]-N-[5-[4-(4-methoxyphenyl)piperidine-l-carbonyl]-
2-methyl-phenyl]pyridine-3-carboxamide
6-[(3-dimethylamino-2,2-dimethyl-propyl)amino]-N-[5-[4-(4-metb.oxyphenyl)piperidine- 1 -carbonyl]-2-methyl-phenyl]pyridine-3-carboxamide
N- [5 - [4- [(4-methoxyphenyl)methyl]piperidine- 1 -carbonyl] -2-methyl-phenyl] -6-morpholin-
4-yl-pyridine-3 -carboxamide
6-dimethylamino-N- [5 - [4- [(4-methoxypheny l)methyl]piperidine- 1 -carbonyl] -2-methyl- pheny l]pyridine-3 -carboxamide 6-[(3-dimethylamino-2,2-dimethyl-propyl)amino]-N-[5-[4-[(4- methoxypb.enyl)methyl]piperidine-l-carbonyl]-2-methyl-plienyl]pyridine-3-carboxamide
-dimethylamino-N-[2-methyl-5-[4-(4-methylsulfonylphenyl)piperidine-l- carbonyl]phenyl]pyridine-3-carboxamide
N-[5-[4-(4-chlorophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]-6-dimethylamino- pyridine-3 -carboxamide
6-(4-amino-l-piperidyl)-N-[5-[4-(4-methoxyphenyl)piperidine-l-carbonyl]-2-methyl- phenyl]pyridine-3 -carboxamide
6-(4-hydroxy-l-piperidyl)-N-[5-[4-(4-methoxyphenyl)piperidine-l-carbonyl]-2-methyl- phenyl]pyridine-3-carboxamide 6-dimethylamino-N-[2-methyl-5-[4-[4-(trifluoromethyl)phenyl]piperidine-l- carbonyl]phenyl]pyridine-3-carboxamide
N-[5 - [4-(3 ,4-dichlorophenyl)ρiperidine- 1 -carbonyl]-2-methyl-phenyl] -6-dimethylamino- pyridine-3 -carboxamide
N-[5-[4-(3,4-dichlorophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]-6-morpholin-4-yl- pyridine-3 -carboxamide
N-[5-[4-(3 ,4-dichlorophenyl)piperidine- 1 -carbonyl]-2-methyl-ρhenyl]-6- [(3 - dimethylamino-2,2-dimethyl-propyl)amino]pyridine-3-carboxamide N-[5-[4-(4-methoxyphenyl)piperidine-l-carbonyl]-2,4-dimethyl-phenyl]-6-morpholin-4- yl-pyridine-3-carboxamide
6-[(3-dimethylamino-2,2-dimethyl-proρyl)amino]-N-[2-methyl-5-[4-[4-
(trifluoromethy^phenylJpiperidine-l-carbonylJphenyypyridine-S-carboxamide N-[5-[4-(4-cyanophenyl)piperidine- 1 -carbonyl]-2-methyl-phenyl]-6-dimethylamino- pyridine-3 -carboxamide
6-dimethylamino-N-[2-metb.yl-5-[4-(4-nitrophenyl)piperidine-l-carbonyl]phenyl]pyridine-
3-carboxamide '
N-[5-[4-(2,4-dichloropb.enyl)piperidine-l-carbonyl]-2-methyl-phenyl]-6-dimethylamino- pyridine-3 -carboxamide methyl 4- [ 1 - [3 - [(6-dimethylaminopyridine-3 -carbonyl)amino] -4-methyl-benzoyl] -4- piperidyljbenzoate
N-[5-[4-(4-chlorophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]-6-methylamino- pyridine-3 -carboxamide N-[5-[4-(4-cyanophenyl)piperidine- 1 -carbonyl]-2-methyl-phenyl]-6-(propan-2- ylamino)pyridine-3-carboxamide
N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]-6-(methyl-propan-2-yl- amino)pyridine-3-carboxamide
N-[5-[4-(4-cyanophenyl)piperidine- 1 -carbonyl]-2-methyl-phenyl]-6-(4-hydroxy- 1 - piperidyl)pyridine-3-carboxamide
N-[5-[4-(4-cyanophenyl)piperidine- 1 -carbonyl]-2-methyl-phenyl]-6-(3-oxopiperazin- 1 - yl)pyridine-3 -carboxamide
N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-plienyl]-6-(2- hydroxyethylamino)pyridine-3-carboxamide N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]-6-[3-(2-oxopyrrolidin-l- yl)propylamino]pyridine-3-carboxamide
N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]-6-(2- methoxyethylamino)pyridine-3-carboxamide
N-[5-[4-(4-cyanophenyl)piperidine- 1 -carbonyl]-2-methyl-phenyl]-6-(l ,4-oxazepan-4- yl)pyridine-3-carboxamide
N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]-6-methylamino- pyridine-3 -carboxamide N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]-6-(3-imidazoH- ylpropylamino)pyridine-3-carboxamide
N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]-6-(4-methylpiperazin-l- yl)pyridine-3 -carboxamide N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]-6-(3- hydroxypropylamino)pyridine-3-carboxamide
N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]-6-(2-hydroxyethyl- methyl-amino)pyridine-3-carboxamide
N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]-6-piperazin-l-yl- ρyridine-3 -carboxamide
N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]-6-pyrrolidin-l-yl- pyridine-3 -carboxamide
6-(4-amino-l-piperidyl)-N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl- phenyl]pyridine-3-carboxamide 6-(azetidin- 1 -y I)-N- [5- [4-(4-cyanophenyl)piperidine- 1 -carbonyl] -2-methy 1- phenyl]pyridine-3 -carboxamide
N- [5- [4-(4-cyanophenyl)piperidine- 1 -carbonyl] -2-methyl-phenyl] -2-(4-hydroxy- 1 - piperidyl)pyridine-4-carboxamide
N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]-2-(3-oxopiperazin-l- yl)pyridine-4-carboxamide
N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]-2-(2- hydroxyethylamino)pyridine-4-carboxamide
N- [5 - [4-(4-cy anopheny l)piperidine- 1 -carbonyl] -2-methyl-phenyl] -2-(4-methylpiperazin- 1 - yl)pyridine-4-carboxamide tert-butyl2-[[5-[[5-[4-(4-cyanophenyl)piperidme-l-carbonyl]-2-methyl- phenyl]carbamoyl]pyridin-2-yl]amino]acetate
2-dimethylamino-N- [2-methyl-5 - [4- [4-(trifluoromethy l)pheny l]piperidine- 1 - carbonyl]pheny 1] acetamide
2-(2-methylρyrrolidin- 1 -yl)-N-[2-methyl-5-[4-[4-(trifluoromethyl)phenyl]piperidine- 1 - carbonyl]phenyl] acetamide
N-[2-methyl-5-[4-[4-(trifluoromethyl)phenyl]piperidine-l-carbonyl]phenyl]-2-(3- oxopiperazin- 1 -yl)acetamide 2-(l,3-dihydroisoindol-2-yl)-N-[2-methyl-5-[4-[4-(trifluoromethyl)phenyl]piperidine-l- carbonyl]phenyl]acetatnide
2-(azetidin- 1 -yl)-N- [2-methyl-5 - [4- [4-(trifluoromethyl)pheny ljpiperidine- 1 - carbonyl]phenyl]acetamide 2-(cyclohexyl-ethyl-amino)-N-[2-methyl-5-[4-[4-(trifluoromethyl)phenyl]piperidine-l- carbonyl]phenyl]acetamide
N-[2-methyl-5 - [4- [4-(trifluoromethyl)pheny ljpiperidine- 1 -carbonyl]phenyl] -2-morpholin-
4-yl-acetamide l-[[2-methyl-5-[4-[4-(trifluoromethyl)phenyl]piperidine-l- carbonyl]phenyl]carbamoylmethyl]piperidine-4-carboxamide
2-(4-hydroxy-l-piperidyl)-N-[2-methyl-5-[4-[4-(trifluoromethyl)phenyl]piperidine-l- carbonyl]phenyl]acetamide
2-(methyl-propyl-amino)-N-[2-methyl-5-[4-[4-(trifluoromethyl)phenyl]piperidine-l- carbonyljphenyl] acetamide 2-(2-dimethylaminoethyl-methyl-amino)-N-[2-methyl-5-[4-[4-
(trifluoromethyl)phenyl]piperidine-l-carbonyl]phenyl]acetamide
2-(methyl-propan-2-yl-amino)-N-[2-methyl-5-[4-[4-(trifluoromethyl)phenyl]piperidine-l- carbonyl]phenyl]acetamide
2-(butyl-methyl-amino)-N-[2-methyl-5-[4-[4-(trifluoromethyl)phenyl]piperidine-l- carbonyl]phenyl]acetamide
2-(2-hydroxyethyl-methyl-amino)-N-[2-methyl-5-[4-[4-
(trifluoromethyl)phenyl]piperidine-l-carbonyl]plienyl]acetamide
2-(2-furylmetb.yl-methyl-amino)-N-[2-methyl-5-[4-[4-(trifluoromethyl)phenyl]piperidine-
1 -carbonyl]phenyl]acetamide 2-[4-(hydroxymethyl)- 1 -piperidyl]-N-[2-methyl-5-[4-[4-
(trifluoromethyl)phenyl]piperidine- 1 -carbonyl]ρhenyl] acetamide
4-(methylaminomethyl)-N-[2-methyl-5-[4-[4-(trifluoromethyl)phenyl]piperidine-l- carbonyl]phenyl]benzamide
4-(dimethylaminomethyl)-N-[2-methyl-5-[4-[4-(trifluoromethyl)plienyl]piperidine-l- carbonyl]phenyl]benzamide
6-hydroxy-N-[2-methyl-5-[4-[4-(trifluoromethyl)phenyl]piperidme-l- carbonyl]phenyl]pyridine-3-carboxamide N-[5-[4-[4-(aminomethyl)phenyl]piρeridine-l-carbonyl]-2-methyl-phenyl]-6- dimethylamino-pyridine-3-carboxamide
N-[5-[4-(4-chlorophenyl)piperidine- 1 -carbonyl]-2-methyl-phenyl]-6-methyl- 1 -oxido- pyridine-3 -carboxamide N-[5-[4-(4-chlorophenyl)piperidine- 1 -carbonyl]-2-methyl-phenyl]- 1 -oxido-6-
(trifluoromethyl)pyridine-3-carboxamide
N-[2-methyl-5-[4-[4-(trifluoromethyl)plienyl]piperidine-l-carbonyl]phenyl]-l-oxido- pyridine-4-carboxamide
N-[5-[4-[4-[(4-fluorophenyl)methylcarbamoyl]phenyl]piperidine-l-carbonyl]-2-methyl- phenyl]pyridine-4-carboxamide
N- [5-[4- [4-(benzyl-methyl-carbamoyl)phenyl]piperidine- 1 -carbonyl] -2-methyl- phenyl]pyridine-4-carboxamide
N-[2-methyl-5-[4-[4-(morpholine-4-carbonyl)phenyl]piperidine-l- carbonyl]phenyl]pyridine-4-carboxamide 5-[[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]carbamoyl]pyridine-2- carboxylic acid
5-[[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]carbamoyl]pyridine-3-
Garboxylic acid
N-[5 - [4-(4-cyanophenyl)piperidine- 1 -carbonyl] -2-methy 1-phenyl] -N',N'-dimethyl- pyridine-3,5-dicarboxamide
N'-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]pyridine-2,5- dicarboxamide
N'-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-plienyl]-N,N-dimethyl-pyridine-
2,5-dicarboxamide N-[5- [4-(4-cy anopheny l)piperidine- 1 -carbonyl] -2-methyl-phenyl] -6-( 1 , 1 -dioxo- 1 ,4- thiazinan-4-yl)pyridine-3-carboxamide
2- [ [5 - [[5 - [4-(4-cyanophenyl)piperidine- 1 -carbony l]-2-methy 1-phenyl] carbamoyl]pyridin-2- yl]amino]acetic acid
N-[2-chloro-5-[4-(4-cyanophenyl)piperidine-l-carbonyl]phenyl]-6-(3-oxopiperazin-l- yl)pyridine-3-carboxamide
N-[2-chloro-5-[4-(4-cyanophenyl)piperidine-l-carbonyl]phenyl]-6-dimethylamino- pyridine-3 -carboxamide N-[2-chloro-5-[4-(4-cyanophenyl)piperidine-l-carbonyl]phenyl]pyridine-3-carboxamide
N- [5 - [4-(4-cyanophenyl)piperidine- 1 -carbonyl] -2-metliyl-phenyl] -2-phenyl-acetamide
N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methoxy-phenyl]pyridine-4- carboxamide N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]-2-pyridin-3-yl- acetamide
N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-(trifluoromethoxy)phenyl]pyridine-4- carboxamide
N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-(trifluorometlioxy)phenyl]-6-oxo-lH- pyridine-3-carboxamide
6-acetamido-N- [5 - [4-(4-cyanopheny l)piperidine- 1 -carbonyl] -2-
(trifluoromethoxy)phenyl]pyridine-3-carboxaniide
N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-fluoro-phenyl]pyridine-4-carboxamide
N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-plienyl]-2-pyridin-4-yl- acetamide;
N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methoxy-phenyl]-2-methyl- propanamide;
N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-(trifluoromethoxy)phenyl]-6-morpholin-
4-yl-pyridine-3-carboxamide; N-[5-[4-(4-cyanophenyl)piperidine- 1 -carbonyl]-2,4-dimethyl- phenyl] cy clobutanecarboxamide;
6-acetamido-N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methoxy-phenyl]pyridine-
3-carboxamide;
N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2,4-dimethyl-phenyl]-6-oxo-lH-pyridine- 3-carboxamide;
N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2,4-dimethyl-phenyl]-6-morpholin-4-yl- pyridine-3-carboxamide;
N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methoxy-phenyl]-6-oxo-lH-pyridine-3- carboxamide; N- [5 - [4-(4-cyanophenyl)piρeridine- 1 -carbonyl] -2-(trifluoromethyl)phenyl]pyridine-4- carboxamide; and N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]-6-thiomorpholin-4-yl- pyridine-3 -carboxamide or a pharmaceutically-acceptable salt thereof.
A compound of the Formula I, or a pharmaceutically-acceptable salt thereof, may be prepared by any process known to be applicable to the preparation of chemically-related compounds. Such processes, when used to prepare a compound of the formula I are provided as a further feature of the invention and are illustrated by the following representative process variants. Necessary starting materials may be obtained by standard procedures of organic chemistiy. The preparation of such starting materials is described in conjunction with the following representative process variants and within the accompanying Examples. Alternatively necessary starting materials are obtainable by analogous procedures to those illustrated that are within the ordinary skill of an organic chemist.
According to a further aspect of the present invention provides a process for preparing a compound of formula I or a pharmaceutically acceptable salt thereof (wherein R1, R2, R3, R4, R5, R5', R6, R6, L, m and n are, unless otherwise specified, as defined in formula I) which process comprises of: (a) reacting a compound of formula VI
Figure imgf000036_0001
Vl with a compound of formula VII
R1COX
VII in which X represents a leaving group for example halo, e.g. chloro, in the presence of a diluent for example a solvent e.g. dichloromethane and optionally in the presence of a base, for example an organic amine e.g DIPEA, at a temperature in the range of 0-1500C b) reacting a compound of formula VI
Figure imgf000037_0001
Vl
with a compound of formula VIII
R1COOH
VIII optionally in the presence of a coupling agent and optionally in the presence of a diluent for example an organic solvent e.g. dichloromethane at a temperature in the range of O0C - 1000C or the boiling point of the diluent, whichever is the lower c) reacting a compound of formula IX
Figure imgf000037_0002
IX with a compound of formula X
Figure imgf000037_0003
optionally in the presence of a coupling agent and optionally in the presence of a diluent for example a solvent at a temperature in the range of 0-1500C d) reacting a compound of formula IX
Figure imgf000038_0001
IX with a compound of formula XI
Figure imgf000038_0002
Xl in which X represents a leaving group for example halo, e.g. chloro, in the presence of a diluent for example a solvent e.g. dichloromethane and optionally in the presence of a base, for example an organic amine e.g DIPEA, at a temperature in the range of 0-1500C; e) reacting a compound of formula XII
Figure imgf000038_0003
in which X represents a replaceable group, eg. F, Cl, Br , I, OMesyl, or OTrifiyl with a compound of formula XIII
R1C(O)NH2
XIII in the presence of a metal catalyst, eg. Pd, Cu or Zn, or derivatives thereof, and of a solvent such as an alcohol, THF, toluene, or DMF, at a temperature in the range 0 - 150°C; or f) reacting a compound of formula XIV
Figure imgf000039_0001
XIV with a compound of formula XV in which X represents a replaceable group, eg. F, Cl, Br, I, OMesyl, or OTriflyl with a compound of formula XV
Figure imgf000039_0002
XV in the presence of carbon monoxide and in the presence of a metal catalyst, eg. Pd or derivatives thereof, and in a solvent such as an alcohol, THF, toluene, or DMF, and in the temperature range 0 - 15O0C. The carbon monoxide may be gaseous or in the form of a metal carbonyl, eg. Molybdenum hexacarbonyl.
It will be appreciated that the transformation in steps b and c above may be carried out with the use of different coupling agents, with or without additives, in various suitable diluents or solvents, and over a range of temperatures.
Examples of coupling agents are Dichlorotriphenyl phosphorane (DCTPP), 1-ethyl- 3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDAC), O-benzotriazol-1-yl- N,N,N',N'-tetramethyluronium hexafluorophosphate (HTBU), O-(7-azabenzotriazol-l-yl)- N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) and 4-(4,6-dimethoxy-l,3,5- triazin-2-yl)-4-methylmorpholinium chloride (DMTMM).
Examples of optional additives are: 1 -hydroxy benzotriazole (HOBt), 4- dimethylamino pyridine (DMAP), di-ώo-propylethylamine (DIPEA), and triethylamine (TEA). Examples of suitable solvents are: dimethyl formamide (DMF), chloroform, dichloromethane (DCM), and tetrahydrofuran (THF). Certain compounds of formula I may be converted into other compounds of formula I by methods known to those skilled in the art. For example, compounds of formula I
Figure imgf000040_0001
in which R1 represents a 6-amino-3-pyridyl or a 6-(substituted-amino)-3-pyridyl group may be prepared by reacting a compound of formula I in which R1 represents a 6-chloro (or 6-bromo)-3-pyridyl group with an compound of ammonia or a salt thereof or a substituted amine or a salt thereof in the presence of a diluent and optionally in the presence of abase, for example an organic base, e.g. triethylamine, at a temperature in the range of 0-2000C. It will be appreciated that the above transformation may be carried out in various suitable solvents and over a range of temperatures. Examples of suitable solvents for microwave heating are methanol, ethanol, ACN, DMF or DMA; additionally, the reaction may typically be carried out in the range from ambient temperature to 2000C, with conventional or microwave heating.
Compounds of formula I in which R1 represents an optionally substituted pyridyl- N-oxide may be prepared by reacting a compound of formula I in which R1 represents an optionally substituted pyridyl with an oxidising agent for example urea hydrogen peroxide or 3-chloroperbenzoic acid, in the presence of a diluent for example dichloromethane or acetonitrile at a temperature in the range of 0-1500C.
In other processes compounds of formula I containing a sulphide group may be oxidised to SO or SO2 for example by use of potassium peroxymonosulfate, nitriles may be reduce to aminomethyl compounds, amines may be acylated or sulphonated to to give amides or sulphonamides, respectively, activated heteroaryl halides may be hydrolysed to hydroxy groups, and esters may be hydrolysed to acids,
Certain intermediates of formula VI are believed to be novel and are herein claimed as another aspect of the present invention. Pharmaceutical preparations
The compounds of the invention will normally be administered via the oral, parenteral, intravenous, intramuscular, subcutaneous or in other injectable ways, buccal, rectal, vaginal, transdermal and/or nasal route and/or via inhalation, in the form of pharmaceutical preparations comprising the active ingredient or a pharmaceutically acceptable addition salt, in a pharmaceutically acceptable dosage form. Depending upon the disorder and patient to be treated and the route of administration, the compositions may be administered at varying doses.
Suitable daily doses of the compounds of the invention in the therapeutic treatment of humans are about 0.001 - 10 mg/kg body weight, preferably 0.01-1 mg/kg body weight. Oral formulations are preferred particularly tablets or capsules which may be formulated by methods known to those skilled in the art to provide doses of the active compound in the range of 0.5mg to 500mg for example 1 mg, 3 mg, 5 mg, 10 mg, 25mg, 50mg, lOOmg and 250mg. According to a further aspect of the invention there is also provided a pharmaceutical formulation comprising a compound of formula I, or pharmaceutically acceptable salt thereof, including the compound of the proviso, in admixture with pharmaceutically acceptable adjuvants, diluents and/or carriers.
Pharmacological properties
The compounds of formula (I) are useful for the treatment of obesity or being overweight, (e.g., promotion of weight loss and maintenance of weight loss), prevention of weight gain (e.g., medication-induced or subsequent to cessation of smoking), for modulation of appetite and/or satiety, eating disorders (e.g. binge eating, bulimia and compulsive eating), dyslipidaemia and the treatment of type 2 diabetes mellitus.
The present compounds of formula (I) are useful for the prophylaxis and/or treatment of clinical conditions associated with inherent or induced reduced sensitivity to insulin (insulin resistance) and associated metabolic disorders (also known as the metabolic syndrome). These clinical conditions will include, but will not be limited to, general obesity, abdominal obesity, arterial hypertension, hyperinsulinaemia, hyperglycaemia, type 2 diabetes and the dyslipidaemia characteristically appearing with insulin resistance. This dyslipidaemia, also known as the atherogenic lipoprotein profile, is characterised by moderately elevated non-esterified fatty acids, elevated very low density lipoprotein (VLDL) triglyceride rich particles, high Apo B levels, low high density lipoprotein (HDL) levels associated with low apoAI particle levels and high Apo B levels in the presence of small, dense, low density lipoproteins (LDL) particles, phenotype B. The compounds of the present invention are expected to be useful in treating patients with combined or mixed hyperlipidemias or various degrees of hypertriglyceridemias and postprandial dyslipidemia with or without other manifestations of the metabolic syndrome.
Treatment with the present compounds is expected to lower the cardiovascular morbidity and mortality associated with atherosclerosis due to their antidyslipidaemic as well as antiinflammatory properties. The cardiovascular disease conditions include macro- angiopathies of various internal organs causing myocardial infarction, congestive heart failure, cerebrovascular disease and peripheral arterial insufficiency of the lower extremities. Because of their insulin sensitizing effect the compounds of formula I are also expected to prevent or delay the development of type 2 diabetes from the metabolic syndrome and diabetes of pregnancy. Therefore the development of long-term complications associated with chronic hyperglycaemia in diabetes mellitus, such as the micro-angiopathies causing renal disease, retinal damage and peripheral vascular disease of the lower limbs, is expected to be delayed. Furthermore the compounds may be useful in treatment of various conditions outside the cardiovascular system whether or not associated with insulin resistance, like polycystic ovarian syndrome, obesity, cancer and states of inflammatory disease including neurodegenerative disorders such as mild cognitive impairment, Alzheimer's disease, Parkinson's disease and multiple sclerosis. The compounds of formula I may also be useful in the treatment of metabolic syndrome and Prader-Willi syndrome.
In another aspect the present invention provides a compound of formula I as previously defined for use as a medicament.
In a further aspect the present invention provides the use of a compound of formula I in the preparation of a medicament for the treatment or prophylaxis of obesity or being overweight, (e.g., promotion of weight loss and maintenance of weight loss), prevention of weight gain (e.g., medication-induced or subsequent to cessation of smoking), for modulation of appetite and/or satiety, eating disorders (e.g. binge eating, bulimia and compulsive eating) and for the treatment or prophylaxis of dyslipidaemia and for the treatment or prophylaxis of type 2 diabetes mellitus.
In a still further aspect the present invention provides a method of treating obesity or being overweight, (e.g., promotion of weight loss and maintenance of weight loss), 5 prevention of weight gain (e.g., medication-induced or subsequent to cessation of smoking), for modulation of appetite and/or satiety, eating disorders (e.g. binge eating, bulimia and compulsive eating) dyslipidaemia and type 2 diabetes mellitus comprising administering a pharmacologically effective amount of a compound of formula I, including the compound of the proviso, to a patient in need thereof. 0
Combination Therapy
The compounds of the invention may be combined with another therapeutic agent that is useful in the treatment of obesity such as other anti-obesity drugs, that affect energy expenditure, glycolysis, gluconeogenesis, glucogenolysis, lipolysis, lipogenesis, fats absorption, fat storage, fat excretion, hunger and/or satiety and/or craving mechanisms, appetite/motivation, food intake, or G-I motility.
The compounds of the invention may further be combined with another therapeutic agent that is useful in the treatment of disorders associated with obesity such as hypertension, hyperlipidaemias, dyslipidaemias, diabetes, sleep apnea, asthma, heartQ disorders, atherosclerosis, macro and micro vascular diseases, liver steatosis, cancer, joint disorders, and gallbladder disorders. For example, a compound of the present invention may be used in combination with a another therapeutic agent that lowers blood pressure or that decreases the ratio of LDL:HDL or an agent that causes a decrease in circulating levels of LDL-cholesterol. In patients with diabetes mellitus the compounds of the invention may5 also be combined with therapeutic agents used to treat complications related to microangiopathies.
The compounds of the invention may be used alongside other therapies for the treatment of obesity and its associated complications the metabolic syndrome and type 2 diabetes, these include biguanide drugs, insulin (synthetic insulin analogues) and oralo antihyperglycemics (these are divided into prandial glucose regulators and alpha- glucosidase inhibitors).
In another aspect of the invention, the compound of formula I, or a pharmaceutically acceptable salt thereof may be administered in association with a PPAR modulating agent. PPAR modulating agents include but are not limited to a PPAR alpha and/or gamma agonist, or pharmaceutically acceptable salts, solvates, solvates of such salts or prodrugs thereof. Suitable PPAR alpha and/or gamma agonists, pharmaceutically acceptable salts, solvates, solvates of such salts or prodrugs thereof are well known in the art.
In addition the combination of the invention may be used in conjunction with a sulfonylurea. The present invention also includes a compound of the present invention in combination with a cholesterol-lowering agent. The cholesterol-lowering agents referred to in this application include but are not limited to inhibitors of HMG-CoA reductase (3- hydroxy-3-methylglutaryl coenzyme A reductase). Suitably the HMG-CoA reductase inhibitor is a statin.
In the present application, the term "cholesterol-lowering agent" also includes chemical modifications of the HMG-CoA reductase inhibitors, such as esters, prodrugs and metabolites, whether active or inactive.
The present invention also includes a compound of the present invention in combination with an inhibitor of the ileal bile acid transport system (IBAT inhibitor). The present invention also includes a compound of the present invention in combination with a bile acid binding resin. The present invention also includes a compound of the present invention in combination with a bile acid sequestering agent, for example colestipol or cholestyramine or cholestagel.
According to an additional further aspect of the present invention there is provided a combination treatment comprising the administration of an effective amount of a compound of the formula I, or a pharmaceutically acceptable salt thereof, optionally together with a pharmaceutically acceptable diluent or carrier, with the simultaneous, sequential or separate administration one or more of the following agents selected from: a CETP (cholesteryl ester transfer protein) inhibitor; a cholesterol absorption antagonist; a MTP (microsomal transfer protein) inhibitor ; a nicotinic acid derivative, including slow release and combination products; a phytosterol compound ; probucol; an anti-coagulant; an omega-3 fatty acid ; another anti-obesity compound for example sibutramine, phentermine, orlistat, bupropion, ephedrine, thyroxine; an aldose reductase inhibitor; a glycogen phosphorylase inhibitor; a glycogen synthase kinase inhibitors; a glucokinase activator; a haemostasis modulator; an antithrombotic; an activator of fibrinolysis; an antiplatelet agent; a thrombin antagonist; a factor Xa inhibitor; a factor Vila inhibitor; an antiplatelet agents; a 5 HT transporter inhibitor; an antihypertensive compound for example an angiotensin converting enzyme (ACE) inhibitor, an angiotensin II receptor antagonist, an adrenergic blocker, an alpha adrenergic blocker, a beta adrenergic blocker, a mixed alplmtoeta adrenergic blocker, an adrenergic stimulant, calcium channel blocker, an AT-I blocker, a saluretic, a diuretic or a vasodilator; a melanin concentrating hormone (MCH) modulator; an NPY receptor modulator; for example an NPY agonist or an NPY2 agonist or an NPY5 antagonist; an Mc4r modulator for example an Mc4r agonist; an Mc3r modulator for example an Mc3r agonist; an orexin receptor modulator for example an antagonist; a phosphoinositide-dependent protein kinase (PDK) modulator; or modulators of nuclear receptors for example LXR, FXR, RXR, GR, ERRα, β, PPARα, β, γ, δ and RORalpha; a monoamine transmission-modulating agent, for example a selective serotonin reuptake inhibitor (SSRI), a noradrenaline reuptake inhibitor (NARI), a noradrenaline-serotonin reuptake inhibitor (SNRI), a monoamine oxidase inhibitor (MAOI), a tricyclic antidepressive agent (TCA), a noradrenergic and specific serotonergic antidepressant (NaSSA); an antipsychotic agent for example olanzapine and clozapine; a serotonin receptor modulator; a leptin/leptin receptor modulator; a CBl receptor modulator for example an inverse agonist or an antagonist; a GLK receptor modulator; a DPP-IV inhibitor; a cholesterol absorption inhibitor; a GLP-I agonist; an SGLT-2 inhibitor; a DGATl inhibitor; a DGAT2 inhibitor; a ghrelin antibody; a ghrelin antagonist; an l lβ HSD-I inhibitor; an UCP- 1,2 or 3 activator; or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, optionally together with a pharmaceutically acceptable diluent or carrier to a warmblooded animal, such as man in need of such therapeutic treatment. According to an additional further aspect of the present invention there is provided a combination treatment comprising the administration of an effective amount of a compound of the formula I, or a pharmaceutically acceptable salt thereof, optionally together with a pharmaceutically acceptable diluent or carrier, with the simultaneous, sequential or separate administration of very low calorie diets (VLCD) or low-calorie diets (LCD). Therefore in an additional feature of the invention, there is provided a method for the treatment of obesity and its associated complications in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof in simultaneous, sequential or separate administration with an effective amount of a compound from one of the other classes of compounds described in this combination section, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof.
Therefore in an additional feature of the invention, there is provided a method of treating hyperlipidemic conditions in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof in simultaneous, sequential or separate administration with an effective amount of a compound from one of the other classes of compounds described in this combination section or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof.
According to a further aspect of the invention there is provided a pharmaceutical composition which comprises a compound of formula I, or a pharmaceutically acceptable salt thereof, and a compound from one of the other classes of compounds described in this combination section or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, in association with a pharmaceutically acceptable diluent or carrier.
According to a further aspect of the present invention there is provided a kit comprising a compound of formula I, or a pharmaceutically acceptable salt thereof, and a compound from one of the other classes of compounds described in this combination section or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof.
According to a further aspect of the present invention there is provided a kit comprising: a) a compound of formula I, or a pharmaceutically acceptable salt thereof, in a first unit dosage form; b) a compound from one of the other classes of compounds described in this combination section or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof; in a second unit dosage form; and c) container means for containing said first and second dosage forms.
According to a further aspect of the present invention there is provided a kit comprising: a) a compound of formula I, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable diluent or carrier, in a first unit dosage form; b) a compound from one of the other classes of compounds described in this combination section or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, in a second unit dosage form; and c) container means for containing said first and second dosage forms.
' According to another feature of the invention there is provided the use of a compound of the formula I, or a pharmaceutically acceptable salt thereof, and one of the other compounds described in this combination section, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, in the manufacture of a medicament for use in the the treatment of obesity and its associated complications in a warm-blooded animal, such as man.
According to another feature of the invention there is provided the use of a compound of the formula I, or a pharmaceutically acceptable salt thereof, and one of the other compounds described in this combination section, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, in the manufacture of a medicament for use in the treatment of hyperlipidaemic conditions in a warm-blooded animal, such as man.
According to a further aspect of the present invention there is provided a combination treatment comprising the administration of an effective amount of a compound of the formula I, or a pharmaceutically acceptable salt thereof, optionally together with a pharmaceutically acceptable diluent or carrier, with the simultaneous, sequential or separate administration of an effective amount of one of the other compounds described in this combination section, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, optionally together with a pharmaceutically acceptable diluent or carrier to a warm-blooded animal, such as man in need of such therapeutic treatment.
Furthermore, a compound of the invention may also be combined with therapeutic agents that are useful in the treatment of disorders or conditions associated with obesity (such as type II diabetes, metabolic syndrome, dyslipidemia, impaired glucose tolerance, hypertension, coronary heart disease, non-alcoholic steatohepatitis, osteoarthritis and some cancers) and psychiatric and neurological conditions. It will be understood that there are medically accepted definitions of obesity and being overweight. A patient may be identified by, for example, measuring body mass index (BMI), which is calculated by dividing weight in kilograms by height'in metres squared, and comparing the result with the definitions. The compounds of the invention may also be useful as anti-cell-proliferation (such as anti-cancer) agents and are therefore useful in methods of treatment of the human or animal body.
Such properties are expected to be of value in the treatment of disease states associated with cell cycle and cell proliferation such as cancers (solid tumors and leukemias), fibroproliferative and differentiative disorders, psoriasis, rheumatoid arthritis, Kaposi's sarcoma, haemangioma, acute and chronic nephropathies, atheroma, atherosclerosis, arterial restenosis, autoimmune diseases, acute and chronic inflammation, bone diseases and ocular diseases with retinal vessel proliferation.
The anti-cancer treatment defined herein may be applied as a sole therapy or may involve, in addition to the compound of the invention, conventional surgery or radiotherapy or chemotherapy. Such chemotherapy may include one or more of the following categories of anti-tumour agents:
(i) antiproliferative/antineoplastic drugs and combinations thereof, as used in medical oncology, such as alkylating agents (for example cis-platin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulphan and nitrosoureas); antimetabolites (for example antifolates such as fluoropyrimidines like 5-fluorouracil and tegafur, raltitrexed, methotrexate, cytosine arabinoside and hydroxyurea); antitumour antibiotics (for example anthracyclines like adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin and mithramycin); antimitotic agents (for example vinca alkaloids like vincristine, vinblastine, vindesine and vinorelbine and taxoids like taxol and taxotere); and topoisomerase inhibitors (for example epipodophyllotoxins like etoposide and teniposide, amsacrine, topotecan and camptothecin); (ii) cytostatic agents such as antioestrogens (for example tamoxifen, toremifene, raloxifene, droloxifene and iodoxyfene), oestrogen receptor down regulators (for example fulvestrant), antiandrogens (for example bicalutamide, flutamide, nilutamide and cyproterone acetate), LHRH antagonists or LHRH agonists (for example goserelin, leuprorelin and buserelin), progestogens (for example megestrol acetate), aromatase inhibitors (for example as anastrozole, letrozole, vorazole and exemestane) and inhibitors of 5α-reductase such as finasteride; (iii) agents which inhibit cancer cell invasion (for example metalloproteinase inhibitors like marimastat and inhibitors of urokinase plasminogen activator receptor function); (iv) inhibitors of growth factor function, for example such inhibitors include growth factor antibodies, growth factor receptor antibodies (for example the anti-erbb2 antibody trastuzumab [Herceptin™] and the anti-erbbl antibody cetuximab [C225]) , farnesyl transferase inhibitors, tyrosine kinase inhibitors and serine/threonine kinase inhibitors, for example inhibitors of the epidermal growth factor family (for example EGFR family tyrosine kinase inhibitors such as N-(3-chloro~4-fluorophenyl)-7-methoxy-6-(3- morpholinopropoxy)quinazolin-4-amine, N-(3-ethynylphenyl)-6,7-bis(2- methoxyethoxy)quinazolin-4-amine (erlotinib, OSI-774) and 6-acrylamido-N-(3-chloro-4- fluorophenyl)-7-(3-moφholinopropoxy)quinazolin-4-amine (CI 1033), for example inhibitors of the platelet-derived growth factor family and for example inhibitors of the hepatocyte growth factor family;
(v) antiangiogenic agents such as those which inhibit the effects of vascular endothelial growth factor, (for example the anti-vascular endothelial cell growth factor antibody bevacizumab [Avastin™], compounds such as those disclosed in International Patent Applications WO 97/22596, WO 97/30035, WO 97/32856 and WO 98/13354) and compounds that work by other mechanisms (for example linomide, inhibitors of integrin αvβ3 function and angiostatin);
(vi) vascular damaging agents such as Combretastatin A4 and compounds disclosed in International Patent Applications WO 99/02166, WO 00/40529, WO 00/41669, WO 01/92224, WO 02/04434 and WO 02/08213;
(vii) antisense therapies, for example those which are directed to the targets listed above, such as ISIS 2503, an anti-ras antisense;
(viii) gene therapy approaches, including for example approaches to replace aberrant genes such as aberrant p53 or aberrant BRCAl or BRC A2, GDEPT (gene-directed enzyme pro-drug therapy) approaches such as those using cytosine deaminase, thymidine kinase or a bacterial nitroreductase enzyme and approaches to increase patient tolerance to chemotherapy or radiotherapy such as multi-drug resistance gene therapy; and (ix) immunotherapy approaches, including for example ex- vivo and in- vivo approaches to increase the immunogenicity of patient tumour cells, such as transfection with cytokines such as interleukin 2, interleukin 4 or granulocyte-macrophage colony stimulating factor, approaches to decrease T-cell anergy, approaches using transfected immune cells such as cytokine-transfected dendritic cells, approaches using cytokine-transfected tumour cell lines and approaches -using anti-idiotypic antibodies.
Such conjoint treatment may be achieved by way of the simultaneous, sequential or separate dosing of the individual components of the treatment. Such combination products employ the compounds of this invention within the dosage range described hereinbefore and the other pharmaceutically-active agent within its approved dosage range.
The compounds of the present invention may also be useful as anti-infective agents or as anti-bacterial agents.
The compounds of the present invention may also be useful as in decreasing sebum production following topical application.
Pharmacological Activity
The compounds of the present invention are Fatty Acid Synthase inhibitors. The activity of the compounds of the invention was demonstrated using the following assay. Human and Rat FAS Enzyme Assay. Fatty acid synthase is an enzyme complex that harbours seven enzymatic activities catalysing the reductive synthesis of long chain fatty acids from acetyl CoA and malonyl CoA to palmitate. When acetyl CoA and malonyl CoA are forming palmitate NADPH is consumed forming NADP. Since NADPH is fluorescent but not NADP the reaction can be measured by analysing the decrease in fluorescence. Compounds were added to a black 384 well plate (Matrix) in a volume of 5μl consisting of 20% DMSO and 80% Tris buffer pH 7.5, at a top concentration of ImM. NADPH, 30μl of 166.6μM, formulated in assay buffer (0.1M Tris ph7.5, O.lmM EDTA5ImM glutathion, 0.05%BSA), was then added to all of the wells of the plate. Fatty acid synthase Human or rat enzyme (0.4μg, produced in house), dissolved in 2OmM Tris/HCl pH 7.5, 5mM BOG5ImM TCEP,10% glycerol,lmM EDTA,150mM NaCl, was then added to the plate in a volume of lOμl. Enzyme was added to all but the last two columns of the plate, to which, lOμl of assay buffer was added (0.1M Tris ph7.5, O.lmM EDTA, ImM glutathion, 0.05%BSA) to provide a no enzyme assay control. Following a 15 -minute incubation period, at room temperature, the plates were read on an Envision plate reader using 340nm excitation and 460nm emission filters. This served as a time zero background read. Substrates (an equal mix of both malonyl and acetyl CoA) were then added to the plates in a total volume of 5μl. The concentrations of malonyl and acetyl CoA in the mixture were 500μM and 150μM respectively. Both were prepared as 1OmM stock solutions in distilled water and were subsequently diluted to working concentrations in assay buffer. Plates were then incubated for a further 60 minutes, at room temperature, before being read again on the Envision reader using the same parameters as previously used. The data was analysed by subtracting the background time zero data from that generated following the final 60 minute incubate and the percent inhibition compared to the maximum and minimum assay controls was determined. Sigmoid curves were fitted using Origin 7.5 Client software and IC50 values were determined.
The compounds of the present invention were found to inhibit the activation of Fatty Acid Synthase with IC5oS in a range of about 0.001 μM to about 30μM in the above assay. In a preferred range, the examples of the present invention inhibited the activition of Fatty Acid Synthase with IC5oS in a range of about O.OOlμM to about 5.0μM. In a more preferred range, the compounds inhibit the activition of Fatty Acid Synthase with ICsos in a range of about O.OOlμM to about 0.1 μM. The results obtained are given in Table 1 in which EX stands for Example Number, Inhib (%) stands for the % inhibition at the concentration given in micromolar in the next column. Where no concentration is given then the figure in the Inhib (%) column is the IC50. Table 1
Figure imgf000052_0001
Figure imgf000052_0002
Figure imgf000053_0001
Figure imgf000053_0002
Figure imgf000054_0001
Figure imgf000054_0002
Figure imgf000055_0001
Figure imgf000055_0002
Figure imgf000056_0001
Figure imgf000056_0002
Figure imgf000057_0001
The following compounds do not have IC50S in the range of about 0.001 μM to about 30μM in the above assay:
N-[5-(4-benzylpiperidine-l-carbonyl)-2-methylphenyl]-3-morpholin-4-ylbenzamide N- [5 -(4-benzylpiperidine- 1 -carbonyl)-2-methoxyphenyl] -3 -morpholin-4-ylbenzamide
6-chloro-N-methyl-N- [2-methyl-5-(4-phenylpiperidine- 1 -carbonyl)phenyl]pyridine-3 - carboxamide
2-(2-methoxyethoxy)-N-[5-[4-(4-methoxyphenyl)piperidine-l-carbonyl]-2- methylphenyl]acetamide N-[5-[4-(4-methoxyphenyl)piperidine- 1 -carbonyl]-2-methylphenyl]pentanamide
N-[5-[4-(4-methoxyphenyl)piperidine-l-carbonyl]-2-methylphenyl]ρyridine-2- carboxamide
2-(methyl-(2-methylpropyl)amino)-N-[2-methyl-5-[4-[4-
(trifluoromethyl)phenyl]piperidine-l-carbonyl]phenyl]acetamide 2-[methyl-[2-[[2-methyl-5-[4-[4-(trifluoromethyl)phenyl]piperidine-l- carbonyl]phenyl]amino]-2-oxoethyl]amino]acetic acid
N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methylphenyl]-5-oxopyrrolidine-2- carboxamide
N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methylphenyl]-3-methylbutanamide N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-niethylphenyl]propanamide
N-[5-[4-(2-methoxyphenyl)piperidine-l-carbonyl]-2-methylphenyl]pyridine-4- carboxamide
2-(4-acetylpiperazin- 1 -yl)-N-[5-[4-(4-cyanophenyl)piperidine- 1 -carbonyl]-2- methylphenyl]acetamide N-[5-[3-(4-methoxyphenyl)pyrrolidine-l-carbonyl]-2-methylphenyl]pyridine-4- carboxamide N-[2-chloro-5-[4-(4-cyanophenyl)piperidine-l-carbonyl]phenyl]-l,3-benzothiazole-2- carboxamide
N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methylphenyl]-6-methyl-2-oxo-lH- quinoline-4-carboxamide 5 N- [5 - [4-(4-cyanophenyl)piperidine- 1 -carbonyl] -2-methylphenyl] -2-oxo- 1 H-pyridine-3 - carboxamide
N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methylphenyl]-2,6- dimethoxypyrimidine-4-carboxamide and
N-[2-chloro-5-[4-(4-cyanophenyl)piperidine- 1 -carbonyl]phenyl]-6-(3-oxopiperazin- 1 - I0 yl)pyridine-3-carboxamide. In an alternative embodiment these compounds are excluded from the claims of the present application.
