WO2011073316A1 - 4-aryl-butane-1,3-diamides - Google Patents

4-aryl-butane-1,3-diamides Download PDF

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WO2011073316A1
WO2011073316A1 PCT/EP2010/069889 EP2010069889W WO2011073316A1 WO 2011073316 A1 WO2011073316 A1 WO 2011073316A1 EP 2010069889 W EP2010069889 W EP 2010069889W WO 2011073316 A1 WO2011073316 A1 WO 2011073316A1
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methyl
carboxamido
carboxamide
pyrrole
phenylbutan
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PCT/EP2010/069889
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French (fr)
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Claudia Betschart
Simona Cotesta
Samuel Hintermann
Jürgen Wagner
Bernard Lucien Roy
Marc Gerspacher
Anette Von Matt
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Novartis Ag
Behnke, Dirk
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Publication of WO2011073316A1 publication Critical patent/WO2011073316A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Definitions

  • the invention relates to 4-aryl-butane-1 , 3-diamides, to their preparation, to their use as medicaments and to medicaments comprising them.
  • Orexins (orexin A OX-A and orexin B/OX-B), which are also known as hypocretins, are neuropeptides. Orexin A is a 33 amino acid peptide and orexin B is a 28 amino acid peptide (Sakurai T. et al., Cell, 1998, 92, 573-585). Orexins are produced in discrete neurons of the lateral hypothalamus and bind to G-protein-coupled receptors, the orexin receptors (also known as hypocretin receptors): known are the orexin-1 receptor (OX1R) and the orexin-2 receptor (OX2R).
  • Orexin A is a 33 amino acid peptide
  • orexin B is a 28 amino acid peptide (Sakurai T. et al., Cell, 1998, 92, 573-585). Orexins are produced in discrete neurons of the lateral hypothalamus and bind to G-protein-coupled receptors, the orex
  • the orexin-1 receptor has some selectivity for OX-A, whereas the orexin-2 receptor binds OX-A and OX-B with similar affinity. Orexins regulate states of sleep and wakefulness, opening potentially novel therapeutic approaches for narcolepsy as well as insomnia and other sleep disorders (Chemelli R.M. et al., Cell, 1999, 98, 437-45 1).
  • orexins were found to stimulate food consumption in rats suggesting a physiological role for these peptides as mediators in the central feedback mechanism that regulates feeding behavior (Sakurai T. et al., Cell, 1998, 92, 573-585). Still furthermore, orexins were shown to play a role in brain reward function/motivation suggesting usefulness to treat substance-related disorders (Harris A.C. et al, Nature, 2005, 437, 556-559).
  • amyloid beta levels inversely correlate with orexin levels in rodents and humans (brain and/or CSF), and that an orexin receptor antagonist reduces both amyloid beta levels and amyloid plaque load in Alzheimer's transgenic mice, thus suggesting usefulness in the treatment of Alzheimers disease (Kang J.E. et al, Science 2009, 326, 1005-1007).
  • Orexin receptors may have numerous implications in disorders such as
  • sleep disorders e.g. sleep apnea, narcolepsy, insomnia, parasomnia, jet lag syndrome, disturbed biological and circadian rhythms; sleep disturbances associated with diseases such as neurological disorders, neuropathic pain and restless leg syndrome;
  • eating disorders e.g. appetite and taste disorders
  • substance-related disorders e.g. substance abuse, substance dependence and substance withdrawal disorders, such as nicotine withdrawal or narcotics withdrawal;
  • psychiatric neurological and neurodegenerative disorders, e.g. depression; anxiety;
  • addictions obsessive compulsive disorder
  • affective neurosis depressive neurosis
  • anxiety neurosis dysthymic disorder
  • mood disorder sexual dysfunction
  • psychosexual dysfunction psychosexual dysfunction
  • sex disorder schizophrenia; manic depression; delirium; dementia; severe mental retardation and dyskinesias such as Huntington's disease and Tourette syndrome; Parkinson's disease; ischemic or hemorrhagic stroke; migraine; and neurodegenerative disorders including nosological entities such as disinhibition-dementia-parkinsonism-amyotrophy complex;