The invention will now be illustrated by the following non-limiting examples in which, unless stated otherwise:
(i) temperatures are given in degrees Celsius (0C); operations were carried out at room or 15 ambient temperature, that is, at a temperature in the range of 18-25 0C, unless otherwise stated;
(ii) organic solutions were dried over anhydrous magnesium sulfate; evaporation of solvent was carried out using a rotary evaporator under reduced pressure (600-4000 Pascals;
4.5-30 mmHg) with a bath temperature of up to 60 0C; 20 (iii) chromatography means flash chromatography on silica gel; thin layer chromatography
(TLC) was carried out on silica gel plates;
(iv) in general, the course of reactions was followed by TLC and / or analytical LC-MS, and reaction times are given for illustration only;
(v) final products had satisfactory proton nuclear magnetic resonance (NMR) spectra 25 and/or mass spectral data;
(vi) yields are given for illustration only and are not necessarily those which can be obtained by diligent process development; preparations were repeated if more material was required;
(vii) when given, NMR data is in the form of delta values for major diagnostic protons, 30 given in parts per million (ppm) relative to tetramethylsilane (TMS) as an internal standard when the solvent is CDCl3 (when the solvent is d6--DMSO, it locks on to the 2.49 DMSO peak), determined at 300 MHz unless otherwise indicated; the following abbreviations have been used: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; b, broad;
(viii) chemical symbols have their usual meanings; SI units and symbols are used;
(ix) solvent ratios are given in volume:volume (v/v) terms; and (x) mass spectra (MS) were run with an electron energy of 70 electron volts in the chemical ionization (CI) mode using a direct exposure probe; where indicated ionization was effected by electron impact (EI), fast atom bombardment (FAB) or electrospray (ESP); values for m/z are given; generally, only ions which indicate the parent mass are reported; and unless otherwise stated, the mass ion quoted is MH+; (xi) unless stated otherwise compounds containing an asymmetrically substituted carbon and/or sulphur atom have not been resolved;
(xii) where a synthesis is described as being analogous to that described in a previous example the amounts used are the millimolar ratio equivalents to those used in the previous example; (xvi) the following abbreviations have been used:
Abbreviations
ACN Acetonitrile
DIPEA Di-ωo-propylethylamine DMA Dimethyl acetamide
DMAP 4-dimethylamino pyridine
DMTMM 4-(4,6-Dimethoxy- 1 ,3 ,5-Triazin-2-yl)-4-Methyhnorpholinium Chloride
DMSO dimethyl sulphoxide (in NMR data the solvent is άβ -deuterioDMSO)
EDAC N-ethyl-N'-(3-dimethylaminopropyl)-carbodiimide hydrochloride EtOAc Ethyl acetate
EtOH Ethanol
HATU O-(7- Azabenzotriazol- 1 -Yl)-N,N,N',N'-Tetramethyluronium Hexafluoro- phosphate
HOBT 1-Hydroxybenzotriazole hrs hours
HTBU O-benzotriazol- 1 -yl-N,N,N',N'-tetramethyluronium hexafluorophosphate
MeOH Methanol nuns minutes
TEA Triethylamine
TFAA Trifluoroacetic Anhydride
THF Tetrahydrofuran [A] When Cl is present in the molecule, the m/z value for the (M+H) molecular ion is based on the 35Cl isotope. When there are multiple chlorine atoms in the molecule, the m/z is based on the first peak of the isotope pattern.
[B] When Br is present in the molecule, the m/z value for the (M+H)+ and / or (M-H)" molecular ions may be based either on the 79Br isotope or the 81Br isotope. As the isotopes are of approximately equal abundance, in many cases both isotopes are seen in the spectrum, but only one is reported.
HPLC Standard Method A: Column: Kromasil C8 lOμ 250 mm x 21.2 id Mobile phase A: 100% ACN Mobile phase B: 5% ACN + 95% 0,1 M NH4OAc Gradient: 30-70% A over 20 minutes.
HPLC Standard Method B :
Column: Kromasil C8 lOμ 250 mm x 21.2 id, Mobile phase A: 100% ACN, Mobilephase B: 5% ACN + 95% 0.1 M NH4OAc, gradient: 20-80% A over 20 minutes.
Example 1 (Method Ia)
N-[5-[4-(4-cyanophenyl)piperidine- 1 -carbonyl]-2-methyl-phenyl]- l-oxido-pyridine-4- carboxamide
Figure imgf000060_0001
A solution ofisσ-nicotinic acid N-oxide (96 mg, 0.69 mmol) and oxalyl chloride (0.66 mL, 0.75 mmol, 1.09 eq) in DCM (5ml) was treated with DMF (2 drops), and the reaction mixture was stirred at ambient temperature for 20 hrs. The solvent was removed in vacuo and the residue redissolved in DCM (5ml). To this was added 4-[l-(3-amino-4-methyl- benzoyl)-4-ρiperidyl]benzonitrile [Intermediate A] (200 mg, 0.63 mmol) followed by DIPEA (0.33 mL, 1.88 mmol, 3 eq), and the mixture stirred at ambient temperature for 2 hrs. The solvent was removed in vacuo and EtOAc (20 mL) was added to the residue. The mixture obtained was then washed with saturated brine (20 mL), dried (MgSO4), filtered and reduced in vacuo to give the crude product as a brown oil, which was purified by chromatography (Optix™ , 12g silica column, eluting with isohexane containing 50-100% EtOAc) to give the title compound as a colourless solid (25 mg, 9% yield), *H NMR (400.132 MHz, CDC13) δ 1.56 - 1.74 (2H, m), 1.79 - 1.89 (IH, m), 1.98 - 2.03 (IH, m), 2.26 (3H, s), 2.81 - 2.94 (2H, m), 3.11 - 3.25 (IH, m), 3.90 - 4.01 (IH, m), 4.79 - 4.92 (IH, m), 7.01 - 7.05 (IH, m), 7.12 - 7.15 (IH, m), 7.25 (IH, s), 7.33 (2H, d), 7.62 (2H, d), 8.01 (2H, d), 8.27 (2H, d), 9.44 (IH, s), m/z 441 (M+H)+.
When the requisite acid chloride was commercially available, it was used directly, with omission of the formation step. Example 2 (Method Ib)
6-acetamido-N-[2-methyl-5-(4-phenylpiperidine-l-carbonyl)phenyl]pyridine-3- carboxamide
Figure imgf000061_0001
(3-amino-4-methyl-phenyl)-(4-phenyl-l-piperidyl)methanone [Intermediate B] (80 mg, 0.27 mmol) and ό-acetamidopyridine-S-carboxylic acid (110 mg, 0.61 mmol, 2.2 eq) were dissolved in DCM (3 mL) and the solution treated sequentially with EDAC (110 mg, 0.57 mmol, 2.1 eq) and DIPEA (0.05 mL, 0.30 mmol, 1.1 eq). The mixture was stirred overnight at ambient temperature. More 6-acetamidopyridine-3-carboxylic acid (30 mg) and EDAC (30 mg) were added and the mixture heated at reflux for 2 hours. Further 6- acetamidopyridine-3-carboxylic acid (30 mg) and EDAC (30 mg) were added, followed by HOBT (45 mg). The reaction was allowed to stand at ambient temperature over the week-end, and then filtered and purified by HPLC (Standard Method A). The fractions containing required product were collected and freeze-dried to give the title compound (60 mg, 48% yield), 1H NMR (CDCl3) δ 2.04-1.51 (4H, m), 2.23 (3H, s), 2.29 (3H, s), 2.92- 2.69 (2H, m), 3.24-3.01 (IH, m), 3.96 (IH, s), 4.83 (IH, s), 7.12-7.07 (IH, m), 7.23-7.14 (4H, m), 7.33-7.26 (4H, m), 7.53 (IH, s), 8.34-8.26 (2H, m), 8.46 (IH, s), 8.70 (IH, s), 8.88 (IH, s), m/z 457 (M + H)+. Example 3 (Method Ic) 6-chloro-N-[2-methyl-5-(4-phenylpiperidine-l-carbonyl)phenyl]pyridine-3-carboxamide
Figure imgf000062_0001
A solution of 3-[(6-chloropyridine-3-carbonyl)amino]-4-methyl-benzoic acid (872 mg, 3 mmol) and DIPEA (0.26 mL, 2.0 mmol) in ACN (10 mL) was cooled to 0 - 50C (ice bath) and to this solution was added sequentially 4-phenyl piperidine (323 mg, 2 mmol) and HBTU (760 mg, 2 mmol). Stirring was continued for 30 minutes at 0 - 5°C and for a further 30 minutes whilst allowing to warm to ambient temperature. The solvent was evaporated in vacuo and the residue taken up into EtOAc (30 mL). The resulting solution was washed sequentially with 20 mL portions of aqueous potassium bisulfate solution (IM) and brine, dried (MgSO4) and evaporated in vacuo. The resulting crude material was adsorbed onto silica (10ml of 60-200mm mesh size) and purified by flash chromatography (200 mL silica, 40-60mm mesh size eluting with EtOAc containing heptane 40 - 30%) to give the title compound (86 mg), Rf 0.42 (silica, EtOAC / Heptane 7 : 3), 1H NMR (CDCl3) δ 1.86-1.50 (3H, m), 2.05-1.91 (IH, m), 2.23 (3H, s), 2.90-2.70 (2H, m), 3.23- 3.02 (IH, m), 3.90 (J=11.7Hz,lH, d), 4.82 (J=I 1.7Hz3IH, d), 7.00 (J=7.8andl.5Hz,lH, dd), 7.10 (J=7.8Hz,lH, d), 7.33-7.13 (6H, m), 7.44 (J=8.4Hz,lH, d), 8.32 (J=8.4and2.4Hz,lH, dd), 9.06 (J=2.0Hz,lH, d), 9.48 (IH, s), m/z 434 (M + IH)+.
The requisite 3-[(6-chloropyridine-3-carbonyl)amino]-4-methyl-benzoic acid starting material was prepared according to the procedure given in Method Ia, starting from 3- amino-4-methylbenzoic acid and 6-chloropyridine-3-carbonyl chloride; the compound was the major component in an approximately 6 : 4 inseparable mixture with 6-chloropyridine-
3-carboxylic acid. The mixture was used as is without purifcation.
The following examples were prepared by methods essentially similar to those described above: Example 4
N-[5-(4-benzylpiperidine-l-carbonyl)-2-methyl-phenyl]-6-chloro-pyridine-3-carboxamide
Figure imgf000063_0001
Method Ia from Intermediate C
1H NMR (CDCl3) δ 9.32 (s, IH), 9.02 (s, IH), 8.29 (dd, J= 8.3 and 1.9 Hz, IH), 7.43 (d, J = 8.3 Hz, IH), 7.31 - 7.04 (m, 7H), 6.94 (d, J= 7.7 Hz, IH), 4.70 - 4.53 (m, IH), 3.83 -
3.66 (m, IH), 3.01 - 2.82 (m, IH), 2.75 - 2.60 (m, IH), 2.54 (d, J= 6.8 Hz, 2H), 2.21 (s,
3H), 1.84 - 1.68 (m, 2H), 1.32 - 1.04 (m, 3H). M/z (M+H)+ 448.
Example 5
N-[5-(4-benzylpiperidine-l-carbonyl)-2-methyl-phenyl]-6-(trifluoromethyl)pyridine-3- carboxamide
Figure imgf000063_0002
Method Ia from Intermediate C 1H NMR (CDCl3) δ 9.85 - 9.68 (m, IH), 9.35 (s, IH), 8.54 (d, J= 7.8 Hz, IH), 7.79 (d, J = 8.1 Hz, IH), 7.30 - 7.02 (m, 7H), 6.91 (d, J= 7.8 Hz, IH), 4.60 (d, J= 12.2 Hz, IH), 3.74 (d, J= 12.2 Hz, IH), 2.92 (t, J= 12.2 Hz, IH), 2.67 (t, J= 12.2 Hz, IH), 2.54 (d, J= 6.9 Hz, 2H), 2.21 (s, 3H), 1.84 - 1.68 (m, 2H), 1.30 - 1.03 (m, 3H). M/z (M+H)+ 482. Example 6 N-[5-(4-benzylpiperidine-l-carbonyl)-2-ethyl-phenyl]-6-chloro-pyridine-3-carboxamide
Figure imgf000063_0003
Method Ia from Intermediate I 1H NMR (CDCl3) δ 9.47 (s, IH), 9.03 (s, IH), 8.34 - 8.27 (m, IH), 7.43 (d, J= 8.3 Hz, IH), 7.29 - 7.21 (m, 2H), 7.21 - 7.14 (m, IH), 7.14 - 7.03 (m, 4H), 7.02 - 6.95 (m, IH), 4.61 (d, J= 12.2 Hz, IH), 3.75 (d, J= 12.2 Hz, IH), 2.92 (t, J= 12.2 Hz, IH), 2.73 - 2.50 (m, 5H), 1.84 - 1.52 (m, 3H), 1.30 - 1.02 (m, 5H). M/z (M+H)+ 462. Example 7 4-chloro-N-[2-methyl-5-(4-phenylpiperidine-l-carbonyl)phenyl]benzamide
Figure imgf000063_0004
Method Ia from Intermediate B 1H NMR (CDCl3) δ 7.94 (s, IH), 7.88 - 7.82 (m, 3H), 7.46 (d, J= 8.2 Hz, 2H), 7.33 - 7.26 (m, 2H), 7.25 - 7.15 (m, 5H), 4.84 (s, IH), 4.00 (s, IH), 3.15 (s, IH), 2.93 - 2.69 (m, 2H), 2.32 (s, 3H), 2.04 - 1.58 (m, 4H). M/z (M+H)+ 433. Example 8
N-[2-methyl-5-(4-phenylpiperidine-l-carbonyl)phenyl]-6-(trifluoromethyl)pyridine-3- carboxamide
Figure imgf000064_0001
Method Ia from Intermediate B 1H NMR (DMSO) δ 10.35 (s, IH), 9.28 (s, IH), 8.58 (d, J= 7.9 Hz, IH), 8.11 (d, J= 8.2 Hz, IH), 7.50 (s, IH), 7.37 (d, J= 7.9 Hz, IH), 7.32 - 7.25 (m, 5H), 7.22 - 7.17 (m, IH), 4.62 (s, IH), 3.79 (s, IH), 3.18 (s, IH), 2.95 - 2.76 (m, 2H), 2.30 (s, 3H), 1.91 - 1.55 (m, 4H). M/z (M+H)+ 468. Example 9
6-dimethylamino-N-[2-methyl-5-(4-phenylpiperidine-l-carbonyl)phenyl]pyridine-3- carboxamide
Figure imgf000064_0002
Method Ia from Intermediate B
1H NMR (CDCl3) δ 8.77 (d, J= 2.3 Hz, IH), 8.34 (s, IH), 8.04 (dd, J= 9.0 and 2.3 Hz, IH), 7.63 (s, IH), 7.32 - 7.25 (m, 2H), 7.22 - 7.11 (m, 4H), 7.11 - 7.05 (m, IH), 6.52 (d, J = 9.0 Hz, IH), 4.84 (s, IH), 3.98 (s, IH), 3.14 (s, 7H), 2.90 - 2.68 (m, 2H), 2.26 (s, 3H), 2.01 - 1.51 (m, 4H). M/z (M+H)+ 443. Example 10
N- [2-methyl-5-(4-phenylpiperidine- 1 -carbony l)phenyl] -6-morpholin-4-yl-pyridine-3 - carboxamide
Figure imgf000064_0003
Method Ia from Intermediate B 1H NMR (CDCl3) δ 8.76 (d, J= 2.2 Hz, IH), 8.14 (s, IH), 8.07 (dd, J= 9.0 and 2.2 Hz, IH), 7.72 (s, IH), 7.32 - 7.26 (m, 2H), 7.22 - 7.15 (m, 4H), 7.14 - 7.10 (m, IH), 6.65 (d, J = 9.0 Hz, IH), 4.84 (s, IH), 3.99 (s, IH), 3.83 - 3.76 (m, 4H), 3.66 - 3.58 (m, 4H), 3.14 (s, IH), 2.92 - 2.68 (m, 2H), 2.28 (s, 3H), 2.00 - 1.54 (m, 4H). M/z (M+H)+ 485. Example 11
6-chloro-N-[5-[4-(4-methoxyρhenyl)piperidine-l-carbonyl]-2-methyl-phenyl]pyridine-3- carboxamide
Figure imgf000065_0001
Method Ia from Intermediate D 1H NMR (CDCl3) δ 9.45 (s, IH), 9.06 (s, IH), 8.35 - 8.29 (m, IH), 7.44 (d, J= 8.4 Hz, IH), 7.17 (s, IH), 7.14 - 7.07 (m, 3H), 6.99 (d, J= 7.7 Hz, IH), 6.84 (d, J= 8.4 Hz, 2H), 4.80 (d, J= 11 Hz, IH), 3.89 (d, J= 11 Hz, IH), 3.77 (s, 3H), 3.18 - 3.02 (m, IH), 2.89 - 2.64 (m, 2H), 2.23 (s, 3H), 2.02 - 1.87 (m, IH), 1.83 - 1.43 (m, 3H). M/z (M+H)+ 464. Example 12
2-bromo-5-methoxy-N-[5-[4-(4-methoxyphenyl)piperidine-l-carbonyl]-2-methyl- phenyl]benzamide
Figure imgf000065_0002
Method Ia from Intermediate D 1H NMR (DMSO) δ 9.97 (s, IH), 7.59 - 7.50 (m, 2H), 7.29 (d, J= 7.8 Hz, IH), 7.22 - 7.12 (m, 4H), 6.97 (dd, J= 8.9 and 3.0 Hz, IH), 6.85 - 6.79 (m, 2H), 4.68 - 4.49 (m, IH), 3.81 - 3.65 (m, 7H), 3.20 - 3.00 (m, IH), 2.89 - 2.64 (m, 2H), 2.29 (s, 3H), 1.87 - 1.45 (m, 4H). M/z (M+H)+ 536. Example 13
N-[5-[4-(4-methoxyphenyl)piperidine-l-carbonyl]-2-methyl-phenyl]benzothiazole-2- carboxamide
Figure imgf000065_0003
Method Ia from Intermediate D 1H NMR (DMSO) δ 10.63 (s, IH), 8.24 (d, J= 7.9 Hz, IH), 8.18 (d, J= 7.9 Hz, IH), 7.67 - 7.51 (m, 3H), 7.34 (d, J= 7.9 Hz, IH), 7.26 - 7.21 (m, IH), 7.18 - 7.12 (m, 2H), 6.85 - 6.79 (m, 2H), 4.70 - 4.42 (m, IH), 3.75 (s, IH), 3.67 (s, 3H), 3.12 (s, IH), 2.90 - 2.65 (m, 2H), 2.29 (s, 3H), 1.90 - 1.45 (m, 4H). M/z (M+H)+486. Example 14
6-acetamido-N-[5-[4-(4-methoxyphenyl)piperidine-l-carbonyl]-2-methyl-phenyl]pyridine- 3-carboxamide
Figure imgf000066_0001
Method Ib from Intermediate D 5 1H NMR (DMSO) δ 10.78 (s, IH), 9.97 (s, IH), 8.89 - 8.83 (m, IH)5 8.30 - 8.24 (m, IH),
8.15 (d, J= 8.7 Hz, IH), 7.39 (s, IH), 7.31 (d, J= 7.9 Hz, IH), 7.23 - 7.11 (m, 3H), 6.85 -
6.79 (m, 2H), 4.56 (s, IH), 3.74 (s, IH), 3.67 (s, 3H), 3.11 (s, IH), 2.90 - 2.66 (m, 2H),
2.24 (s, 3H), 2.10 (s, 3H), 1.85 - 1.44 (m, 4H). M/z (M+H)+487.
Example 15 I0 N-[5-[4-(4-methoxyphenyl)piperidine-l-carbonyl]-2-methyl-phenyl]benzamide
Figure imgf000066_0002
Method Ia from Intermediate D 1H NMR (CDCl3) δ 8.04 (s, IH), 7.90 (d, J= 7.3 Hz, 2H), 7.78 (s, IH), 7.62 - 7.47 (m, 3H), 7.31 - 7.20 (m, 2H), 7.15 (d,J= 8.5 Hz, 2H), 6.86 (d, J= 8.5 Hz, 2H), 4.86 (s, IH), 4.04 (s, IH), 3.79 (s, 3H), 3.17 (s, IH), 2.94 - 2.68 (m, 2H), 2.36 (s, 3H), 2.03 - 1.51 (m, 15 4H). M/z (M+H)+429. Example 16 N-[5-[4-(4-methoxyphenyl)piperidine-l-carbonyl]-2-methyl-phenyl]-4-phenyl-benzamide
Figure imgf000066_0003
Method Ia from Intermediate D
1H NMR (CDCl3) δ 8.05 (s, IH), 7.95 (d, J= 8.3 Hz, 2H), 7.77 (s, IH), 7.71 (d, J= 8.3 Hz, 20 2H), 7.64 - 7.59 (m, 2H), 7.52 - 7.34 (m, 3H), 7.29 - 7.20 (m, 2H), 7.13 (d, J= 8.6 Hz, 2H),
6.84 (d, J= 8.6 Hz, 2H), 4.85 (s, IH), 4.02 (s, IH), 3.77 (s, 3H), 3.15 (s, IH), 2.90 - 2.66
(m, 2H), 2.37 (s, 3H), 1.99 - 1.47 (m, 4H). M/z (M+H)+ 505.
Example 17
2-chloro-N-[5-[4-(4-methoxyphenyl)piperidine-l-carbonyl]-2-methyl-phenyl]pyridine-3- 25 carboxamide
Figure imgf000067_0001
Method Ia from Intermediate D 1H NMR (CDCl3) δ 8.79 - 8.67 (m, IH), 8.50 - 8.46 (m, IH), 8.13 (d, J= 6.7 Hz, IH), 7.84 (s, IH), 7.41 - 7.35 (m, IH), 7.19 (d, J= 7.7 Hz5 IH), 7.16 - 7.07 (m, 3H), 6.83 (d, J= 8.7 Hz, 2H), 4.70 (s, IH), 3.95 (s, IH), 3.76 (s, 3H), 3.11 (s, IH), 2.86 - 2.64 (m, 2H), 2.32 (s, 3H), 1.98 - 1.50 (m, 4H). M/z (M+H)+ 464. Example 18 2-methoxy-N-[5-[4-(4-methoxyphenyl)piperidine-l-carbonyl]-2-methyl-phenyl]benzamide
Figure imgf000067_0002
Method Ia from Intermediate D
M/z (M+H)+ 459. Example 19
N-[5-[4-(4-methoxyphenyl)piperidine-l-carbonyl]-2-methyl-phenyl]pyridine-3- carboxamide
Figure imgf000067_0003
Method Ia from Intermediate D 1H NMR (CDCl3) δ 9.24 - 9.14 (m, IH), 8.82 - 8.55 (m, 2H), 8.33 - 8.26 (m, IH), 7.65 - 7.54 (m, IH), 7.47 - 7.40 (m, IH), 7.22 - 7.06 (m, 4H), 6.83 (d, J= 8.7 Hz, 2H), 4.81 (s, IH), 3.94 (s, IH), 3.77 (s, 3H), 3.20 - 3.03 (m, IH), 2.88 - 2.65 (m, 2H), 2.33 - 2.27 (m, 3H), 1.98 - 1.53 (m, 4H). M/z (M+H)+ 430. Example 20 N-[5-[4-(4-methoxyphenyl)piperidine-l-carbonyl]-2-methyl-phenyl]-3-methyl-benzamide
Figure imgf000067_0004
Method Ia from Intermediate D
1H NMR (CDCl3) δ 8.21 (s, IH), 7.84 (s, IH), 7.78 (s, IH), 7.76 - 7.70 (m, IH), 7.44 - 7.34 (m, 2H), 7.24 (d, J= 7.8 Hz, IH), 7.21 - 7.12 (m, 3H), 6.87 (d, J= 8.6 Hz, 2H), 4.85 (s, IH), 4.04 (s, IH), 3.80 (s, 3H), 3.17 (s, IH), 2.93 - 2.69 (m, 2H), 2.46 (s, 3H), 2.35 (s, 3H), 2.07 - 1.57 (m, 4H). M/z (M+H)+ 443. Example 21 3-chloro-N-[5-[4-(4-metlioxyphenyl)piperidine-l-carbonyl]-2-methyl-phenyl]benzaπiide
Figure imgf000068_0001
Method Ia from Intermediate D 1H NMR (CDCl3) δ 8.12 (s, IH), 7.92 (s, IH), 7.82 - 7.73 (m, 2H), 7.54 - 7.49 (m, IH), 7.42 (t, J= 7.9 Hz, IH), 7.23 - 7.19 (m, IH), 7.18 - 7.08 (m, 3H), 6.84 (d, J= 8.6 Hz, 2H), 4.84 (s, IH), 3.97 (s, IH), 3.77 (s, 3H), 3.13 (s, IH), 2.82 (s, IH), 2.76 - 2.65 (m, IH), 2.31 (s, 3H), 1.98 - 1.52 (m, 4H). M/z (M+H)+ 463. Example 22
N-[5-[4-(4-methoxyphenyl)piperidine-l-carbonyl]-2-methyl-phenyl]-4-tert-butyl- benzamide
Figure imgf000068_0002
Method Ia from Intermediate D
1H NMR (CDCl3) δ 7.97 (s, IH), 7.93 (s, IH), 7.87 (d, J= 8.3 Hz, 2H), 7.53 (d, J- 8.3 Hz, 2H), 7.27 (s, IH), 7.23 - 7.18 (m, IH), 7.15 (d, J= 8.5 Hz, 2H), 6.87 (d, J= 8.5 Hz, 2H),
4.86 (s, IH), 4.05 (s, IH), 3.80 (s, 3H), 3.17 (s, IH), 2.94 - 2.68 (m, 2H), 2.35 (s, 3H), 2.01
- 1.58 (m, 4H), 1.37 (s, 9H). M/z (M+H)+ 485.
Example 23
2-chloro-6-methoxy-N-[5-[4-(4-methoxyphenyl)piperidine-l-carbonyl]-2-methyl- phenyl]pyridine-4-carboxamide
Figure imgf000068_0003
Method Ia from Intermediate D 1HNMR (CDCl3) δ 9.11 (s, IH), 7.48 (s, IH), 7.33 (s, IH), 7.22 (s, IH), 7.14 - 7.07 (m, 3H), 7.07 - 7.01 (m, IH), 6.84 (d, J= 8.6 Hz, 2H), 4.91 - 4.78 (m, IH), 3.97 (s, 3H), 3.94 3.83 (m, IH), 3.77 (s, 3H), 3.18 - 3.01 (m, IH), 2.90 - 2.64 (m, 2H), 2.24 (s, 3H), 2.00 - 1.50 (m, 4H). M/z (M+H)+ 494. Example 24
N-[5-[4-(4-methoxyphenyl)piperidine-l-carbonyl]-2-methyl-phenyl]-4-methyl-benzamide
Figure imgf000069_0001
Method Ia from Intermediate D
1H NMR (CDCl3) δ 8.04 (s, IH), 7.76 (d, J= 8.0 Hz, 2H), 7.68 (s, IH), 7.32 - 7.18 (m, 4H), 7.12 (d, J= 8.6 Hz, 2H), 6.83 (d, J= 8.6 Hz, 2H), 4.83 (s, IH), 4.01 (s, IH), 3.77 (s,
3H), 3.14 (s, IH), 2.90 - 2.66 (m, 2H), 2.42 (s, 3H), 2.33 (s, 3H), 1.98 - 1.55 (m, 4H). M/z
(M+H)+ 443.
Example 25
2-chloro-N-[5-[4-(4-methoxyphenyl)piperidine-l-carbonyl]-2-methyl-phenyl]pyridine-4- carboxamide
Figure imgf000069_0002
Method Ia from Intermediate D 1H NMR (CDCl3) δ 9.59 (s, IH), 8.54 (d, J= 5.1 Hz, IH), 8.01 (s, IH), 7.82 (d, J= 4.8 Hz, IH), 7.19 (s, IH), 7.13 - 7.06 (m, 3H), 7.01 - 6.97 (m, IH), 6.84 (d, J= 8.6 Hz, 2H), 4.84 (d, J= 11.7 Hz, IH), 3.88 (d, J= 11.7 Hz, IH), 3.77 (s, 3H), 3.18 - 3.03 (m, IH), 2.92 - 2.77 (m, IH), 2.77 - 2.66 (m, IH), 2.23 (s, 3H), 2.03 - 1.89 (m, IH), 1.85 - 1.47 (m, 3H). M/z (M+H)+ 464. Example 26
N-[5-[4-(4-methoxyphenyl)piperidine-l-carbonyl]-2-methyl-phenyl]-4- (trifluoromethoxy)benzamide
Figure imgf000069_0003
Method Ia from Intermediate D
1H NMR (CDCl3) δ 8.12 (s, IH), 7.98 (d, J= 8.7 Hz, 2H), 7.76 (s, IH), 7.32 (d, J= 8.3 Hz, 2H), 7.23 - 7.18 (m, IH), 7.18 - 7.08 (m, 3H), 6.84 (d, J= 8.7 Hz, 2H), 4.82 (s, IH), 3.98 (s, IH), 3.77 (s, 3H), 3.13 (s, IH), 2.89 - 2.66 (m, 2H), 2.31 (s, 3H), 1.99 - 1.53 (m, 4H). M/z (M+H)+ 513. Example 27
2-chloro-N- [5 -[4-(4-methoxyρheny l)piperidine- 1 -carbonyl] -2-methyl-phenyl] -6-methyl- pyridine-4-carboxamide
Figure imgf000070_0001
Method Ia from Intermediate D
M/z (M+H)+ 478.
Example 28
2,4-dichloro-N-[5-[4-(4-methoxyphenyl)piperidme-l-carbonyl]-2-methyl- phenyl]benzamide
Figure imgf000070_0002
Method Ia from Intermediate D
1H NMR (CDCl3) δ 8.11 (s, IH), 7.91 (s, IH), 7.81 (d, J= 8.2 Hz, IH), 7.51 (s, IH), 7.40 (d, J= 8.2 Hz, IH), 7.31 - 7.22 (m, 2H), 7.15 (d, J= 8.4 Hz, 2H), 6.87 (d, J= 8.4 Hz, 2H), 4.86 (s, IH), 4.03 (s, IH), 3.80 (s, 3H), 3.17 (s, IH), 2.93 - 2.69 (m, 2H), 2.37 (s, 3H), 2.03 - 1.47 (m, 4H). 497 Example 29 N-[5-[4-(4-methoxyphenyl)piperidme-l-carbonyl]-2-methyl-phenyl]-3- (trifluoromethoxy)benzamide
Figure imgf000070_0003
Method Ia from Intermediate D 1H NMR (CDCl3) δ 8.27 (s, IH), 7.87 - 7.80 (m, 2H), 7.71 (s, IH), 7.53 (t, J= 8.0 Hz, IH), 7.42 - 7.38 (m, IH), 7.23 - 7.17 (m, IH), 7.17 - 7.08 (m, 3H), 6.84 (d, J= 8.7 Hz, 2H), 4.83 (s, IH), 3.96 (s, IH), 3.77 (s, 3H), 3.13 (s, IH), 2.89 - 2.65 (m, 2H), 2.31 (s, 3H), 1.99 - 1.52 (m, 4H). M/z (M+H)+ 513. Example 30
N-[5-[4-(4-methoxyphenyl)piperidine-l-carbonyl]-2-methyl-phenyl]pyridine-4- carboxamide
Figure imgf000071_0001
Method Ia from Intermediate D 1H NMR (CDCl3) δ 8.80 (s, 2H), 8.36 (s, IH), 7.85 - 7.71 (m, 3H), 7.22 (s, IH), 7.19 - 7.15 (m, IH), 7.12 (d, J= 8.7 Hz, 2H), 6.84 (d, J= 8.7 Hz, 2H), 4.82 (s, IH), 3.96 (s, IH), 3.77 (s, 3H), 3.13 (s, IH), 2.91 - 2.66 (m, 2H), 2.32 (s, 3H), 2.00 - 1.42 (m, 4H). M/z (M+H)+ 430.
Example 31
N- [5 - [4-(4-methoxyphenyl)piperidine- 1 -carbonyl] -2-methyl-phenyl] -2-methylsulfanyl- pyridine-3-carboxamide
Figure imgf000071_0002
Method Ia from Intermediate D 1H NMR (CDCl3) δ 8.54 (dd, J= 4.8 and 1.5 Hz, IH), 8.24 (s, IH), 8.02 - 7.91 (m, 2H), 7.24 (s, IH), 7.17 (dd, J= 7.7 and 1.5 Hz, IH), 7.15 - 7.08 (m, 3H), 6.86 - 6.81 (m, 2H), ■ 4.80 (s, IH), 3.98 (s, IH), 3.76 (s, 3H), 3.13 (s, IH), 2.89 - 2.65 (m, 2H), 2.36 (s, 3H), 2.00 - 1.50 (m, 4H). M/z (M+H)+ 476. Example 32 N- [5 - [4-(4-methoxyphenyl)piperidine- 1 -carbonyl] -2-methyl-phenyl] quinoline-2- carboxamide
Figure imgf000071_0003
Method Ia from Intermediate D
1H NMR (CDCl3) δ 10.40 (s, IH), 8.45 - 8.42 (m, IH), 8.38 - 8.36 (m, 2H), 8.15 (d, J= 8.5
Hz, IH), 7.91 (d, J= 8.2 Hz, IH), 7.82 - 7.77 (m, IH), 7.68 - 7.62 (m, IH), 7.30 (d, J= 7.8 Hz, IH), 7.25 - 7.19 (m, IH), 7.14 (d, J= 8.7 Hz, 2H), 6.85 (d, J= 8.7 Hz, 2H), 4.87 (s,
IH), 4.05 (s, IH), 3.77 (s, 3H), 3.18 (s, IH), 2.85 (s, IH), 2.77 - 2.68 (m, IH), 2.51 (s, 3H),
2.00 - 1.59 (m, 4H). M/z (M+H)+ 480.
Example 33
6-acetamido-N-[2-methyl-5-[4-(4-methylsulfonylphenyl)piperidine-l- carbonyl]phenyl]pyridine-3-carboxamide
Figure imgf000072_0001
Method Ib from Intermediate E 1H NMR (CDCl3) δ 8.88 (s, IH), 8.72 (s, IH), 8.52 (s, IH), 8.34 - 8.24 (m, 2H), 7.86 (d, J - 8.3 Hz, 2H), 7.52 (s, IH), 7.39 (d, J= 8.3 Hz, 2H), 7.16 (d, J= 7.9 Hz, IH), 7.11 - 7.05 (m, IH), 4.85 (s, IH), 4.00 (s, IH), 3.15 (s, IH), 3.02 (s, 3H), 2.95 - 2.77 (m, 2H), 2.28 (s, 3H), 2.23 (s, 3H), 2.03 - 1.53 (m, 4H). M/z (M+H)+ 535. Example 34
N-[5-[4-(4-chlorophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]-6-methyl-pyridine-3- carboxamide
Figure imgf000072_0002
Method Ib from Intermediate F 1H NMR (DMSO) δ 10.05 (s, IH), 9.04 - 9.00 (m, IH), 8.20 (dd, J= 8.1 and 1.7 Hz, IH), 7.47 - 7.40 (m, 2H), 7.38 - 7.29 (m, 5H), 7.27 - 7.22 (m, IH), 4.72 - 4.49 (m, IH), 3.91 - 3.67 (m, IH), 3.25 - 3.05 (m, IH), 2.94 - 2.76 (m, 2H), 2.56 (s, 3H), 2.28 (s, 3H), 1.92 - 1.52 (m, 4H). M/z (M -H)' 446. Example 35
6-chloro-N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]pyridine-3- carboxamide
Figure imgf000072_0003
Method Ia from Intermediate A 1H NMR (400.132 MHz, CDC13) δ 1.47 - 1.80 (3H, m),1.88 - 1.98 (IH, m),2.20 (3H, s),2.72 - 2.86 (2H, m),3.02 - 3.15 (IH, m),3.82 - 3.96 (IH, m),4.75 - 4.85 (IH, m),6.93 - 6.97 (IH, m),7.07 (IH, d),7.16 (IH, s),7.26 (2H, d),7.40 (IH, d),7.55 (2H, d),8.24 - 8.27 (IH, m),9.00 (IH, d),9.34 (IH, s). M/z (M+H)+ 459. Example 36
N-[5-[4-(4-chlorophenyl)ρiperidine-l-carbonyl]-2-methyl-phenyl]-6- (trifluoromethyl)pyridine-3-carboxamide
Figure imgf000073_0001
Method Ia from Intermediate F 1H NMR (DMSO) δ 10.30 (s, IH), 9.23 (s, IH), 8.54 (d, J= 7.8 Hz, IH), 8.07 (d, J= 8.1 Hz, IH), 7.46 (s, IH), 7.36 - 7.21 (m, 6H), 4.69 - 4.44 (m, IH), 3.87 - 3.62 (m, IH), 3.24 - 3.02 (m, IH), 2.94 - 2.73 (m, 2H), 2.26 (s, 3H), 1.88 - 1.48 (m, 4H). M/z (M+H)+ 502 Example 37
N-[2-methyl-5-[4-[4-(trifluoromethyl)phenyl]piperidine-l-carbonyl]phenyl]pyridine-4- carboxamide
Figure imgf000073_0002
Method Ib from Intermediate G 1H NMR (DMSO) δ 10.19 (s, IH), 8.77 - 8.73 (m, 2H), 7.86 -.7.82 (m, 2H), 7.62 (d, J = 8.1 Hz, 2H), 7.49 (d, J= 8.1 Hz, 2H), 7.42 (s, IH), 7.33 (d, J= 7.9 Hz, IH), 7.26 - 7.22 (m, IH), 4.72 - 4.47 (m, IH), 3.87 - 3.66 (m, IH), 3.23 - 3.04 (m, IH), 2.98 - 2.73 (m, 2H), 2.24 (s, 3H), 1.90 - 1.54 (m, 4H). M/z (M+H)+ 468. Example 38 N-[5-[4-(4-fluorophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]pyridine-4-carboxamide
Figure imgf000073_0003
Method Ia from Intermediate H
1H NMR (DMSO) δ 10.19 (s, IH), 8.77 - 8.74 (m, 2H), 8.45 - 8.42 (m, 2H), 7.84 (d, J = 5.3 Hz, 2H), 7.42 (s, IH), 7.33 (d, J= 7.8 Hz, IH), 7.29 - 7.26 (m, 2H), 7.23 (dd, J= 7.8 and 1.5 Hz, IH), 4.69 - 4.47 (m, IH), 3.88 - 3.64 (m, IH), 3.22 - 2.75 (m, 3H), 2.24 (s, 3H), 2.07 - 1.51 (m, 4H). M/z (M+H)+ 418. Example 39 N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]pyridine-4-carboxamide
Figure imgf000073_0004
Method Ia from Intermediate A 1H NMR (300.073 MHz, dmso) 51.52 - 1.72 (m, 2H) ,1.72 - 1.92 (m, 2H), 2.27 (s, 3H), 2.84 - 3.01 (m, 2H), 3.57 - 4.00 (m, IH), 4.40 - 4.79 (m, IH), 7.26 (d, IH), 7.36 (d, IH), 7.42 (s, IH), 7.52 (d, 2H), 7.76 (d, 2H), 7.87 (d, 2H), 8.79 (d, 2H), 10.20 (s, IH); signal for IH not apparent - may be v br or hidden under other signals (piperidine 4-H). 423 (M- H)" 425 (M+H)+. Example 40
N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl- phenyljcyclopropanecarboxamide
Figure imgf000074_0001
Method Ia from Intermediate A 1H NMR (400.132 MHz, CDC13) δ 0.81 - 0.89 (2H, m),1.01 - 1.08 (2H, m),1.52 - 1.85
(4H5 m),1.90 - 2.01 (IH, m),2.23 (3H, s),2.76 - 2.90 (2H, m),3.08 - 3.24 (IH, m),3.93 -
4.04 (IH, m),4.82 - 4.91 (IH, m),7.06 (IH, d),7.13 (IH, d),7.32 (2H, d),7.59 - 7.62 (3H, m),8.12 (IH, s). M/z (M+H)+ 388.
Example 41 N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]-6-oxo-lH-pyridine-3- carboxamide
Figure imgf000074_0002
Method Ib from Intermediate A 1H NMR (400.132 MHz, CDC13) δl.47 - 1.80 (3H, m),1.88 - 1.98 (IH, m),2.20 (3H, s),2.72 - 2.86 (2H, m),3.02 - 3.15 (IH, m),3.82 - 3.96 (IH, m),4.75 - 4.85 (IH, m),6.93 - 6.97 (IH, m),7.07 (IH, d),7.16 (IH, s),7.26 (2H, d),7.40 (IH, d),7.55 (2H, d),8.24 - 8.27 (IH, m),9.00 (IH, d),9.34 (IH, s). M/z (M+H)+ 441. Example 42
N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]-6-morpholin-4-yl- pyridine-3 -carboxamide
Figure imgf000074_0003
Method Ia from Intermediate A
1H NMR (400.132 MHz, CDC13) δl.58 - 2.01 (4H, m),2.32 (3H, s),2.80 - 2.92 (2H, m),3.12 - 3.24 (IH, m),3.66 (4H, t),3.83 (4H, t),3.99 - 4.10 (IH, m),4.82 - 4.95 (IH, m),6.68 (IH, d),7.14 - 7.16 (IH, m),7.22 (IH, d),7.33 (2H, d),7.61 (2H, d),7.80 (IH, s),8.O8 (IH, dd),8.13 (IH, s),8.78 (IH, d). M/z (M+H)+ 510 Example 43
6-acetamido-N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]pyridine-3- carboxamide
Figure imgf000075_0001
Method Ia from Intermediate A 1H NMR (400.132 MHz, CDC13) δl.54 - 1.76 (2H, m),1.78 - 1.87 (IH, m),1.93 - 2.03 (IH, m),2.26 (3H, s),2.31 (3H, s),2.79 - 2.92 (2H, m),3.11 - 3.25 (IH, m),3.96 - 4.07 (IH, m),4.81 - 4.93 (IH, m),7.08 - 7.11 (IH, m),7.19 (IH, d),7.33 (2H, d),7.54 (IH, s),7.61 (2H,o d),8.31 - 8.33 (2H, m),8.35 (IH, s),8.77 (IH, s),8.92 (IH, s). M/z (M+H)+ 482 Example 44 N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]cyclobutanecarboxamide
Figure imgf000075_0002
Method Ia from Intermediate A
1H NMR (300.072 MHz, cdcl3) δ 1.59 - 2.12 (6H, m),2.22 (3H, s),2.26 - 2.46 (4H,s m),2.78 - 3.04 (2H, m),3.04 - 3.32 (2H, m),3.91 - 4.17 (IH, m),4.68 - 5.02 (IH, m),7.05 - 7.19 (2H, m),7.33 (2H, d),7.43 (IH, s),7.61 (2H, d),7.75 (IH, s). 402. Example 45 N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]butanamide
Figure imgf000075_0003
Method Ia from Intermediate A o 1H NMR (300.072 MHz, cdcl3) δ 1.03 (3H, t),1.59 - 2.08 (6H, m),2.24 (3H, s),2.38 (2H, t),2.79 - 2.89 (2H, m),3.01 - 3.28 (IH, m),3.86 - 4.15 (IH, m),4.73 - 5.00 (IH, m),7.10 - 7.18 (2H, m),7.32 (2H, d),7.46 (IH, s),7.60 (2H, d),7.74 (IH, s). M/z (M+H)+ 389. Example 46 N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]-3,3-dimethyl-5 butanamide
Figure imgf000075_0004
Method Ia from Intermediate A 1H NMR (300.072 MHz, cdcl3) δ 1.12 (9H, s),1.57 - 1.97 (4H, m),2.24 (3H, s),2.27 (2H, s),2.79 - 2.89 (2H, m),3.01 - 3.27 (IH, m),3.88 - 4.13 (IH, m),4.75 - 4.96 (IH, m),7.10 - 7.18 (2H, m),7.31 - 7.33 (3H, m),7.60 (2H, d),7.77 (IH, s). M/z (M+H)+ 418 Example 47 N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]benzamide
Figure imgf000076_0001
Method Ia from Intermediate A 1H NMR (300.072 MHz, cdcl3) δ 1.58 - 1.99 (4H, m),2.32 (3H, s),2.79 - 2.94 (2H, m),3.04 - 3.27 (IH, m),3.91 - 4.21 (IH, m),4.70 - 4.98 (IH, m),7.08 - 7.23 (2H, m),7.32 (2H, d),7.46 - 7.63 (5H, m),7.76 (IH, s),7.95 (2H, d),8.35 (IH, s). M/z (M+H)+ 424. I0 Example 48
N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]pyridine-3-carboxamide
Figure imgf000076_0002
Method Ia from Intermediate A 1H NMR (300.072 MHz, cdcl3) δl.64 - 2.01 (4H, m),2.36 (3H, s),2.78 - 3.00 (2H, m),3.06 - 3.29 (IH, m),3.93 - 4.17 (IH, m),4.75 - 4.95 (IH, m),7.16 - 7.21 (IH, m),7.24 - 7.28 (IH, is m),7.34 (2H, d),7.45 - 7.52 (IH, m),7.62 (2H, d),7.82 (IH, s),8.25 - 8.31 (2H, m),8.82 (IH, s),9.19 (IH, s). M/z (M+H)+ 425. Example 49 N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]cyclohexanecarboxamide
Figure imgf000076_0003
Method Ib from Intermediate A 20 1H NMR (400.132 MHz, CDC13) δl.23 - 1.40 (3H, m),1.49 - 1.59 (3H, m),1.69 - 1.76
(2H, m),1.83 - 1.89 (3H, m),1.94 - 2.03 (3H, m),2.27 (3H, s),2.28 - 2.35 (IH, m),2.78 -
2.91 (2H, m),3.09 - 3.25 (IH, m),3.96 - 4.10 (IH, m),4.79 - 4.94 (IH, m),7.13 - 7.23 (3H, m),7.33 (2H, d),7.62 (2H, d),7.92 (IH, s). M/z (M+H)+ 430.
Example 50 25 N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]-2-(3-oxopiperazin-l- yl)acetamide
Figure imgf000076_0004
Method Ib from Intermediate A 1H NMR (400.132 MHz, DMSO) δl.43 - 1.83 (4H, m),2.17 (3H, s),2.63 - 2.89 (2H, m),2.96 - 3.02 (2H, m),3.13 - 3.30 (2H, m),3.30 - 3.40 (2H, m),3.55 - 3.65 (2H, m),4.45 - 4.54 (2H, m),4.66 (IH, s),7.06 - 7.11 (IH, m),7.20 - 7.24 (IH, m),7.43 (2H, d),7.56 (IH, s),7.70 (2H, d),8.09 (IH, s),9.59 (IH, s). M/z (M+H)+ 460. Example 51 l-acetyl-N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]piperidine-4- carboxamide
yO OO- Method Ib from Intermediate A
1H NMR (400.132 MHz, DMSO) 61.39 - 1.50 (IH, m),1.55 - 1.93 (7H, m),2.01 (3 H, s),2.22 (3H, s),2.53 - 2.72 (2H, m),2.72 - 2.96 (2H, m),3.05 - 3.22 (2H, m),3.69 - 3.85 (IH, m),3.87 (IH, d),4.40 (IH, d),4.53 - 4.72 (IH, m),7.15 (IH, d),7.28 (IH, d),7.47 (IH, s),7.51 (2H, d),7.78 (2H, d),9.40 (IH, s). M/z (M+H)+ 473.
Example 52
N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl- phenyljcyclopentanecarboxamide
Figure imgf000077_0001
Ib from Intermediate A 1H NMR (400.132 MHz, CDC13) 51.62 - 1.70 (2H, m),1.75 - 1.83 (2H, m),1.86 - 2.02 (8H, m),2.27 (3H, s),2.72 - 2.79 (IH, m),2.79 - 2.89 (2H, m),3.10 - 3.25 (IH, m),3.97 - 4.12 (IH, m),4.79 - 4.94 (IH, m),7.12 - 7.23 (3H, m),7.33 (2H, d),7.61 (2H, d),7.92 (IH, s). M/z (M+H)+ 416. Example 53 N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-ρhenyl]-2-methyl-propanamide
Figure imgf000077_0002
Ib from Intermediate A 1H NMR (400.132 MHz, CDC13) δl.27 (6H, d),1.53 - 2.01 (4H, m),2.24 (3H, s),2.60 (IH, septet),2.80 - 2.88 (2H, m),3.09 - 3.25 (IH, m),3.97 - 4.08 (IH, m),4.83 - 4.93 (IH, m),7.10 - 7.18 (2H, m),7.32 (2H, d),7.51 (IH, s),7.61 (2H, d),7.74 (IH, s). M/z (M+H)+ 390. Example 54
N- [5 - [4-(4-cy anophenyl)piperidine- 1 -carbony 1] -2-methyl-phenyl] -6-oxo- 1 H-pyridazine-3 - carboxamide
Figure imgf000078_0001
Method Ib from Intermediate A 1H NMR (300.073 MHz, dmso) δl.54 - 1.84 (4H, m),2.26 (3H, s),2.91 - 3.20 (3H, m),3.66 - 3.98 (IH, m),4.42 - 4.76 (IH, m),7.00 (IH, d),7.20 - 7.34 (2H, m),7.50 (2H, d),7.61 (IH, s),7.76 (2H, d),7.90 (IH, d),9.83 (IH, s),13.51 (IH, s). M/z (M+H)+ 442. Example 55 N-[2-chloro-5-[4-(4-cyanophenyl)piperidine-l-carbonyl]phenyl]pyridine-4-carboxamide
Figure imgf000078_0002
Method Ib from Intermediate J
1H NMR (300.073 MHz, dmso) δ 1.47 - 1.95 (m, 4H), 2.75 - 3.38 (m, 3H), 3.58 - 3.85 (m, IH), 4.41 - 4.81 (m, IH), 7.40 (d, IH), 7.51 (d, 2H), 7.64 (s, IH), 7.68 (d, IH), 7.76 (d, 2H), 7.96 (d, 2H), 8.85 (d, 2H), 10.52 (s, IH). M/z (M+H)+ 445. Example 56 N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]-l-hydroxy-cyclohexane- 1 -carboxamide
Figure imgf000078_0003
Method Ib from Intermediate A
1H NMR (300.072 MHz, cdcl3) δ 1.28 - 1.40 (2H, m),1.54 - 1.81 (8H, m),1.86 - 2.01 (4H, m),2.06 (3H, s),2.71 - 2.99 (2H, m),3.02 - 3.35 (IH, m),3.91 - 4.06 (IH, m),4.33 (IH, s),4.74 - 5.03 (IH, m),7.15 (2H, q),7.32 (2H, d),7.60 (2H, d),8.00 (IH, s),8.57 (IH, s). M/z (MH-H)+ 446. Example 57 N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]-2-phenoxy-acetamide
Figure imgf000078_0004
Method Ib from Intermediate A 1H NMR (300.072 MHz, cdcB) δ 1.66 - 1.99 (4H, m),2.25 (3H, s),2.77 - 2.96 (2H, m),2.94 - 3.17 (IH, m),3.85 - 4.14 (IH, m),4.68 (2H, s),4.76 - 5.06 (IH, m),6.93 - 7.01
(2H, m),7.03 - 7.12 (IH, m),7.19 - 7.27 (2H, m),7.30 - 7.39 (4H, m),7.61 (2H, d),8.14 (IH, s),8.33 (IH, s). M/z (M+H)+ 454
Example 58
1 -[[5-[4-(4-cyanophenyl)piperidine- 1 -carbonyl]-2-methyl- ρhenyl]carbamoylmethyl]piperidine-4-carboxamide
Figure imgf000079_0001
Method Ib from Intermediate A
1H NMR (300.072 MHz, cdcl3) δ 1.63 - 1.99 (8H, m), 2.14 - 2.25 (IH, m),2.30 (3H, s),2.30 - 2.39 (2H, m),2.76 - 2.92 (2H, m),2.98 - 3.05 (2H, m),3.09 - 3.22 (IH, m),3.18 (2H, s),3.95 - 4.06 (IH, m),4.70 - 5.01 (IH, m),5.46 (IH, s),5.67 (IH, s),7.13 - 7.25 (2H, m),7.33 (2H, d),7.60 (2H, d),8.27 (IH, s),9.33 (IH, s). M/z (M+H)+ 488. Example 59 N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]-3-hydroxy-butanamide
Figure imgf000079_0002
Method Ib from Intermediate A
1H NMR (300.072 MHz, cdcl3) δl.32 (3H, d),1.62 - 1.99 (4H, m),2.14 (3H, s),2.45 - 2.58 (2H, m),2.81 - 2.92 (2H, m),2.99 - 3.23 (IH, m),3.52 - 3.74 (IH, m),3.90 - 4.11 (IH, m),4.19 - 4.31 (IH, m),4.71 - 5.02 (IH, m),7.09 - 7.19 (2H, m),7.33 (2H, d),7.61 (2H, d),8.01 (IH, s),8.39 (IH, s). M/z (M+H)+ 406. Example 60
N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]oxolane-3-carboxamide
Figure imgf000079_0003
Method Ib from Intermediate A
1H NMR (300.072 MHz, cdcl3) δ 1.70 - 1.99 (4H, m),2.21 (3H, s),2.27 (2H, q),2.77 - 2.91 (2H, m),3.07 - 3.21 (2H, m),3.82 - 4.09 (5H, m),4.72 - 5.01 (IH, m),7.06 - 7.17 (2H, m),7.32 (2H, d),7.61 (2H, d),7.69 (IH, s),8.07 (IH, s). M/z (M+H)+ 418. Example 61
N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]-2-hydroxy-cyclohexane- 1-carboxamide
Figure imgf000080_0001
Method Ib from Intermediate A
1H NMR (300.072 MHz, cdcl3) δ 1.31 - 1.93 (12H, m),2.10 (3H, s),2.46 - 2.55 (IH, m),2.77 - 2.97 (2H, m),3.04 - 3.26 (IH, m),3.91 - 4.09 (IH, m),4.20 - 4.30 (IH, m),4.78 - 4.95 (IH, m),7.05 - 7.17 (2H, m),7.33 (2H, d),7.61 (2H, d),8.01 (IH, s),8.81 (IH, s). M/z (M+H)+ 446. Example 62
N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]-4-methoxy- cyclohexane- 1 -carboxamide
Figure imgf000080_0002
Method Ib from Intermediate A 1H NMR (300.072 MHz, cdcl3) δ 1.21 - 2.08 (12H, m),2.24 (3H, s),2.30 - 2.41 (IH, tt),2.77 - 2.88 (2H, m),3.00 - 3.23 (IH, m), 3.33 (3H, s),3.45 - 3.51 (IH, m), ,3.92 - 4.11 (IH, m),4.78 - 5.03 (IH, m),7.15 - 7.23 (3H, m),7.32 (2H, d),7.61 (2H, d),7.86 (IH, s). M/z (M+H)+ 460 Example 63
N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]-4-methoxy- cyclohexane- 1 -carboxamide
Figure imgf000080_0003
Method Ib from Intermediate A 1H NMR (300.072 MHz, cdcl3) δl.21 - 1.36 (2H, m),1.50 - 1.95 (6H, m),1.99 - 2.11 (2H, m),2.15 - 2.22 (2H, m),2.24 (3H, s),2.26 - 2.36 (IH5 tt),2.79 - 2.88 (2H, m),3.13 - 3.23 (2H, m+tt),3.38 (3H, s),3.88 - 4.11 (IH, m),4.73 - 5.03 (IH, m),7.10 - 7.19 (2H, m),7.32 (2H, d),7.38 (IH, s),7.61 (2H, d),7.79 (IH, s). M/z (M+H)+ 460 Example 64
N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]-3-methoxy- cyclohexane- 1 -carboxamide
Figure imgf000080_0004
Method Ib from Intermediate A 1H NMR (300.072 MHz, cdcl3) δ 1.30 - 1.49 (4H, m), 1.60 - 2.00 (8H, m),2.27 (3H, s),2.63 - 2.70 (IH, m),2.77 - 2.91 (2H, m),3.04 - 3.15 (IH, m),3.34 (3H, s),3.60 - 3.67 (IH, m),3.91 - 4.04 (IH, m),4.69 - 4.97 (IH, m),7.06 (IH, s),7.13 - 7.24 (2H, m),7.32 (2H, d),7.61 (2H, d),7.95 (IH, S1H NMR (300.072 MHz, cdcl3) δ 1.30 - 1.49 (4H, m),1.60 - 2.00 (8H, m),2.27 (3H, s),2.63 - 2.70 (IH, m),2.77 - 2.91 (2H, m),3.04 - 3.15 (IH, m),3.34 (3H, s),3.60 - 3.67 (IH, m),3.91 - 4.04 (IH, m),4.69 - 4.97 (IH, m),7.06 (IH, s),7.13 - 7.24 (2H, m),7.32 (2H, d),7.61 (2H, d),7.95 (IH, s). M/z (M+H)+ 460 Example 65 6-chloro-N- [2-chloro-5- [4-(4-cyanophenyl)piperidine- 1 -carbonyl]phenyl]pyridine-3 - carboxamide
Figure imgf000081_0001
Method Ia from Intermediate J
1H NMR (300.073 MHz, dmso) δ 1.51 - 2.06 (m, 4H), 2.77 - 3.14 (m, 3H), 3.58 - 3.90 (m, IH), 4.42 - 4.82 (m, IH), 7.39 (d, IH), 7.51 (d, 2H), 7.63 - 7.78 (m, 5H), 8.35 (d, IH), 8.95 (s, IH), 10.44 (s, IH). M/z (M+H)+ 479481 [A]. Example 66
N-[2-chloro-5-[4-(4-cyanophenyl)piperidine-l-carbonyl]phenyl]butanamide
Figure imgf000081_0002
Method Ia from Intermediate J 1H NMR (300.073 MHz, dmso) δ 0.93 (t, 3H), 1.35 - 2.01 (m, 6H), 2.37 (t, 2H), 2.74 - 3.04 (m, 3H), 3.56 - 3.91 (m, IH), 4.46 - 4.76 (m, IH), 7.24 (d, IH), 7.41 - 7.58 (m, 3H), 7.76 (d, 3H), 9.51 (s, IH). M/z (M+H)+ 410. Example 67 methyl 5 - [ [5 - [4-(4-cyanopheny l)piperidine- 1 -carbonyl] -2-methyl- phenyi]carbamoyl]pyridine-2-carboxylate
Figure imgf000081_0003
Method Ib from Intermediate A 1H NMR (300.072 MHz, cdcl3) δl.66 - 2.00 (4H, m),2.31 (3H, s),2.78 - 2.90 (2H, m),3.05 - 3.26 (IH, m),3.92 - 4.02 (IH, m),4.05 (3H, s),4.78 - 4.95 (IH, m),7.06 - 7.21 (2H, m),7.33 (2H, d),7.42 (IH, s),7.61 (2H, d),8.27 (IH, d),8.44 - 8.50 (IH, m),9.14 (IH, s),9.34 (IH, s). M/z (M+H)+ 483. Example 68 ethyl 5-[[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl- 5 phenyl] carbamoyl]pyridine-3 -carboxylate
Figure imgf000082_0001
Method Ib from Intermediate A
1H NMR (300.072 MHz, cdcl3) δ 1.44 (3H, t),1.61 - 2.01 (4H, m),2.33 (3H, s),2.81 - 2.92 (2H, m),3.08 - 3.21 (IH, m),3.89 - 4.10 (IH, m),4.47 (2H, q),4.79 - 4.99 (IH, m),7.12 - 7.23 (2H, m),7.33 (2H, d),7.54 (IH, s),7.61 (2H, d),8.85 - 8.88 (2H, m),9.34 - 9.39 (2H, I0 m). M/z (M+H)+ 497. Example 69
N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]-2-(4-hydroxy-l- piperidyl)acetamide
Figure imgf000082_0002
Method Ib from Intermediate A is I 1iH NMR (300.072 MHz, cdcl3) δ 1.59 - 1.78 (6H, m),1.90 - 2.01 (3H, m),2.32 (3H, s),2.42 - 2.53 (2H, m),2.79 - 2.93 (4H, m),3.04 - 3.17 (IH, m),3.17 (2H, s),3.73 - 3.87 (IH, m),3.95 - 4.12 (IH, m),4.74 - 5.03 (IH, m),7.13 - 7.25 (2H, m),7.33 (2H, d),7.61 (2H, d),8.30 (IH, s),9.43 (IH, s). M/z (M+H)+ 461. Example 70
20 6-cyano-N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]pyridine-3- carboxamide
Figure imgf000082_0003
Method Ib from Intermediate A 1H NMR (300.073 MHz, dmso) δ 1.55 - 1.91 (4H, m),2.29 (3H, s),2.84 - 3.00 (2H, m),3.04 - 3.24 (IH, m),3.67 - 4.00 (IH, m),4.50 - 4.74 (IH, m),7.25 - 7.39 (2H, m),7.47 - 25 7.53 (3H, m),7.76 (2H, d),8.23 (IH, d),8.52 (IH, d),9.23 (IH, s),10.33 (IH, s). M/z (M+H)+ 450. Example 71
N- [5 - [4-(4-cyanophenyl)piperidine- 1 -carbony l]-2-methyl-pheny 1] -2- [(4- methoxyphenyl)amino]pyridine-4-carboxamide
Figure imgf000083_0001
Method Ib from Intermediate A 1H NMR (300.073 MHz, dmso) δ 1.55 - 1.91 (4H, m),2.29 (3H, s),2.84 - 3.00 (2H, m),3.04 - 3.24 (IH, m),3.67 - 4.00 (IH, m), 3.72 (3H, s),4.50 - 4.74 (IH, m),6.87 (2H,d),
7.11 (lH,d), 7.20 (lH,s)7.25 - 7.39 (2H, m),7.43 (lH,s),7.50 - 7.58 (4H, m),7.76 (2H, d),8.23 (IH, d),9.03 (IH, s), 10.03 (IH, s). M/z (M+H)+ 546
Example 72 N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]-2-fluoro-pyridine-3- carboxamide
Figure imgf000083_0002
Method Ib from Intermediate A 1H NMR (300.072 MHz, cdcl3) δ 1.62 - 2.00 (4H, m),2.41 (3H, s), 2.77 - 2.91 (2H, m),3.00 - 3.26 (IH, m),4.04 - 4.11 (IH m),4.78 - 4.98 (IH, m), 7.21 - 7.31 (2H, m), 7.35 (2H, d), 7.41 - 7.48 (IH, m), 7.61 (2H, d),8.25 (IH, s),8.40 (IH, m),8.58 (IH, d),8.63-8.71 (IH, m). M/z (M+H)+ 443. Example 73
N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]-6-(l-piperidyl)pyridine- 3-carboxamide
Figure imgf000083_0003
Method Ib from Intermediate A
1H NMR (300.072 MHz, cdcl3) δ 1.65 - 2.00 (1OH, m),2.23 (3H, s),2.77 - 2.97 (2H, m),3.08 - 3.28 (IH, m),3.67 - 3.80 (4H, m),3.85 - 4.03 (IH, m),4.71 - 4.94 (IH, m),7.02 (IH, d),7.18 - 7.25 (2H, m),7.36 (2H, d),7.57 - 7.62 (3H, m),8.19 - 8.32 (2H, m),8.86 (IH, s). M/z (M+H)+ 508 Example 74
N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]-2-pyrrolidin-l-yl- pyridine-4-carboxamide
Figure imgf000084_0001
Method Ib from Intermediate A 1H NMR (300.073 MHz, dmso) δ 1.54 - 1.87 (4H, m),1.91 - 2.04 (4H, m),2.26 (3H, s),2.86 - 3.01 (2H, m),3.07 - 3.19 (IH, m),3.37 - 3.49 (4H, m),3.63 - 3.93 (IH, m),4.43 -
4.74 (IH, m),6.90 (IH, s),6.98 (IH, d),7.24 - 7.37 (2H, m),7.42 (IH, s),7.51 (2H, d),7.76
(2H, d),8.20 (IH, d),9.99 (IH, s). M/z (M+H)+ 494.
Example 75 N-[5 - [4-(4-cyanophenyl)piperidine- 1 -carbony 1] -2-methy 1-pheny 1] -2-( 1 -piperidyl)pyridine-
4-carboxamide
Figure imgf000084_0002
Method Ib from Intermediate A 1H NMR (300.072 MHz, cdcl3) δ 1.55 - 1.98 (1OH, m),2.32 (3H, s),2.75 - 2.92 (2H, m),3.05 - 3.27 (IH, m),3.53 - 3.70 (4H, m),3.94 - 4.06 (IH, m),4.72 - 4.97 (IH, m),6.91 (IH, d),7.11 - 7.25 (3H, m),7.33 (2H, d),7.61 (2H, d),7.73 (IH, s),8.29 (IH, d),8.34 (IH, s). M/z (M+H)+508. Example 76
N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]-2-(l,2,4-triazol-l- yl)pyridine-4-carboxamide
Figure imgf000084_0003
Method Ib from Intermediate A
1H NMR (300.073 MHz, dmso) δ 1.56 - 1.88 (4H, m),2.29 (3H, s),2.91 - 3.01 (2H, m),3.06 - 3.21 (IH, m),3.65 - 3.95 (IH, m),4.41 - 4.81 (IH, m),7.27 - 7.39 (2H, m),7.47 - 7.52 (3H, m),7.76 (2H, d),7.96 (IH, d),8.34 - 8.38 (2H, m),8.75 (IH, d),9.44 (IH, s),10.46 (IH, s). M/z (M+H)+492. Example 77
N-[5 - [4-(4-cyanophenyl)piperidine- 1 -carbony 1] -2-methy 1-pheny 1] quinoline-3 -carboxamide
Figure imgf000085_0001
Method Ib from Intermediate A 1H NMR (300.072 MHz, cdcl3) δ 1.51 - 1.99 (4H, m),2.36 (3H, s),2.75 - 2.90 (2H, m),3.01 - 3.25 (IH, m),3.88 - 4.06 (IH, m),4.70 - 4.97 (IH, m),7.02 - 7.20 (2H, m),7.29 (2H, d),7.51 (IH, s),7.60 (2H, d),7.63 - 7.67 (IH, m),7.79 - 7.86 (IH, m),7.97 (IH, d),8.18 (IH, d),8.85 (IH, d),9.21 (IH, s),9.48 (IH, d). M/z (M+H)+475. Example 78
6-amino-N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]pyridine-3- carboxamide
Figure imgf000085_0002
Method Ib from Intermediate A
1H NMR (300.073 MHz, dmso) δ 1.55 - 1.91 (4H, m),2.24 (3H, s),2.84 - 3.00 (2H, m),3.04 - 3.24 (IH, m),3.67 - 4.00 (IH, m),4.50 - 4.74 (IH, m),6.48 (lH,d), 6.58(2H,s),
7.20 - 7.33 (2H, m), 7.41 (lH,s), 7.51 (2H, d),7.76 (2H, d), 7.88 - 7.94 (IH, m), 8.59 (IH, d),9.59 (IH, s). M/z (M+H)+440.
Example 79
N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]-6-methyl-pyridine-3- carboxamide
Figure imgf000085_0003
Method Ib from Intermediate A 1H NMR (300.072 MHz, cdcl3) δ 1.52 - 1.99 (4H, m),2.30 (3H, s),2.65 (3H, s),2.77 - 2.90 (2H, m),3.05 - 3.26 (IH, m),3.93 - 4.07 (IH, m),4.76 - 5.00 (IH, m),7.09 - 7.21 (2H, m),7.28 - 7.35 (3H, m),7.55 (IH, s),7.61 (2H, d),8.17 - 8.22 (IH, m),8.72 (IH, s),9.11 (IH, d). M/z (M+H)+439. Example 80 2-chloro-N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]pyridine-4- carboxamide
Figure imgf000085_0004
Method Ib from Intermediate A 1H NMR (300.073 MHz, dmso) δ 1.58 - 1.90 (4H, m),2.26 (3H, s),2.85 - 3.01 (2H, m),3.07 - 3.20 (IH, m),3.65 - 3.90 (IH, m),4.53 - 4.76 (IH, m),7.23 - 7.36 (2H, m),7.44
(IH, s),7.50 (2H, d),7.76 (2H, d),7.86 (IH, d), 8.00 (IH, s), 8.61 (IH, d),10.29 (IH, s). M/z
(M+H)+459.
Example 81
N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]-l-oxido-pyridine-5- carboxamide
Figure imgf000086_0001
Method Ib from Intermediate A
1H NMR (300.072 MHz, cdcl3) δ 1.53 - 2.02 (4H, m),2.29 (3H, s),2.78 - 2.94 (2H, m),3.05 - 3.27 (IH, m),3.85 - 4.09 (IH, m),4.70 - 5.01 (IH, m),7.09 - 7.24 (2H, m),7.30 -
7.35 (3H, m),7.40 (IH, t),7.61 (2H, d),7.93 (IH, d),8.31 (IH, d),8.98 (IH, s),9.67 (IH, s).
M/z (M+H)+441.
Example 82
5 -bromo-N- [5- [4-(4-cyanophenyl)piperidine- 1 -carbonyl] -2-methyl-phenyl]pyridine-3 - carboxamide
Figure imgf000086_0002
Method Ib from Intermediate A 1H NMR (400.132 MHz, DMSO) δ 1.59 - 1.88 (4H, m),2.30 (3H, s),2.92 - 3.00 (2H, m),3.05 - 3.23 (IH, m),3.70 - 4.09 (IH, m),4.41 - 4.74 (IH, m),7.26 - 7.39 (2H, m),7.48 (IH, s),7.51 (2H, d),7.77 (2H, d),8.55 (IH, s),8.92 (IH, d),9.10 (IH, s),10.21 (IH, s). M/z (M+H)+505 [A]. Example 83
N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]-6-methoxy- benzothiazole-2-carboxamide
Figure imgf000086_0003
Method Ib from Intermediate A
I 1H1 NMR (400.132 MHz, CDC13, 30 deg. C) δ 1.65 - 2.08 (3H, m), 2.50 (3H, s), 2.82 - 2.98 (2H, m), 2.99 - 3.39 (2H, m), 3.95 (3H, s), 4.02 - 4.23 (IH, m), 4.72 - 5.10 (IH, m), 7.16 - 7.47 (5H, m), 7.60 - 7.69 (2H, m), 7.98 - 8.06 (IH, m), 8.34 (IH, s), 9.26 (IH, s). M/z (M+H)+ 511. Example 84
N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]-2-methyl-6-oxo-lH- pyridine-4-carboxamide
Figure imgf000087_0001
Method Ib from Intermediate A 1H NMR (400.132 MHz, DMSO) δ 1.59 - 1.97 (4H, m),2.21 (3H, s), 2.23 (3H, s),2.89 - 2.98 (2H, m),3.06 - 3.21 (IH, m),3.71 - 3.87 (IH, m), 4.49 - 4.75 (IH, m), 6.35 (IH, s), 6.67 (IH, s),7.20 - 7.37 (2H, m),7.40 (IH, s),7.50 (2H, d),7.77 (2H, d),9.98 (IH, s), 11.85 (IH, s). M/z (M+H)+ 455. Example 85
6-[(4-acetamidophenyl)amino]-N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl- phenyl]pyridine-3 -carboxamide
Figure imgf000087_0002
Method Ib from Intermediate A 1H NMR (300.073 MHz, DMSO) δ 1.54 - 1.86 (4H, m),2.02 (3H, s),2.28 (3H, s),2.85 - 3.00 (2H, m),3.05 - 3.20 (IH, m),3.66 - 3.92 (IH, m),4.46 - 4.73 (IH, m),6.83 (IH, d),7.17 - 7.37 (2H, m),7.42 - 7.55 (5H, m),7.59 (2H, d),7.76 (2H, d),8.01 - 8.07 (IH, m),8.77 (IH, d),9.37 (IH, s),9.71 (IH, s),9.81 (IH, s). M/z (M+H)+ 573. Example 86 2- [(3 -carbamoylphenyl)amino] -N- [5 - [4-(4-cyanophenyl)piperidine- 1 -carbonyl]-2-methyl- phenyl]pyridine-4-carboxamide
Figure imgf000087_0003
Method Ib from Intermediate A 1H NMR (300.073 MHz, DMSO) δ 1.54 - 1.90 (4H, m),2.29 (3H, s),2.86 - 3.01 (2H, m),3.02 - 3.21 (IH, m),3.67 - 3.92 (IH, m),4.45 - 4.75 (IH, m),7.21 - 7.55 (1OH, m),7.76 (2H, d),7.83 - 7.94 (2H, m),8.12 (IH, s),8.33 (IH, d),9.41 (IH, s),10.09 (IH, s). M/z (M+H)+ 559. Example 87
2,5-dichloro-N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-ρhenyl]pyridine-4- carboxamide
Figure imgf000088_0001
Method Ib from Intermediate A 5 1H NMR (SOOOVS MHZ5 DMSO) B 1.51 - 1.92 (4H, m),2.31 (3H, s),2.87 - 3.04 (2H, m),3.10 - 3.18 (IH, m),3.66 - 3.85 (IH, m),4.46 - 4.79 (IH, m),7.23 - 7.39 (2H, m),7.50
(2H, d),7.59 (IH, s),7.77 (2H, d),7.95 (IH, s),8.66 (IH, s),10.29 (IH, s). M/z (MH-H)+ 493
[A].
Example 88 o N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]-6-(2-pyrrolidin-l- ylethyl)pyridine-3-carboxamide
Figure imgf000088_0002
Method Ib from Intermediate A
1H NMR (300.072 MHz, CDCl3) δ 1.54 - 2.11 (8H, m),2.31 (3H, s),2.53 - 2.68 (4H, m),2.78 - 2.97 (4H, m),3.05 - 3.25 (3H, m),3.94 - 4.13 (IH, m),4.74 - 5.02 (IH, m),7.12 -s 7.23 (2H, m),7.30 - 7.38 (3H, m),7.57 - 7.66 (3H, m),8.20 (IH, d),8.56 (IH, s),9.12 (IH, s). 522.
Example 89 tert-butyl 4-[5-[[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl- phenyl]carbamoyl]pyridin-2-yl]piperazine-l-carboxylate
o
Figure imgf000088_0003
Method Ib from Intermediate A
1H NMR (300.072 MHz, CDCl3) δ 1.49 (9H, s),1.66 - 2.04 (4H, m),2.32 (3H, s),2.76 - 2.95 (2H, m),3.05 - 3.26 (IH, m),3.51 - 3.59 (4H, m),3.65 - 3.72 (4H, m),3.92 - 4.28 (IH, m),4.68 - 4.92 (IH, m),6.67 (IH, d),7.11 - 7.25 (2H, m),7.33 (2H, d),7.61 (2H, d),7.86 (IH, s),7.98 (IH, s),8.02 - 8.09 (IH, m),8.75 (IH, d). M/z (M+H)+ 609. 5 Example 90
N- [5 - [4-(4-cyanophenyl)piperidine- 1 -carbonyl] -2-methy 1-pheny 1] -2-morpholin-4-yl- pyridine-4-carboxamide
Figure imgf000089_0001
Method Ib from Intermediate A 1H NMR (300.072 MHz, CDCl3) δ 1.60 - 2.04 (4H, m),2.32 (3H, s),2.76 - 2.95 (2H, m),3.01 - 3.26 (IH, m),3.61 - 3.66 (4H, m),3.8O - 3.86 (4H, m),3.92 - 4.20 (IH, m),4.78 -
4.92 (IH, m), 7.04 - 7.25 (4H, m),7.33 (2H, d),7.61 (2H, d),7.66 (IH, s),8.35 (IH, d),8.50(lH, s). M/z (M+H)+ 510.
Example 91 N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]-6-(2- methoxyethoxy)pyridine-3-carboxamide
Figure imgf000089_0002
Method Ib from Intermediate A 1H NMR (300.072 MHz, CDCl3) δ 1.61 - 1.99 (4H, m),2.31 (3H, s),2.76 - 2.89 (2H, m),3.02 - 3.21 (IH, m),3.45 (3H, s),3.77 (2H, t),3.95 - 4.13 (IH, m),4.56 (2H, t),4.75 - 4.98 (IH, m),6.89 (IH, d),7.09 - 7.22 (2H, m),7.33 (2H, d),7.61 (2H, d),7.66 (IH, s),8.14 - 8.20 (IH, m),8.41 (IH, s),8.77 (IH, d). M/z (M+H)+ 499. Example 92
2-amino-N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]pyridine-4- carboxamide
Figure imgf000089_0003
Method Ib from Intermediate A
1H NMR (300.073 MHz, DMSO) δ 1.55 - 1.91 (4H, m),2.24 (3H, s),2.84 - 3.00 (2H, m),3.04 - 3.24 (IH, m),3.67 - 4.00 (IH, m),4.50 - 4.70 (IH, m),6.20 (2H,s), 6.90(lH,s), 6.95 (IH, d), 7.20 - 7.38 (2H, m), 7.42 (lH,s), 7.51 (2H, d),7.77 (2H, d), 8.04 (IH, d), 9.95 (IH, s). M/z (M+H)+ 440. Example 93
3-chloro-N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]pyridine-4- carboxamide
Figure imgf000090_0001
Method Ib from Intermediate A 1H NMR (300.073 MHz, DMSO) δ 1.52 - 1.92 (4H, m),2.32 (3H, s),2.78 - 3.02 (2H, m),3.07 - 3.20 (IH, m),3.62 - 4.02 (IH, m),4.46 - 4.81 (IH, m),7.22 - 7.39 (2H, m),7.51 (2H, d),7.57 (IH, s),7.69 (IH, d),7.76 (2H, d),8.67 (IH, d),8.78 (IH, s),10.24 (IH, s). M/z (M+H)+ 459. Example 94
N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]-6-ethoxy-pyridine-3- carboxamide
Figure imgf000090_0002
Method Ib from Intermediate A
1H NMR (300.072 MHz, CDCl3) δ 1.42 (3H, t),1.56 - 1.99 (4H, m),2.28 (3H, s),2.83 - 2.92 (2H, m),3.05 - 3.25 (IH, m),3.89 - 4.12 (IH, m),4.44 (2H, q),4.77 - 4.96 (IH, m),6.80 (IH, d),7.06 - 7.20 (2H, m),7.33 (2H, d),7.54 (IH, s),7.61 (2H, d),8.14 - 8.22 (IH, m),8.67 (IH, s),8.81 (IH, d). M/z (M+H)+ 469. Example 95
N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]-6-propan-2-yloxy- pyridine-3 -Garboxamide
Figure imgf000090_0003
1HNMR (300.072 MHz, CDCl3) δ 1.38 (6H, d),1.57 - 1.95 (4H, m),2.31 (3H, s),2.84 -
2.91 (2H, m),2.98 - 3.25 (IH, m),3.92 - 4.14 (IH5 m),4.71 - 5.01 (IH, m),5.39 (IH, septet),6.76 (IH, d),7.10 - 7.21 (2H, m),7.32 (2H, d),7.61 (2H, d),7.66 (IH, s),8.11 - 8.17
(IH, m),8.40 (IH, s),8.77 (IH, d). M/z (M+H)+ 483.
Example 96 tert-butyl N-[[5-[[5-[4-(4-cyanophenyl)piperidine- 1 -carbonyl]-2-methyl- phenyl]carbamoyl]pyridin-2-yl]methyl]carbamate
Figure imgf000090_0004
Method Ib from Intermediate A 1H NMR (300.072 MHz, CDCl3) δ 1.47 (9H, s), 1.69 - 1.98 (4H, m),2.32 (3H, s),2.80 - 2.93 (2H, m),3.08 - 3.26 (IH, m),3.97 - 4.11 (IH, m),4.52 (2H, d),4.74 - 4.95 (IH, m),5.42
- 5.61 (IH, m),7.11 - 7.24 (2H, m),7.33 (2H, d),7.41 (IH, d),7.61 (2H, d),7.64 (IH, s),8.23
- 8.28 (IH, m),8.58 (IH, s),9.12 (IH, d). M/z (M+H)+ 554. Example 97
N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]- 4-azabenzimidazol-6- carboxamide
Figure imgf000091_0001
Method Ib from Intermediate A
1H NMR (300.073 MHz, DMSO) δ 1.57 - 1.92 (4H, m),2.31 (3H, s),2.88 - 2.99 (2H, m),3.12 - 3.20 (IH, m),3.24 - 3.39 (IH, m),3.71 - 4.09 (IH, m),4.41 - 4.76 (IH, m),7.24 -
7.39 (2H, m),7.50 (2H, d),7.76 (2H, d),8.59 (2H, s),8.97 (IH, s),10.06 (IH, s),13.22 (IH, s). M/z (M+H)+ 465.
Example 98
N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]pyrimidine-5- carboxamide
Figure imgf000091_0002
Method Ib from Intermediate A
I 1H1 NMR (300.073 MHz, DMSO, 300C) δ 1.51 - 1.98 (4H, m), 2.30 (3H, s), 2.75 - 3.25 (3H, m), 3.61 - 4.07 (IH, m), 4.38 - 4.81 (IH, m), 7.21 - 7.31 (IH, m), 7.32 - 7.41 (IH, m), 7.43 - 7.57 (3H, m), 7.68 - 7.83 (2H, m), 9.28 (2H, s), 9.37 (IH, s), 10.26 (IH, s). M/z 424 (M-H)" 426 (M+H)+. Example 99
6-chloro-N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]cinnoline-3- carboxamide
Figure imgf000091_0003
Method Ib from Intermediate A 1H NMR (300.073 MHz, DMSO, 30°C) δ 1.55 - 1.99 (4H, m), 2.40 (3H, s), 2.78 - 3.22 (3H, m), 3.69 - 4.07 (IH, m), 4.42 - 4.86 (IH, m), 7.21 - 7.31 (IH, m), 7.34 - 7.43 (IH, m), 7.45 - 7.57 (2H, m), 7.70 - 7.82 (2H, m), 7.82 - 7.91 (IH, m), 8.06 - 8.16 (IH, m), 8.46 - 8.54 (IH, m), 8.60 - 8.70 (IH, m), 8.88 - 9.00 (IH, m), 10.92 (IH, s). M/z 510 (M-H)' 512 (M+H)+. Example 100
N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]pyriniidine-4- carboxamide
Figure imgf000092_0001
Method Ib from Intermediate A
1 H NMR (300.073 MHz, DMSO, 30°C) δ 1.53 - 1.96 (4H, m), 2.33 (3H, s), 2.80 - 3.02 (2H, m), 3.04 - 3.21 (IH, m), 3.65 - 4.02 (IH, m), 4.42 - 4.93 (IH, m), 7.19 - 7.29 (IH, m), 7.32 - 7.41 (IH, m), 7.45 - 7.56 (2H, m), 7.69 - 7.82 (3H, m), 8.09 - 8.17 (IH, m), 9.08 - 9.18 (IH, m), 9.43 (IH, s), 10.45 (IH, s). M/z (M+H)+ 426 . Example 101
N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]pyridazine-4- carboxamide
Figure imgf000092_0002
Method Ib from Intermediate A
1 H NMR (300.073 MHz, DMSO, 300C) δ 1.52 - 1.95 (4H, m), 2.29 (3H, s), 2.77 - 3.24 (3H, m), 3.57 - 4.04 (IH, m), 4.34 - 4.81 (IH, m), 7.21 - 7.32 (IH, m), 7.33 - 7.42 (IH, m), 7.44 - 7.57 (3H, m), 7.69 - 7.83 (2H, m), 8.06 - 8.17 (IH, m), 9.43 - 9.55 (IH, m), 9.65 (IH, s), 10.41 (IH, s). M/z (M+H)+ 426. Example 102
N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]l,3-thiazole-4- carboxamide
Figure imgf000092_0003
Method Ib from Intermediate A 1H NMR (300.073 MHz, DMSO, 30°C) δ 1.50 - 2.03 (4H, m), 2.31 (3H, s), 2.75 - 3.24
(3H, m), 3.63 - 4.08 (IH, m), 4.39 - 4.83 (IH, m), 7.15 - 7.26 (IH, m), 7.28 - 7.39 (IH, m),
7.44 . 7.57 (2H, m), 7.70 - 7.85 (3H, m), 8.50 (IH, s), 9.27 (IH, s), 9.88 (IH, s). M/z
(M+H)+ 431.
Example 103
N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]l,3-thiazole-5- carboxamide
Figure imgf000093_0001
Method Ib from Intermediate A
1H NMR (300.073 MHz, DMSO, 3O0C) δ 1.51 - 1.95 (4H, m), 2.27 (3H, s), 2.75 - 3.23 (3H, m), 3.61 - 4.01 (IH, m), 4.39 - 4.80 (IH, m), 7.22 - 7.31 (IH, m), 7.31 - 7.44 (2H, m),
7.45 - 7.57 (2H, m), 7.71 - 7.80 (2H, m), 8.66 (IH, s), 9.30 (IH, s), 10.19 (IH, s). M/z
(M+H)+ 431.
Example 104
N-[5-[4-(4-cyanophenyl)piperidine- 1 -carbonyl]-2-methyl-phenyl]-2-morpholin-4-yl- 1,3- thiazole-4-carboxamide
Figure imgf000093_0002
Method Ib from Intermediate A 1H NMR (300.073 MHz, DMSO, 30° C) δ 1.48 - 1.96 (4H, m), 2.29 (3H, s), 2.75 - 3.22 (3H, m), 3.39 - 3.55 (4H, m), 3.61 - 3.97 (5H, m), 4.33 - 4.90 (IH, m), 7.13 - 7.22 (IH, m), 7.27 - 7.37 (IH, m), 7.45 - 7.54 (2H, m), 7.62 (IH, s), 7.70 - 7.82 (2H, m), 7.87 (IH, s), 9.54 (IH, s). M/z (M+H)+ 516. Example 105
N-[5-[4-(4-cyanophenyl)piperidine- 1 -carbonyl]-2-methyl-phenyl]-2,4-dimethyl- 1,3- thiazole-5-carboxamide
Figure imgf000093_0003
Method Ib from Intermediate A 1H NMR (300.073 MHz, DMSO, 300C) δ 1.50 - 1.96 (4H, m), 2.24 (3H, s), 2.56 (3H, s), 2.64 (3H, s), 2.77 - 3.19 (3H, m), 3.55 - 4.03 (IH, m), 4.32 - 4.83 (IH, m), 7.18 - 7.27 (IH, m), 7.28 - 7.37 (IH, m), 7.39 - 7.56 (3H, m), 7.69 - 7.80 (2H, m), 9.64 (IH, s). M/z (M+H)+ 459. Example 106 N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]pyrazine-2-carboxamide
from Intermediate A
Figure imgf000094_0001
δ 1.53 - 1.95 (4H, m), 2.32 (3H, s), 2.75 - 3.23 (3H, m), 3.65 - 3.98 (IH, m), 4.41 - 4.79 (IH, m), 7.20 - 7.27 (IH, m), 7.32 - 7.39 (IH, m), 7.46 - 7.54 (2H, m), 7.71 - 7.80 (3H, m), 8.79 - 8.84 (IH, m), 8.92 - 8.97 (IH, m), 9.27 - 9.32 (IH, m), 10.32 (IH, s). M/z (M+H)+ 426. Example 107
N- [5 - [4-(4-cyanophenyl)piperidine- 1 -carbony 1] -2-methyl-phenyl] -5-methyl-pyrazine-2- carboxamide
Figure imgf000094_0002
Method Ib from Intermediate A
1H NMR (300.073 MHz, DMSO, 30C) δ 1°- 1.93 (4H, m), 2.31 (3H, s), 2.63 (3H, s), 2.80 - 3.04 (2H, m), 3.08 - 3.24 (IH, m), 3.68 - 3.95 (IH, m), 4.44 - 4.76 (IH, m), 7.19 - 7.26
(IH, m), 7.31 - 7.38 (IH, m), 7.46 - 7.54 (2H, m), 7.72 - 7.80 (3H, m), 8.70 (IH, s), 9.15
(IH, s), 10.24 (IH, s). M/z (M+H)+ 440.
Example 108
2-acetamido-N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]-4-methyl- l,3-thiazole-5-carboxamide
Figure imgf000094_0003
Method Ib from Intermediate A 1H NMR (300.073 MHz, DMSO, 300C) δ 1.50 - 1.92 (4H, m), 2.16 (3H, s), 2.25 (3H, s), 2.54 (3H, s), 2.77 - 3.23 (3H, m), 3.61 - 3.94 (IH, m), 4.32 - 4.79 (IH, m), 7.16 - 7.26 (IH, m), 7.27 - 7.36 (IH, m), 7.40 - 7.46 (IH, m), 7.46 - 7.55 (2H, m), 7.69 - 7.82 (2H, m), 9.52 (IH, s), 12.31 (IH, s). M/z (M+H)+ 502. Example 109
N-[2-chloro-5-[4-(4-cyanophenyl)piperidine-l-carbonyl]phenyl]cycloρropanecarboxamide
Figure imgf000095_0001
Method Ib from Intermediate J 1H NMR (300.073 MHz, DMSO) δ 0.69 - 1.01 (m, 4H), 1.49 - 1.92 (m, 4H), 1.98 - 2.10 (m, IH), 2.67 - 3.06 (m, 3H), 3.56 - 3.81 (m, IH), 4.47 - 4.72 (m, IH), 7.17 - 7.26 (m, IH), 7.45 - 7.59 (m, 3H), 7.70 - 7.85 (m, 3H), 9.81 (s, IH). M/z (MH-H)+ 408. Example 110
3,5-dichloro-N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]pyridine-4- carboxamide
Figure imgf000095_0002
Method Ia from Intermediate A
1H NMR (300.072 MHz, CDCl3) δ 1.60 - 1.98 (4H, m),2.22 (3H, s),2.74 - 2.92 (2H, m),3.04 - 3.26 (IH, m),3.85 - 3.99 (IH, m), 4.38 - 4.58 (IH, m), 7.01 - 7.12 (2H, m),7.32 (2H, d),7.56 (IH, s),7.63 (2H, d),8.60 (2H, s),9.05 (IH, s). M/z (M+H)+ 493. Example 111 N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]-2,4-dimethyl-pyridine- 3-carboxamide
Figure imgf000095_0003
Method Ia from Intermediate A
1H NMR (300.072 MHz, CDCl3) δ 1.59 - 1.99 (4H, m), 2.33 (3H, s),2.44 (3H, s),2.65 (3H, s),2.78 - 2.94 (2H, m),3.08 - 3.27 (IH, m),3.93 - 4.04 (IH, m),4.66 - 4.89 (IH, m),7.05 (IH, d),7.18 - 7.29 (2H, m),7.33 (2H, d),7.61 (2H, d),7.66 (IH, s),7.96 (IH, s),8.42 (IH, d). M/z (MH-H)+ 453. Example 112
N-[5-(4-benzylpiperidine-l-carbonyl)-2-methyl-phenyl]-6-morpholin-4-yl-pyridine-3- carboxamide
Figure imgf000096_0001
A solution of N-[5-(4-benzylpiperidine-l-carbonyl)-2-methyl-phenyl]-6-chloro-pyridine-3- carboxamide (Example 4 ) (40 mg, 0.089 mmol), morpholine (39 nig, 0.447 mmol, 5 eq) and triethylamine (45 mg, 0.447 mmol, 5 eq) in ethanol (1 niL) was heated in the microwave oven at 150°C for Ih. The reaction mixture was concentrated in vacuo and the residue dissolved in a mixture of ACN and water. The crude product was purified by HPLC (Standard method B); the eluent containing pure product was collected and evaporated in vacuo to remove ACN. The residual water was extracted with DCM, the organic extracts washed with saturated NaHCO3 solution, dried (Phase Separator) and concentrated to give the title compound (20 mg), 1H NMR (CDCl3) δ 8.76 (d, J= 2.2 Hz, IH), 8.21 (s, IH), 8.07 (dd, J= 9.0 and 2.2 Hz, IH), 7.62 (s, IH), 7.27 - 7.22 (m, 2H), 7.20 - 7.08 (m, 4H), 7.07 - 7.02 (m, IH), 6.64 (d, J= 9.0 Hz, IH), 4.72 - 4.55 (m, IH), 3.88 - 3.75 (m, 5H), 3.66 - 3.59 (m, 4H), 3.03 - 2.85 (m, IH), 2.76 - 2.59 (m, IH), 2.54 (d, J= 6.9 Hz, 2H), 2.25 (s, 3H), 1.83 - 1.52 (m, 3H), 1.33 - 1.08 (m, 2H), m/z 499 (M + IH)+. It will be appreciated that the above transformation may be carried out in various suitable solvents and over a range of temperatures. Examples of suitable solvents for microwave heating are methanol, ethanol, ACN, DMF or DMA; additionally, the reaction may typically be carried out in the range from ambient temperature to 2000C, with conventional or microwave heating. The following Examples 113- 187 were prepared from the intermediate listed in a similar manner to that described in Example 112 above: Example 113
N-[5-(4-benzylpiperidine-l-carbonyl)-2-methyl-phenyl]-6-[(3-dimethylamino-2,2- dimethyl-propyl)amino]pyridine-3-carboxamide
Figure imgf000096_0002
Intermediate Example 4
1H NMR (CDCl3) δ 8.63 (d, J= 2.0 Hz, IH), 7.97 - 7.91 (m, IH), 7.88 (s, IH), 7.78 (s, IH), 7.28 - 7.21 (m, 2H), 7.20 - 7.04 (m, 5H), 6.40 (d, J= 8.6 Hz, IH), 4.63 (s, IH), 3.83 (s, IH), 3.24 (s, 2H), 2.94 (s, IH), 2.67 (s, IH), 2.54 (d, J= 7.1 Hz, 2H), 2.32 (s, 6H), 2.31 (s, 3H), 2.27 (s, 3H), 1.85 - 1.52 (m, 3H), 1.22 (s, 2H), 0.99 (s, 6H). M/z (M+H)+ 542. Example 114
6-[(3-dimethylamino-2,2-dimethyl-propyl)amino]-N-[2-methyl-5-(4-phenylpiperidine-l- carbonyl)phenyl]pyridine-3-carboxamide
Figure imgf000097_0001
Intermediate Example 3 1H NMR (CDCl3) δ 8.61 (d, J= 1.9 Hz, 1H),'7.94 (BB, J= 8.9 and 1.9 Hz, IH), 7.91 - 7.85 (m, IH), 7.84 - 7.77 (m, IH), 7.32 - 7.25 (m, 2H), 7.23 - 7.12 (m, 5H), 6.42 (d, J= 8.9 Hz, IH), 4.85 (s, IH), 4.24 - 3.63 (m, 2H), 3.24 (s, 2H), 3.15 (s, IH), 2.91 - 2.69 (m, 2H), 2.33 (s, 8H), 2.30 (s, 3H), 2.00 - 1.55 (m, 4H), 0.99 (s, 6H). M/z (M+H)+ 528. Example 115
6-(3-dimemylammopropylammo)-N-[2-methyl-5-(4-phenylpiperidine-l- carbonyl)phenyl]pyridine-3-carboxamide
Figure imgf000097_0002
Intermediate Example 3 1H NMR (CDCl3) δ 8.62 (d, J= 2.3 Hz, IH), 7.96 (s, IH), 7.92 (dd, J= 8.8 and 2.3 Hz, IH), 7.67 (s, IH), 7.33 - 7.26 (m, 2H), 7.23 - 7.14 (m, 5H), 6.40 (d, J= 8.8 Hz, IH), 6.12 - 6.05 (m, IH), 4.85 (s, IH), 4.01 (s, IH), 3.46 - 3.38 (m, 2H), 3.15 (s, IH), 2.92 - 2.69 (m, 2H), 2.41 (t, J= 6.4 Hz, 2H), 2.31 (s, 3H), 2.23 (s, 6H), 2.01 - 1.56 (m, 6H). M/z (MH-H)+ 500. Example 116
6-(3-methylbutylamino)-N-[2-methyl-5-(4-phenylpiperidine-l-carbonyl)phenyl]pyridine- 3-carboxamide
Figure imgf000097_0003
Intermediate Example 3 1H NMR (CDCl3) δ 8.62 (s, IH), 7.94 (s, IH), 7.89 (d, J= 8.5 Hz, IH), 7.70 (s, IH), 7.33 7.13 (m, 6H), 6.47 (d, J= 8.5 Hz, 2H), 4.93 - 4.76 (m, IH), 4.12 - 3.90 (m, IH), 3.58 (s, 2H), 3.24 - 3.06 (m, IH), 2.93 - 2.69 (m, 4H), 2.41 (s, 6H), 2.31 (s, 3H), 2.00 - 1.54 (m, 4H). M/z (M+H)+ 486. Example 117
6-(4-dimethylamino-l-piperidyl)-N-[2-methyl-5-(4-phenylpiperidine-l- carbonyl)phenyl]pyridine-3 -carboxamide
Figure imgf000098_0001
Intermediate Example 3 1H NMR (CDCl3) δ 8.72 (d, J= 2.2 Hz, IH), 8.04 - 7.99 (m, 2H), 7.79 (s, IH), 7.32 - 7.25 (m, 2H), 7.22 - 7.16 (m, 4H), 7.15 - 7.10 (m, IH), 6.67 (d, J= 9.1 Hz, IH), 4.84 (s, IH), 4.47 (d, J= 13.2 Hz, 2H), 4.00 (s, 2H), 3.14 (s, IH), 2.97 - 2.69 (m, 4H), 2.58 - 2.48 (m, IH), 2.32 (s, 6H), 2.29 (s, 3H), 2.03 - 1.43 (m, 7H). M/z (M+H)+ 526. Example 118
N-[2-methyl-5-(4-phenylpiperidine-l-carbonyl)phenyl]-6-piperazin-l-yl-pyridine-3- carboxamide
Figure imgf000098_0002
Intermediate Example 3 1H NMR (CDCl3) δ 8.77 (s, IH), 8.42 - 8.31 (m, IH), 8.08 (d, J= 9.0 Hz, IH), 7.71 - 7.65 (m, IH), 7.32 - 7.25 (m, 2H), 7.22 - 7.14 (m, 4H), 7.13 - 7.08 (m, IH), 6.64 (d, J= 9.0 Hz, IH), 4.83 (s, IH), 4.50 - 3.90 (m, 4H), 3.75 - 3.64 (m, 4H), 3.14 (s, IH), 3.04 - 2.92 (m, 4H), 2.89 - 2.68 (m, 2H), 2.28 (s, 3H), 2.01 - 1.53 (m, 2H). M/z (M+H)+ 484. Example 119 6-(4-amino- 1 -piperidyl)-N-[2-metbyl-5-(4-phenylpiperidine- 1 -carbonyl)phenyl]pyridine-3- carboxamide
Figure imgf000098_0003
Intermediate Example 4 1H NMR (CDCl3) δ 8.84 (s, IH), 8.71 (s, IH), 7.98 (d, J= 8.8 Hz, IH), 7.58 (s, IH), 7.27 - 7.22 (m, 2H), 7.19 - 7.11 (m, 4H), 7.10 - 7.04 (m, IH), 6.59 (d, J= 8.8 Hz, IH), 6.10 (s, 2H), 4.75 (s, IH), 4.34 (d, J= 10.3 Hz, 2H), 3.94 (s, IH), 3.19 - 3.00 (m, 2H), 2.96 - 2.63 (m, 4H), 2.22 (s, 3H), 2.03 - 1.41 (m, 8H). M/z (M+H)+ 498. Example 120
N-[5-[4-(4-methoxyphenyl)piperidine-l-carbonyi]-2-methyl-phenyl]-6-morpholin-4-yl- pyridine-3-carboxamide
Figure imgf000099_0001
Intermediate Example 3 1H NMR (CDCl3) δ 8.79 - 8.75 (m, IH), 8.20 (s, IH), 8.08 (dd, J= 9.0 and 2.1 Hz, IH), 7.68 (s, IH), 7.19 - 7.08 (m, 4H), 6.83 (d, J= 8.3 Hz, 2H), 6.64 (d, J= 9.0 Hz, IH), 4.83 (s, IH), 3.97 (s, IH), 3.83 - 3.77 (m, 4H), 3.76 (s, 3H), 3.66 - 3.59 (m, 4H), 3.12 (s, IH), 2.93 - 2.62 (m, 2H), 2.28 (s, 3H), 2.00 - 1.48 (m, 4H). M/z (M+H)+ 415. Example 121
6-dimethylamino-N-[5-[4-(4-methoxyphenyl)piperidine-l-carbonyl]-2-metliyl- phenyl]pyridine-3 -carboxamide
Figure imgf000099_0002
Intermediate Example 11 1H NMR (CDCl3) δ 8.75 - 8.71 (m, IH), 8.04 - 7.98 (m, 2H), 7.81 (s, IH), 7.21 - 7.07 (m,
4H), 6.83 (d, J= 8.4 Hz, 2H), 6.53 (d, J= 9.0 Hz, IH), 4.83 (s, IH), 3.98 (s, IH), 3.76 (s,
3H), 3.15 (s, 7H), 2.92 - 2.63 (m, 2H), 2.29 (s, 3H), 2.05 - 1.47 (m, 4H). M/z (M+H)+ 473.
Example 122
N-[2-methyl-5-[4-(4-metliylphenyl)piperidine-l-carbonyl]plienyl]-6-moφholin-4-yl- pyridine-3-carboxamide
Figure imgf000099_0003
From intermediate AA
1H NMR (DMSO) δ 8.72 (d, J= 2.3 Hz, IH), 8.05 (dd, J= 9.0 and 2.4 Hz, IH), 7.40 - 7.38 (m, IH), 7.28 (d, J= 7.7 Hz, IH), 7.17 (dd, J= 7.7 and 1.4 Hz, IH), 7.10 (d, J= 8.0 Hz, 2H), 7.05 (d, J= 8.0 Hz, 2H), 6.86 (d, J= 9.0 Hz, IH), 4.68 - 4.45 (m, IH), 3.84 - 3.69 (m, IH), 3.69 - 3.63 (m, 4H), 3.58 - 3.52 (m, 4H), 3.19 - 3.02 (m, IH), 2.88 - 2.65 (m, 2H), 2.22 (s, 3H), 2.21 (s, 3H), 1.84 - 1.46 (m, 4H). M/z (M+H)+ 499. Example 123
6-dimethylamino-N-[5-[3-(4-methoxyphenyl)pyrrolidine-l-carbonyl]-2-methyl- phenyl]pyridine-3-carboxamide
Figure imgf000100_0001
From intermediate BB
1H NMR (CDCl3) δ 8.62 (s, IH), 7.99 - 7.84 (m, 2H), 7.70 (s, IH), 7.34 - 7.12 (m, 6H), 6.47 (d, J= 8.6 Hz, 2H), 4.96 - 4.72 (m, IH), 4.12 - 3.46 (m, 4H), 3.25 - 3.04 (m, IH), 2.95 - 2.68 (m, 4H), 2.41 (s, 6H), 2.31 (s, 3H), 2.00 - 1.54 (m, 4H). M/z (M+H)+ 459. I0 Example 124
6-dimethylamino-N-[5-[4-(4-methoxyphenyl)piperidine-l-carbonyl]-2- (trifluoromethyl)phenyl]pyridine-3-carboxamide
Figure imgf000100_0002
From intermediate CC
1H NMR (CDCl3) δ 8.67 (s, IH), 8.51 (s, IH), 8.11 (s, IH), 7.92 (d, J= 8.9 Hz, IH), 7.67 is (d, J= 8.0 Hz, IH), 7.29 (d, J= 8.0 Hz, IH), 7.13 (d, J= 8.2 Hz, 2H), 6.84 (d, J= 8.2 Hz,
2H), 6.54 (d, J= 8.9 Hz, IH), 4.85 (d, J= 12.0 Hz, IH), 3.89 (d, J= 12.0 Hz, IH), 3.77 (s,
3H), 3.26 - 3.13 (m, IH), 3.16 (s, 6H), 2.92 - 2.65 (m, 2H), 2.02 - 1.52 (m, 4H). M/z
(M+H)+ 527.
Example 125 20 N-[5-[4-(4-methoxypb.enyl)piperidine-l-carbonyl]-2-(trifluoromethyl)phenyl]-6- morpholin-4-yl-pyridine-3-carboxamide
Figure imgf000100_0003
From intermediate CC 1H NMR (CDCl3) δ 8.67 (d, J= 2.2 Hz, IH), 8.47 (s, IH), 8.13 (s, IH), 7.96 (BB, J= 9.0 and 2.2 Hz, IH), 7.68 (d, J= 8.0 Hz, IH), 7.30 (d, J= 8.0 Hz, IH), 7.12 (d, J= 8.3 Hz, 2H), 6.84 (d, J= 8.3 Hz, 2H), 6.65 (d, J= 9.0 Hz, IH), 4.84 (d, J= 12.2 Hz, IH), 3.88 (d, J = 12.6 Hz, IH), 3.82 - 3.78 (m, 4H), 3.77 (s, 3H), 3.67 - 3.62 (m, 4H), 3.19 (t, J= 12.6 Hz, IH), 2.85 (t, J= 12.2 Hz, IH), 2.78 - 2.67 (m, IH), 1.95 - 1.55 (m, 4H). M/z (M+H)+ 569. Example 126
N-[2-methyl-5-[4-[4-(trifluoromethyl)phenyl]piperidine-l-carbonyl]phenyl]-6-morpholin- 4-yl-pyridine-3-carboxamide
Figure imgf000101_0001
From intermediate DD 1H NMR (CDCl3) δ 8.75 (s, IH), 8.12 - 8.03 (m, 2H), 7.78 (s, IH), 7.55 (d, J= 8.0 Hz, 2H), 7.31 (d, J= 8.0 Hz, 2H), 7.19 (d, J= 7.8 Hz, IH), 7.13 (d, J= 7.8 Hz, IH), 6.65 (d, J = 9.0 Hz, IH), 4.86 (s, IH), 4.02 (s, IH), 3.83 - 3.76 (m, 4H), 3.66 - 3.59 (m, 4H), 3.15 (s, IH), 2.89 - 2.75 (m, 2H), 2.29 (s, 3H), 2.00 - 1.56 (m, 4H). M/z (M+H)+ 553. Example 127
N- [5 - [4-(4-chlorophenyl)piperidine- 1 -carbony 1] -2-methy 1-phenyl] -6-morpholin-4-y 1- pyridine-3-carboxamide
Figure imgf000101_0002
From intermediate EE
1H NMR (CD3OD) δ 8.73 (d, J= 2.2 Hz, IH), 8.08 (dd, J= 9.1 and 2.4 Hz, IH), 7.46 - 7.43 (m, IH), 7.37 (d, J= 7.9 Hz, IH), 7.29 - 7.21 (m, 5H), 6.85 (d, J= 9.1 Hz, IH), 4.79 - 4.68 (m, IH), 4.04 - 3.90 (m, IH), 3.80 - 3.73 (m, 4H), 3.66 - 3.59 (m, 4H), 3.25 - 3.16 (m, IH), 2.99 - 2.79 (m, 2H), 2.32 (s, 3H), 2.01 - 1.56 (m, 4H). M/z (M+H)+ 519. Example 128
N-[2-methyl-5-[4-(4-methylsulfonylphenyl)piperidine-l-carbonyl]phenyl]-6-moφholin-4- yl-pyridine-3 -carboxamide
Figure imgf000102_0001
From intermediate FF
1H NMR (DMSO) δ 8.72 - 8.68 (m, IH), 8.03 (dd, J= 9.0 and 2.4 Hz, IH), 7.79 (d, J= 8.2 Hz, 2H), 7.50 (d, J= 8.2 Hz, 2H), 7.41 - 7.39 (m, IH), 7.28 (d, J= 7.8 Hz, IH), 7.19 - 7.15 (m, IH), 6.82 (d, J= 9.0 Hz, IH), 4.73 - 4.50 (m, IH), 3.90 - 3.73 (m, IH), 3.68 - 3.61 (m, 4H), 3.57 - 3.51 (m, 4H), 3.13 - 3.05 (m, 4H), 2.97 - 2.77 (m, 2H), 2.22 (s, 3H), 1.90 - 1.54 (m, 4H). M/z (M+H)+ 563. Example 129
N-[5-[4-(4-methoxyphenyl)piperidine-l-carbonyl]-2-methyl-phenyl]-6-(l- piperidyl)pyridine-3-carboxamide
Figure imgf000102_0002
Intermediate Example 11
1H NMR (DMSO) δ 9.60 (s, IH), 8.68 (d, J= 2.3 Hz, IH), 7.99 (dd, J= 9.1 and 2.3 Hz, IH), 7.40 - 7.36 (m, IH), 7.28 (d, J= 7.8 Hz, IH), 7.19 - 7.12 (m, 3H), 6.87 - 6.79 (m, 3H), 4.66 - 4.45 (m, IH), 3.83 - 3.68 (m, IH), 3.67 (s, 3H), 3.64 - 3.57 (m, 4H), 3.20 - 3.02 (m, IH), 2.89 - 2.64 (m, 2H), 2.22 (s, 3H), 1.82 - 1.45 (m, 10H). M/z (M+H)+ 513 Example 130
6-(2-methoxyethylamino)-N-[5-[4-(4-methoxyplienyl)piperidine-l-carbonyl]-2-methyl- phenyl]pyridine-3 -carboxamide
Figure imgf000102_0003
Intermediate Example 11 1H NMR (DMSO) δ 9.54 (s, IH), 8.61 (d, J= 2.2 Hz, IH), 7.85 (dd, J= 8.8 and 2.3 Hz, IH), 7.40 - 7.36 (m, IH), 7.28 (d, J= 7.8 Hz, IH), 7.23 - 7.11 (m, 4H), 6.84 - 6.79 (m, 2H), 6.52 (d, J= 8.8 Hz, IH), 4.67 - 4.44 (m, IH), 3.85 - 3.67 (m, IH), 3.67 (s, 3H), 3.50 - 3.41 (m, 4H), 3.24 (s, 3H), 3.19 - 3.00 (m, IH), 2.91 - 2.65 (m, 2H), 2.22 (s, 3H), 1.85 - 1.43 (m, 4H). M/z (M+H)+ 503. Example 131
N-[5-[4-(4-methoxyphenyl)piperidine-l-carbonyl]-2-methyl-phenyl]-6-[2-(2- oxoimidazolidin- 1 -yl)ethylamino]pyridine-3-carboxamide
Figure imgf000103_0001
Intermediate Example 11 1H NMR (DMSO) δ 9.56 (s, IH), 8.62 (d, J= 2.2 Hz, IH), 7.87 (dd, J= 8.8 and 2.2 Hz, IH), 7.40 - 7.36 (m, IH), 7.28 (d, J= 7.8 Hz, IH), 7.22 - 7.11 (m, 4H), 6.84 - 6.79 (m, 2H), 6.49 (d, J= 8.8 Hz, IH), 6.24 (s, IH), 4.67 - 4.44 (m, IH), 3.85 - 3.67 (m, IH), 3.67 (s, 3H), 3.44 - 3.32 (m, 4H), 3.22 - 3.14 (m, 5H), 2.88 - 2.65 (m, 2H), 2.22 (s, 3H), 1.86 - 1.60 (m, 2H), 1.60 - 1.44 (m, 2H). M/z (M+H)+ 557. Example 132
N-[5-[4-(4-methoxyphenyl)piperidine-l-carbonyl]-2-metliyl-phenyl]-6-(3-oxopiperazin-l- yl)pyridine-3 -carboxamide
Figure imgf000103_0002
Intermediate Example 11
1H NMR (DMSO) δ 9.69 (s, IH), 8.73 (d, J= 2.2 Hz, IH), 8.15 - 8.09 (m, IH), 8.07 (dd, J = 9.0 and 2.2 Hz, IH), 7.40 - 7.37 (m, IH), 7.29 (d, J= 7.8 Hz, IH), 7.20 - 7.11 (m, 3H),
6.86 (d, J= 9.0 Hz, IH), 6.84 - 6.79 (m, 2H), 4.66 - 4.47 (m, IH), 4.08 (s, 2H), 3.86 - 3.68
(m, 3H), 3.67 (s, 3H), 3.28 - 3.24 (m, 2H), 3.21 - 3.01 (m, IH), 2.92 - 2.66 (m, 2H), 2.22
(s, 3H), 1.87 - 1.43 (m, 4H). M/z (M+H)+ 528.
Example 133 6-[(l -ethyl-3-piperidyl)amino]-N-[5-[4-(4-methoxyphenyl)piperidine- l-carbonyl]-2- methyl-phenyl]pyridine-3-carboxarnide
Figure imgf000103_0003
Intermediate Example 11 1H NMR (DMSO) δ 9.53 (s, IH), 8.60 (d, J= 2.1 Hz, IH), 7.84 (dd, J= 8.8 and 1.9 Hz, IH), 7.39 - 7.36 (m, IH), 7.28 (d, J= 7.8 Hz, IH), 7.18 - 7.12 (m, 3H), 7.02 - 6.95 (m, IH), 6.84 - 6.79 (m, 2H), 6.50 (d, J= 8.8 Hz, IH), 4.66 - 4.46 (m, IH), 4.01 - 3.87 (m, IH), 3.83 - 3.68 (m, IH), 3.67 (s, 3H), 3.20 - 2.96 (m, IH), 2.92 - 2.56 (m, 4H), 2.34 - 2.25 (m, 2H),
2.21 (s, 3H), 2.01 - 1.40 (m, 9H), 1.29 - 1.16 (m, IH), 0.95 (t, J= 7.0 Hz, 3H). M/z
(M+H)+ 556.
Example 134
6-(3-methoxyazetidin- 1 -yl)-N-[5-[4-(4-methoxyphenyl)piperidine- 1 -carbonyl]-2-methyl- phenyl]pyridine-3 -carboxamide
Figure imgf000104_0001
Intermediate Example 11 1H NMR (DMSO) δ 9.65 (s, IH), 8.67 (d, J= 2.2 Hz, IH), 8.01 (dd, J= 8.8 and 2.2 Hz, IH), 7.37 (s, IH), 7.29 (d, J= 7.8 Hz, IH), 7.19 - 7.12 (m, 3H), 6.84 - 6.79 (m, 2H), 6.41 (d, J= 8.8 Hz, IH), 4.67 - 4.45 (m, IH), 4.36 - 4.28 (m, IH), 4.24 - 4.15 (m, 2H), 3.84 - 3.77 (m, 2H), 3.80 - 3.68 (m, IH), 3.67 (s, 3H), 3.23 (s, 3H), 3.19 - 3.00 (m, IH), 2.91 - 2.65 (m, 2H), 2.22 (s, 3H), 1.86 - 1.43 (m, 4H). M/z (M+H)+ 515. Example 135
N-[5-[4-(4-methoxyphenyl)piperidine-l-carbonyl]-2-methyl-phenyl]-6-pyrrolidin-l-yl- pyridine-3-carboxamide
Figure imgf000104_0002
Intermediate Example 11 1H NMR (DMSO) δ 9.58 (s, IH), 8.69 (d, J= 2.2 Hz, IH), 7.99 (dd, J= 9.0 and 2.4 Hz, IH), 7.41 - 7.36 (m, IH), 7.28 (d, J= 7.8 Hz, IH), 7.18 - 7.12 (m, 3H), 6.84 - 6.79 (m, 2H), 6.47 (d, J= 9.0 Hz, IH), 4.68 - 4.44 (m, IH), 3.83 - 3.68 (m, IH), 3.67 (s, 3H), 3.48 - 3.35 (m, 4H), 3.20 - 3.00 (m, IH), 2.89 - 2.64 (m, 2H), 2.22 (s, 3H), 1.98 - 1.87 (m, 4H), 1.83 - 1.44 (m, 4H). M/z (M+H)+ 499. Example 136
6-(2-hydroxyethyl-methyl-amino)-N-[5-[4-(4-methoxyphenyl)piperidine-l-carbonyl]-2- methyl-phenyl]pyridine-3-carboxamide
Figure imgf000104_0003
Intermediate Example 11 1H NMR (DMSO) δ 9.59 (s, IH), 8.67 (d, J= 2.3 Hz, IH), 7.98 (dd, J= 9.0 and 2.3 Hz, IH), 7.40 - 7.37 (m, IH), 7.28 (d, J= 7.8 Hz, IH), 7.19 - 7.11 (m, 3H), 6.84 - 6.79 (m, 2H),
6.66 (d, J= 9.0 Hz, IH), 4.68 (t, J= 5.2 Hz, IH), 4.65 - 4.46 (m, IH), 3.85 - 3.66 (m, IH),
3.67 (s, 3H), 3.64 - 3.51 (m, 4H), 3.20 - 3.02 (m, IH), 3.08 (s, 3H), 2.89 - 2.65 (m, 2H), 2.22 (s, 3H), 1.83 - 1.61 (m, 2H), 1.59 - 1.45 (m, 2H). M/z (M+H)+ 503.
Example 137
N-[5-[4-(4-methoxyphenyl)piperidine-l-carbonyl]-2-methyl-phenyl]-6-[(l-methyl-4- piperidyl)amino]pyridine-3-carboxamide
Figure imgf000105_0001
Intermediate Example 11 1H NMR (DMSO) δ 9.51 (s, IH), 8.59 (d, J= 2.3 Hz, IH), 7.84 (dd, J= 8.8 and 2.3 Hz, IH), 7.40 - 7.37 (m, IH), 7.28 (d, J= 7.9 Hz, IH), 7.18 - 7.11 (m, 3H), 7.05 (d, J= 7.6 Hz, IH), 6.84 - 6.79 (m, 2H), 6.47 (d, J= 8.8 Hz, IH), 4.65 - 4.45 (m, IH), 3.79 - 3.67 (m, IH), 3.67 (s, 3H), 3.18 - 2.99 (m, IH), 2.89 - 2.64 (m, 4H), 2.21 (s, 3H), 2.13 (s, 3H), 2.02 - 1.90 (m, 2H), 1.88 - 1.35 (m, 9H). M/z (M+H)+ 541.9. Example 138
6-(3-imidazol-l-ylpropylamino)-N-[5-[4-(4-methoxyphenyl)piperidine-l-carbonyl]-2- methyl-phenyl]pyridme-3-carboxamide
Figure imgf000105_0002
Intermediate Example 11
1H NMR (DMSO) δ 9.56 (s, IH), 8.61 (d, J= 2.2 Hz, IH), 7.88 (dd, J= 8.8 and 2.2 Hz, IH), 7.62 (s, IH), 7.39 - 7.36 (m, IH), 7.28 (d, J= 7.8 Hz, IH), 7.24 (t, J= 5.6 Hz, IH),
7.18 - 7.12 (m, 4H), 6.86 (s, IH), 6.84 - 6.79 (m, 2H), 6.48 (d, J= 8.8 Hz, IH), 4.65 - 4.47
(m, IH), 4.01 (t, J= 6.8 Hz, 2H), 3.82 - 3.67 (m, IH), 3.67 (s, 3H), 3.23 (q, J= 6.3 Hz,
2H), 3.20 - 3.00 (m, IH), 2.89 - 2.65 (m, 2H), 2.21 (s, 3H), 1.94 (quintet, J= 6.8 Hz, 2H),
1.84 - 1.44 (m, 4H). M/z (M+H)+ 552.9. Example 139
6-(azetidin-l-yl)-N-[5~[4-(4-methoxyphenyl)piperidine-l-carbonyl]-2-methyl- phenyl]pyridine-3-carboxamide
Figure imgf000106_0001
Intermediate Example 11 1H NMR (DMSO) δ 9.63 (s, IH), 8.65 (d, J= 2.1 Hz, IH), 7.99 (dd, J= 8.8 and 2.4 Hz, IH), 7.39 - 7.35 (m, IH), 7.28 (d, J= 7.9 Hz, IH), 7.19 - 7.12 (m, 3H), 6.84 - 6.79 (m, 2H), 6.35 (d, J= 8.8 Hz, IH), 4.67 - 4.43 (m, IH), 4.00 (t, J= 7.4 Hz, 4H), 3.84 - 3.64 (m, IH), 3.67 (s, 3H), 3.21 - 2.97 (m, IH), 2.92 - 2.66 (m, 2H), 2.36 - 2.26 (m, 2H), 2.21 (s, 3H), 1.83 - 1.44 (m, 4H). M/z (M+H)+ 485. Example 140
N-[5-[4-(4-methoxyphenyl)piperidine- 1 -carbonyl]-2-methyl-phenyl]-6-( 1 ,4-oxazepan-4- yl)pyridine-3-carboxamide
Figure imgf000106_0002
Intermediate Example 11
1H NMR (DMSO) δ 9.61 (s, IH), 8.68 (d, J= 2.3 Hz, IH), 8.00 (dd, J= 9.1 and 2.4 Hz, IH), 7.41 - 7.37 (m, IH), 7.29 (d, J= 7.9 Hz, IH), 7.19 - 7.12 (m, 3H), 6.84 - 6.78 (m, 2H), 6.75 (d, J= 9.1 Hz, IH), 4.67 - 4.45 (m, IH), 3.83 - 3.64 (m, 10H), 3.57 (t, J= 5.5 Hz, 2H), 3.20 - 2.99 (m, IH), 2.88 - 2.65 (m, 2H), 2.22 (s, 3H), 1.85 (quintet, J= 5.8 Hz, 2H), 1.82 - 1.61 (m, 2H), 1.59 - 1.45 (m, 2H). M/z (M+H)+ 529. Example 141
N-[5-[4-(4-methoxyphenyl)piperidine-l-carbonyl]-2-methyl-phenyl]-6-[3-(2- oxopyrrolidin- 1 -yl)propy lamino]pyridine-3 -carboxamide
Figure imgf000106_0003
Intermediate Example 11 1H NMR (DMSO) δ 9.55 (s, IH), 8.61 (d, J= 2.2 Hz, IH), 7.86 (dd, J= 8.8 and 2.2 Hz, IH), 7.40 - 7.36 (m, IH), 7.28 (d, J= 7.9 Hz, IH), 7.18 - 7.11 (m, 4H), 6.84 - 6.79 (m, 2H), 6.48 (d, J= 8.8 Hz, IH), 4.67 - 4.45 (m, IH), 3.83 - 3.66 (m, IH), 3.67 (s, 3H), 3.34 - 3.17 (m, 6H), 3.17 - 3.01 (m, IH), 2.88 - 2.65 (m, 2H), 2.22 (s, 3H), 2.17 (t, J= 8.1 Hz, 2H), 1.88 (quintet, J= 7.5 Hz, 2H), 1.81 - 1.62 (m, 4H), 1.59 - 1.44 (m, 2H). M/z (M+H)+ 570. Example 142
N- [5 - [4-(4-methoxyphenyl)piperidine- 1 -carbonyl] -2-methyl-phenyl] -6-(propan-2- ylamino)pyridine-3-carboxamide
Figure imgf000107_0001
Intermediate Example 11 1H NMR (DMSO) δ 9.52 (s, IH), 8.60 (d, J= 2.3 Hz, IH), 7.84 (dd, J- 8.8 and 2.3 Hz, IH), 7.39 - 7.36 (m, IH), 7.32 (d, J= 7.8 Hz, IH), 7.28 (d, J= 7.8 Hz, IH), 7.18 - 7.11 (m, 3H), 6.84 - 6.79 (m, 2H), 6.44 (d, J = 8.8 Hz, IH), 4.65 - 4.47 (m, IH), 4.10 - 4.00 (m, IH), 3.82 - 3.68 (m, IH), 3.67 (s, 3H), 3.20 - 3.00 (m, IH), 2.89 - 2.64 (m, 2H), 2.22 (s, 3H), 1.86 - 1.43 (m, 4H), 1.13 (d, J= 6.5 Hz, 6H). M/z (M+H)+ 487. Example 143
6-(2-hydroxyethylamino)-N-[5-[4-(4-methoxyphenyl)piperidine-l-carbonyl]-2-methyl- phenyl]pyridine-3-carboxamide
Figure imgf000107_0002
Intermediate Example 11 1K NMR (DMSO) δ 9.54 (s, IH), 8.60 (d, J= 2.2 Hz, IH), 7.86 (dd, J= 8.8 and 2.2 Hz, IH), 7.39 - 7.36 (m, IH), 7.28 (d, J= 7.9 Hz, IH), 7.18 - 7.11 (m, 4H), 6.84 - 6.79 (m, 2H), 6.51 (d, J= 8.8 Hz, IH), 4.70 (t, J= 5.4 Hz, IH), 4.65 - 4.46 (m, IH), 3.84 - 3.67 (m, IH), 3.67 (s, 3H), 3.50 (q, J= 5.8 Hz, 2H), 3.35 (q, J= 5.8 Hz, 2H), 3.20 - 2.98 (m, IH), 2.90 - 2.64 (m, 2H), 2.22 (s, 3H), 1.86 - 1.42 (m, 4H). M/z (M+H)+ 489. Example 144
N-[5-[4-(4-methoxyphenyl)piperidine- 1 -carbonyl]-2-methyl-phenyl]-6-[3-(l - piperidyl)propylamino]pyridine-3-carboxamide
Figure imgf000107_0003
Intermediate Example 11 1H NMR (DMSO) δ 9.53 (s, IH), 8.61 - 8.59 (m, IH), 7.86 (dd, J= 8.9 and 2.1 Hz, IH), 7.40 - 7.36 (m, IH), 7.28 (d, J= 7.8 Hz, IH), 7.20 - 7.11 (m, 4H), 6.84 - 6.79 (m, 2H), 6.46 (d, J= 8.9 Hz, IH), 4.75 - 4.36 (m, IH), 3.88 - 3.67 (m, IH), 3.67 (s, 3H), 3.19 - 2.98 (m, IH), 2.89 - 2.64 (m, 2H), 2.37 - 2.23 (m, 6H), 2.22 (s, 3H), 1.85 - 1.59 (m, 4H)5 1.58 - 1.40 (m, 7H), 1.38 - 1.28 (m, 3H). M/z (M+H)+ 570. Example 145
N-[5-[4-(4-methoxyphenyl)piperidine-l-carbonyl]-2-methyl-phenyl]-6-(3-(morpholin-4- yl)propylamino)pyridine-3 -carboxamide
Figure imgf000108_0001
Intermediate Example 11 1H NMR (DMSO) δ 9.54 (s, IH), 8.60 (d, J= 2.2 Hz, IH), 7.85 (dd, J= 8.9 and 2.1 Hz, IH), 7.39 - 7.36 (m, IH), 7.28 (d, J= 7.8 Hz, IH), 7.19 - 7.12 (m, 4H), 6.84 - 6.79 (m, 2H), 6.47 (d, J= 8.9 Hz, IH), 4.68 - 4.44 (m, IH), 3.84 - 3.65 (m, IH), 3.67 (s, 3H), 3.57 - 3.50 (m, 4H), 3.33 - 3.25 (m, 3H), 3.20 - 2.99 (m, IH), 2.88 - 2.65 (m, 2H), 2.35 - 2.27 (m, 5H), 2.21 (s, 3H), 1.84 - 1.43 (m, 6H). M/z (M+H)+ 572. Example 146
6-[4-(2-methoxyethyl)piperazin-l-yl]-N-[5-[4-(4-methoxyphenyl)piperidine-l-carbonyl]- 2-methyl-phenyl]pyridine-3-carboxamide
Figure imgf000108_0002
Intermediate Example 11
1H NMR (DMSO) δ 9.65 (s, IH), 8.69 (d, J= 2.3 Hz, IH), 8.02 (dd, J= 9.0 and 2.3 Hz, IH), 7.40 - 7.36 (m, IH), 7.29 (d, J= 7.8 Hz, IH), 7.19 - 7.12 (m, 3H), 6.86 (d, J= 9.0 Hz, IH), 6.84 - 6.79 (m, 2H), 4.64 - 4.48 (m, IH), 3.83 - 3.68 (m, IH), 3.67 (s, 3H), 3.60 - 3.55 (m, 4H), 3.43 (t, J= 5.7 Hz, 2H), 3.30 - 3.27 (m, 4H), 3.21 (s, 3H), 3.18 - 3.03 (m, IH), 2.89 - 2.65 (m, 2H), 2.51 - 2.46 (m, 2H), 2.22 (s, 3H), 1.84 - 1.60 (m, 2H), 1.60 - 1.44 (m, 2H). M/z (M+H)+ 572. Example 147
6-[(3-dimethylamino-2,2-dimethyl-propyl)amino]-N-[5-[4-(4-methoxyphenyl)piperidine- l-carbonyl]-2-methyl-phenyl]pyridine-3-carboxamide
Figure imgf000108_0003
Intermediate Example 11 1H NMR (DMSO) δ 9.52 (s, IH), 8.58 (d, J= 2.2 Hz5 IH), 7.84 (dd, J= 8.8 and 2.2 Hz, IH), 7.39 - 7.37 (m, IH), 7.28 (d, J= 7.8 Hz, IH), 7.17 - 7.12 (m, 3H), 7.04 - 6.97 (m, IH), 6.84 - 6.79 (m, 2H), 6.58 (d, J= 8.8 Hz, IH), 4.66 - 4.45 (m, IH), 3.83 - 3.68 (m, IH), 3.67 (s, 3H), 3.22 (d, J= 5.6 Hz, 2H), 3.18 - 3.02 (m, IH), 2.87 - 2.66 (m, 2H), 2.22 (s, 3H), 2.20 (s, 6H), 2.12 (s, 2H), 1.84 - 1.43 (m, 4H), 0.85 (s, 6H). M/z (M+H)+558. Example 148
N-[5-[4-[(4-methoxyphenyl)methyl]piperidine-l-carbonyl]-2-methyl-phenyl]-6-morpliolin- 4-yl-pyridine-3-carboxamide
Figure imgf000109_0001
From intermediate GG 1H NMR (CDCl3) δ 8.79 (d, J= 2.1 Hz, IH), 8.44 (s, IH), 8.09 (dd, J= 8.9 and 2.1 Hz, IH), 7.49 (s, IH), 7.12 - 7.07 (m, IH), 7.04 - 6.99 (m, 3H), 6.79 (d, J= 8.3 Hz, 2H), 6.63 (d, J= 8.9 Hz, IH), 4.72 - 4.54 (m, IH), 3.84 - 3.76 (m, 5H), 3.75 (s, 3H), 3.65 - 3.58 (m, 4H), 2.99 - 2.84 (m, IH), 2.73 - 2.58 (m, IH), 2.47 (d, J= 6.1 Hz, 2H), 2.23 (s, 3H), 1.76 - 1.52 (m, 3H), 1.27 - 1.06 (m, 2H). M/z (M+H)+ 529. Example 149
6-dimethylamino-N-[5-[4-[(4-methoxyphenyl)methyl]piperidine-l-carbonyl]-2-methyl- phenyl]pyridine-3-carboxatnide
Figure imgf000109_0002
From intermediate GG
1U NMR (CDCl3) δ 8.75 - 8.71 (m, IH), 8.10 - 7.98 (m, 2H), 7.75 - 7.67 (m, IH), 7.17 - 7.12 (m, IH), 7.08 - 6.99 (m, 3H), 6.79 (d, J= 8.3 Hz, 2H), 6.52 (d, J= 9.0 Hz, IH), 4.71 -
4.56 (m, IH), 3.90 - 3.75 (m, IH), 3.75 (s, 3H), 3.15 (s, 6H), 3.00 - 2.86 (m, IH), 2.73 -
2.59 (m, IH), 2.47 (d, J= 6.7 Hz, 2H), 2.26 (s, 3H), 1.77 - 1.53 (m, 3H), 1.29 - 1.09 (m,
2H). M/z (M+H)+487.
Example 150 6-[(3-dimethylamino-2,2-dimethyl-propyl)amino]-N-[5-[4-[(4- methoxyphenyl)methyl]piperidine-l-carbonyl]-2-methyl-phenyl]pyridine-3-carboxamide
Figure imgf000109_0003
From intermediate GG 1H NMR (CDCl3) δ 8.66 - 8.61 (m, IH), 8.01 (s, IH), 7.95 (dd, J= 8.8 and 1.6 Hz, IH), 7.69 (s, IH), 7.14 (d, J= 7.8 Hz, IH), 7.08 - 6.98 (m, 3H), 6.79 (d, J= 8.3 Hz, 2H), 6.40 (d, J= 8.8 Hz, IH), 4.70 - 4.56 (m, IH), 3.89 - 3.77 (m, IH), 3.75 (s, 3H), 3.23 (s, 2H), 3.01 - 2.85 (m, IH), 2.75 - 2.58 (m, IH), 2.47 (d, J= 6.8 Hz, 2H), 2.32 (s, 6H), 2.31 (s, 2H), 2.26 (s, 3H), 1.78 - 1.52 (m, 3H), 1.30 - 1.08 (m, 2H), 0.99 (s, 6H). 572. Example 151
6-dimethylamino-N-[2-methyl-5-[4-(4-methylsulfonylphenyl)piperidine-l- carbonyl]phenyl]pyridine-3-carboxamide
Figure imgf000110_0001
From intermediate FF 1H NMR (CDCl3) δ 8.70 (d, J= 2.3 Hz, IH), 8.02 - 7.95 (m, 2H), 7.86 (d, J= 8.3 Hz, 2H),
7.79 (s, IH), 7.40 (d, J= 8.3 Hz, 2H), 7.24 (s, IH), 7.18 - 7.13 (m, IH), 6.54 (d, J= 9.0
Hz, IH), 4.87 (s, IH), 4.06 (s, IH), 3.19 (s, IH), 3.16 (s, 6H), 3.02 (s, 3H), 2.92 - 2.78 (m,
2H), 2.31 (s, 3H), 2.02 - 1.57 (m, 4H). M/z (M+H)+ 521.
Example 152 N-[5-[4-(4-chlorophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]-6-dimethylamino- pyridine-3 -carboxamide
Figure imgf000110_0002
From intermediate EE 1H NMR (DMSO) δ 9.60 (s, IH), 8.69 (d, J= 2.2 Hz, IH), 8.00 (dd, J= 9.0 and 2.4 Hz, IH), 7.41 - 7.38 (m, IH), 7.33 - 7.25 (m, 5H), 7.19 - 7.15 (m, IH), 6.67 (d, J= 9.0 Hz, IH), 4.67 - 4.47 (m, IH), 3.89 - 3.63 (m, IH), 3.19 - 3.08 (m, IH), 3.07 (s, 6H), 2.92 - 2.66 (m, 2H), 2.22 (s, 3H), 1.87 - 1.47 (m, 4H). 477. M/z (M+H)+477. Example 153
6-(4-amino-l-piperidyl)-N-[5-[4-(4-methoxyphenyl)piperidine-l-carbonyl]-2-methyl- phenyl]pyridine-3-carboxamide
Figure imgf000111_0001
Intermediate Example 11 1H NMR (DMSO) δ 9.62 (s, IH), 8.68 (d, J= 2.2 Hz, IH), 8.00 (dd, J= 9.1 and 2.4 Hz, IH), 7.39 - 7.37 (m, IH), 7.29 (d, J= 7.8 Hz, IH), 7.19 - 7.12 (m, 3H), 6.87 (d, J= 9.1 Hz, IH), 6.84 - 6.79 (m, 2H), 4.68 - 4.43 (m, IH), 4.34 - 4.25 (m, 2H), 3.67 (s, 3H), 3.31 - 2.65 (m, 7H), 2.22 (s, 3H), 1.81 - 1.44 (m, 6H), 1.26 - 1.11 (m, 2H). M/z (M+H)+ 528. Example 154
6-(4-hydroxy-l-piperidyl)-N-[5-[4-(4-methoxyphenyl)piperidine-l-carbonyl]-2-methyl- phenyl]pyridine-3 -carboxamide
Figure imgf000111_0002
Intermediate Example 11 1H NMR (DMSO) δ 9.62 (s, IH), 8.68 (d, J= 2.3 Hz, IH), 7.99 (dd, J= 9.1 and 2.3 Hz, IH), 7.39 - 7.37 (m, IH), 7.28 (d, J= 7.9 Hz, IH), 7.19 - 7.12 (m, 3H), 6.87 (d, J= 9.1 Hz, IH), 6.83 - 6.79 (m, 2H), 4.70 (d, J= 4.3 Hz, IH), 4.66 - 4.45 (m, IH), 4.12 - 4.01 (m, 2H), 3.79 - 3.66 (m, 2H), 3.67 (s, 3H), 3.24 - 3.01 (m, 3H), 2.90 - 2.65 (m, 2H), 2.22 (s, 3H), 1.85 - 1.44 (m, 6H), 1.37 - 1.25 (m, 2H). M/z (M+H)+ 528. Example 155
6-dimethylamino-N-[2-methyl-5-[4-[4-(trifluoromethyl)phenyl]piperidine-l- carbonyl]phenyl]pyridine-3-carboxamide
Figure imgf000111_0003
From Intermediate DD 1H NMR (CDCl3) δ 8.73 - 8.70 (m, IH), 8.00 (dd, J= 9.0 and 2.2 Hz, IH), 7.93 (s, IH), 7.85 (s, IH), 7.55 (d, J= 8.0 Hz, 2H), 7.31 (d, J= 8.0 Hz, 2H), 7.24 - 7.19 (m, IH), 7.18 - 7.13 (m, IH), 6.55 (d, J= 9.0 Hz, IH), 4.98 - 4.76 (m, IH), 4.16 - 3.93 (m, IH), 3.16 (s, 6H), 3.19 - 3.06 (m, IH), 2.95 - 2.76 (m, 2H), 2.31 (s, 3H), 2.02 - 1.57 (m, 4H). M/z (M+H)+ 511. Example 156
N-[5-[4-(3,4-dichlorophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]-6-dimethylamino- pyridine-3-carboxamide
Figure imgf000112_0001
From Intermediate II 1H NMR (CDCl3) δ 8.73 - 8.69 (m, IH), 8.02 - 7.96 (m, 2H), 7.81 (s, IH), 7.33 (d, J= 8.3
Hz, IH), 7.26 (s, IH), 7.20 - 7.07 (m, 2H), 7.04 - 6.98 (m, IH), 6.52 (d, J- 9.0 Hz, IH),
4.82 (s, IH), 3.99 (s, IH), 3.20 - 3.01 (m, 7H), 2.89 - 2.62 (m, 2H), 2.27 (s, 3H), 1.99 -
1.48 (m, 4H). M/z (M+H)+ 511.
Example 157 N-[5-[4-(3,4-dichlorophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]-6-morpholin-4-yl- pyridine-3-carboxamide
Figure imgf000112_0002
From Intermediate II
1H NMR (CDCl3) δ 8.75 (d, J= 2.3 Hz, IH), 8.16 (s, IH), 8.05 (dd, J= 9.0 and 2.3 Hz,
IH), 7.69 (s, IH), 7.33 (d, J= 8.3 Hz, IH), 7.26 (d, J= 1.9 Hz, IH), 7.15 (d, J= 7.8 Hz, IH), 7.11 - 7.06 (m, IH), 7.01 (BB, J= 8.3 and 1.9 Hz, IH), 6.63 (d, J= 9.0 Hz, IH), 4.82
(s, IH), 3.98 (s, IH), 3.81 - 3.74 (m, 4H), 3.64 - 3.58 (m, 4H), 3.09 (s, IH), 2.86 - 2.64 (m,
2H), 2.26 (s, 3H), 1.98 - 1.48 (m, 4H). M/z (M+H)+ 553.
Example 158
N-[5-[4-(3,4-dichlorophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]-6-[(3- dimethylamino-2,2-dimethyl-propyl)aniino]pyridine-3-carboxamide
Figure imgf000112_0003
From Intermediate II
1H NMR (CDCl3) δ 8.63 (d, J = 2.0 Hz, IH), 7.94 - 7.88 (m, 2H), 7.81 (s, IH), 7.33 (d, J= 8.3 Hz, IH), 7.26 (d, J= 1.7 Hz, IH), 7.20 - 7.08 (m, 3H), 7.01 (BB5 J= 8.3 and 1.7 Hz, IH), 6.37 (d, J= 8.8 Hz, IH), 4.81 (s, IH), 3.99 (s, IH), 3.22 (d, J= 4.3 Hz, 2H), 3.10 (s, IH), 2.88 - 2.64 (m, 2H), 2.32 - 2.24 (m, 1 IH), 1.98 - 1.47 (m, 4H), 0.96 (s, 6H). M/z (M+H)+ 596. Example 159
N-[5-[4-(4-methoxyphenyl)piperidine-l-carbonyl]-2,4-dimeth.yl-phenyl]-6-morpholin-4- yl-pyridine-3 -carboxamide
Figure imgf000113_0001
From Intermediate JJ
1H NMR (DMSO), rotameric mixture, δ 9.64 (s, IH), 8.75 (d, J= 1.9 Hz, IH), 8.09 (dd, J = 9.0 and 2.2 Hz, IH), 7.26 - 7.10 (m, 4H), 6.91 (d, J= 9.0 Hz, IH), 6.85 (d, J= 8.1 Hz, 2H), 4.66 (BB, br, IH), 3.71-3.67 (m, 7H), 3.57 (t, br, 4H), 3.44 (t, br, IH), 3.10 (t, br, IH), 2.81 (t, br, IH), 2.73 (t, br, IH), 2.25-2.16 (m, 6H), 1.83-1.45 (m, 4H). (M+H)+ 529. Example 160
6-[(3-dimethylamino-2,2-dimethyl-propyl)amino]-N-[2-methyl-5-[4-[4- (trifluoromethy^phenyljpiperidine-l-carbonylJphenyypyridine-S-carboxamide
Figure imgf000113_0002
From Intermediate DD 1H NMR (DMSO) δ 9.56 (s, IH), 8.64 - 8.61 (m, IH), 7.88 (d, J= 8.8 Hz, IH), 7.66 (d, J= 7.9 Hz, 2H), 7.53 (d, J= 7.9 Hz, 2H), 7.44 (s, IH), 7.32 (d, J= 7.8 Hz, IH), 7.21 (d, J= 7.8 Hz, IH), 7.06 - 7.01 (m, IH), 6.62 (d, J= 8.8 Hz, IH), 4.74 - 4.50 (m, IH), 3.91 - 3.72 (m, IH), 3.26 (d, J= 5.3 Hz, 2H), 3.24 - 3.10 (m, IH), 3.02 - 2.77 (m, 2H), 2.26 (s, 3H), 2.23 (s, 6H), 1.92 - 1.57 (m, 4H), 1.88 (s, 2H), 0.89 (s, 6H). (M+H)+ 596. Example 161
N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]-6-dimethylamino- pyridine-3-carboxamide
Figure imgf000113_0003
Intermediate Example 35 1H NMR (DMSO) δ 9.60 (s, IH), 8.69 (d, J= 2.3 Hz, IH), 8.00 (dd, J= 9.0 and 2.3 Hz, IH), 7.73 (d, J= 8.2 Hz, 2H), 7.47 (d, J= 8.2 Hz, 2H), 7.40 (s, IH), 7.29 (d, J= 7.8 Hz, IH), 7.21 - 7.14 (m, IH), 6.67 (d, J= 9.0 Hz, IH), 4.58 (s, IH), 3.77 (s, IH), 3.19 - 3.02 (m, 7H), 2.95 - 2.73 (m, 2H), 2.22 (s, 3H), 1.87 - 1.52 (m, 4H). (M+H)+ 468. Example 162
6-dimethylamino-N-[2-methyl-5-[4-(4-nitrophenyl)piperidine-l-carbonyl]phenyl]pyridme- 3-carboxamide
Figure imgf000114_0001
From Intermediate KK
1H NMR (CDCl3) δ 8.73 (d, J= 2.2 Hz, IH), 8.15 (d, J= 8.6 Hz, 2H), 8.03 - 7.94 (m, 2H), 7.86 (s, IH), 7.36 (d, J= 8.6 Hz, 2H), 7.19 (d, J= 7.8 Hz, IH), 7.15 - 7.10 (m, IH), 6.53
(d, J= 9.0 Hz, IH), 4.87 (s, IH), 4.05 (s, IH), 3.25 - 2.74 (m, 9H), 2.29 (s, 3H), 2.01 - 1.57
(m, 4H). (M+H)+ 488.
Example 163
N-[5-[4-(2,4-dichlorophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]-6-dimethylamino- pyridine-3-carboxamide
Figure imgf000114_0002
From Intermediate LL 1H NMR (CDCl3) δ 8.68 (d, J= 2.3 Hz, IH), 8.07 (s, IH), 7.98 (dd, J= 9.0 and 2.3 Hz, IH), 7.58 (s, IH), 7.35 (d, J= 1.9 Hz, IH), 7.26 - 7.15 (m, 4H), 6.55 (d, J= 9.0 Hz, IH), 4.87 (s, IH), 4.04 (s, IH), 3.29 - 3.01 (m, 8H), 2.86 (s, IH), 2.33 (s, 3H), 1.98 - 1.45 (m, 4H). (M+H)+ 511. Example 164 methyl 4- [ 1 - [3 - [(6-dimethylaminopyridine-3 -carbony l)amino] -4-methyl-benzoyl] -A- piperidyl]benzoate
Figure imgf000114_0003
From Intermediate MM 1H NMR (CDCl3) δ 8.76 - 8.73 (m, IH), 8.22 - 8.10 (m, IH), 8.01 (dd, J= 9.0 and 2.4 Hz, IH), 7.95 (d, J= 8.2 Hz, 2H), 7.77 - 7.70 (m, IH), 7.25 (d, J= 8.2 Hz, 2H), 7.16 (d, J= 7.8 Hz, IH), 7.09 (d, J= 7.8 Hz, IH), 6.52 (d, J= 9.0 Hz, IH), 4.94 - 4.76 (m, IH), 4.10 - 3.93 (m, IH), 3.87 (s, 3H), 3.22 - 3.02 (m, IH), 3.13 (s, 6H), 2.94 - 2.72 (m, 2H), 2.27 (s, 3H), 2.17 - 1.54 (m, 4H). (M+H)+ 501. Example 165
N-[5-[4-(4-chlorophenyl)piperidine-l-carbonyl]-2-meth.yl-phenyl]-6-methylamino- pyridine-3-carboxamide
Figure imgf000115_0001
From Intermediate EE 1H NMR (DMSO) δ 9.55 (s, IH), 8.63 (d, J= 2.2 Hz, IH), 7.88 (dd, J= 8.8 and 2.2 Hz,
IH), 7.41 - 7.36 (m, IH), 7.33 - 7.25 (m, 5H), 7.19 - 7.05 (m, 2H), 6.45 (d, J= 8.8 Hz, IH),
4.57 (s, IH), 3.75 (s, IH), 3.18 - 3.00 (m, IH), 2.84 - 2.74 (m, 5H), 2.22 (s, 3H), 1.87 -
1.47 (m, 4H). (M+H)+ 463.
Example 166 N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]-6-(propan-2- ylamino)pyridine-3-carboxamide
Figure imgf000115_0002
Intermediate Example 35
1H NMR (DMSO) δ 9.55 (s, IH), 8.64 (d, J= 2.4 Hz, IH), 7.87 (dd, J= 8.8 and 2.4 Hz,
IH), 7.76 (d, J= 8.0 Hz, 2H), 7.51 (d, J= 8.4 Hz, 2H), 7.40 - 7.45 (m, IH), 7.31 (d, J= 8.0 Hz, IH), 7.20 (BB, J= 7.6 and 1.6 Hz, IH), 7.02 (d, J= 7.6 Hz, IH), 6.47 (d, J= 8.8 Hz,
IH), 4.70 - 4.50 (m, IH), 4.03 - 4.13 (m, IH), 3.90 - 3.68 (m, IH), 3.25 - 3.05 (m, IH),
2.98 - 2.79 (m, 2H), 2.24 (s, 3H), 1.90 - 1.55 (m, 4H), 1.16 (d, J= 6.4 Hz, 6H). ). (M+H)+
482.
Example 167 N-[5-[4-(4-cyanophenyl)piperidine- 1 -carbonyl]-2-methyl-ρhenyl]-6-(methyl-propan-2-yl- amino)pyridine-3 -carboxamide
Figure imgf000116_0001
Intermediate Example 35 XR NMR (DMSO) δ 9.59 (s, IH), 8.68 (d, J= 2.4 Hz, IH), 7.99 (dd, J= 9.1 and 2.4 Hz, IH), 7.73 (d, J= 8.3 Hz, 2H), 7.47 (d, J= 8.3 Hz, 2H), 7.42 - 7.38 (m, IH), 7.29 (d, J= 7.8 Hz, IH), 7.17 (BB, J= 7.8 and 1.4 Hz, IH), 6.65 (d, J= 9.1 Hz, IH), 4.97 - 4.84 (m, IH), 5 4.70 - 4.45 (m, IH), 3.89 - 3.65 (m, IH), 3.22 - 3.01 (m, IH), 2.98 - 2.76 (m, 2H), 2.84 (s, 3H), 2.22 (s, 3H), 2.13 - 1.52 (m, 4H), 1.11 (d, J= 6.7 Hz, 6H). (M+H)+ 496. Example 168
N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]-6-(4-hydroxy-l- piperidyl)pyridine-3-carboxamide 0 HOΛ_-J f^ Intermediate Example 35
1H NMR (300.072 MHz, CDCl3) δ 1.53 - 1.82 (5H, m), 1.82 - 2.03 (4H, m), 2.33 (3H, s), 2.79 - 2.88 (2H, m), 3.01 - 3.24 (IH, m), 3.30 - 3.38 (2H, m), 3.95 - 4.03 (IH, m), 4.11 - 4.18 (3H, m), 4.75 - 4.96 (IH, m), 6.70 (IH, d), 7.14 - 7.17 (IH, m), 7.22 - 7.25 (IH, m), 7.33 (2H, d), 7.60 (2H, d), 7.87 (IH, s), 7.92 (IH, d), 7.99 - 8.03 (IH, m), 8.72 (IH, d).s (MH-H)+ 524. Example 169
N-[5-[4-(4-cyanophenyl)piperidine- 1 -carbonyl]-2-methyl-phenyl]-6-(3-oxopiperazin- 1 - yl)pyridine-3 -carboxamide
Figure imgf000116_0002
Intermediate Example 35 o 1H NMR (300.072 MHz, CDCl3) δ 1.63 - 1.82 (2H, m), 1.82 - 2.03 (2H, m), 2.33 (3H, s),
2.79 - 2.88 (2H, m), 3.01 - 3.24 (IH, m), 3.50 - 3.58 (2H, m), 3.98 - 4.03 (2H, t), 4.24 (3H, s), 4.75 - 4.96 (IH, m), 6.21 (IH, s), 6.72 (IH, d), 7.17 - 7.19 (IH, m), 7.22 - 7.25 (IH, m),
7.33 (2H, d), 7.61 (2H, d), 7.87 (IH, s), 7.92 (IH, d), 8.07 - 8.10 (IH, m), 8.74 (IH, d).
(M+H)+ 523. 5 Example 170
N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-prienyl]-6-(2- hydroxyethylamino)pyridine-3-carboxamide
Figure imgf000117_0001
Intermediate Example 35 1H NMR (400.132 MHz, DMSO) δ 1.55 - 1.92 (4H, m), 2.26 (3H, s), 2.74 - 2.98 (2H, m), 3.09 - 3.25 (IH, m), 3.36 - 3.45 (2H, m), 3.54 (2H, q), 3.70 - 3.89 (IH, m), 4.56 - 4.69 (IH, m), 4.76 (IH, t), 6.56 (IH, d), 7.19 - 7.24 (2H, m), 7.33 (IH, d), 7.43 (IH, d), 7.52 (2H, d), 7.78 (2H, d), 7.88 - 7.91 (IH, m), 8.64 (IH, d), 9.60 (IH, s). (M+H)+ 484. Example 171
N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]-6-[3-(2-oxopyrrolidin-l- yl)propylamino]pyridine-3-carboxamide
Figure imgf000117_0002
Intermediate Example 35 1H NMR (300.072 MHz, CDCl3) δ 1.72 - 1.97 (6H, m),1.98 - 2.10 (2H, m),2.34 (3H, s),2.43 (2H, t),2.79 - 2.88 (2H, m),3.02 - 3.26 (IH, m),3.36 - 3.47 (6H, m),3.98 - 4.19 (IH, m),4.74.4.95 (m, m),5.90 (IH, t),6.48 (IH, d),7.15 - 7.25 (2H, m),7.33 (2H, d),7.61 (2H, d),7.75 (IH, s),7.88 - 7.93 (IH, m),7.98 (IH, s),8.65 (IH, d). (M+H)+ 565. Example 172 N-[5-[4-(4-cyanophenyl)piperidine- 1 -carbonyl]-2-methyl-phenyl]-6-(2- methoxyethylamino)pyridine-3-carboxamide
Figure imgf000117_0003
Intermediate Example 35 1H NMR (400.132 MHz, DMSO) δ 1.55 - 1.92 (4H, m),2.26 (3H, s),2.74 - 2.98 (2H, m),3.09 - 3.38 (5H, m), 3.50 (3H, s), 3.70 - 3.89 (IH, m),4.56 - 4.69 (IH, m),6.56 (IH, d),7.17 - 7.24 (2H, m),7.33 (IH, d),7.43 (IH, d),7.52 (2H, d),7.78 (2H, d),7.88 - 7.91 (IH, m),8.64 (IH, d),9.58 (IH, s). (M+H)+ 498. Example 173
N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]-6-(l,4-oxazepan-4- yl)pyridine-3-carboxamide
Figure imgf000117_0004
Intermediate Example 35 1H NMR (300.072 MHz, CDCl3) δ 1.63 - 1.96 (4H, m),2.02 - 2.11 (2H, m),2.34 (3H, s),2.77 - 2.94 (2H, m),3.02 - 3.24 (IH, m),3.68 - 3.78 (2H, m),3.81 - 3.93 (6H, m),4.00 - 4.20 (IH, m),4.72 - 4.97 (IH, m),6.59 (IH, d),7.16 - 7.26 (2H, m),7.33 (2H, d),7.61 (2H, d),7.70 (IH, s),7.99 - 8.02 (2H, m),8.70 (IH, d) (85% pure). (MH-H)+ 524. Example 174
N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]-6-methylamino- pyridine-3 -carboxamide
Figure imgf000118_0001
1H NMR (300.072 MHz, cdcl3) δ 1.66 - 1.99 (4H, m),2.34 (3H, s),2.80 - 2.91 (2H, m),3.01 (3H, d),3.06 - 3.23 (IH, m),3.92 - 4.24 (IH, m),4.78 - 4.95 (IH, m),4.94 - 5.04
(IH, m),6.45 (IH, d),7.15 - 7.26 (2H, m),7.33 (2H, d),7.61 (2H, d),7.73 (IH, s),7.94 - 8.03
(2H, m),8.67 (IH, s). (M+H)+ 454.
Example 175
N-[5-[4-(4-cyanophenyl)piperidine- 1 -carbonyl]-2-methyl-phenyl]-6-(3-imidazol- 1 - ylpropylamino)pyridine-3~carboxamide
Figure imgf000118_0002
Intermediate Example 35 1H NMR (300.072 MHz, CDCl3) δ 1.70 - 1.98 (4H, m),2.14 (2H, quintet),2.34 (3H, s),2.77 - 2.92 (2H, m),2.96 - 3.24 (IH, m),3.42 (2H, q),4.08 (2H, t),4.08 - 4.13 (IH, m),4.77 - 4.91 (IH, m),5.00 (IH, t),6.40 (IH, d),6.95 (IH, s),7.08 (IH, s),7.15 - 7.25 (2H, m),7.33 (2H, d),7.51 (IH, s),7.61 (2H, d),7.85 (IH, s),7.92 - 7.98 (2H, m),8.66 (IH, d). (M+H)+ 548. Example 176 N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]-6-(4-methylpiperazin-l- yl)pyridine-3 -carboxamide
Figure imgf000118_0003
1H NMR (300.072 MHz, CDCl3) δ 1.64 - 1.99 (4H, m),2.32 (3H, s),2.35 (3H, s),2.51 (4H, t),2.77 - 2.91 (2H, m),3.05 - 3.25 (IH, m),3.71 (4H, t),3.92 - 4.15 (IH, m),4.75 - 5.06 (IH, m),6.68 (IH, d),7.14 - 7.25 (2H, m),7.33 (2H, d),7.60 (2H, d),7.90 (2H, s),8.03 (IH, d),8.73 (IH, d). (M+H)+ 523. Example 177
N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]-6-(3- hydroxypropylamino)pyridine-3 -carboxamide
Figure imgf000119_0001
Intermediate Example 35
1H NMR (300.073 MHz, DMSO) δ 1.51 - 1.87 (6H, m),2.25 (3H, s),2.89 - 2.97 (2H, m),3.04 - 3.20 (IH, m),3.32 - 3.39 (2H, m),3.43 - 3.55 (2H, m),3.67 - 3.96 (IH, m),4.48 (IH, t),4.54 - 4.66 (IH, m),6.50 (IH, d),7.13 (IH, t),7.17 - 7.22 (IH, m),7.31 (IH, d),7.43 (IH, s),7.50 (2H, d),7.76 (2H, d),7.86 - 7.93 (IH, m),8.63 (IH, d),9.55 (IH, s). (M+H)+ 498.
Example 178
N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]-6-(2-hydroxyethyl- methyl-amino)pyridine-3-carboxamide
Figure imgf000119_0002
Intermediate Example 35
1H NMR (300.072 MHz, CDCl3) δ 1.55 - 1.96 (4H, m),2.30 (3H, s),2.74 - 2.91 (2H, m),2.98 - 3.10 (IH, m),3.14 (3H, s),3.75 - 3.91 (4H, m),3.96 - 4.07 (IH, m),4.23 - 4.36 (IH, m),4.75 - 4.93 (IH, m),6.58 (IH, d),7.10 - 7.21 (2H, m),7.32 (2H, d),7.60 (2H, d),7.69 (IH, s),8.03 - 8.07 (IH, m),8.35 (IH, s),8.69 (IH, s). (M+H)+ 498. Example 179
N-[5 - [4-(4-cyanophenyl)piperidine- 1 -carbonyl] -2-methyl-pheny 1] -6-piperazin- 1 -yl- pyridine-3 -carboxamide
Figure imgf000119_0003
Intermediate Example 35 1H NMR (300.072 MHz, CDCl3) δ 1.60 - 1.99 (4H, m),2.32 (3H, s), 2.77 - 2.91 (2H, m), 2.97 (4H, t),3.05 - 3.25 (IH, m),3.64 (4H, t),3.92 - 4.15 (IH, m),4.75 - 5.06 (IH, m),6.65 (IH, d),7.10 - 7.22 (2H, m),7.33 (2H, d),7.60 (2H, d),7.80 (IH, s),8.01-8.07 (IH, m), 8.10 (IH, s),8.77 (IH, d). (M+H)+ 509. Example 180
N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]-6-pyrrolidin-l-yl- pyridine-3 -carboxamide
Figure imgf000120_0001
Intermediate Example 35 1H NMR (300.073 MHz, DMSO) δ 1.55 - 1.80 (4H, m),1.91 - 2.01 (4H, m),2.26 (3H, s),2.83 - 3.02 (2H, m),3.08 - 3.22 (IH, m),3.39 - 3.55 (4H, m),3.68 - 3.98 (IH, m),4.43 -
4.74 (IH, m),6.50 (IH, d),7.18 - 7.34 (2H, m),7.43 (IH, s),7.50 (2H, d),7.76 (2H, d),7.99 -
8.04 (IH, m),8.72 (IH, d),9.60 (IH, s). (M+H)+ 494.
Example 181 6-(4-amino-l-piperidyl)-N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl- pheny l]pyridine-3 -carboxamide
Figure imgf000120_0002
Intermediate Example 35
1H NMR (300.072 MHz, CDCl3) δ 1.34 - 1.79 (4H, m),1.84 - 2.02 (4H, m),2.35 (3H, s),2.53 - 2.65 (IH, m),2.78 - 2.92 (2H, m),2.93 - 3.27 (5H, m),3.98 - 4.24 (IH, m),4.38 (2H, d),4.75 - 5.00 (IH, m),6.70 (IH, d),7.17 - 7.28 (2H, m),7.33 (2H, d),7.61 (2H, d),7.65 (IH, s),7.94 - 8.01 (IH, m),8.O5 (IH, s),8.69 (IH, d). (M+H)+ 523. Example 182
6-(azetidin- 1 -yl)-N- [5-[4-(4-cyanophenyl)piperidine- 1 -carbonyl] -2-methyl- phenyl]pyridine-3 -carboxamide
Figure imgf000120_0003
Intermediate Example 35
1H NMR (300.073 MHz, DMSO) δ 1.54 - 1.87 (4H, m),2.25 (3H, s),2.36 (2H, quintet),2.84 - 2.99 (2H, m),3.04 - 3.19 (IH, m),3.67 - 3.89 (IH, m),4.03 (4H, t),4.49 - 4.71 (IH, m),6.38 (IH, d),7.19 - 7.33 (2H, m),7.42 (IH, s),7.50 (2H, d),7.76 (2H, d),8.01 - 8.04 (IH, m),8.69 (IH, d),9.65 (IH, s). (M+H)+ 480. Example 183
N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]-2-(4-hydroxy-l- piperidyl)pyridine-4-carboxamide
Figure imgf000121_0001
Intermediate Example 80 1H NMR (300.072 MHz, CDCl3) δ 1.50 - 2.02 (8H, m),2.31 (3H, s),2.78 - 2.92 (2H, m),3.03 - 3.17 (IH, m),3.23 - 3.34 (2H, m),3.91 - 4.01 (IH, m),4.11 - 4.21 (3H, m),4.72 - 5.01 (IH, m),6.97 (IH, d),7.12 - 7.24 (3H, m),7.33 (2H, d),7.61 (2H, d),7.67 (IH, s),8.30 (IH, d),8.46 (IH, s). (M+H)+ 524. Example 184
N-[5- [4-(4-cyanophenyl)piperidine- 1 -carbonyl]-2-methyl-phenyl] -2-(3 -oxopiperazin- 1 - yl)pyridine-4-carboxamide
Figure imgf000121_0002
Intermediate Example 80 1H NMR (300.072 MHz, CDCl3) δ 1.54 - 1.91 (4H, m),2.33 (3H, s),2.79 - 2.92 (2H, m),3.07 - 3.26 (IH, m),3.50 - 3.56 (2H, m),3.97 - 4.04 (3H, m),4.26 (2H, s),4.75 - 4.94 (IH, m),6.54 (IH, s),7.15 - 7.24 (2H, m),7.28 - 7.35 (4H, m),7.56 - 7.68 (3H, m),8.34 (IH, d),9.05 (IH, s). (M+H)+ 523. Example 185
N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]-2-(2- hydroxyethylamino)pyridine-4-carboxamide
Figure imgf000121_0003
Intermediate Example 80 1H NMR (300.072 MHz, CDCl3) δ 1.59 - 1.96 (4H, m),2.32 (3H, s), 2.78 - 2.93 (2H, m), 3.06 - 3.25 (IH, m), 3.53 - 3.62 (2H, m), 3.81 - 3.88 (2H, m),4.04 - 4.13 (IH, m), 4.75 - 4.96 (IH, m), 5.26 - 5.32 (IH, m), 6.90 - 6.97 (2H, m), 7.16 - 7.25 (2H, m),7.33 (2H, d), 7.61 (2H, d),7.86 (IH, s), 8.13 - 8.18 (2H, m). (M+H)+ 484. Example 186
N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]-2-(4-methylpiperazin-l- yl)pyridine-4-carboxamide
Figure imgf000121_0004
Intermediate Example 80 1H NMR (300.072 MHz, CDCl3) δ 1.57 - 2.01 (4H, m),2.30 (3H, s),2.35 (3H, s),2.48 -
2.58 (4H, m),2.78 - 2.93 (2H, m),3.04 - 3.22 (IH, m),3.61 - 3.72 (4H, m),3.90 - 4.08 (IH, m),4.70 - 4.97 (IH, m),7.05 (IH, d),7.09 - 7.21 (2H, m),7.24 (IH, s),7.32 (2H, d),7.57 -
7.64 (3H, m),8.32 (IH, d),8.63 (IH, s). (M+H)+523.
Example 187 tert-butyl 2-[[5-[[5-[4-(4-cyanophenyl)piperidine- 1 -carbonyl]-2-methyl- phenyl] carbamoyl]pyridin-2-yl] amino] acetate Intermediate Example 35
1H NMR (300.073 MHz, DMSO) δ 1.41 (9H, s),1.56 - 1.87 (4H, m),2.26 (3H, s),2.84 - 2.99 (2H, m),3.14 - 3.19 (IH, m),3.73 - 3.90 (IH, m),3.99 (2H, d),4.41 - 4.77 (IH, m),6.63
(IH, d),7.15 - 7.34 (2H, m),7.39 - 7.57 (4H, m),7.76 (2H, d),7.94 (IH, d),8.63 (IH, s),9.62
(IH, s). (M+H)+ 554.
Example 188
2-dimethylamino-N- [2-methyl-5 - [4- [4-(trifluoromethyi)pheny ljpiperidine- 1 - carbonyl]phenyl] acetamide
Figure imgf000122_0002
A solution of 2-chloro-N-[2-niethyl-5-[4-[4-(trifluoromethyl)phenyl]piperidine- 1 - carbonyl]phenyl]acetamide (Intermediate NN) (44 mg, 0.1 mmol) in DMSO (1.5 mL) was treated with dimethylamine (0.054 mL of a 5.6M solution in ethanol, 0.3 mmol, 3 eq), and the reaction mixture was agitated at ambient temperature overnight (reaction shown to be incomplete by LCMS). A further portion of dimethylamine (0.108 mL, 0.6 mmol, 6 eq) was added, and the reaction mixture was further agitated at ambient temperature overnight. The crude product was purified by preparative HPLC (Waters Fraction Lynx Purification System with Kromasil C 8 5μ 20mm x 100mm columns. The mobile phase used was varying gradients of acetonitrile and ammonium acetate buffer; flow rate 30 ml/min; MS triggered fraction collection was used; MS spectra were recorded either on a Micromass ZQ single quadrupole or on a Micromass Qattro micro, both equipped with a pneumatically assisted electro spray interface) to give the title compound (21 mg, 47% yield), 1H NMR (DMSO) δ 9.37 (s, IH), 7.73 (s, IH), 7.62 (d, J= 8.2 Hz, 2H), 7.48 (d, J = 8.2 Hz, 2H), 7.25 (d, J= 7.7 Hz, IH), 7.10 (BB, J= 7.7 and 1.3 Hz, IH), 4.67 - 4.49 (m, IH), 3.82 - 3.65 (m, IH), 3.19 - 3.03 (m, IH), 3.05 (s, 2H), 2.96 - 2.75 (m, 2H), 2.29 (s, 6H), 2.21 (s, 3H), 1.90 - 1.50 (m, 4H), (M+H)+m/z 448.
The following Examples 189-203 were prepared from Intermediate NN in a similar manner to that described in Example 188 above: Example 189
2-(2-methylpyrrolidin-l-yl)-N-[2-methyl-5-[4-[4-(trifluoromethyl)phenyl]piperidine-l-0 carbonyl]phenyl]acetamide
Figure imgf000123_0001
1H NMR (DMSO) δ 9.51 (s, IH), 7.94 - 7.88 (m, IH), 7.63 (d, J= 8.2 Hz, 2H), 7.48 (d, J = 8.2 Hz, 2H), 7.26 (d, J= 7.8 Hz, IH), 7.08 (dd, J= 7.8 and 1.4 Hz, IH), 4.70 - 4.43 (m, IH), 3.83 - 3.60 (m, IH), 3.44 (d, J= 16.5 Hz, IH), 3.18 - 3.08 (m, 2H), 2.98 (d, J= 16.55 Hz, IH), 2.95 - 2.75 (m, 2H), 2.64 - 2.53 (m, IH), 2.38 - 2.28 (m, IH), 2.21 (s, 3H), 1.99 - 1.50 (m, 7H), 1.41 - 1.30 (m, IH), 1.06 (d, J= 6.1 Hz, 3H). (M+H)+ 488. Example 190
N-[2-methyl-5-[4-[4-(trifluoromethyl)phenyl]piperidine-l-carbonyl]phenyl]-2-(3- oxopiperazin- 1 -yl)acetamide
Figure imgf000123_0002
(M+H)+ 503. Example 191
2-(l,3-dihydroisoindol-2-yl)-N-[2-methyl-5-[4-[4-(trifluoromethyl)phenyl]piperidine-l- carbonyljphenyl] acetamide
5
Figure imgf000123_0003
1H NMR (DMSO) δ 9.47 (s, IH), 7.68 - 7.66 (m, IH), 7.62 (d, J= 8.1 Hz5 2H), 7.48 (d, J = 8.1 Hz, 2H), 7.28 - 7.15 (m, 5H), 7.14 - 7.08 (m, IH), 4.70 - 4.48 (m, IH), 4.06 (s, 4H), 3.83 - 3.65 (m, IH), 3.54 (s, 2H), 3.21 - 3.02 (m, IH), 2.97 - 2.72 (m, 2H), 2.18 (s, 3H), 1.92 - 1.50 (m, 4H). (M+H)+ 522. Example 192
2-(azetidin-l-yl)-N-[2-methyl-5-[4-[4-(trifluoromethyl)phenyl]piperidine-l- carbonyljphenyl] acetamide
Figure imgf000124_0001
(M+H)+ 460. Example 193
2-(cyclohexyl-ethyl-amino)-N-[2-methyl-5-[4-[4-(trifluoromethyl)phenyl]piperidine-l- carbonyl]phenyl] acetamide
Figure imgf000124_0002
1H NMR (DMSO) δ 9.63 (s, IH), 8.09 - 8.06 (m, IH), 7.62 (d, J= 8.2 Hz, 2H), 7.48 (d, J= 8.2 Hz, 2H), 7.26 (d, J= 7.8 Hz, IH), 7.06 (dd, J= 7.8 and 1.4 Hz, IH), 4.69 - 4.49 (m,
IH), 3.82 - 3.64 (m, IH), 3.17 - 3.06 (m, IH), 3.14 (s, 2H), 2.98 - 2.73 (m, 2H), 2.60 (q, J
= 7.1 Hz, 2H), 2.55 - 2.49 (m, IH), 2.23 (s, 3H), 1.90 - 1.46 (m, 9H), 1.26 - 0.96 (m, 8H).
(M+H)+ 530.
Example 194 N-[2-methyl-5-[4-[4-(trifluoromethyl)phenyl]piperidine- 1 -carbonyl]phenyl]-2-morpholin-
4-yl-acetamide
Figure imgf000124_0003
1H NMR (DMSO) δ 9.45 (s, IH), 7.85 - 7.82 (m, IH), 7.62 (d, J= 8.1 Hz, 2H), 7.48 (d, J= 8.1 Hz, 2H), 7.26 (d, J= 7.8 Hz, IH), 7.09 (dd, J= 7.8 and 1.4 Hz, IH), 4.68 - 4.49 (m, IH), 3.84 - 3.65 (m, IH), 3.65 - 3.58 (m, 4H), 3.20 - 3.05 (m, IH), 3.11 (s, 2H), 2.95 - 2.72 (m, 2H), 2.56 - 2.50 (m, 4H), 2.24 (s, 3H), 1.90 - 1.51 (m, 4H). (M+H)+ 490. Example 195 l-[[2-methyl-5-[4-[4-(trifluoromethyl)phenyl]piperidine-l- carbonyl]phenyl]carbamoylmethyl]piperidine-4-carboxamide
Figure imgf000125_0001
1H NMR (DMSO) δ 9.45 (s, IH), 7.93 - 7.90 (m, IH), 7.62 (d, J= 8.2 Hz, 2H), 7.48 (d, J=
8.2 Hz, 2H), 7.26 (d, J= 7.8 Hz, IH), 7.20 (s, IH), 7.08 (dd, J= 7.8 and 1.4 Hz, IH), 6.71
(s, IH), 4.66 - 4.50 (m, IH), 3.82 - 3.65 (m, IH), 3.19 - 3.02 (m, IH), 3.07 (s, 2H), 2.95 -
2.73 (m, 4H), 2.24 (s, 3H), 2.20 - 2.10 (m, 2H), 2.10 - 2.00 (m, IH), 1.90 - 1.50 (m, 8H).
(M+H)+ 531.
Example 196
2-(4-hydroxy- 1 -piρeridyl)-N-[2-methyl-5-[4-[4-(trifluoromethyl)phenyl]piperidine- 1 - carbonyl]phenyl]acetamide
Figure imgf000125_0002
1H NMR (DMSO) δ 9.49 (s, IH), 7.95 - 7.93 (m, IH), 7.62 (d, J= 8.2 Hz, 2H), 7.48 (d, J= 8.2 Hz, 2H), 7.26 (d, J= 7.8 Hz, IH), 7.08 (dd, J= 7.8 and 1.4 Hz, IH), 4.64 - 4.52 (m, 2H), 3.84 - 3.63 (m, IH), 3.52 - 3.42 (m, IH), 3.19 - 3.03 (m, IH), 3.06 (s, 2H), 2.95 - 2.70 (m, 4H), 2.31 - 2.22 (m, 2H), 2.24 (s, 3H), 1.90 - 1.51 (m, 6H), 1.51 - 1.39 (m, 2H). (M+H)+ 504. Example 197
2-(methyl-propyl-amino)-N-[2-niethyl-5-[4-[4-(trifluoromethyl)phenyl]piperidine-l- carbonyljphenyl] acetamide
Figure imgf000125_0003
1H NMR (DMSO) δ 9.40 (s, IH), 7.90 - 7.87 (m, IH), 7.62 (d, J= 8.1 Hz, 2H), 7.48 (d, J= 8.1 Hz, 2H), 7.26 (d, J= 7.8 Hz, IH), 7.08 (dd, J= 7.8 and 1.4 Hz, IH), 4.70 - 4.46 (m, IH), 3.85 - 3.62 (m, IH), 3.18 - 3.07 (m, IH), 3.09 (s, 2H), 2.96 - 2.73 (m, 2H), 2.40 (t, J= 7.4 Hz, 2H), 2.28 (s, 3H), 2.21 (s, 3H), 1.90 - 1.52 (m, 4H), 1.46 (sextet, J= 7.4 Hz, 2H), 0.85 (t, J= 7.4 Hz, 3H). (M+H)+ 476. Example 198
2-(2-dimethylaminoethyl-methyl-amino)-N-[2-methyl-5-[4-[4- (trifluoromethyl)phenyl]piperidine-l-carbonyl]phenyl]acetamide
Figure imgf000126_0001
1H NMR (DMSO) δ 9.69 (s, IH), 7.92 - 7.90 (m, IH), 7.62 (d, J= 8.2 Hz, 2H), 7.48 (d, J= 8.2 Hz, 2H), 7.25 (d, J= 7.8 Hz, IH), 7.07 (dd, J= 7.8 and 1.4 Hz, IH), 4.70 - 4.46 (m, IH), 3.85 - 3.63 (m, IH), 3.18 - 3.02 (m, IH), 3.13 (s, 2H), 2.96 - 2.73 (m, 2H), 2.55 (t, J= 6.4 Hz, 2H), 2.35 - 2.30 (m, 5H), 2.23 (s, 3H), 2.07 (s, 6H), 1.88 - 1.50 (m, 4H). (M+H)+ 505.
Example 199
2-(methyl-propan-2-yl-amino)-N-[2-methyl-5-[4-[4-(trifluoromethyl)phenyl]piperidine-l- carbonyljphenyl] acetamide
Figure imgf000126_0002
1H NMR (DMSO) δ 9.58 (s, IH), 7.97 - 7.95 (m, IH), 7.62 (d, J= 8.1 Hz, 2H), 7.48 (d, J= 8.1 Hz, 2H), 7.26 (d, J= 7.8 Hz, IH), 7.07 (dd, J= 7.8 and 1.3 Hz, IH), 4.69 - 4.49 (m, IH), 3.84 - 3.63 (m, IH), 3.18 - 3.03 (m, IH), 3.07 (s, 2H), 2.97 - 2.75 (m, 3H), 2.26 (s, 3H), 2.22 (s, 3H), 1.91 - 1.51 (m, 4H), 0.99 (d, J= 6.6 Hz, 6H). (M+H)+ 476. Example 200
2-(butyl-methyl-amino)-N-[2-methyl-5-[4-[4-(trifluoromethyl)phenyl]piperidine-l- carbonyl]phenyl]acetamide
Figure imgf000126_0003
1H NMR (DMSO) δ 9.39 (s, IH), 7.89 - 7.87 (m, IH), 7.62 (d, J= 8.2 Hz, 2H), 7.48 (d, J= 8.2 Hz, 2H), 7.26 (d, J= 7.9 Hz, IH), 7.10 - 7.07 (m, IH), 4.67 - 4.50 (m, IH), 3.83 - 3.65 (m, IH), 3.20 - 3.02 (m, IH), 3.09 (s, 2H), 2.97 - 2.72 (m, 2H), 2.52 - 2.41 (m, 2H), 2.28 (s, 3H), 2.21 (s, 3H), 1.92 - 1.51 (m, 4H), 1.49 - 1.38 (m, 2H), 1.34 - 1.23 (m, 2H), 0.85 (t, J= 7.3 Hz, 3H). (M+H)+ 490. Example 201
2-(2-hydroxyethyl-methyl-amino)-N-[2-methyl-5-[4-[4- (trifluoromethyl)phenyl]piperidine- 1 -carbonyl]phenyl]acetamide
Figure imgf000127_0001
1H NMR (DMSO) δ 9.60 (s, IH), 7.85 - 7.82 (m, IH), 7.62 (d, J= 8.1 Hz, 2H), 7.51 - 7.45 (m, 2H), 7.25 (d, J= 7.8 Hz, IH), 7.09 (dd, J= 7.8 and 1.5 Hz, IH), 4.70 - 4.43 (m, 2H), 3.87 - 3.63 (m, IH), 3.53 - 3.44 (m, 2H), 3.15 - 3.02 (m, IH), 3.14 (s, 2H), 2.96 - 2.71 (m, 2H), 2.54 (t, J= 5.5 Hz, 2H), 2.33 (s, 3H), 2.23 (s, 3H), 1.89 - 1.48 (m, 4H). (M+H)+ 478. Example 202 2-(2-furylmethyl-methyl-amino)-N-[2-methyl-5-[4-[4-(trifluoromethyl)phenyl]piperidine- 1 -carbonyl]phenyl]acetamide
Figure imgf000127_0002
1H NMR (DMSO) δ 9.43 (s, IH), 7.85 - 7.83 (m, IH), 7.62 (d, J= 8.2 Hz, 2H), 7.57 - 7.55
(m, IH), 7.48 (d, J= 8.2 Hz, 2H), 7.26 (d, J= 7.8 Hz, IH), 7.08 (dd, J= 7.8 and 1.4 Hz, IH), 6.39 - 6.36 (m, IH), 6.35 - 6.32 (m, IH), 4.70 - 4.46 (m, IH), 3.85 - 3.64 (m, IH),
3.69 (s, 2H), 3.21 - 3.02 (m, IH), 3.16 (s, 2H), 2.97 - 2.73 (m, 2H), 2.30 (s, 3H), 2.23 (s,
3H), 1.92 - 1.51 (m, 4H). (M+H)+ 514.
Example 203
2-[4-(hydroxymethyl)-l-piperidyl]-N-[2-methyl-5-[4-[4- (trifluoromethyl)phenyl]piperidine- 1 -carbonyl]phenyl]acetamide
Figure imgf000127_0003
1H NMR (DMSO) δ 9.47 (s, IH), 7.94 - 7.92 (m, IH), 7.62 (d, J= 8.1 Hz, 2H), 7.48 (d, J= 8.1 Hz, 2H), 7.26 (d, J= 7.8 Hz, IH), 7.10 - 7.06 (m, IH), 4.67 - 4.49 (m, IH), 4.45 - 4.36 (m, IH), 3.81 - 3.65 (m, IH), 3.26 - 3.20 (m, 2H), 3.18 - 3.02 (m, IH), 3.06 (s, 2H), 2.97 - 2.72 (m, 4H), 2.23 (s, 3H), 2.18 - 2.09 (m, 2H), 1.91 - 1.50 (m, 6H), 1.40 - 1.12 (m, 3H). (MH-H)+ 518. Example 204
4-(methylaminomethyl)-N-[2-methyl-5-[4-[4-(trifluorometliyl)phenyl]piperidine-l- carbonyl]phenyl]benzamide
Figure imgf000128_0001
5 A solution of 4-(chloromethyl)-N-[2-methyl-5-[4-[4-(trifluoromethyl)phenyl]piperidine-l- carbonyl]phenyl]benzamide ( Intermediate OO )(100 mg, 0.194 mmol) in methylamine (5 niL of a 2M solution in THF, 10 mmol, 51.5 eq) was stirred at ambient temperature overnight. The solvent was evaporated in vacuo and the residue purified by preparative HPLC using a standard programme. Fractions containing the required product wereQ collected, evaporated in vacuo, and the residue further purified as described previously.
Fractions containing pure product were collected and freeze-dried to give the acetate salt of the title compound as a colourless solid (12 mg), 1H NMR (CDCl3) δ 8.31 (s, IH), 7.89 (d, J= 8.0 Hz, 2H), 7.78 (s, IH), 7.54 (d, J= 8.0 Hz, 2H), 7.45 (d, J= 8.0 Hz, 2H), 7.31 (d, J = 8.0 Hz, 2H), 7.22 (d, J= 7.9 Hz, IH), 7.18 - 7.13 (m, IH), 4.91 - 4.75 (m, IH), 4.48 (br5 s, 2H), 4.11 - 3.95 (m, IH), 3.86 (s, 2H), 3.22 - 3.05 (m, IH), 2.94 - 2.76 (m, 2H), 2.45 (s, 3H), 2.30 (s, 3H), 2.02 - 1.57 (m, 4H), 1.96 (s, 3H) m/z 510 (M+H)+. Example 205
4-(dimethylaminomethyl)-N-[2-methyl-5-[4-[4-(trifluoromethyl)phenyl]piperidine-l- carbonyl]phenyl]benzamide
Figure imgf000128_0002
The title compound was prepared by a method analogous to that described above, starting from 4-(chloromethyl)-N-[2-methyl-5-[4-[4-(trifluoromethyl)phenyl]piperidine- 1 - carbonyl]phenyl]benzamide ( Intermediate OO ), and using instead a mixture of DCM (2 mL) and dimethylamine (2 mL of a 5.6M solution in ethanol, 11.2 mmol, 57.7 eq) as the5 reaction medium, to give the title compound (17.8 mg), 1H NMR (CDCl3) δ 8.05 (s, IH), 7.88 - 7.84 (m, 3H), 7.53 (d, J= 8.1 Hz, 2H), 7.43 (d, J= 8.1 Hz, 2H), 7.29 (d, J= 8.1 Hz, 2H), 7.23 - 7.21 (m, IH), 7.17 - 7.13 (m, IH), 4.93 - 4.74 (m, IH), 4.17 - 3.92 (m, IH), 3.51 (s, 2H), 3.25 - 3.02 (m, IH), 2.96 - 2.72 (m, 2H), 2.31 (s, 3H), 2.26 (s, 6H), 1.99 - 1.55 (m, 4H), m/z 524 (M+H)+. Example 206
6-hydroxy-N-[2-methyl-5-[4-[4-(trifluoromethyl)plienyl]piperidine-l- 5 carbonyl]phenyl]pyridine-3 -carboxamide
Figure imgf000129_0001
A suspension of 6-chloro-N-[2-methyl-5-[4-[4-(trifluoromethyl)phenyl]piperidine-l- carbonyl]phenyl]pyridine-3-carboxamide (Intermediate DD) (52 mg, 0.104 mmol) 49 mg, 0.499 mmol, 4.8 eq) in a mixture of glacial acetic acid and water (4ml of 5:1) was treatedo with potassium acetate (49 mg, 0.499 mmol, 4.8 eq), and the reaction mixture was then heated by microwave at 2000C for 10 mins. The crude clear mixture was concentrated and diluted with neutral buffer (5% ACN in 0.1 M aq. NH4OAc) plus the minimum amount of ACN. The product was then purified by preparative HPLC using a standard programme. Fractions containing product were freeze dried to give the title compound (7 mg) as as brownish solid, 1H NMR (DMSO) δ 9.66 (s, IH), 8.12 (d, J= 2.0 Hz, IH), 7.91 (DD, J= 9.7 and 2.5 Hz, IH), 7.62 (d, J= 8.2 Hz, 2H), 7.49 (d, J= 8.2 Hz, 2H), 7.35 (s, IH), 7.29 (d, J= 7.9 Hz, IH), 7.21 - 7.17 (m, IH), 6.36 (d, J= 9.7 Hz, IH), 4.71 - 4.46 (m, IH), 3.85 - 3.66 (m, IH), 3.23 - 3.02 (m, IH), 2.98 - 2.71 (m, 2H), 2.20 (s, 3H), 1.90 - 1.53 (m, 4H), m/z 484 (M+H)+. o Example 207
N- [5 - [4- [4-(aminomethyl)phenyl]piperidine- 1 -carbonyl] -2-methyl-phenyl] -6- dimethylamino-pyridine-3-carboxamide
Figure imgf000129_0002
A suspension of N-[5-[4-(4-cyanophenyl)piperidine- 1 -carbonyl]-2-methyl-phenyl]-6- dimethylamino-pyridine-3-carboxamide (Example 161) (40 mg, 0.086 mmol) in MeOH (5 mL) was treated with cobalt (II) chloride hexahydrate (61 mg, 0.26 mmol, 3 eq). A water bath was used to control the possible warming of the reaction mixture. The reaction mixture was then treated with sodium borohydride (33 mg, 0.87 mmol, 10.2 eq), added in 5 small portions over 5 minutes. A colour change from violet to black was observed. After 35 minutes the reaction was quenched by the addition of dilute hydrochloric acid HCl (5 mL of 2.5M). The solvent was evaporated in vacuo and the resulting aqueous phase was basified by the addition of ammonia solution (20 mL of 13%). The resulting aqueous phase was extracted with DCM (3 x 20ml). The washings were combined, washed with brine, dried (MgSO4), filtered and evaporated. The product was purified by preparative HPLC (neutral system) to give the title compound (lOmg, 85% pure) as the acetate salt, 1H NMR (DMSO) δ 9.61 (s, IH), 8.69 (d, J= 2.4 Hz, IH), 8.00 (dd, J= 9.0 and 2.4 Hz, IH), 7.40 - 7.38 (m, IH), 7.29 (d, J= 7.9 Hz, IH), 7.25 - 7.14 (m, 5H), 6.67 (d, J= 9.0 Hz, IH), 4.70 - 4.45 (m, IH), 4.12 - 3.45 (m, 4H), 3.21 - 2.99 (m, IH), 3.07 (s, 6H), 2.92 - 2.67 (m, 2H), 2.22 (s, 3H), 1.86 - 1.47 (m, 4H), 1.81 (s, 3H), M/z 472.4 (M + IH)+. Example 208 N-[5-[4-(4-chlorophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]-6-methyl-l-oxido- pyridine-3-carboxamide
Figure imgf000130_0001
A solution ofN-[5-[4-(4-chlorophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]-6-methyl- pyridine-3-carboxamide (Example 34) (12 mg, 0.027 mmol) in ACN (5 mL) was treated with urea hydrogen peroxide (13 mg, 0.138 mmol, 5.16 eq) and the solution cooled to 0- 50C (ice bath). TFAA (0.02 mL, 0.1366 mmol, 5.1 eq) was then added dropwise, the reaction mixture stirred for 5 mins, and the cooling bath removed. The reaction was stirred for 4 hrs and then quenched by the addition of dilute ammonium acetate solution (5 mL of 0.1M NH4OAc) in 95/5 water/ACN (neutral buffer HPLC) and the crude directly purified by preparative HPLC in (neutral system) to give the title compound (8mg) as a colourless solid, 1H NMR (DMSO) δ 10.09 (s, IH), 8.73 (s, IH), 7.69 (d, J= 7.9 Hz, IH), 7.58 (d, J = 7.9 Hz, IH), 7.37 (s, IH), 7.32 - 7.22 (m, 5H), 7.21 - 7.17 (m, IH), 4.63 - 4.45 (m, IH), 3.83 - 3.59 (m, IH), 3.19 - 2.99 (m, IH), 2.88 - 2.69 (m, 2H), 2.36 (s, 3H), 2.21 (s, 3H), 1.86 - 1.44 (m, 4H), m/z 464.2 (M + IH)+. Example 209
N-[5-[4-(4-chlorophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]-l-oxido-6- (trifluoromethyl)pyridine-3-carboxamide
Figure imgf000131_0001
The title compound was prepared using a method essentially similar to that given for Example 208, starting fromN-[5-[4-(4-chlorophenyl)piperidine~l-carbonyl]-2-methyl- phenyl]-6-(trifluoromethyl)pyridine-3-carboxamide, [Example 36] 1H NMR (DMSO) δ 10.38 - 10.15 (br s, IH), 8.88 (s, IH), 8.07 (d, J= 8.5 Hz, IH), 7.87 (d, J= 8.5 Hz, IH), 7.43 (s, IH), 7.33 - 7.18 (m, 6H), 4.64 - 4.46 (m, IH), 3.81 - 3.62 (m, IH), 3.22 - 3.02 (m, IH), 2.92 - 2.71 (m, 2H), 2.22 (s, 3H), 1.86 - 1.46 (m, 4H), m/z 518.2 (M + IH)+. Example 210
N- [2-methyl-5 - [4- [4-(trifluoromethyl)phenyl]piperidine- 1 -carbony l]phenyl] - 1 -oxido- pyridine-4-carboxamide
Figure imgf000131_0002
The title compound was prepared using a method essentially similar to that given for Example 208, starting from N-[2-methyl-5-[4-[4-(trifluoromethyl)phenyl] piperidine-1- carbonyl]phenyl]pyridine-4-carboxamide [Example 37 ], 1H NMR (DMSO) δ 10.12 (s, IH), 8.33 (d, J= 6.9 Hz, 2H), 7.91 (d, J= 6.9 Hz, 2H), 7.62 (d, J= 8.1 Hz, 2H), 7.49 (d, J = 8.1 Hz, 2H), 7.39 (s, IH), 7.32 (d, J= 7.8 Hz, IH), 7.25 - 7.21 (m, IH), 4.69 - 4.48 (m, IH), 3.86 - 3.65 (m, IH), 3.25 - 3.02 (m, IH), 2.98 - 2.73 (m, 2H), 2.23 (s, 3H), 1.90 - 1.54 (m, 4H), m/z 484.2 (M + IH)+. Example 211
N-[5-[4-[4-[(4-fluorophenyl)methylcai-bamoyl]phenyl]piperidine-l-carbonyl]-2-methyl- phenyl]pyridine-4-carboxamide
Figure imgf000132_0001
A suspension of 4- [ 1 - [4-methyl-3 -(pyridine-4-carbonylamino)benzoy 1] -4- piperidyljbenzoic acid (267 mg, 0.60 mmol), (4-fluorophenyl)methanamine (Intermediate PP) (75 mg, 0.60 mmol, 1 eq), DMAP (162 mg, 1.32 mmol, 2.2 eq) and EDAC (139 mg, 0.72 mmol, 1.2 eq) in DCM (2 mL) was allowed to stand overnight. The reaction mixture was concentrated and then purified by chromatography (Companion™, 12g silica column, eluting with a gradient of DCM containing 5-15% MeOH) to give the title compound, H NMR (400.132 MHz, CDCl3) δ 1.73 (bs, 2H), 1.85 (bs, IH), 2.01 (bs, IH), 2.90 (bs, 2H), 3.02 (s, 3H), 3.21 (bs, IH), 4.02 (bs, IH), 4.53 (d, 2H), 4.87 (bs, IH), 6.47 (d, IH), 6.98 (dd, 2H), 7.07 (d, IH), 7.15 (dd, 2H), 7.22 (d, 2H), 7.27 (dd, 2H), 7.75 (d, 2H), 7.88 (d, 2H), 8.74 (d, 2H), m/z 551 (M+H)+.
The following examples 212 and 213 were prepared by a method essentially similar to that described in Example 211 above: Example 212 N-[5-[4-[4-(benzyl-methyl-carbamoyl)phenyl]piperidine- 1 -carbonyl]-2-methyl- phenyl]pyridine-4-carboxamide
Figure imgf000132_0002
1H NMR (400.132 MHz, CDCl3) δ 1.75 (bs, 2H), 1.88 (bs, IH), 2.00 (bs, IH), 2.31 (s, 3H), 2.46 (bs, 2H), 2.72 - 2.92 (m, 3H), 3.21 (bs, IH), 4.03 (bs, IH), 4.57 (bs, IH), 4.76 (bs, IH), 4.88 (bs, IH), 7.06 (d, IH), 7.14 (d, IH), 7.17 - 7.32 (m, 8H), 7.35 (d, 2H), 7.40 (d, 2H), 7.91 (d, 2H), 8.76 (d, 2H). (M+H)+ 547. Example 213
N-[2-methyl-5-[4-[4-(morpholme-4-carbonyl)phenyl]piperidine-l- carbonyl]phenyl]pyridine-4-carboxamide
Figure imgf000133_0001
1H NMR (300.073 MHz, DMSO) δ 1.48 - 1.93 (m, 4H), 2.28 (s, 3H), 2.77 - 3.04 (m,
3H), 3.37 - 3.69 (m, 8H), 3.71 - 4.00 (m, IH), 4.39 - 4.83 (m, IH), 7.22 - 7.52 (m, 7H),
7.87 (d, 2H), 8.78 (d, 2H), 10.20 (s, IH). (M+H)+ 513.
Example 214
5-[[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]carbamoyl]pyridine-2- carboxylic acid
Figure imgf000133_0002
A solution of lithium hydroxide monohydrate (87 mg, 2.05 nimol, 1.5 eq) in water (3 niL) was added to a solution of methyl 5-[[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2- methyl-phenyl] carbamoyl]pyridine-2-carboxylate [Example 67] (660 mg, 1.37 mmol) in THF (6 niL) and the mixture stirred at ambient temperature for 1 lir. The THF was removed in vacuo and the aqueous residue washed with EtOAc (30ml) to remove any impurities. The pH of the aqueous fraction was adjusted to approx. pH3 with citric acid solution. EtOAc was added and a colourless solid was filtered off. This was washed with EtOAc and dried in vacuo to give the title compound as a yellow solid (350 mg), *H NMR (300.073 MHz, DMSO) δ 1.54 - 1.90 (4H, m), 2.29 (3H, s),2.85 - 3.00 (2H, m),3.07 - 3.20 (IH, m),3.67 - 4.00 (IH, m),4.52 - 4.77 (IH, m),7.25 - 7.38 (2H, m),7.45 - 7.53 (3H, m),7.76 (2H, d),8.17 (IH, d),8.45 (IH, d),9.21 (IH, s),10.27 (IH, s),13.68 (IH, s), m/z 469 (M+H)+. Example 215 5-[[5-[4-(4-cyanophenyl)piperidine- 1 -carbonyl]-2-methyl-phenyl]carbamoyl]pyridine-3- carboxylic acid
Figure imgf000134_0001
This was prepared in a manner analogouus to that described for Example 214, starting from ethyl 5 - [ [5 - [4-(4-cyanophenyl)piperidine- 1 -carbonyl] -2-methy 1- phenyl]carbamoyl]pyridine-3-carboxylate [Example 68], 1H NMR (300.073 MHz, DMSO) δ 1.54 - 1.89 (4H, m),2.29 (3H, s),2.85 - 3.00 (2H, m),3.07 - 3.20 (IH, m),3.67 - 4.00 (IH, m),4.40 - 4.77 (IH, m),7.25 - 7.38 (2H, m),7.45 - 7.53 (3H, m),7.76 (2H, d),8.77 (IH, s),9.22 (IH, d),9.31 (IH, d),10.32 (IH, s),13.68 (IH, s), m/z 469 (M+H)+.
Table 5:
The following three examples were made by the method indicated in Example 214, starting from the pyridine acids described above:
Example 216
N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]-N',N'-dimethyl- pyridine-3,5-dicarboxamide
Figure imgf000134_0002
Method Ia Example 215 1H NMR (300.072 MHz, CDCl3) δ 1.60 - 2.00 (4H, m), 2.32 (3H, s),2.80 - 2.91 (2H, m),3.05 (4H, s),3.15 (3H, s),3.88 - 4.17 (IH, m),4.75 - 4.97 (IH, m),7.08 - 7.22 (2H, m),7.33 (2H, d),7.47 (IH, s),7.61 (2H, d),8.34 (IH, t),8.80 (IH, d),9.22 (IH, s),9.24 (IH, d). (M+H)+ 496.
Example 217 N'-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]pyridine-2,5- dicarboxamide
b Example 214
Figure imgf000134_0003
1.54 - 1.97 (4H, m),2.29 (3H, s),2.85 - 3.02 (2H, m),3.06 - 3.17 (IH, m),3.66 - 3.95 (IH, m),4.46 - 4.74 (IH, m),7.22 - 7.41 (2H, m),7.50 (3H, d),7.76 (3H, d),8.17 (IH, d),8.23 (IH, s),8.47 (IH, d),9.13 (IH, s),10.24 (IH, s). (M+H)+ 468. Example 218
N'-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]-N,N-dimethyl-pyridine- 2,5-dicarboxaniide
Figure imgf000135_0001
Method Ib Example 214 1H NMR (300.073 MHz, DMSO) δ 1.54 - 1.87 (4H, m),2.29 (3H, s),2.88 - 2.96 (2H, m),2.94 (3H, s),3.03 (3H, s),3.09 - 3.15 (IH, m),3.69 - 3.92 (IH, m),4.45 - 4.76 (IH, m),7.23 - 7.40 (2H, m),7.46 - 7.55 (3H3 m),7.70 (IH, d),7.76 (2H, d),8.40 (IH, d),9.11 (IH, s), 10.20 (IH, s). (M+H)+ 496.
Example 219 N-[5-[4-(4-cyanophenyl)piperidine- 1 -carbonyl]-2-methyl-phenyl]-6-(l , 1 -dioxo- 1 ,4- thiazinan-4-yl)pyridine-3-carboxamide
Figure imgf000135_0002
Oxone (potassium peroxymonosulfate) (158 mg, 0.26 mmol) was added to a solution of N- [5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]-6-tliioniorpholin-4-yl- pyridine-3-carboxamide(Example 240) (90 mg, 0.17 mmol) in methanol (2 mL), and the reaction mixture stirred at ambient temperature for 4 hrs. Water (2 mL) was added, and stirring continued for a further 20 hrs. The reaction mixture was reduced in vacuo to give a colourless oil; EtOAc (20 mL) was added and the resulting solution was washed sequentially with saturated sodium bicarbonate solution (20 mL), brine (20 mL), dried (MgSO4), filtered and evaporated in vacuo to give a colourless oil. This was purified by chromatography on silica (eluting with a gradient of 50-100% EtOAc in isohexane) to give the title compound as a colourless solid (45 mg), 1H NMR (300.072 MHz, CDCl3) δ 1.65 - 2.00 (4H, m),2.33 (3H, s),2.78 - 2.91 (2H, m),3.05 - 3.12 (4H, m),3.13 - 3.27 (IH, m),3.98 - 4.13 (IH, m),4.21 - 4.35 (4H, m),4.75 - 5.00 (IH, m),6.82 (IH, d),7.15 - 7.26 (2H, m),7.33 (2H, d),7.61 (2H, d),7.83 (IH, s),8.03 (IH, s),8.12 - 8.16 (IH, m),8.79 (IH, d), m/z 558 (M+H)+. Example 220
2-[[5-[[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]carbamoyl]pyridin-2- yl] amino] acetic acid
Figure imgf000136_0001
A solution of tert-butyl 2-[[5-[[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl- phenyl]carbamoyl]pyridin-2-yl]amino]acetate (Example 187) (150 mg, 0.27 mmol) in DCM (2 mL) was treated with trifluoroacetic acid (0.8ml), and the reaction mixture stirred at ambient temperature for 5hrs. The solvent was removed in vacuo, the residue dissolved in EtOAc (30 mL) and the resulting solution was washed sequentially with water (30 mL) and brine (30 mL), dried (MgSO4), filtered and evaporated in vacuo to give the title compound as a colourless solid (30 mg), 1H NMR (300.073 MHz, DMSO) δ 1.55 - 1.85 (4H5 m),2.25 (3H, s),2.88 - 2.97 (2H, m),2.98 - 3.10 (IH, m),3.67 - 3.92 (IH, m),4.02 - 4.12 (2H, m),4.44 - 4.75 (IH, m),6.63 (IH, d),7.17 - 7.34 (2H, m),7.42 - 7.53 (4H, m),7.75 (2H, d),7.89 - 7.96 (IH, m),8.63 (IH, d),9.60 (IH, s),12.26 (IH, s), m/z 498 (M+H)+. Example 221
N-[2-chloro-5-[4-(4-cyanophenyl)piperidme- 1 -carbonyl]phenyl]-6-(3-oxopiperazin- 1 - yl)pyridine-3 -carboxamide
Figure imgf000136_0002
Method 2 from Intermediate NN
1H NMR (300.073 MHz, dmso) δ 1.50 - 1.99 (m, 4H), 2.84 - 3.04 (m, 3H), 3.05 - 3.22 (m, 2H), 3.53 - 3.79 (m, IH), 3.79 - 3.88 (m, 2H), 4.12 (s, 2H), 4.39 - 4.78 (m, IH), 6.89 (d, IH), 7.33 (d, IH), 7.51 (d, 2H), 7.61 (d, IH), 7.69 (s, IH), 7.76 (d, 2H), 8.04 8.21 (m, 2H), 8.77 (d, IH), 9.89 (s, IH), m/z 543 (MH-H)+ [A]. Example 222
N-[2-chloro-5-[4-(4-cyanophenyl)piperidine-l-carbonyl]phenyl]-6-dimethylamino- pyridine-3 -carboxamide
Figure imgf000137_0001
Method 2 from Intermediate NN
1 H NMR (300.073 MHz, dmso) δ 1.48 - 1.99 (m, 4H), 2.77 - 3.04 (m, 3H), 3.16 (s, 6H), 3.59 - 3.87 (m, IH), 4.49 - 4.75 (m, IH), 6.87 (d, IH), 7.30 - 7.39 (m, IH), 7.51 (d, 2H), 7.62 (d, IH), 7.68 (d, IH), 7.76 (d, 2H), 8.07 - 8.19 (m, IH), 8.68 (d, IH), 9.93 (s, IH), m/z 488 (M+H)+ [A]. Example 223 N-[2-chloro-5-[4-(4-cyanophenyl)piperidine-l-carbonyl]phenyl]pyridine-3-carboxamide
Figure imgf000137_0002
Method Ib from Intermediate J
1 H NMR (300.073 MHz, dmso) δ 1.34 - 2.06 (m, 4H), 2.61 - 3.12 (m, 3H), 3.60 - 3.97Q (m, IH), 4.45 - 4.80 (m, IH), 7.35 - 7.44 (m, IH), 7.51 (d, 2H), 7.56 - 7.73 (m, 3H), 7.76 (d, 2H), 8.27 - 8.39 (m, IH), 8.75 - 8.84 (m, IH), 9.10 - 9.19 (m, IH), 10.39 (s, IH), m/z 445 (M+H)+ [A]. Example 224 N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]-2-phenyl-acetamide
5
Figure imgf000137_0003
Method Ia from Intermediate A 1H NMR (300.073 MHz, dmso) δ 1.47 - 1.91 (m, 4H),2.20 (s, 3H),2.74 - 2.98 (m, 2H),2.98 - 3.22 (m, 1H),3.68 (s, 2H),3.58 - 3.84 (m, 1H),4.41 - 4.70 (m, 1H),7.13 (d, 1H),7.19 - 7.39 (m, 6H),7.44 - 7.53 (m, 3H),7.76 (d, 1H),9.49 (s, IH), m/z 438 (M+H)+. Example 225 Q N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methoxy-phenyl]pyridine-4- carboxamide
Figure imgf000138_0001
Method Ia from Intermediate K
1 H NMR (300.072 MHz, CDCl3, 3O0C) δ 1.65 - 2.07 (5H, m), 2.79 - 3.30 (2H, m), 3.99 (3H, s), 4.05 - 4.45 (IH, m), 4.51 - 5.00 (IH, m), 7.00 (IH, dJ = 8.7 Hz), 7.29 - 7.40 (3H, m), 7.62 (2H, dJ = 8.7 Hz), 7.74 (2H, dJ = 6.1 Hz), 8.55 - 8.65 (2H, m), 8.83 (2H, dJ = 4.9 Hz), m/z 441 (M+H)+. Example 226
N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]-2-pyridin-3-yl- acetamide
Figure imgf000138_0002
Method Ib from Intermediate A 1H NMR (300.073 MHz, dmso) δ 1.48 - 1.91 (m, 4H),2.25 (s, 3H),2.82 - 3.23 (m, 3H),3.54 - 3.83 (m, 1H),3.99 (s, 2H),4.43 - 4.71 (m, 1H),7.16 (d, 1H),7.28 (d, 1H),7.42 - 7.54 (m, 3H),7.75 (d, 2H),7.87 - 7.97 (m, 1H),8.39 (d, 1H),8.76 (d, 1H),8.8O (s, 1H),9.69 (s, IH), m/z 439 (M+H)+. Example 227
N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-(trifluoromethoxy)phenyl]pyridine-4- carboxamide
Figure imgf000138_0003
Method Ib from Intermediate L 1H NMR (300.072 MHz, CDCl3) δ 1.64 - 2.02 (4H, m),2.82 - 2.96 (2H, m),3.13 - 3.33 (IH, m),3.89 - 4.05 (IH, m),4.76 - 5.04 (IH, m),7.28 - 7.40 (4H, m),7.63 (2H, d),7.71 (2H, d),8.39 (IH, s),8.59 (IH, d),8.86 (2H, d), m/z 495 (M+H)+. Example 228
N-[5-[4-(4-cyanophenyl)piperidine- 1 -carbonyl]-2-(trifluoromethoxy)phenyl]-6-oxo- IH- pyridine-3 -carboxamide
Figure imgf000139_0001
Method Ib from Intermediate L
1 H NMR (300.072 MHz, CDCl3) δl.42 - 1.94 (4H, m),2.81 - 2.96 (2H, m),3.07 - 3.27 (IH, m),3.90 - 3.99 (IH, m),4.82 - 4.98 (IH, m),6.68 (IH, d),7.08 - 7.16 (IH, m),7.29 - 7.38 (3H, m),7.58 - 7.67 (3H, m),7.78 - 7.84 (IH, m),8.00 (IH, s),8.11 (IH, d),8.54 (IH, d), m/z 511 (M+H)+. Example 229
6-acetamido-N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-(trifluoromethoxy)phenyl] pyridine-3 -carboxamide
Figure imgf000139_0002
Method Ib from Intermediate L 1H NMR (300.072 MHz, CDCl3) δ 1.64 - 1.97 (4H, m),2.26 (3H, s),2.82 - 2.92 (2H, m),3.12 - 3.25 (IH, m),3.91 - 4.06 (IH, m),4.76 - 5.00 (IH, m),7.28 - 7.38 (4H, m),7.62 (2H, d),8.13 - 8.21 (IH, m),8.32 - 8.38 (2H, m),8.44 (IH, s),8.55 (IH, d),8.82 (IH, d), m/z 552 (M+H)+. Example 230
Figure imgf000139_0003
N-[5 -[4-(4-cyanophenyl)piperidine- 1 -carbonyl]-2-fluoro-phenyl]ρyridine-4-carboxamide Example 231
N-[5-t4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]-2-pyridin-4-yl- acetamide
Figure imgf000139_0004
Method Ib from Intermediate A 1H NMR (300.073 MHz, dmso) δ 1.49 - 1.69 (m, 2H),1.69 - 1.94 (m, 2H),2.21 (s, 3H),2.75 - 2.99 (m, 2H),2.99 - 3.22 (m, 1H),3.58 - 3.90 (m, 1H),3.75 (s, 2H),4.34 - 4.76 (m, 1H),7.15 (d, 1H),7.26 (d, 1H),7.31 - 7.39 (m, 2H),7.43 - 7.55 (m, 3H),7.71 - 7.80 (m, 2H),8.46 - 8.56 (m, 2H),9.66 (s, IH), m/z 437 (M-Hy, 439 (M+H)+. Example 232 N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methoxy-ρhenyl]-2-methyl-propanamide
Figure imgf000140_0001
Method Ia from Intermediate K
1 H NMR (300.072 MHz, CDCl3, 3O0C) δ 1.22 - 1.31 (6H, m), 1.56 - 2.08 (5H, m), 2.49 - 2.65 (IH, m), 2.74 - 2.91 (IH, m), 2.91 - 3.27 (IH, m), 3.93 (3H, s), 4.00 - 4.44 (IH, m), 4.50 - 5.00 (IH, m), 6.92 (IH, dJ = 8.0 Hz), 7.20 - 7.26 (IH, m), 7.33 (2H5 dJ = 8.0 Hz), 7.61 (2H, dJ - 7.7 Hz), 7.81 (IH, s), 8.51 (IH, dJ = 3.0 Hz), m/z 406 (M+H)+. Example 233
N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-(trifluoromethoxy)phenyl]-6-morpholin- 4-yl-pyridine-3 -carboxamide
Figure imgf000140_0002
Method Ib from Intermediate L 1H NMR (300.072 MHz, CDCl3) δ 1.67 - 1.97 (4H, m),2.83 - 2.93 (2H, m),3.04 - 3.26 (IH, m),3.54 - 3.70 (4H, m),3.79 - 3.87 (4H, m),3.97 - 4.03 (IH, m),4.81 - 4.96 (IH, m),6.63 - 6.69 (IH, m),7.23 - 7.30 (IH, m),7.32 - 7.38 (3H, m),7.62 (2H, d),7.97 - 8.01 (IH, m),8.08 (IH, s),8.66 - 8.69 (2H, m), m/z 580 (M+H)+. Example 234
N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2,4-dimethyl-phenyl] cyclobutanecarboxamide
Figure imgf000140_0003
Method Ib from Intermediate M 1H NMR (300.072 MHz, CDCl3) δl.73 (2H, m), 1.91 - 2.10 (3H, m), 2.20 (3H, s), 2.27 (3H, s), 2.37 (2H, m), 2.80 (2H, m), 3.15 - 3.26 (2H, m), 3.74 (IH, m), 4.95 (IH, m), 6.96 (IH, s), 7.02 (IH, s), 7.32 (2H, d), 7.61 (2H, d), m/z 416 (M+H)+. Example 235
6-acetamido-N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methoxy-phenyl]pyridine- 3-carboxamide
Figure imgf000141_0001
Method Ib from Intermediate K
1 H NMR (400.132 MHz, DMSO, 200C) δ 1.59 - 1.73 (2H, m), 1.74 - 1.89 (2H, m), 2.14 (3H, s), 2.73 - 3.25 (3H, m), 3.53 - 3.70 (IH, m), 3.89 (3H, s), 4.37 - 4.75 (IH, m), 7.16 (IH, dJ= 6.9 Hz), 7.32 (IH, dJ = 8.6 Hz), 7.52 (2H, dJ = 9.8 Hz), 7.78 (2H, dJ = 8.6 Hz), 7.83 - 7.86 (IH, m), 8.19 (IH, dJ = 9.2 Hz), 8.31 (IH, dJ = 9.3 Hz), 8.87 - 8.90 (IH, m), 9.71 (IH, s), 10.85 (IH, s), m/z 498 (M+H)+. Example 236
N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2,4-dimethyl-phenyl]-6-oxo-lH-pyridine- 3-carboxamide
Figure imgf000141_0002
Method Ib from Intermediate M 1H NMR (400.13 MHz, DMSO-d6) δl.56 - 1.74 (3H, m), 1.87 (IH, d), 2.17 - 2.26 (6H, m), 2.88 (2H, d), 3.12 (IH, d), 3.44 (IH, m), 4.69 (IH, m), 6.40 (IH, d), 7.08 - 7.21 (2H, m), 7.49 (2H, s), 7.78 (2H, d), 7.93 - 7.96 (IH, m), 8.15 (IH, d), 9.63 (IH, s), 12.08 (IH, s), m/z 455 (M+H)+. Example 237
N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2,4-dimethyl-phenyl]-6-morpholin-4-yl- pyridine-3-carboxamide
Figure imgf000142_0001
Method Ib from Intermediate M 1H NMR (400.13 MHz, DMSO-d6) δl.56 - 1.74 (3H, m), 1.87 (IH, d), 2.22 (6H, d), 2.88 (2H, m), 3.14 (IH, m), 3.48 (IH, t), 3.59 (4H, t), 3.69 - 3.72 (4H, m), 4.70 (IH, d), 6.92 (IH, d), 7.19 (2H, m), 7.49 - 7.52 (2H, m), 7.77 (2H, d), 8.07 - 8.10 (IH, m), 8.75 (IH, d), 9.66 (IH, s), m/z 524 (M+H)+. Example 238
N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methoxy-phenyl]-6-oxo-lH-pyridine-3- carboxamide
Figure imgf000142_0002
Method Ib from Intermediate K
1 H NMR (400.132 MHz, DMSO, 19.7°C) δ 1.56 - 1.71 (2H, m), 1.73 - 1.90 (2H, m), 2.71 - 3.27 (3H, m), 3.70 - 4.03 (4H, m), 4.38 - 4.73 (IH, m), 6.39 (IH, dJ = 9.6 Hz), 7.14 (IH, dJ - 8.0 Hz), 7.26 - 7.32 (IH, m), 7.52 (2H, dJ = 8.0 Hz), 7.74 - 7.81 (3H, m), 7.90 - 7.98 (IH, m), 8.14 - 8.20 (IH, m), 9.44 (IH, s), 12.08 (IH, s), m/z 457 (M+H)+. Example 239
N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-(trifluoromethyl)phenyl]pyridine-4- carboxamide
Figure imgf000142_0003
. Method Ib from Intermediate N
1 H NMR (300.073 MHz, dmso, 300C) δ 1.55 - 1.96 (4H, m), 2.75 - 3.02 (2H, m), 3.13 - 3.28 (IH, m), 3.51 - 3.71 (IH, m), 4.54 - 4.74 (IH, m), 7.51 (2H, dJ = 8.4 Hz), 7.58 - 7.68 (2H, m), 7.76 (2H, dJ = 8.4 Hz), 7.83 (2H, dJ = 6.0 Hz), 7.90 (IH, dJ = 8.1 Hz), 8.80 (2H, dJ = 5.2 Hz), 10.54 (IH, s), m/z 479 (M+H)+. Example 240
N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]-6-thiomoφholin-4-yl- pyridine-3 -carboxamide
Figure imgf000143_0001
The title compound was prepared in a manner analogous to that described for Example 112 , starting from 6-chloro-N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl- phenyl]pyridine-3 -carboxamide (Example 35) and thiomorpholine, *H NMR (300.072 MHz, cdcl3) δ 1.58 - 2.00 (4H, m),2.33 (3H, s),2.64 - 2.73 (4H, m),2.77 - 2.91 (2H, m),3.00 - 3.26 (IH, m),4.04 - 4.11 (5H, m),4.78 - 4.98 (IH, m),6.66 (IH, d),7.15 - 7.26 (IH, m),7.24 (IH, d),7.32 (2H, d),7.61 (2H, d),7.85 (IH, s),7.93 (IH, s),8.00 - 8.06 (IH, m),8.73 (IH, d), m/z 526 (M+H)+. Preparation of Intermediates and Starting Materials Intermediate A 4-[ 1 -(3-amino-4-methyl-benzoyl)-4-piperidyl]benzonitrile
Figure imgf000143_0002
A solution of 3-amino-4-methyl benzoic acid (4.05 g, 26.792 mmol), 4-(4'-cyanophenyl) piperidine (5 g, 26.79 mmol), N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride [EDAC] (5.64 g, 29.47 mmol, 1.1 eq) and DMAP (328 mg, 2.68 mmol, 0.1 eq) in DMF (60 mL) was stirred at ambient temperature for 2 hrs. Ethyl acetate (200 mL) was added and the resulting solution was washed sequentially with KHSO4 solution (100 mL of 2M), and brine (100ml); a precipitate formed and was filtered off to give the title compound as a colourless solid (5.25 g), 1H NMR (300.073 MHz, DMSO- d6, 30 0C) δ 1.47 - 1.67 (2H, m), 1.68 - 1.89 (2H, m), 2.05 (3H, s), 2.68 - 3.15 (3H, m), 3.59 - 4.13 (IH, m), 4.22 - 4.76 (IH, m), 4.97 (2H, s), 6.45 - 6.53 (IH, m), 6.63 (IH, s), 6.90 - 6.99 (IH, m), 7.44 - 7.54 (2H, m), 7.71 - 7.81 (2H, m), m/z 320 (M+H)+. Intermediate B (3 -amino-4-methyl-phenyl)-(4-phenyl- 1 -piperidyl)methanone
Figure imgf000144_0001
The title compound was prepared in a manner essentially similar to that described for Intermediate A, starting from 3-amino-4-methyl benzoic acid and 4-phenyl piperidine, and performing the reaction in DCM-1H NMR (CDCl3) δ 1.50 - 2.00 (4H, m), 2.18 (3H, s), 2.70 - 3.20 (3H, m), 3.68 (2H, s br), 3.98 (IH, s, br), 4.85 (IH, s br), 6.72-6.77 (2H, m), 7.06 (IH, d, J= 7.5 Hz ), 7.18 - 7.35 (5H, m), m/z 295.6 (M+H)+. Intermediate C (3-amino-4-methyl-phenyl)-(4-benzyl-l-piperidyl)methanone
Figure imgf000144_0002
The title compound was prepared in a manner essentially similar to that described for
Intermediate A, starting from 3-amino-4-methyl benzoic acid and 4-benzyl piperidine, and performing the reaction in DCM. 1H NMR (CDCl3) δ 1.04 - 1.30 (2H, m), 1.50 - 1.80 (3H, m), 2.14 (3H, s), 2.54 (2H, d, J= 6.8 Hz), 2.60 - 3.00 (2H, m br), 3.50 - 3.90 (3H, m br), 4.64 (IH, s, br), 6.64-6.69 (2H, m), 6.98 - 7.03 (IH, m ), 7.08 - 7.13 (2H, m), 7.14-7.20 (IH, m), 7.22-7.29 (2H, m), m/z 309.3 (M+H)+. Intermediate D (3-amino-4-methyl-phenyl)-[4-(4-methoxyphenyl)-l-piperidyl]methanone
Figure imgf000144_0003
The title compound was prepared in a manner essentially similar to that described for Intermediate A, starting from 3-amino-4-methyl benzoic acid and 4-(4-methoxyphenyl) piperidine hydrochloride (commercially available), and performing the reaction in DCM, m/z 325 (M+H)+, retention time 2.77 min. Intermediate E (3-amino-4-methyl-phenyl)-[4-(4-methylsulfonylphenyl)-l-piperidyl]methanone
Figure imgf000144_0004
The title compound was prepared in a manner essentially similar to that described for Intermediate A, starting from 3-amino-4-methyl benzoic acid and 4-(4- methylsulfonylphenyl) piperidine, and performing the reaction in DCM, m/z 373 (M+H)+, retention time 2.48 min. Intermediate F (3-amino-4-methyl-phenyl)-[4-(4-chlorophenyl)-l-piperidyl]methanone
The title compound was prepared in a manner essentially similar to that described for Intermediate A, starting from 3-amino-4-methyl benzoic acid and 4-(4- chlorophenyl)piperidine hydrochloride, LCMS m/z 329 (M+H)+, retention time 3.04 min. Intermediate G (3-amino-4-methyl-phenyl)-[4-[4-(trifluoromethyl)phenyl]-l-piperidyl]methanone
Figure imgf000145_0002
The title compound was prepared in a manner essentially similar to that described for Intermediate A, starting from 3-amino-4-methyl benzoic acid and 4- [4-
(trifluoromethyl)phenyl] piperidine hydrochloride, and performing the reaction in DCM, m/z 363 (M+H)+, retention time 3.09 min. Intermediate H (3-amino-4-methyl-phenyl)-[4-(4-fluorophenyl)-l-piperidyl]methanone
Figure imgf000145_0003
Step 1 : Preparation of derivatised tetrafluorophenol resin (filled circle denotes polystyrene resin)
Figure imgf000146_0001
This was prepared by the method described in Journal of Combinatorial Chemistry 2(6) p691 (2000), starting from PL-TFP resin (commercially available from Polymer
Laboratories) and 3-amino-4-methyl-benzoic acid to give the derivatised resin, which was used without characterisation.
Step 2: Preparation of (3-amino-4-methyl-phenyl)-[4-(4-fiuorophenyl)-l- piperidyl]methanone
Figure imgf000146_0002
A solution of 4-(4-fluorophenyl)piperidine hydrochloride (42 mg, 0.198 mmol) in DCM (2.5 1.TiL) was treated with PS-trisamine (5 eq) in a 10ml syringe equipped with a frit. After 30 mins the resin was removed by filtration and the amine solution directly transferred into a reaction vessel (5 mL capacity) charged with the activated ester resin from Step 1. The PS-trisamine resin was rinsed twice with DCM (1 mL and 0.5 mL) and the washings added to the reaction vessel. The resulting slurry was then agitated for 24 hrs at ambient temperature. After this time the resin was removed by filtration and washed sequentially with DCM (2 x 2 mL) and MeOH (1 x 2 mL). The filtrate and washings were combined and dried to give the title compound (41 mg) as a colorless oil which was used directly in the next step, m/z 313 (M+H)+, retention time 2.90 min. Intermediate I (3 -amino-4-ethyl-phenyl)-(4-benzyl- 1 -piperidyl)methanone
Figure imgf000146_0003
Step 1: Preparation of (4-benzyl-l-piperidyl)-(4-ethyl-3-nitro-phenyl)methanone
Figure imgf000146_0004
The intermediate was prepared according to the procedure given in Method Ib, starting from 4-ethyl-3-nitro-benzoic acid and 4-benzylpiperidine, H NMR (400 MHz, CDCl3) δ 1.05 - 1.30 (2H, m), 1.27 (2H, t, J= 7.7), 1.53 - 1.86 (3H, m), 2.52 - 2.58 (2H, m), 2.66 - 2.78 (IH, m), 2.86 - 3.04 (3H, m), 3.60 - 3.73 (IH, m), 4.56 - 4.72 (IH, m), 7.09 - 7.13 (2H, m), 7.15 - 7.20 (IH, m), 7.23 - 7.28 (2H, m), 7.36 - 7.40 (IH, m), 7.53 (IH, dd, J1 = 7.9 andJ2 = 1.6 Hz), 7.89 (IH, d, J= 1.6 Hz), m/z 353.8 (M+H)+. Step 2: Preparation of (3-amino-4-ethyl-phenyl)-(4-benzyl- 1 -piperidyl)methanone
Figure imgf000147_0001
A solution of (4-benzyl-l-piperidyl)-(4-ethyl-3-nitro-phenyl)methanone (Step 1) (100 mg, 0.28 mmol) in EtOAc was treated with palladium on charcoal (30 mg of 10% Pd/C). The mixture was hydrogenated at ambient temperature and pressure over night. The mixture was filtered through celite to remove catalyst; the filtrate was then evaporated in vacuo, dissolved in ACN and purified by preparative HPLC using standard method B to give the title compound (55 mg), 1H NMR (400 MHz, CDCl3) δ 1.08 - 1.30 (2H, m), 1.21 (3H, t, J = 7.5 Hz), 1.48 - 1.82 (3H, m), 2.48 (2H, q, J= 7.5 Hz), 2.54 (2H, d, J= 6.7 Hz), 2.58 - 2.94 (2H, m), 3.40 - 3.90 (3H, m), 4.52 - 4.74 (IH, m), 6.66 - 6.72 (2H, m), 7.02 (IH, d, J = 7.7 Hz), 7.11 (2H, d, J= 7.1 Hz), 7.14 - 7.20 (IH, m), 7.23 - 7.29 (2H, m), m/z 323.8 (M+H)+. Intermediate J 4-[ 1 -(3-amino-4-chloro-benzoyl)-4-piperidyl]benzonitrile
Figure imgf000147_0002
The title compound was prepared according to the procedure given in Method Ib, starting from 3-amino-4-chloro-benzoic acid and 4-(4-piperidyl)benzonitrile, H NMR (300.073 MHz, dmso) δ 1.38 - 2.05 (m, 4H), 2.68 - 3.20 (m, 3H), 3.55 - 3.94 (m, IH), 4.30 - 4.79 (m, IH), 5.50 (s, 2H), 6.56 (d, IH), 6.81 (s, IH), 7.22 (d, IH), 7.49 (d, 2H), 7.76 (d, 2H), m/z 340 (M+H)+. Intermediate K
4-[ 1 -(3-amino-4-methoxy-benzoyl)-4-piperidyl]benzonitrile
Figure imgf000148_0001
A stirred mixture of 4-(4'-cyanophenyl)piperidine (3 g, 16 mmol); 3-amino-4- methoxybenzoic acid (2.675 g, 16 mmol, 1 eq) and DIPEA (4.2 ml, 24 mmol, 1.5 eq) in DCM (100 mL) was blanketed with nitrogen and treated with N-(3-Dimethylaminopropyl)- N'-ethylcarbodiimide hydrochloride (EDAC) (3.4 g, 17.6 mmol, 1.1 eq). The reaction mixture was stirred for three days. Addition of water to the reaction mixture resulted in an emulsion and a colourless precipitate. The solid was isolated by filtration and washed with EtOAc (2 x 75 mL portions) to give a colourless solid (2.5 g). The ethyl acetate washings were combined, washed with water, dried (MgSO4) and evaporated to give a further 2 g; the solids thus prepared were identical and combined to give the title compound as (4.5 g, 83%), 1H NMR (300.073 MHz, dmso, 30 deg. C) δ 1.48 - 1.67 (2H, m), 1.71 - 1.87 (2H, m), 2.80 - 3.08 (3H, m), 3.78 (3H, s), 3.88 - 4.63 (2H, m), 4.84 (2H, s), 6.56 - 6.64 (IH, m), 6.67 - 6.73 (IH, m), 6.80 (IH, dJ = 8.1 Hz), 7.49 (2H, dJ = 8.1 Hz), 7.76 (2H, dJ = 9.4 Hz), m/z 336 (M+H)+. Intermediate L 4- [ 1 - [3 -amino-4-(trifluoromethoxy)benzoyl] -4-piperidyl]benzonitrile
Figure imgf000148_0002
Step 1: 3-nitro-4-(trifluoromethoxy)benzoic acid
Figure imgf000148_0003
4-(trifluoromethoxy) benzoic acid (4 g, 26.3 mmol) was added slowly to a stirred mixture of concentrated sulfuric acid ((6.6 mL, 65.7 mmol) and concentrated nitric acid (4 mL, 44.7 mmol) at 400C. When the addition was complete, the reaction mixture was heated to 5O0C and became a pale yellow slurry. After Ih the reaction appeared to have gone to completion and so was poured onto ice and water. A white precipitate formed which was isolated by filtration and washed with water to give the title compound as a colourless crystalline solid (4.2 g), 1H NMR (300.073 MHz, DMSOd6) 57.83 - 7.87 (IH, m), 8.32 - 8.36 (IH, m), 8.56 (IH, d), m/z 198 (M+H)+. Step 2: 3-amino-4-(trifluoromethoxy)benzoic acid
Figure imgf000149_0001
A solution of 3-nitro-4-(trifluoromethoxy)benzoic acid (Step 1) (3.51 g, 14 mmol) in MeOH (150 mL) was hydrogenated at ambient temperature and pressure in the presence of 10% palladium on charcoal catalyst (500 mg). The catalyst was removed by filtration and washed through with more MeOH; the filtrate and washings were combined and evaporated to give the title compound as a pale cream solid (2.9 g), ^H NMR (300.073 MHz, dmso) δ 5.60 (br s, 2H),7.07 - 7.23 (m, 2H),7.39 - 7.46 (m, 1H),12.O2 - 13.40 (br s, IH), m/z 220 (M-H)".
Step 3 : 4- [ 1 - [3 -amino-4-(trifluoromethoxy)benzoyl] -4-piperidyl]benzonitrile
Figure imgf000149_0002
A mixture of 3-amino-4-trifluoromethoxy benzoic acid (Step 2) (2.8 g, 12.66 mmol), 4-(4'- cyanophenyl)piperidine (2.36 g, 12.66 mmol, 1 eq), N-(3-Dimethylaminopropyl)-N'- ethylcarbodiimide hydrochloride (EDAC) (2.67 g, 13.93 mmol, 1.1 eq) and DMAP (155 mg, 1.27 mmol, 0.1 eq) in DMF (30 mL) was stirred at room temperature for 2 hrs. EtOAc (200 mL) was added and the resulting mixture washed sequentially with aqueous potassium bisulfate solution (100 mL of 2M KHSO4), brine (100 mL), dried (MgSO4), filtered and reduced in vacuo to give a brown oil. Ethyl acetate was added and the resulting colourless solid isolated by filtration. A precipitate also appeared during the extraction process; this was isolated and the solids combined to give the title compound (3.16 g), H NMR (300.072 MHz, cdcl3) δ 1.43 - 2.02 (4H, m),2.77 - 3.22 (3H, m),3.80 - 4.21 (3H, m),4.63 - 5.03 (IH, m),6.72 - 6.77 (IH, m),6.87 (IH, d),7.13 - 7.18 (IH, m),7.32 (2H, d),7.61 (2H, d), m/z 390 (M+H)+.
Intermediate M
4-[ 1 -(5-amino-2,4-dimethyl-benzoyl)-4-piperidyl]benzonitrile
Figure imgf000150_0001
Step 1 : 4-[ 1 -(2,4-dimethyl-5-nitro-benzoyl)-4-piperidyl]benzonitrile
Figure imgf000150_0002
The title compound was prepared in a manner similar to that described for Intermediate A, starting from 2,4-dimethyl-5-nitro-benzoic acid and 4-(4'-cyanophenyl)piperidine; ^H
NMR (300.072 MHz, cdcl3) δ 1.44 - 1.64 (m, IH), 1.66 - 1.91 (m, 2H), 1.95 - 2.09 (m,
IH) ,2.30 - 2.49 (br s, 3H), 2.61 (s, 3H), 2.79 - 2.95 (m, 2H), 3.05 - 3.26 (m, IH), 3.59 (d,
IH), 4.95 (d, IH), 7.22 (s, IH), 7.32 (d, 2H), 7.61 (d, 2H), 7.81 (br s, IH), m/z 405
(M+MeCN+H)+.
Step 2: 4-[l-(5-amino-2,4-dimethyl-benzoyl)-4-piperidyl]benzonitrile
Figure imgf000150_0003
The title compound was prepared in a manner similar to that described for Intermediate D, Step 2, starting from 4-[l-(2,4-dimethyl-5-nitro-benzoyl)-4-piperidyl]benzonitrile (Step 1), and using a methanol / THF mixture (1 : 1) as solvent; 1H NMR (300.073 MHz, dmso) δ 1.36 - 1.63 (m, 2H), 1.64 - 1.79 (m, IH), 1.80 - 1.95 (m, IH), 1.96 - 2.08 (br s, 3H), 2.02 (s, 3H), 2.69 - 2.85 (m, IH), 2.85 - 2.97 (m, IH), 2.98 - 3.12 (m, IH), 3.40 - 3.56 (m, IH), 4.59 - 4.70 (m, IH), 4.73 (br s, 2H), 6.30 - 6.55 (br m, IH), 6.78 (s, IH), 7.47 (d, 2H), 7.77 (d, 2H); peak broadening is observed due to conformations of amide group, m/z 334 (M+H)+. Intermediate N
4-[l-[3-amino-4-(trifluoromethyl)benzoyl]-4-piperidyl]benzonitrile
Figure imgf000151_0001
Step 1: 3-amino-4-(trifluorometliyl)benzoic acid
Figure imgf000151_0002
A mixture of 3-nitro-4-(trifluoromethyl)benzoic acid (4.56 g, 19.39 mmol) and palladium- on-charcoal catalyst (500 mg, 10% Pd) in methanol (100 ml) was stirred under an atmosphere of hydrogen until uptake of hydrogen was complete. The solvent was removed under reduced pressure to give the title compound as a cream solid (3.7 g), 1H NMR (300.073 MHz, DMSOd6) 55.81 (2H, s), 7.12 (IH, d), 7.40 - 7.45 (2H, m). Step 2 : 4- [ 1 - [3 -amino-4-(trifluoromethyl)benzoyl] -4-piperidyl]benzonitrile
Figure imgf000151_0003
A stirred solution of 17029/82/1 (3.7 g, 18 mmol), 4-(4'-cyanophenyl)piperidine (3.36 g, 18 mmol) and DIPEA (9.4 ml, 54.1 mmol) in DCM (100 ml) was treated with N-(3- dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDAC) (3.8 g, 19.8 mmol), and the reaction mixture stirred for 24 hrs and then allowed to stand for a further 24 hrs at ambient temperature. The bulk of the DCM was removed in vacuo and the residue partioned between water and EtOAc was attempted. The organic phase was separated and dried (MgSO4); evaporation of the solvent gave a gum (~ 5.8 g) which was recrystallised from EtOH (100 rnL) to give a solid (2.2 g) which was purified by column chromatography
(120 g silica cartridge, eluting with a gradient of 0 - 50 % MeOH in DCM to give the title compound as a pale yellow solid (1.6 g 24 %), 1H NMR (300.073 MHz, dmso, 30 deg. C) δ 1.49 - 1.95 (4H, m), 2.70 - 3.01 (2H, m), 3.02 - 3.23 (IH, m), 3.54 - 3.78 (IH, m), 4.49 - 4.71 (IH, m), 5.75 (2H, s), 6.63 (IH, dJ = 7.3 Hz), 6.83 (IH, s), 7.37 (IH, dJ = 8.5 Hz), 7.49 (2H, dJ = 7.3 Hz), 7.77 (2H, dJ = 7.9 Hz). Intermediate AA
6-chloro-N-[2-methyl-5-[4-(4-methylphenyl)piperidine-l-carbonyl]phenyl]pyridine-3- s carboxamide
Figure imgf000152_0001
Step 1: Preparation of derivatised tetrafluorophenol resin (filled circle denotes polystyrene resin)
Figure imgf000152_0002
o This was prepared as described in Journal of Combinatorial Chemistry 2(6) ρ691 (2000), starting from PL-TFP resin (commercially available from Polymer Laboratories) and 3- amino-4-methyl-benzoic acid to give the derivatised resin, which was used without characterisation. Step 2: Preparation of (3-amino-4-methyl-phenyl)-[4-(4-methylphenyl)-l -s piperidyl]methanone
Figure imgf000152_0003
A solution of 4-(4-methylρhenyl)piperidine hydrochloride (42 mg, 0.198 mmol) in DCM (2.5 mL) was treated with PS-trisamine (5 eq) in a 10ml syringe equipped with a frit. After 30 mins the resin was removed by filtration and the amine solution directly transferredo into a reaction vessel (5 mL capacity) charged with the activated ester resin from Step 1. The PS-trisamine resin was rinsed twice with DCM (1 mL and 0.5 mL) and the washings added to the reaction vessel. The resulting slurry was then agitated for 24 hrs at ambient temperature. After this time the resin was removed by filtration and washed sequentially with DCM (2 x 2 mL) and MeOH (1 x 2 mL). The filtrate and washings were combined5 and dried to give the title compound (41 mg) as a colorless oil which was used directly in the next step. LCMS indicated that the product contained 9% of unreacted amine. The crude product was used in the next step without purification or characterisation. Step 3: 6-chloro-N-[2-methyl-5-[4-(4-methylphenyl)piperidine-l- carbonyl]phenyl]pyridine-3-carboxamide
Figure imgf000153_0001
This was prepared in a manner exactly analogous to that described for Example 1 (Method Ia), starting from (3-amino-4-methyl-phenyl)-[4-(4-methylphenyl)-l-piperidyl]methanone (Step 2) and ό-chloropyridine-S-carbonyl chloride, 1H NMR (400. MHz, DMSO-dό) δ 1.45 - 1.85 (m, 4H), 2.22 (s, 3H), 2.24 (s, 3H), 2.65 - 2.90 (m, 2H), 3.07 (m, IH), 3.75 (bs, IH), 4.58 (bs, IH), 7.06 (d, 2H), 7.11 (d, 2H), 7.22 (d, IH), 7.32 (d, IH), 7.42 (bs, IH), 7.68 (d, IH), 8.35 (d, IH), 8.93 (bs, IH), 10.16 (s, IH). Intermediate BB
6-chloro-N-[5-[3-(4-methoxyphenyl)pyrrolidine-l-carbonyl]-2-methyl-phenyl]pyridine-3- carboxamide
Figure imgf000153_0002
Step 1: Preparation of (3-amino-4-methyl-phenyl)-[3-(4-memoxyphenyl)pyrrolidin- l-yl]methanone
Figure imgf000153_0003
This was prepared in a manner analogous to that described for Intermediate AA (Step 2), starting from activated ester resin (Intermediate AA, Step 1) and 3-(4-methoxyphenyl) pyrrolidine, m/z 311.13 (M+H)+, retention time 3.21 min. The requisite 3-(4- methoxyphenyl) pyrrolidine starting material is available from ARCH/ENNOVA (catalogue number AR02270). Step 2: 6-chloro-N-[5-[3-(4-methoxyphenyl)pyrrolidine-l-carbonyl]-2-methyl- phenyl]pyridine-3 -carboxamide
Figure imgf000154_0001
This was prepared in a manner exactly analogous to that described for Example 1 (Method Ia), starting from (3-amino-4-methyl-phenyl)-[3-(4-methoxyphenyl)pyrrolidin-l- yljmethanone (Step 1) and 6-chloropyridine-3-carbonyl chloride, m/z 448.24 (M-H)", retention time 3.55 min.
Intermediate CC
6-chloro-N- [5 - [4-(4-methoxyphenyl)piperidine- 1 -carbony 1] -2-(trifluor omethyl)phenyl] pyridine-3 -carboxamide
Figure imgf000154_0002
Step 1: Preparation of [4-(4-methoxyphenyl)-l-piperidyl]-[3-nitro-4-
(trifluoromethyl)phenyl]methanone
Figure imgf000154_0003
The title compound was prepared in a manner essentially similar to that described for Intermediate A, starting from 3-nitro-4-(trifluoromethyl)benzoic acid and 4-(4- methoxyphenyl) piperidine hydrochloride, and performing the reaction in DCM, m/z 409.16 (M+H)+, retention time 4.05 min. Step 2 : [3 -amino-4-(trifluoromethyl)phenyl]- [4-(4-methoxyphenyl)- 1 - piperidyl]methanone
Figure imgf000154_0004
A mixture of [4-(4-methoxyphenyl)-l-piperidyl]-[3-nitro-4-(trifluoromethyl)phenyl] methanone (Step 1, 273 mg, 0.669 mmol), ammonium chloride (179 mg, 3.34 mmol, 5 eq) and iron powder (187 mg, 3.34 mmol, 5 eq) in ethanol (15 mL) and water (3.5 mL) was refluxed for Ih 15 min. The reaction mixture was filtered through a plug of celite, and the residue washed three times with DCM. The filtrate and washings were combined, filtered through a phase separator, and evaporated to give a colourless foam (247 mg), m/z 379.20 (M+H)+, retention time 3.83 min.
Step 3: 6-chloro-N-[5-[4-(4-methoxyphenyl)piperidine-l-carbonyl]-2-
(trifluoromethy l)pheny 1] pyridine-3 -carboxamide
Figure imgf000155_0001
This was prepared in a manner exactly analogous to that described for Example 1 (Method Ia), starting from [3-amino-4-(trifluoromethyl)phenyl]-[4-(4-methoxyphenyl)-l- piperidyl]methanone (Step 2) and 6-chloropyridine-3-carbonyl chloride, m/z 518.16 (M+H)+, retention time 3.93 min. Intermediate DD
6-chloro-N-[2-methyl-5-[4-[4-(trifluoromethyl)phenyl]piperidine-l-carbonyl]phenyl] pyridine-3-carboxamide
Figure imgf000155_0002
This was prepared in a manner exactly analogous to that described for Example 1 (Method Ia), starting from (3-amino-4-methyl-phenyl)-[4-[4-(trifluoromethyl)phenyl]-l- piperidyrjmethanone (Intermediate G) and ό-chloropyridine-S-carbonyl chloride, m/z 502
(M+H)+, retention time 2.57 min.
Intermediate EE
6-chloro-N-[5-[4-(4-chlorophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]pyridine-3- carboxamide
Figure imgf000156_0001
This was prepared in a manner exactly analogous to that described for Example 1 (Method
Ia), starting from (3-amino-4-methyl-phenyl)-[4-(4-chlorophenyl)-l-piperidyl]methanone
(Intermediate F) and β-chloropyridine-S-carbonyl chloride, m/z 468 (M+H)+, retention time 2.54 min.
Intermediate FF
6-chloro-N-[2-methyl-5-[4-(4-methylsulfonylphenyl)piperidine-l- carbonyl]phenyl]pyridine-3-carboxamide
Figure imgf000156_0002
This was prepared in a manner exactly analogous to that described for Example 1 (Method Ia), starting from (3-amino-4-methyl-ρhenyl)-[4-(4-methylsulfonylphenyl)-l- piperidyl]methanone (Intermediate E) and 6-chloropyridine-3-carbonyl chloride, m/z 512 (M+H)+, retention time 2.16 min. Intermediate GG
Figure imgf000156_0003
This was prepared in a manner exactly analogous to that described for Example 1 (Method Ia), starting from (3-amino-4-methyl-phenyl)-[4-[(4-methoxyphenyl)methyl]-l- piperidyl]methanone (Intermediate ) and θ-chloropyridine-S-carbonyl chloride, m/z 478.17 (M+H)+, retention time 3.86 min. Intermediate HH
6-chloro-N-[5-[3-(4-methoxyphenoxy)azetidine-l-carbonyl]-2-methyl-phenyl]pyridine-3- carboxamide
Figure imgf000156_0004
Step 1 : Preparation of (3-amino-4-methyl-phenyl)-[3-(4-methoxyphenoxy)azetidin- l-yl]methanone
Figure imgf000157_0001
The title compound was prepared in a manner essentially similar to that described for
Intermediate A, starting from 3-amino-4-methyl benzoic acid and 3-(4-methoxyphenoxy) azetidine (available from Buttpark, catalogue number 75\04-75), and performing the reaction in DCM, no NMR, m/z 313.2 (M+H)+, retention time 3.23 min.
Step 2 : 6-chloro-N- [5 - [3 -(4-methoxyphenoxy)azetidine- 1 -carbonyl] -2-methy 1- phenyl]pyridine-3-carboxamide
Figure imgf000157_0002
This was prepared in a manner exactly analogous to that described for Example 1 (Method Ia), starting from (3-amino-4-methyl-phenyl)-[3-(4-methoxyphenoxy)azetidin-l- yljmethanone (Step 1) and 6-chloropyridine-3 -carbonyl chloride, m/z 452.1 (M+H)+, retention time 3.51 min. s Intermediate II
6-chloro-N-[5-[4-(3,4-dichlorophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]pyridine-3- carboxamide
Figure imgf000157_0003
Step 1: Preparation of tert-butyl 4-(3,4-dichlorophenyl)piperidine-l-carboxylate
Figure imgf000157_0004
The title compound was prepared using the method described in Journal of Organic Chemistry (2004), 69(15), 5120 - 5123, starting from tert-butyl 4-hydroxypiperidine-l- carboxylate and 4-bromo-l,2-dichloro-benzene, 1H NMR (CDCl3) δ 1.46 (9H, s), 1.47 - 1.60 (2H, m), 1.74 - 1.81 (2H, m), 2.54 - 2.64 (IH, m), 2.70 -2.81 (2H, m), 4.17 - 4.27 (2H, m), 6.98 - 7.04 (IH, m), 7.25 - 7.28 (IH, m), 7.32 - 7.37 (IH, m), m/z 274.17 (M - 1- butyl+H)+. (t-butyl cleaved off in LC-MS), retention time 3.64 min.
Step 2: Preparation of 4-(3,4-dichlorophenyl)piperidine hydrochloride
Figure imgf000158_0001
A solution of tert-butyl 4-(3,4-dichlorophenyl)piperidine-l-carboxylate (Step 1) (500 mg, 1.51 mmol) in a solution of hydrogen chloride in dioxane (approx. 4M in HCl) was stirred at ambient temperature for 40 min. Diethylether (approx. 5 mL) was added until the product started to precipitate. The mixture was left to stand for 45 min and the precipitate then filtered off to give the title compound as a white solid (311 mg), which was used directly in the next step. No NMR, m/z 230.20 (M+H)+, retention time 2.21 min. Step 3: Preparation of (3-amino-4-methyl-phenyl)-[4-(3,4-dichlorophenyl)-l- piperidyl]methanone
Figure imgf000158_0002
The title compound was prepared in a manner essentially similar to that described for Intermediate A, starting from 3-amino-4-methyl benzoic acid and 4-(3,4-dichlorophenyl) piperidine (Step 2) and performing the reaction in DCM; No NMR, m/z 363.24 (M+H)+, retention time 3.16 min.
Step 4: Preparation of 6-chloro-N-[5-[4-(3,4-dichlorophenyl)piperidine-l- carbonyl]-2-methyl-phenyl]pyridine-3-carboxamide
Figure imgf000158_0003
This was prepared in a manner exactly analogous to that described for Example 1 (Method Ia), starting from (3-amino-4-methyl-phenyl)-[4-(3,4-dichlorophenyl)-l- piperidyl]methanone (Step 3) and 6-chloropyridine-3-carbonyl chloride, m/z 504.15 (M+H)+, retention time 3.24 min. Intermediate JJ
6-chloro-N-[5-[4-(4-methoxyphenyl)piperidine-l-carbonyl]-2,4-dimethyl-phenyl]pyridine- 3-carboxamide
Figure imgf000159_0001
Step 1: 2,4-dimethyl-5-nitro-benzoic acid
Figure imgf000159_0002
The title compound was prepared by the method described in Journal of Organic Chemistry (1999), 64(3), 713-720, m/z 194.27 (M-H)", retention time 2.95 min. Step 2: 5-amino-2,4-dimethyl-benzoic acid
Figure imgf000159_0003
The title compound was prepared by reduction of 2,4-dimethyl-5-nitro-benzoic acid (Step 1) using ammonium chloride and iron powder in a manner analogous to that described for Intermediate CC, Step 2, m/z 166.24 (M+H)+, retention time 2.15 min. Step 3: (5-amino-2, 4-dimethy 1-pheny I)- [4-(4-methoxypheny I)-I- piρeridyl]methanone
Figure imgf000159_0004
The title compound was prepared in a manner essentially similar to that described for Intermediate A, starting from 5-amino-2, 4-dimethyl-benzoic acid and 4-(4- methoxyphenyl) piperidine (commercially available), and performing the reaction in DCM, m/z 339.24 (M+H)+, retention time 3.56 min.
Step 4: 6-chloro-N-[5-[4-(4-methoxyphenyl)piperidine- 1 -carbonyl]-2,4-dimethyl- pheny l]pyridine-3 -carboxamide
Figure imgf000159_0005
This was prepared in a manner exactly analogous to that described for Example 1 (Method Ia), starting from (5-amino-2, 4-dimethyl-phenyl)-[4-(4-methoxyphenyl)-l- piperidyljmethanone (Step 3) and ό-chloropyridine-S-carbonyl chloride, No NMR, m/z 478.10 (M+H)+, retention time 3.16 tnin, or 3.28 min (cmpd is 50% mixture with regioisomer. Separated in next step. Do not now if product has retention time 3.16 min, or 3.28 min.) Intermediate KK
6-chloro-N-[2-methyl-5-[4-(4-nitrophenyl)piperidine-l-carbonyl]phenyl]pyridine-3- carboxamide
Figure imgf000160_0001
Step 1: tert-butyl 4-(4-nitrophenyl)piperidine-l-carboxylate
Figure imgf000160_0002
The title compound was prepared using the method described in Journal of Organic Chemistry (2004), 69(15), 5120 - 5123, starting from tert-butyl 4-hydroxypiperidine-l- carboxylate and l-bromo-4-nitro-benzene, 1H-NMR consistent with that reported (loc cit), m/z 251.26 (M-tBu+H)+ (t-bu cleaved in LC-MS), retention time 2.95 min. Step 2: Preparation of 4-(4-nitrophenyl)piperidine
Figure imgf000160_0003
A solution of tert-butyl 4-(4-nitrophenyl)piperidine-l -carboxylate (240 mg, 0.78 mmol) in DCM (5 mL) was treated with trifluoroacetic acid (0.5 mL, 6.75 mmol, 8.6 eq), and the reaction mixture stirred at ambient temperature for 2 hours. The solution was then diluted with more DCM (approx. 40 mL) and washed with sodium hydroxide solution (30 mL of 2M); the aqueous washings were extracted once with DCM (approx. 40 mL), and the combined organic layers dried (Phase Separating cartridge) and concentrated in vacuo to give the title compound (152 mg), no NMR, m/z 207.3 (M+H)+, retention time 1.51 min. Step 3 : Preparation of (3-amino-4-methyl-phenyl)-[4-(4-nitrophenyl)- 1 - piperidyl]methanone
Figure imgf000161_0001
The title compound was prepared in a manner essentially similar to that described for Intermediate A, starting from 3-amino-4-methyl benzoic acid and 4-(4- nitrophenyl)piperidine (Step 2) and performing the reaction in DCM, no NMR, m/z 340.2 (M+H)+, retention time 3.10 min.
Step 4: Preparation of 6-chloro-N-[2-methyl-5-[4-(4-nitrophenyl)piperidine-l- carbonyljphenyl] pyridine-3-carboxamide
Figure imgf000161_0002
This was prepared in a manner exactly analogous to that described for Example 1 (Method
Ia), starting from (3-amino-4-methyl-phenyl)-[4-(4-nitrophenyl)-l-piperidyl]methanone
(Step 3) and 6-chloropyridine-3-carbonyl chloride, m/z 479.3 (M+H)+, retention time: 3.31 min.
Intermediate LL
6-chloro-N-[5-[4-(2,4-dichlorophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]pyridine-3- carboxamide
Figure imgf000161_0003
Step 1: Preparation of tert-butyl 4-(2,4-dichlorophenyl)piperidine- 1 -carboxylate
Figure imgf000161_0004
The title compound was prepared using the method described in Journal of Organic Chemistry (2004), 69(15), 5120 - 5123, starting from tert-butyl 4-hydroxypiperidine-l- carboxylate and l-bromo-2,4-dichloro-benzene, m/z 274.17 (M - t-Bu+H)+ (t-Bu cleaved in LC-MS), retention time 3.36 min.
Step 2 : Preparation of 4-(2,4-dichlorophenyl)piperidine
Figure imgf000162_0001
The title compound was prepared in a manner identical to that described for Intermediate
KK, Step 2, staring from tert-butyl 4-(2,4-dichlorophenyl)piperidine-l-carboxylate (Step
1), no NMR, m/z 230.1 (M+H)+, retention time 2.22 min.
Step 3 : Preparation of (3-amino-4-methyl-phenyl)-[4-(2,4-dichlorophenyl)- 1 - piperidyl]methanone
Figure imgf000162_0002
The title compound was prepared in a manner essentially similar to that described for Intermediate A, starting from 3-amino-4-methyl benzoic acid and 4-(2,4-dichlorophenyl) piperidine (Step 2), and performing the reaction in DCM, m/z 363.2 (M+H)+, retention time 3.72 min. Step 4: Preparation of 6-chloro-N-[5-[4-(2,4-dichlorophenyl)piperidine-l- carbonyl] -2-methy 1-pheny l]pyridine-3 -carboxamide
Figure imgf000162_0003
This was prepared in a manner exactly analogous to that described for Example 1 (Method Ia), starting from (3-amino-4-methyl-phenyl)-[4-(2,4-dichlorophenyi)-l- piperidyl]methanone (Step 3) and 6-chloropyridine-3-carbonyl chloride, H NMR (400 MHz, CDCl3) δ 1.50 - 2.00 (4H, m), 2.29 (3H, s), 2.75 - 2.95 (IH, m), 3.10 - 3.30 (2H, m), 3.89 - 4.02 (IH, m), 4.79 - 4.94 (IH, m), 7.08 - 7.12 (IH, m), 7.14 - 7.23 (3H, m), 7.36 (IH, d, J= 2.0 Hz), 7.46 (IH, d, J= 8.5 Hz), 7.51 - 7.56 (IH, m), 8.24 (IH, dd, J1 = 8.3 and J2 = 2.2 Hz), 8.59 - 8.67 (IH, m), 8.94 - 9.00 (IH, m), m/z 504.0 (M+H)+. Intermediate MM
Methyl 4-[l-[3-[(6-chloropyridine-3-carbonyl)amino]-4-methyl-benzoyl]-4- piperidyl]benzoate
Figure imgf000163_0001
Step 1: Preparation of methyl 4-[l-(3-amino-4-methyl-benzoyl)-4- piperidyl]benzoate
Figure imgf000163_0002
The title compound was prepared in a manner essentially similar to that described for Intermediate A, starting from 3-amino-4-methyl benzoic acid and methyl 4-(4-piperidyl) benzoate (Available from ARCH / ENNOVA, catalogue number AR02095) and performing the reaction in DCM; No NMR, m/z 353.19 (M+H)+, retention time 3.09 min. Step 2: Preparation of methyl 4-[l-[3-[(6-chloropyridine-3-carbonyl)amino]-4- methyl-benzoyl]-4-piperidyl]benzoate
Figure imgf000163_0003
This was prepared in a manner exactly analogous to that described for Example 1 (Method Ia), starting from methyl 4-[l-(3-amino-4-methyl-benzoyl)-4-piperidyl]benzoate (Step 1) and 6-chloropyridine-3-carbonyl chloride, m/z 492.26 (M+H)+, retention time 2.58 min. Intermediate NN
2-chloro-N-[2-methyl-5-[4-[4-(trifluoromethyl)phenyl]piperidine-l-carbonyl]phenyl] acetamide
Figure imgf000163_0004
A solution of (3-amino-4-methyl-phenyl)-[4-[4-(trifluoromethyl)phenyl]-l-piperidyl] methanone (Intermediate G) (1.683 g, 4.64 mmol) and DIPEA (1.8 g, 2.48 mL, 13.9 mmol, 3 eq) in DCM (150 mL) was cooled to 0 °C, and a solution of chloroacetyl choride (1.31 g, 0.93 mL, 11.6 mmol, 2.5 eq) in DCM (10 mL) was added dropwise. The reaction mixture
5 was allowed to warm to ambient temperature over 1.5, and was then washed sequentially with IM HCl (100 mL), saturated NaHCO3 solution (100 mL) and water (100 mL). The organic phase was filtered through a phase separator and evaporated to give a brownish solid foam (2.48 g) which was used in the next stage without further purification, No NMR, m/z 439.25 (M+H)+, retention time 3.11 min.
I0 Intermediate OO
4-(Chloromethyl)-N-[2-methyl-5-[4-[4-(trifluoromethyl)phenyl]piperidine-l- carbonyl]phenyl]benzamide
Figure imgf000164_0001
The intermediate was prepared according to the procedure given in Method Ia, starting 15 from (3-amino-4-methyl-phenyl)-[4-[4-(trifluoromethyl)phenyl]- 1 -piperidyl]methanone
(Intermediate G) and 4-(chloromethyl)benzoyl chloride, m/z 515.16 (M+H)+, retention time 4.23 min.
Intermediate PP
Step 1 : Preparation of tert-butyl 4-(4-methoxycarbonylphenyl)piperidine- 1 -
20 carboxylate
Figure imgf000164_0002
A solution of 4-[l-[(2-methylpropan-2-yl)oxycarbonyl]-4-piperidyl]benzoic acid (850 mg, 2.78 mmol) in MeOH (9.7 mL) was treated with EDAC (641 mg, 3.34 mmol, 1.2 eq) and DMAP (341 mg, 2.78 mmol, 1 eq), and the reaction mixture allowed to stir overnight at 25 ambient temperature. TLC (5% Methanol in dichloromethane) indicated that the reaction was complete. Silica was added to the reaction mixture, which was then concentrated in vacuo and dry loaded onto a 12g silica column and purified by chromatography (Companion™ , eluting with a gradient of 0-5% MeOH in DCM) to give the title compound as a pale yellow oil (855 mg), 1H NMR (300.072 MHz, CDCl3) δ 1.51 (s, 9H), 1.65 (dd, 2H), 1.88 (bs, 2H), 2.64 - 2.89 (m, 3H), 3.94 (s, 3H), 4.33 (bs, 2H), 7.28 (d, 2H), 7.98 (d, 2H). 5 Step 2: Preparation of methyl 4-(4-piperidyl)benzoate
Figure imgf000165_0001
tert-butyl 4-(4-methoxycarbonylphenyl)piperidine-l-carboxylate (Step 1) (4.25 g) was added to a solution of hydrogen chloride gas in 1,4-dioxane (20 rriL of 4M) and the reaction mixture allowed to stir overnight. The solvent was evaporated in vacuo and theQ residue isolated as the hydrochloride salt (2.8g of a colourless solid) which was used without further purification 1H NMR (300.073 MHz, DMSO) δ 1.76 - 2.01 (m, 4H), 2.84 - 3.10 (m, 3H), 3.24 - 3.44 (m, 2H), 3.87 (s, 3H), 7.38 (d, 2H), 7.92 (d, 2H), 9.14 (bs, IH). Step 3 : Preparation of methyl 4-[ 1 -[4-methyl-3-(pyridine-4- carbonylamino)benzoyl]-4-piperidyl]benzoate
Figure imgf000165_0002
A suspension of methyl 4-(4-piperidyl)benzoate hydrochloride (5 g, 22.8 mmol), 4-methyl- 3-(pyridine-4-carbonylamino)benzoic acid [see below] (5.87 g, 22.8 mmol, 1 eq) and DMAP (6.13 g, 50.2 mmol, 2.2 eq) in DCM (80 mL) was treated with EDAC (5.25 g, 27.36 mmol, 1.2 eq), and the reaction mixture was stirred overnight under argon at ambientQ temperature. The reaction mixture was then concentrated in vacuo and the product purified by flash column chromatography (Companion™ , 2x12Og silica columns, eluting with a gradient of 5-7% MeOH in DCM) to give the title compound as a colourless solid (9.54 g, 91% yield), 1H NMR (400.132 MHz, MeOD) δ 1.83 (bs, 2H), 1.95 (bs, IH), 2.09 (bs, IH), 2.40 (s, 3H), 3.00 (bs, 2H), 3.31 (bs, IH), 3.95 (s, 3H), 4.13 (bs, IH), 4.90 (bs, IH),5 7.28 (dd, IH), 7.33 (d, 2H), 7.37 (dd, IH), 7.56 (s, IH), 7.90 (d, 2H), 7.99 (d, 2H), 8.75 (d, 2H).
Step 4: Preparation of 4-[l-[4-methyl-3-(pyridine-4-carbonylamino)benzoyl]-4- piperidyl]benzoic acid
Figure imgf000166_0001
A suspension of methyl 4-[l-[4-methyl-3-(pyridine-4-carbonylamino)benzoyl]-4- piperidyl]benzoate (Step 3) (9.54 g, 20.81 mmol)in THF (85 mL) was treated with a solution of lithium hydroxide (1.31 g, 31.21 mmol, 1.5 eq) in water (42.5 mL), and the
5 reaction mixture was stirred overnight at ambient temperature. A solution of citric acid (31 mL of IM, 31 mmol, 1 eq. based on LiOH) was added to the reaction mixture and the organic solvent evaporated in vacuo. The resulting solid was isolated by filtration to give the title compound as a colourless solid (7.8 g, 84% yield), 1H NMR (300.073 MHz, dmso) δ 1.62 (dd, 2H), 1.92 (bs, 2H), 2.32 (s, 3H), 2.97 (bs, 2H), 3.43 (bs, IH), 7.26 (dd,o IH), 7.37 (dd, 3H), 7.48 (s, IH), 7.86 (dd, 4H), 8.77 (d, 2H), 10.27 (s, IH).
The requisite 4-methyl-3-(pyridine-4-carbonylarnino)benzoic acid starting material (Step
3) was prepared as follows:
Step 1: Preparation of methyl 4-methyl-3-(pyridine-4-carbonylamino)benzoate
Figure imgf000166_0002
s A solution of methyl 3-amino-4-methyl-benzoate (8.255 g, 50 mmol) and TEA (13.9 mL, 100 mmol, 2 eq) in DCM (200 mL) was cooled in an ice-bath and pyridine-4-carbonyl chloride (9.795 g, 55 mmol, 1.1 eq) was added portionwise as a solid. The reaction mixture was stirred for 30 mins, the ice-bath was removed, and stirring continued for a further 1 hr. Extra acid chloride (2 g, 0.2 eq) was added and the reaction mixture stirred a further 1 hr. Ito was then diluted with more DCM and the resulting solution washed sequentially with water (twice), saturated sodium bicarbonate solution, and brine. At this stage a solid started to precipitate out, so more DCM was added. The solid precipitate (2 g) was isolated by titration and the filtrate dried (PS Paper) and evaporated to give a solid (10.7 g). The two fractions were identical (NMR, LCMS) and combined to give the title compound (12.7 g)5 as a yellow solid, 1H NMR (400.132 MHz, DMSO) 62.33 (s, 3H),3.86 (s, 3H),7.46 (d, 1H),7.79 (d, 1H),7.87 -7.94 (m, 2H),7.98 - 8.05 (m, 1H),8.81 (d, 2H),10.35 (s, IH), m/z 271 (M+H+) 269 (M-H"). Step 2: Preparation of 4-methyl-3-(pyridine-4-carbonylamino)benzoic acid
Figure imgf000167_0001
A solution of methyl 4-methyl-3-(pyridine-4-carbonylamino)benzoate (Step 1) (12.5 g, 46.3 mmol) in a mixture of MeOH (100 mL), THF (50 mL) and water (100 mL) was stirred at ambient temperature and sodium hydroxide (2.78 g, 69.4 mmol, 1.5 eq) added as a solid. Stirring was continued for several hours and a further portion of sodium hydroxide (1 g) added. The reaction mixture was then allowed to stand at ambient temperature overnight. A solution of citric acid (110 mL of IM, slight excess based on NaOH) was added to the reaction mixture and the resulting solid was isolated by filtration to give the title compound as a pale yellow solid (10.5 g), 1H NMR (300.073 MHz, DMSO) δ 2.31 (s, 3H),7.41 (d, 1H),7.75 (d, 1H),7.83 - 7.92 (m, 2H),7.92 - 8.00 (m, 1H),8.73 - 8.84 (m, 2H),10.17 (s, IH); signal due to carboxylic acid proton probably at ~ δ 3.3, obscured by HOD signal, m/z 257 (M+H*) 255 (M-HO-

Claims

Claims
1 ) A compound of formula I
Figure imgf000168_0001
or a pharmaceutically acceptable salt thereof, in which R1 represents a) a Ci-βalkyl group, a C2-6alkenyl group or a C2-6alkynyl group each of which is optionally substituted; b) an optionally substituted C3.i0cycloalkyl group which may be monocyclic, bicyclic or tricyclic and optionally may be bridged; c) an optionally substituted carbon linked saturated or partially saturated 3 to 8 membered heterocyclic group containing one or more N, S, SO, SO2 or O; d) optionally substituted heteroaryl including N-oxides thereof; or e) optionally substituted phenyl;
wherein optionally substituted means that any available carbon in R1 is optionally substituted by one or more of the followingl) hydroxy 2) halo, 3) a C1-6alkoxy group optionally substituted by one or more of the following: halo, OH , Ci-βalkoxy, phenyl or by a group of formula NRcRd in which Rc and Rd are as defined below 4) carboxy 5) C1-6 alkoxycarbonyl 6) carbamoyl 7) N-Ci-6alkylcarbamoyl 8) N, N-diCi-oalkylcarbamoyl 9) sulphamoyl 10) N-C1-6alkylsulphamoyl 11) N, N-diC].6alkylsulphamoyl 12) Ci- 6alkanoylamino 13)
Figure imgf000168_0002
14) N-Ci.6alkylsulphonylamino 15) Ci-6alkylthio 16) Ci-βalkylsulfinyl 17) Ci-6alkylsulfonyl 18) C i^alkylsulfonyloxy wherein the alkyl is optionally substituted by one or more fiuoro 19) cyano 20) phenyl 21) heteroaryl 22) substituted phenoxy 23) oxo or
24) a group ΝRaRb in which Ra and Rb independently represent i) H ii) Ci_6alkanoyl iii) a carbon linked saturated or partially unsaturated 3 to 8 membered heterocyclic group containing one or more N, S, SO, SO2 or O which is optionally fused to a benz ring and/or is optionally substituted by one or more of the following: hydroxy, oxo, a C^alkoxy group hydroxy, C1-4acyl, amino, C1-3alkylamino, di(Ci-3 alkyl)amino or a C1-6alkyl optionally substituted by one or more hydroxy or Ci^alkoxy iv) a Ci-βalkyl group optionally substituted by one or more of the following: hydroxy; carboxy; a Q-βalkoxycarbonyl group; a Ci^alkoxy group; heteroaryl; a group of formula
NR°Rd in which Rc and Rd independently represent H; a C^alkanoyl group; a Q- δalkylsulphonyl group; a Ci-6alkoxycarbonyl group; a Ci-6alkyl group optionally substituted by one or more hydroxy or C^alkoxy , or Rc and Rd together with the nitrogen atom to which they are attached represent a saturated or partially unsaturated 3 to 8 membered heterocyclic ring optionally containing an additional sulphur including oxidised as SO or SO2 , oxygen or nitrogen and/or optionally fused to a benz ring and/or optionally substituted by one or more of the following: a Ci-6alkoxy group; hydroxy; oxo; or a Ci-
6alkyl group optionally substituted by one or more hydroxy or
Figure imgf000169_0001
v) a C3-iocycloalkyl group which may be monocyclic, bicyclic or tricyclic and optionally may be bridged ; vi) phenyl optionally substituted by one or more of the following: halo; Ci^alkyl; Q- 3alkoxy; a Ci.βacylamino group; carbamoyl; N-Ci-δalkylcarbamoyl; N,N-diCi.
6alkylcarbamoyl; vii) heteroaryl; viii) a Ci_6alkoxycarbonyl group; ix) Ra and Rb together with the nitrogen atom to which they are attached represent a saturated or partially unsaturated 3 to 8 membered heterocyclic ring optionally containing an additional oxygen, sulphur, SO, SO2 or nitrogen and/or optionally fused to a benz ring and/or optionally substituted by one or more of the following: a Ci^aUcoxy group; a Ci-
6acyl group; a Ci-βalkoxycarbonyl group; carbamoyl; N-Ci.6alkylcarbamoyl; N, N-diCi.
6alkylcarbamoyl; hydroxy; oxo; a Ci^alkyl group (which is optionally substituted by one or more of the following: a Ci_6alkoxy group, hydroxy or a group of formula ΝRcRd in which Rc and Rd are as defined above) or a group of formula NRcRd in which Rc and Rd are as defined above; x) a Q-βalkylsulphonyl group;
25) a C3-iocycloalkyl group which may be monocyclic, bicyclic or tricyclic and optionally may be bridged; 26) a carbon linked saturated or partially saturated 3 to 8 membered heterocyclic group containing one or more N, S, SO, SO2 or O which is optionally substituted by one or more of the following: a Ci-6alkoxy group; a Ci-βalkanoyl group; a Q-βalkoxycarbonyl group; carbamoyl; N-C1-6alkylcarbamoyl; N, N-diCi-6alkylcarbamoyl; hydroxy; oxo; a
Figure imgf000170_0001
group (which is optionally substituted by one or more of the following: a Q^alkoxy group, hydroxy or a group of formula ΝRcRd in which R° and Rd are as defined above) or 27) by a Ci-βalkyl group optionally substituted by one or more groups as described in 1 -26 above; 28) a C2-4alkenyl or 29) a C2-4alkynyl; wherein any cycloalkyl, phenyl, heteroaryl ring or carbon linked saturated or partially saturated 3 to 8 membered heterocyclic group in this list of optional substituents in 1 to 27 above is optionally substituted by one or more of the following: i) a Ci^alkyl group optionally substituted by one or more halo ii) a
Figure imgf000170_0002
group optionally substituted by one or more halo iii) halo, iv) nitro, v) cyano vi) hydroxy vii) a group of formula NRcRd in which Rc and Rd are as defined above viii) carboxy ix) a Ci-βalkylsulphonyl group optionally substituted by one or more halo; x) a Ci-βalkylsulphonyloxy group optionally substituted by one or more halo xi) carbamoyl xii) N-Ci..3alkylcarbamoyl xiii) N, N-diCi. 3alkylcarbamoyl xiv) sulphamoyl xv)
Figure imgf000170_0003
xvi) N, N-diQ. 3alkylsulphamoyl and any alkyl, alkenyl or alkynyl chain in this list of optional substituents 1 to 29 above is optionally substituted by one or more of the following: i) a Ci- 3alkyl group optionally substituted by one or more halo ii) a Ci-3alkoxy group optionally substituted by one or more halo iii) halo, iv) nitro v) cyano vi) hydroxy vii) a group of formula ΝRcRd in which Rc and Rd are as defined above; and wherein an optionally substituted carbon linked saturated or partially saturated 3 to 8 membered heterocyclic group containing one or more N, S, SO, SO2 or O described in c) above is optionally substituted on nitrogen by: a Ci^alkyl group optionally substituted by one or more hydroxy or a group of formula NRcRd in which Rc and Rd are as defined above; or by Ci- 6alkanoyl; R2 represents halo; hydroxy; a Ci-3alkyl group optionally substituted by one or more halo; a Ci-3alkoxy group optionally substituted by one or more halo; or cyano;
R3 represents H; halo; hydroxy; a C^alkyl group optionally substituted by one or more halo; a Ci-3alkoxy group optionally substituted by one or more halo; or cyano;
R4 represents i) H, ii) a C1-3alkyl group optionally substituted by one or more halo iii) a C1. 3alkoxy group optionally substituted by one or more halo iv) halo, v) nitro, vi) cyano, vii) a Ci-6alkylS(O)y(O)z- wherein y is 0,1 or 2 and z is 0 except when y is 2 when z is 0 or 1 viii) a group CH2NRURV in which Ru and Rv independently represent H, a Ci-6alkylsulphonyl group, a Ci-6alkanoyl group or a C^aUcyl group optionally substituted by one or more of the following: hydroxy, a
Figure imgf000171_0001
group or a group of formula NRcRd in which Rc and Rd are as defined above or Ru and Rv together with the nitrogen atom to which they are attached represent a saturated or partially unsaturated 3 to 8 membered heterocyclic ring optionally containing an N, S, SO, SO2 or O; ix) a group CO2RW in which Rw is a C1- 3alkyl group; or x) a group C0NRxRy in which Rx and Ry independently represent H; or a group optionally substituted by phenyl wherein the phenyl is optionally substituted by one or more C1-3alkyl, halo or Ci-3alkoxy; or Rx and Ry together with the nitrogen atom to which they are attached represent a saturated or partially unsaturated 3 to 8 membered heterocyclic ring optionally containing an additional sulphur, oxygen or nitrogen, wherein any ring carbon or is optionally substituted by one or more of the following: a
Figure imgf000171_0002
a C^alkoxy group; hydroxy; C1-OaCyI or oxo and any additional ring nitrogen is optionally substituted by a C1^aCyI or a Ci-6alkyl group optionally substituted by one or more hydroxy or C^alkoxy;
R5 and R5 independently represent H, halo, cyano, C1-3alkyl optionally substituted by one or more halo or Ci-3alkoxy optionally substituted by one or more halo; R6 and R6' independently represent H, halo, cyano, C1-3alkyl optionally substituted by one or more halo or C1-3alkoxy optionally substituted by one or more halo; L represents a bond or CH2; m and n independently represent 0 or 1; with the proviso that when R1 is CH3, R2 is CH3, and R3 , R4, R5, R5', R6, R6' are each H, m is 1 and n is 1 then L is not CH2.
2) A compound according to claim 1 in which.R1 represents an optionally substituted 5 Ci_6alkyl group.
3) A compound according to claim 1 in which R1 represents an optionally substituted C3-iocycloalkyl group which may be monocyclic, bicyclic or tricyclic and optionally may be bridged. 0
4) A compound according to claim 1 in which R1 represents an optionally substituted carbon linked saturated or partially saturated 3 to 8 membered heterocyclic group containing one or more N, S, SO5 SO2 or O. s 5) A compound according to claim 1 in which R1 represents an optionally substituted heteroaryl including N-oxides thereof.
6) A compound according to claim 1 in which R1 represents an optionally substituted phenyl. 0
7) A compound according to claim 1 in which R1 represents an optionally substituted pyridyl.
8) A compound according to any one of claims 1 to 7 in which m and n are each 1.5
9) A compound according to any one of claims 1 to 8 in which L represents a bond.
10) A compound according to any one of claims 1 to 8 in which R2 represents halo; hydroxy; a C]-3alkyl group optionally substituted by one or more halo; a C1-3alkoxy groupo optionally substituted by one or more halo; or cyano and R3 represents halo; hydroxy; a C1- 3alkyl group optionally substituted by one or more halo; a Ci-3alkoxy group optionally substituted by one or more halo; or cyano. 11) A compound selected from one or more of the following compounds:
N-[5-[4-(4-cyanophenyl)piperidine- 1 -carbonyl]-2-methyl-phenyl]- 1 -oxido-pyridine-4- carboxamide
6-acetamido-N-[2-methyl-5-(4-phenylpiperidine-l-carbonyl)phenyl]pyridine-3- carboxamide
6-chloro-N-[2-methyl-5-(4-phenylpiperidine-l-carbonyl)phenyl]pyridine-3-carboxamide
N-[5-(4-ben2ylpiperidine-l-carbonyl)-2-methyl-phenyl]-6-chloro-pyridine-3-carboxamide
N-[5-(4-benzylpiperidine-l-carbonyl)-2-methyl-phenyl]-6-(trifluoromethyl)pyridine-3- carboxamide N-[5-(4-benzylpiperidine-l-carbonyl)-2-ethyl-phenyl]-6-chloro-pyridine-3-carboxamide
4-chloro-N-[2-methyl-5-(4-phenylpiperidine-l-carbonyl)phenyl]benzamide
N-[2-methyl-5-(4-phenylpiperidine-l-carbonyl)phenyl]-6-(trifluoromethyl)pyridine-3- carboxamide
6-dimethylamino-N-[2-methyl-5-(4-phenylpiperidine-l-carbonyl)phenyl]pyridine-3- carboxamide
N-[2-methyl-5-(4-phenylpiperidine-l-carbonyl)phenyl]-6-morpholin-4-yl-pyridine-3- carboxamide
6-chloro-N-[5-[4-(4-methoxyplienyl)piperidine-l-carbonyl]-2-methyl-plienyl]pyridine-3- carboxamide 2-bromo-5-methoxy-N-[5-[4-(4-methoxyphenyl)piperidine-l-carbonyl]-2-methyl- phenyl]benzamide
N-[5-[4-(4-methoxyphenyl)piperidine-l-carbonyl]-2-methyl-phenyl]benzothiazole-2- carboxamide
6-acetamido-N-[5-[4-(4-methoxyphenyl)piperidine-l-carbonyl]-2-methyl-phenyl]pyridine- 3 -carboxamide
N-[5-[4-(4-methoxyphenyl)piperidine-l-carbonyl]-2-methyl-phenyl]benzamide
N-[5-[4-(4-methoxyphenyl)piperidine-l-carbonyl]-2-methyl-phenyl]-4-phenyl-benzamide
2-chloro-N-[5-[4-(4-methoxyphenyl)piperidine-l-carbonyl]-2-methyl-phenyl]pyridine-3- carboxamide 2-methoxy-N-[5-[4-(4-methoxyphenyl)piperidine- 1 -carbonyl]-2-methyl-phenyl]benzaniide
N-[5-[4-(4-methoxyphenyl)piperidine-l-carbonyl]-2-methyl-phenyl]pyridine-3- carboxamide N-[5-[4-(4-methoxyphenyl)piperidine-l-carbonyl]-2-methyl-phenyl]-3-methyl-benzamide
3-chloro-N-[5-[4-(4-methoxyphenyl)piperidine-l-carbonyl]-2-methyl-phenyl]benzamide
N- [5 - [4-(4-methoxyphenyl)piperidine- 1 -carbonyl] -2-methyl-plienyl] -4-tert-butyl- benzamide 2-chloro-6-methoxy-N-[5-[4-(4-methoxyphenyl)piperidine-l-carbonyl]-2-methyl- phenyl]pyridine-4-carboxamide
N-[5-[4-(4-methoxyphenyl)piperidine-l-carbonyl]-2-methyl-phenyl]-4-methyl-benzaniide
2-chloro-N-[5-[4-(4-methoxyphenyl)piperidine-l-carbonyl]-2-methyl-phenyl]pyridine-4- carboxamide N-[5-[4-(4-methoxyphenyl)piperidine- 1 -carbonyl]-2-methyl-phenyl]-4-
(trifluoromethoxy)benzamide
2-chloro-N-[5-[4-(4-methoxyplienyl)piperidine-l-carbonyl]-2-methyl-phenyl]-6-methyl- pyridine-4-carboxamide
2,4-dichloro-N-[5-[4-(4-methoxyphenyl)piperidine-l-carbonyl]-2-methyl- phenyl]benzamide
N-[5-[4-(4-methoxyphenyl)piperidine-l-carbonyl]-2-methyl-phenyl]-3-
(trifluoromethoxy)benzamide
N-[5-[4-(4-methoxyphenyl)piperidine-l-carbonyl]-2-methyl-plienyl]pyridine-4- carboxamide N-[5-[4-(4-methoxyphenyl)piperidine-l-carbonyl]-2-methyl-phenyl]-2-methylsulfanyl- pyridine-3-carboxamide
N-[5-[4-(4-methoxyphenyl)piperidine-l-carbonyl]-2-methyl-phenyl]quinoline-2- carboxamide
6-acetamido-N-[2-methyl-5-[4-(4-methylsulfonylphenyl)piperidine-l- carbonyl]phenyl]pyridine-3-carboxamide
N-[5-[4-(4-chlorophenyl)piperidine-l-carbonyl]-2-meihyl-phenyl]-6-methyl-pyridine-3- carboxamide
6-chloro-N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-plienyl]pyridine-3- carboxamide N-[5-[4-(4-chlorophenyl)piperidine- 1 -carbonyl]-2-methyl-phenyl]-6-
(trifluoromethyl)pyridine-3-carboxamide N-[2-methyl-5-[4-[4-(trifluoromethyl)phenyl]piperidine-l-carbonyl]phenyl]pyridine-4- carboxamide
N-[5-[4-(4-fluorophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]pyridine-4-carboxamide
N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]pyridine-4-carboxamide N-[5-[4-(4~cyanophenyl)piperidine-l-carbonyl]-2-methyl- pheny 1] cyclopropanecarboxamide
N-[5-[4-(4-cyanophenyl)piperidine- 1 -carbonyl]-2-methyl-phenyl]-6-oxo- 1 H-pyridine-3- carboxamide
N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]-6-morpliolin-4-yl- pyridine-3 -carboxamide
6-acetamido-N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-metliyl-plienyl]pyridine-3- carboxamide
N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]cyclobutanecarboxamide
N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]butanamide N-[5 - [4-(4-cy anophenyl)piperidine- 1 -carbonyl] -2-methyl-phenyl] -3 ,3 -dimethyl- butanamide
N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]benzamide
N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]pyridine-3-carboxamide
N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]cyclohexanecarboxamide N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]-2-(3-oxopiperazin-l- yl)acetamide
1 -acetyl-N-[5-[4-(4-cyanophenyl)piperidine- 1 -carbonyl]-2-methyl-phenyl]piperidine-4- carboxamide
N-[5-[4-(4-cyanophenyl)piperidine- 1 -carbonyl]-2-methyl- phenyljcyclopentanecarboxamide
N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]-2-methyl-propanamide
N-[5-[4-(4-cyanophenyl)piperidine- 1 -carbonyl]-2-methyl-phenyl]-6-oxo- 1 H-pyridazine-3- carboxamide
N-[2-chloro-5-[4-(4-cyanophenyl)piperidine-l-carbonyl]phenyl]pyridine-4-carboxamide N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]-l-hydroxy-cyclohexane-
1 -carboxamide
N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]-2-phenoxy-acetamide 1 -[[5-[4-(4-cyanoρhenyl)piperidine- 1 -carbonyl]-2-methyl- phenyl]carbamoylmethyl]piperidine-4-carboxamide
N- [5 - [4-(4-cyanoρhenyl)piperidine- 1 -carbonyl] -2-methyl-phenyl] -3 -hydroxy-butanamide
N-[5-[4-(4-cyanoρhenyl)piperidine-l-carbonyl]-2-methyl-phenyl]oxolane-3-carboxamide N-[5-[4-(4-cyanophenyl)piperidine- 1 -carbonyl]-2-methyl-phenyl]-2-hydroxy-cyclohexane-
1-carboxamide
N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]-4-methoxy- cyclohexane- 1 -carboxamide
N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]-4-methoxy- cyclohexane-1 -carboxamide
N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]-3-methoxy- cyclohexane- 1 -carboxamide
6-chloro-N-[2-chloro-5-[4-(4-cyanophenyl)piperidine-l-carbonyl]ρhenyl]pyridine-3- carboxamide N-[2-chloro-5-[4-(4-cyanophenyl)piperidine-l-carbonyl]phenyl]butanamide methyl 5-[[5-[4-(4-cyanophenyl)piperidme-l-carbonyl]-2-methyl- phenyl]carbamoyl]pyridine-2-carboxylate ethyl 5 - [[5 - [4-(4-cyanopheny l)piperidine- 1 -carbonyl] -2-methyl- phenyl]carbamoyl]pyridine-3-carboxylate N-[5- [4-(4-cyanophenyl)piperidine- 1 -carbonyl]-2-methyl-phenyl]-2-(4-hydroxy- 1 - piperidyl)acetamide
6-cyano-N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]pyridine-3- carboxamide
N- [5 - [4-(4-cyanophenyl)piperidine- 1 -carbonyl] -2-methyl-phenyl] -2- [(4- methoxyphenyl)amino]pyridine-4-carboxamide
N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]-2-fluoro-pyridine-3- carboxamide
N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]-6-(l-piperidyl)pyridine-
3 -carboxamide N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]-2-pyrrolidin-l-yl- pyridine-4-carboxamide N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]-2-(l-piperidyl)pyridine-
4-carboxamide
N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]-2-(l,2,4-triazol-l- yl)pyridine-4-carboxamide N-[5-[4-(4-cyanophenyl)piperidine- 1 -carbonyl]-2-methyl-phenyl]quinoline-3-carboxamide
6-amino-N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]pyridine-3- carboxamide
N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]-6-methyl-pyridine-3- carboxamide 2-chloro-N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]pyridine-4- carboxamide
N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]-l-oxido-pyridine-5- carboxamide
5 -bromo-N- [5 - [4-(4-cyanophenyl)piperidine- 1 -carbonyl] -2-methyl-phenyl]pyridine-3 - carboxamide
N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]-6-methoxy- benzothiazole-2-carboxamide
N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]-2-metliyl-6-oxo-lH- pyridine-4-carboxamide 6r[(4-acetamidophenyl)amino]-N-[5-[4-(4-cyanophenyl)piperidine- 1 -carbonyl]-2-methyl- phenyl]pyridine-3 -carboxamide
2-[(3-carbamoylphenyl)amino]-N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl- phenyl]pyridine-4-carboxamide
2,5-dichloro-N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]pyridine-4- carboxamide
N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]-6-(2-pyrrolidin-l- y lethyl)pyridine-3 -carboxamide tert-butyl 4-[5-[[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl- phenyl]carbamoyl]pyridin-2-yl]piperazine- 1 -carboxylate N-[5-[4-(4-cyanophenyl)piperidine- 1 -carbonyl]-2-methyl-phenyl]-2-moφholin-4-yl- pyridine-4-carboxamide N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]-6-(2- methoxyethoxy)pyridine-3-carboxamide
2-amino-N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]pyridine-4- carboxamide 3-chloro-N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-plienyl]pyridine-4- carboxamide
N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]-6-ethoxy-pyridine-3- carboxamide
N- [5- [4-(4-cy anophenyl)piperidine- 1 -carbonyl] -2-methyl-phenyl] -6-propan-2-yloxy- pyridine-3-carboxamide tert-butyl N-[[5-[[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl- phenyl]carbamoyl]pyridin-2-yl]methyl]carbamate
N-[5-[4-(4-cyanophenyl)piperidine- 1 -carbonyl]-2-methyl-phenyl]- 4-azabenzimidazol-6- carboxamide N- [5 - [4-(4-cy anophenyl)piperidine- 1 -carbonyl] -2-methyl-phenyl]pyrimidine-5- carboxamide
6-chloro-N- [5 - [4-(4-cyanopheny l)piperidine- 1 -carbonyl]-2-methyl-phenyl] cinnoline-3 - carboxamide
N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]pyrimidine-4- carboxamide
N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]pyridazine-4- carboxamide
N-[5-[4-(4-cyanophenyl)piperidine- 1 -carbonyl]-2-methyl-plienyl] 1 ,3-thiazole-4- carboxamide N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]l,3-thiazole-5- carboxamide
N- [5- [4-(4-cyanophenyl)piperidine- 1 -carbonyl] -2-methyl-phenyl] -2-morpholin-4-yl- 1,3- thiazole-4-carboxamide
N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]-2,4-dimethyl-l,3- thiazole-5 -carboxamide
N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]pyrazine-2-carboxamide N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]-5-methyl-pyrazine-2- carboxamide
2-acetamido-N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]-4-methyl-
1 ,3 -thiazole-5-carboxamide N-[2-chloro-5-[4-(4-cyanophenyl)piperidine-l-carbonyl]phenyl]cyclopropanecarboxamide
3 , 5 -dichloro-N- [5 - [4-(4-cy anophenyl)piperidine- 1 -carbonyl] -2-methyl-phenyl]pyridine-4- carboxamide
N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]-2,4-dimethyl-pyridine-
3-carboxamide N-[5-(4-benzylpiperidine-l-carbonyl)-2-methyl-phenyl]-6-moφholin-4-yl-pyridine-3- carboxamide
N-[5-(4-benzylpiperidine-l-carbonyl)-2-methyl-phenyl]-6-[(3-dimethylamino-2,2- dimethyl-propyl)amino]pyridine-3-carboxamide
6-[(3-dimethylamino-2,2-dimethyl-propyl)amino]-N-[2-methyl-5-(4-phenylpiperidine-l- carbonyl)phenyl]pyridine-3 -carboxamide
6-(3-dimethylaminopropylamino)-N-[2-methyl-5-(4-phenylpiperidine-l- carbonyl)phenyl]pyridine-3-carboxamide
6-(3-methylbutylamino)-N-[2-metliyl-5-(4-phenylpiperidine-l-carbonyl)phenyl]pyridine-
3 -carboxamide 6-(4-dimethylamino-l-piperidyl)-N-[2-methyl-5-(4-phenylpiperidine-l- carbonyl)phenyl]pyridine-3-carboxamide
N- [2-methyl-5 -(4-phenylpiperidine- 1 -carbonyl)phenyl]-6-piperazin- 1 -yl-pyridine-3 - carboxamide
6-(4-amino- 1 -piperidyl)-N-[2-methyl-5-(4-phenylpiperidine- 1 -carbonyl)phenyl]pyridine-3 - carboxamide
N-[5-[4-(4-methoxyphenyl)piperidine-l-carbonyl]-2-methyl-phenyl]-6-moφholin-4-yl- pyridine-3-carboxamide
6-dimethylamino-N-[5-[4-(4-methoxyphenyl)piperidine-l-carbonyl]-2-methyl- phenyl]pyridine-3-carboxamide N-[2-methyl-5-[4-(4-methylpb.enyl)piperidine-l-carbonyl]phenyl]-6-morpholin-4-yl- pyridine-3-carboxamide 6-dimethylamino-N- [5 - [3 -(4-methoxyphenyl)pyrrolidine- 1 -carbonyl]-2-methyl- phenyl]pyridine-3-carboxamide
6-diniethylamino-N-[5-[4-(4-methoxyphenyl)piperidine-l-carbonyl]-2-
(trifluoromethyl)phenyl]pyridine-3-carboxamide N-[5-[4-(4-methoxyphenyl)piperidine-l-carbonyl]-2-(trifluoromethyl)phenyl]-6- morpholin-4-yl-pyridine-3-carboxamide
N-[2-methyl-5-[4-[4-(trifluoromethyl)phenyl]piperidine-l-carbonyl]phenyl]-6-moφholin-
4-yl-pyridine-3 -carboxamide
N-[5-[4-(4-clilorophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]-6-morpholin-4-yl- pyridine-3 -carboxamide
N-[2-methyl-5-[4-(4-methylsulfonylphenyl)piperidine-l-carbonyl]phenyl]-6-moφholin-4- yl-pyridine-3-carboxamide
N-[5-[4-(4-methoxyphenyl)piperidine-l-carbonyl]-2-methyl-phenyl]-6-(l- piperidyl)pyridine-3-carboxamide 6-(2-methoxyethylamino)-N-[5-[4-(4-methoxyphenyl)piperidine-l-carbonyl]-2-methyl- phenyl]pyridine-3 -carboxamide
N-[5-[4-(4-methoxyphenyl)piperidine-l-carbonyl]-2-methyl-phenyl]-6-[2-(2- oxoimidazolidin- 1 -yl)ethylamino]pyridine-3-carboxamide
N-[5-[4-(4-methoxyphenyl)piperidine-l-carbonyl]-2-methyl-phenyl]-6-(3-oxopiperazin-l- yl)pyridine-3 -carboxamide
6-[(l-ethyl-3-piperidyl)amino]-N-[5-[4-(4-methoxyphenyl)piperidine-l-carbonyl]-2- methyl-phenyl]pyridine-3-carboxamide
6-(3-methoxyazetidin-l-yl)-N-[5-[4-(4-methoxyphenyl)piperidine-l-carbonyl]-2-methyl- phenyl]pyridine-3 -carboxamide N-[5-[4-(4-methoxyphenyl)piperidine-l-carboiiyl]-2-methyl-phenyl]-6-pyrrolidin-l-yl- pyridine-3 -carboxamide
6-(2-hydroxyethyl-methyl-amino)-N-[5-[4-(4-methoxyphenyl)piperidine-l-carbonyl]-2- methyl-phenyl]pyridine-3-carboxamide
N-[5-[4-(4-methoxyphenyl)piperidine-l-carbonyl]-2-methyl-phenyl]-6-[(l-methyl-4- piperidyl)amino]pyridine-3-carboxamide
6-(3-imidazol-l-ylpropylamino)-N-[5-[4-(4-methoxyphenyl)piperidine-l-carbonyl]-2- methyl-phenyl]pyridine-3-carboxamide 6-(azetidin- 1 -y I)-N- [5 - [4-(4-methoxyphenyl)piperidine- 1 -carbonyl] -2-methyl- phenyl]pyridine-3 -carboxamide
N-[5-[4-(4-methoxyphenyl)piperidine-l-carbonyl]-2-methyl-phenyl]-6-(l,4-oxazepan-4- yl)pyridine-3-carboxamide N-[5-[4-(4-methoxyphenyl)piperidine-l-carbonyl]-2-methyl-phenyl]-6-[3-(2- oxopyrrolidin- 1 -yl)propylamino]pyridine-3-carboxamide
N-[5-[4-(4-methoxyphenyl)piperidine-l-carbonyl]-2-methyl-phenyl]-6-(propan-2- ylamino)pyridine-3 -carboxamide
6-(2-hydroxyethylamino)-N-[5-[4-(4-methoxyphenyl)piperidine-l-carbonyl]-2-methyl- phenyl]pyridine-3 -carboxamide
N-[5-[4-(4-methoxyphenyl)piperidine-l-carbonyl]-2-methyl-plienyl]-6-[3-(l- piperidyl)propylamino]pyridine-3-carboxamide
N-[5-[4-(4-methoxyphenyl)piperidine-l-carbonyl]-2-methyl-phenyl]-6-(3-morpholin-4- ylpropylamino)pyridine-3-carboxamide 6- [4-(2-methoxyethyl)piperazin- 1 -yl] -N- [5 - [4-(4-methoxyphenyl)piperidine- 1 -carbonyl] -
2-methyl-phenyl]pyridine-3-carboxamide
6- [(3 -dimethylamino-2,2-dimethyl-propyl)amino] -N- [5 - [4-(4-methoxyphenyl)piperidine- l-carbonyl]-2-methyl-phenyl]pyridine-3-carboxamide
N-[5-[4-[(4-methoxyphenyl)methyl]piperidine-l-carbonyl]-2-metliyl-prienyl]-6-moφholin- 4-yl-pyridine-3-carboxamide
6-dimethylamino-N-[5-[4-[(4-methoxyphenyl)methyl]piperidine-l-carbonyl]-2-methyl- phenyl]pyridine-3-carboxamide
6- [(3 -dimethylamino-2,2-dimethy l-propyl)amino] -N- [5- [4- [(4- methoxyphenyl)methyl]piperidine-l-carbonyl]-2-methyl-phenyl]pyridine-3-carboxamide -dimethylamino-N-[2-methyl-5-[4-(4-methylsulfonylphenyl)piperidine-l- carbonyl]phenyl]pyridine-3-carboxamide
N-[5-[4-(4-chlorophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]-6-dimethylamino- pyridine-3 -carboxamide
6-(4-amino- 1 -piperidyl)-N-[5-[4-(4-methoxyphenyl)piperidine- 1 -carbonyl]-2-methyl- phenyl]pyridine-3-carboxamide
6-(4-hydroxy- 1 -piperidyl)-N- [5 - [4-(4-methoxyphenyl)piperidine- 1 -carbonyl] -2-methyl- phenyl]pyridine-3-carboxamide 6-dimethylamino-N-[2-methyl-5-[4-[4-(trifluoromethyl)phenyl]piperidine-l- carbonyl]phenyl]pyridine-3-carboxamide
N- [5 - [4-(3 ,4-dichlorophenyl)piperidine- 1 -carbony l]-2-methyl-phenyl] -6-dimethy lamino- pyridine-3-carboxamide N-[5-[4-(3,4-dichlorophenyl)piperidine- 1 -carbonyl]-2-methyl-phenyl]-6-morpholin-4-yl- pyridine-3-carboxamide
N-[5-[4-(3,4-dichlorophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]-6-[(3- dimethylamino-2,2-dimethyl-propyl)amino]pyridine-3-carboxamide
N-[5-[4-(4-methoxyphenyl)piperidine-l-carbonyl]-2,4-dimethyl-phenyl]-6-moφholin-4- yl-pyridine-3-carboxamide
6-[(3-dimethylamino-2,2-dimethyl-propyl)amino]-N-[2-methyl-5-[4-[4-
(trifluoromemytyphenylJpiperidine-l-carbonyljphenyljpyridine-S-carboxamide
N- [5 - [4-(4-cyanopheny l)piperidine- 1 -carbony 1] -2-methy 1-pheny 1] -6-dimethy lamino- pyridine-3-carboxamide 6-dimethylamino-N-[2-methyl-5-[4-(4-nitrophenyl)piperidine- 1 -carbonyl]phenyl]pyridine-
3-carboxamide
N-[5-[4-(2,4-dichlorophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]-6-dimethylamino- pyridine-3 -carboxamide methyl 4- [ 1 - [3 - [(6-dimethy laminopyridine-3 -carbony l)amino] -4-methyl-benzoyl] -A- piperidyljbenzoate
N-[5-[4-(4-chlorophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]-6-methylamino- pyridine-3 -carboxamide
N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]-6-(propan-2- ylamino)pyridine-3-carboxamide N-[5-[4-(4-cyanophenyl)piperidine- 1 -carbonyl]-2-methyl-phenyl]-6-(methyl-propan-2-yl- amino)pyridine-3 -carboxamide
N- [5 - [4-(4-cyanophenyl)piperidine- 1 -carbonyl] -2-methyl-pheny 1] -6-(4-hydroxy- 1 - piperidyl)pyridine-3-carboxamide
N-[5-[4-(4-cyanophenyl)piperidine- 1 -carbonyl]-2-methyl-phenyl]-6-(3-oxopiperazin- 1 - yl)pyridine-3 -carboxamide
N- [5 - [4-(4-cyanophenyl)piperidine- 1 -carbonyl] -2-methyl-pheny 1] -6-(2- hydroxyethylamino)pyridine-3-carboxamide N-[5 - [4-(4-cyanopheny l)piperidine- 1 -carbony l]-2-methy 1-phenyl] -6- [3 -(2-oxopyrrolidin- 1 - yl)propylamino]pyridine-3-carboxamide
N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]-6-(2- methoxyethylamino)pyridine-3-carboxamide N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]-6-(l,4-oxazepan-4- yl)pyridine-3-carboxamide
N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]-6-methylamino- pyridine-3 -carboxamide
N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]-6-(3-imidazol-l- ylpropylamino)pyridine-3 -carboxamide
N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]-6-(4-methylpiperazin-l- yl)pyridine-3 -carboxamide
N- [5 - [4-(4-cyanopheny l)piperidine- 1 -carbony 1] -2-methy 1-phenyl] -6-(3 - hydroxypropylamino)pyridine-3-carboxamide N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]-6-(2-hydroxyethyl- methyl-amino)pyridine-3-carboxamide
N-[5-[4-(4-cyanophenyl)piperidine- 1 -carbony 1] -2-methy 1-phenyl] -6-piperazin- 1 -yl- pyridine-3-carboxamide
N-[5-[4-(4-cyanophenyl)piperidine- 1 -carbonyl]-2-methyl-phenyl]-6-pyrrolidin- 1 -yl- pyridine-3-carboxamide
6-(4-amino-l-piperidyl)-N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl- pheny l]pyridine-3 -carboxamide
6-(azetidin-l-yl)-N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl- phenyl]pyridine-3-carboxamide N-[5-[4-(4-cyanophenyl)piperidine- 1 -carbony 1] -2-methy 1-phenyl] -2-(4-hydroxy- 1 - piperidyl)pyridine-4-carboxamide
N-[5-[4-(4-cyanophenyl)piperidine- 1 -carbonyl]-2-methyl-phenyl]-2-(3-oxopiperazin- 1 - yl)pyridine-4-carboxamide
N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]-2-(2- hydroxyethylamino)pyridine-4-carboxamide
N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]-2-(4-methylpiperazin-l- yl)pyridine-4-carboxamide tert-butyl 2-[[5-[[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2~methyl- phenyl]carbamoyl]pyridin-2-yl]amino]acetate
2-dimethylamino-N-[2-methyl-5-[4-[4-(trifluoromethyl)phenyl]piperidine-l- carbonyl]phenyl]acetamide 2-(2-methylpyrrolidin-l-yl)-N-[2-methyl-5-[4-[4-(trifluoromethyl)phenyl]piperidine-l- carbonyl]phenyl]acetamide
N-[2-methyl-5-[4-[4-(trifluoromethyl)phenyl]piperidine-l-carbonyl]phenyl]-2-(3- oxopiperazin- 1 -yl)acetamide
2-(l,3-dihydroisoindol-2-yl)-N-[2-methyl-5-[4-[4-(trifluoromethyl)phenyl]piperidine-l- carbonyl]phenyl]acetamide
2-(azetidin-l-yl)-N-[2-methyl-5-[4-[4-(trifluoromethyl)phenyl]piperidine-l- carbonyl]phenyl]acetamide
2-(cyclohexyl-ethyl-amino)-N- [2-methyl-5 - [4- [4-(trifluoromethyl)phenyl]piperidine- 1 - carbonyl]phenyl]acetamide N-[2-methyl-5-[4-[4-(trifluorometliyl)phenyl]piperidine- 1 -carbonyl]phenyl]-2-morpholin-
4-yl-acetamide
1 - [ [2-methy 1-5 - [4- [4-(trifluoromethyl)phenyl]piperidine- 1 - carbonyl]phenyl]carbamoylmethyl]piperidine-4-carboxamide
2-(4-hydroxy-l-piperidyl)-N-[2-methyl-5-[4-[4-(trifluoromethyl)phenyl]piperidine-l- carbonyl]phenyl]acetamide
2-(methyl-propyl-amino)-N-[2-methyl-5-[4-[4-(trifluoromethyl)phenyl]piperidine-l- carbonyl]phenyl]acetamide
2-(2-dimethylaminoethyl-methyl-amino)-N-[2-metliyl-5-[4-[4-
(trifluoroniethyl)phenyl]piperidme-l-carbonyl]phenyl]acetamide 2-(methyl-propan-2-yl-amino)-N-[2-methyl-5-[4-[4-(trifluoromethyl)phenyl]piperidine- 1 - carbonyl]phenyl]acetamide
2-(butyl-methyl-amino)-N-[2-methyl-5-[4-[4-(trifluoromethyl)phenyl]piperidine-l- carbonyl]phenyl]acetamide
2-(2-hydroxyethyl-methyl-amino)-N-[2-methyl-5-[4-[4- (trifluoromethyl)phenyl]piperidine- 1 -carbonyl]phenyl]acetamide
2-(2-furylmethyl-methyl-amino)-N-[2-methyl-5-[4-[4-(trifluoromethyl)phenyl]piperidine-
1 -carbonyl]phenyl]acetamide 2-[4-(hydroxymethyl)- 1 -piperidyl]-N-[2-methyl-5-[4-[4-
(trifluoromethyl)phenyl]piperidine-l-carbonyl]phenyl]acetamide
4-(methylaminomethyl)-N-[2-methyl-5-[4-[4-(trifluoromethyl)phenyl]piperidine-l- carbonyl]phenyl]benzamide 4-(dimethylaminomethyl)-N-[2-methyl-5-[4-[4-(trifluoromethyl)phenyl]piperidine- 1 - carbonyl]phenyl]benzamide
6-hydroxy-N-[2-methyl-5-[4-[4-(trifluoromethyl)phenyl]piperidine-l- carbonyl]phenyl]pyridine-3-carboxamide
N-[5-[4-[4-(aminomethyl)phenyl]piperidine-l-carbonyl]-2-methyl-phenyl]-6- dimethylamino-pyridine-3-carboxamide
N-[5-[4-(4-chlorophenyl)piperidine- 1 -carbonyl]-2-methyl-phenyl]-6-methyl- 1 -oxido- pyridine-3 -carboxamide
N- [5 - [4-(4-chlorophenyl)piperidine- 1 -carbonyl] -2-methyl-pheny 1] - 1 -oxido-6-
(trifluoromethyl)pyridine-3-carboxamide N-[2-methyl-5-[4-[4-(trifluoromethyl)phenyl]piperidine- 1 -carbonyl]phenyl]- 1 -oxido- pyridine-4-carboxamide
N-[5-[4-[4-[(4-fluorophenyl)methylcarbamoyl]phenyl]piperidine-l-carbonyl]-2-methyl- phenyl]pyridine-4-carboxamide
N-[5-[4-[4-(benzyl-methyl-carbamoyl)phenyl]piperidine-l-carbonyl]-2-methyl- phenyl]pyridine-4-carboxamide
N-[2-methyl-5-[4-[4-(moφholine-4-carbonyl)phenyl]piperidine-l- carbonyl]phenyl]pyridine-4-carboxamide
5-[[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]carbamoyl]pyridine-2- carboxylic acid 5-[[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]carbamoyl]pyridine-3- carboxylic acid
N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]-N',N'-dimethyl- pyridine-3,5-dicarboxamide
N'-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]pyridine-2,5- dicarboxamide
N'-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]-N,N-dimethyl-pyridine-
2,5-dicarboxamide N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]-6-(l,l-dioxo-l,4- thiazinan-4-yl)pyridine-3-carboxamide
2-[[5-[[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]carbamoyl]pyridin-2- yl] amino] acetic acid N-[2-chloro-5-[4-(4-cyanophenyl)piperidine-l-carbonyl]phenyl]-6-(3-oxopiperazin-l- yl)pyridine-3-carboxamide
N-[2-chloro-5-[4-(4-cyanophenyl)piperidine-l-carbonyl]phenyl]-6-dimethylamino- pyridine-3 -carboxamide
N- [2-chloro-5 - [4-(4-cyanophenyl)piperidine- 1 -carbonyl]phenyl]pyridine-3 -carboxamide N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]-2-phenyl-acetamide
N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methoxy-phenyl]pyridine-4- carboxamide
N- [5 - [4-(4-cyanophenyl)piperidine- 1 -carbonyl] -2-methyl-phenyl] -2-pyridin-3 -yl- acetamide N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-(trifluoromethoxy)phenyl]pyridine-4- carboxamide
N-[5-[4-(4-cyanophenyl)piperidine- 1 -carbonyl]-2-(trifluoromethoxy)phenyl]-6-oxo- IH- pyridine-3-carboxamide
6-acetamido-N-[5-[4-(4-cyanophenyl)piperidine- 1 -carbonyl]-2- (trifluoromethoxy)phenyl]pyridine-3-carboxamide
N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-fluoro-phenyl]pyridine-4-carboxamide
N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]-2-pyridin-4-yl- acetamide;
N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methoxy-phenyl]-2-methyl- propanamide;
N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-(trifluoromethoxy)phenyl]-6-moφholin-
4-yl-pyridine-3 -carboxamide ;
N-[5-[4-(4-cyanophenyl)piperidine- 1 -carbonyl]-2,4-dimethyl- phenyl] cyclobutanecarboxamide; 6-acetamido-N-[5-[4-(4-cyanophenyl)piperidine- 1 -carbonyl]-2-methoxy-phenyl]pyridine-
3-carboxamide; N- [5 - [4-(4-cyanopheny l)piperidine- 1 -carbonyl] -2,4-dimethyl-phenyl] -6-oxo- 1 H-pyridine-
3-carboxamide;
N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2,4-dimethyl-phenyl]-6-morpholin-4-yl- pyridine-3-carboxamide; 5 N-[5 - [4-(4-cyanopheny l)piperidine- 1 -carbonyl] -2-methoxy-pheny 1] -6-oxo- 1 H-pyridine-3 - carboxamide;
N-[5-[4-(4-cyanopheiiyl)piperidine-l-carbonyl]-2-(trifluoromethyl)phenyl]pyridine-4- carboxamide; and
N-[5-[4-(4-cyanophenyl)piperidine-l-carbonyl]-2-methyl-phenyl]-6-thiomorpholin-4-yl-Q pyridine-3 -carboxamide or a pharmaceutically-acceptable salt thereof.
12) A method of treating obesity or being overweight, eating disorders, dyslipidaemia and type 2 diabetes mellitus comprising administering a pharmacologically effectives amount of a compound of formula I as defined in any one of claims 1 to 11 to a patient in need thereof.
13) A pharmaceutical formulation comprising a compound of formula I as claimed in any one of claims 1 to 11, or pharmaceutically acceptable salt thereof, including theo compound of the proviso, in admixture with pharmaceutically acceptable adjuvants, diluents and/or carriers.
14) A process for preparing a compound of formula I or a pharmaceutically acceptable salt thereof wherein R1, R2, R3, R4, R5, R5', R6, R6, L, m and n are, unless otherwise5 specified, as defined in claim 1 which process comprises: (a) reacting a compound of formula VI
Figure imgf000187_0001
Vl with a compound of formula VII
R1COX vπ in which X represents a leaving group in the presence of a diluent and optionally in the presence of a base at a temperature in the range of 0- 1500C b) reacting a compound of formula VI
Figure imgf000188_0001
Vl
with a compound of formula VIII
R1COOH VIII
optionally in the presence of a coupling agent and optionally in the presence of a diluent at a temperature in the range of 0°C - 1000C or the boiling point of the diluent, whichever is the lower c) reacting a compound of formula IX
Figure imgf000188_0002
IX with a compound of formula X
Figure imgf000189_0001
X optionally in the presence of a coupling agent and optionally in the presence of a diluent d) reacting a compound of formula IX
Figure imgf000189_0002
IX with a compound of formula XI
Figure imgf000189_0003
Xl in which X represents a leaving group in the presence of a diluent and optionally in the presence of a base at a temperature in the range of 0-1500C; e) reacting a compound of formula XII
Figure imgf000189_0004
in which X represents a replaceable group with a compound of formula XIII
R1C(O)NH2 XIII in the presence of a metal catalyst and of a solvent at a temperature in the range 0 - 150°C; or f) reacting a compound of formula XIV
Figure imgf000190_0001
XIV with a compound of formula XV in which X represents a replaceable group with a compound of formula XV
Figure imgf000190_0002
XV in the presence of carbon monoxide and in the presence of a metal catalyst and in a solvent at a temperature in the range 0 - 150°C. 15) A compound of formula VI
Figure imgf000190_0003
Vl
Figure imgf000190_0004
R)4 4, R5, R ,5^' R6, R j 6b' , L, m and n are as defined in claim 1.
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US8304547B2 (en) 2007-10-24 2012-11-06 Astellas Pharma Inc. Azolecarboxamide compound or salt thereof
WO2014008197A1 (en) * 2012-07-03 2014-01-09 3-V Biosciences, Inc. Heterocyclic modulators of lipid synthesis
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