  • cardiovascular diseases diabetes; asthma; Cushing's syndrome/disease; basophile adenoma; prolactinoma; hyperprolactinemia; hypopituitarism; hypophysis tumor/adenoma; hypothalamic diseases; Froehlich's syndrome; hypophysis diseases, hypothalamic hypogonadism; Kallman's syndrome (anosmia, hyposmia); functional or psychogenic amenorrhea; hypopituitarism; hypothalamic hypothyroidism; hypothalamic-adrenal dysfunction; idiopathic hyperprolactinemia; hypothalamic disorders of growth hormone deficiency; idiopathic growth deficiency; dwarfism; gigantism; acromegaly; heart and lung diseases, acute and congestive heart failure; hypotension; hypertension; urinary retention; osteoporosis; angina pectoris; myocardial infarction; subarachnoid hemorrhage
  • allergies benign prostatic hypertrophy; chronic renal failure; renal disease; impaired glucose tolerance; vomiting and nausea; inflammatory bowel disease; gastric dyskinesia; gastric ulcers; urinary bladder incontinence e.g. urge incontinence; hyperalgesia; pain; enhanced or exaggerated sensitivity to pain such as hyperalgesia, causalgia, and allodynia; acute pain; burn pain; atypical facial pain; neuropathic pain; back pain; complex regional pain syndrome I and II; arthritic pain; sports injury pain; pain related to infection e.g. HIV, post-chemotherapy pain; post-stroke pain; post-operative pain; neuralgia; conditions associated with visceral pain such as irritable bowel syndrome, migraine and angina; and
  • Orexin receptor antagonists are considered to be useful in the treatment of a wide range of disorders, in particular sleep disorders, eating disorders and substance-related disorders.
  • preferred compounds should bind potently to the orexin receptors (either as OX1 R or OX2R subtype selective antagonists or as dual OX1 R/OX2R antagonists) whilst showing little affinity for other receptors. They should be well absorbed from the gastrointestinal tract, be sufficiently metabolically stable and possess favorable
  • the ideal drug candidate When targeted against receptors in the central nervous system they should cross the blood brain barrier freely and when targeted selectively against receptors in the peripheral nervous system they should not cross the blood brain barrier. They should be non-toxic and demonstrate few side-effects. Furthermore, the ideal drug candidate will be able to exist in a physical form that is stable, non-hygroscopic and easily formulated.
  • the compounds of the invention are orexin receptor antagonists and are therefore potentially useful in the treatment of a wide range of disorders, particularly sleep disorders, eating disorders, substance-related disorders and Alzheimers disease.
  • the invention relates to a compound of the formula I
  • Ri is C 1-6 alkyl, C -6 halogenalkyl, C 3 . 7 cycloalkyl or C 3-7 cycloalkyl(C - alkyl);
  • R2, R3, R5 and R 6 are each independently selected from hydrogen, halogen, hydroxyl, C ⁇ .
  • R 2 and R 3 together with the carbon atom to which they are bound form a C 3 . 7 cycloalkyl; or R 5 and R 6 together are oxo;
  • R 5 and R 6 together with the carbon atom to which they are bound form a C 3 . 7 cycloalkyl;
  • R 4 is hydrogen or C 1-6 alkyl;
  • A is a group A1 , A2, A3 or A4
  • A1a is a five- to six-membered monocyclic aromatic ring system which contains from 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur, wherein the ring system may contain not more than 2 oxygen atoms and not more than 2 sulfur atoms, and wherein the ring system may be substituted once or more than once by R 7 , and wherein a substituent on a nitrogen in a heterocyclic ring system may not be halogen;
  • A1 b is a five- to six-membered monocyclic aromatic ring system which may contain from 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur, wherein the ring system may contain not more than 2 oxygen atoms and not more than 2 sulfur atoms, and wherein the ring system is fused to ring system A1a via carbon and/or nitrogen atoms, and wherein the ring system may be substituted once or more than once by R 8 , and wherein a substituent on a nitrogen in a heterocyclic ring system may not be halogen;
  • each R 7 or R 8 independently is halogen, C 1-6 alkyl, d. 6 halogenalkyl, C 3-7 cycloalkyl, C 3 .
  • A2a is a five- to six-membered monocyclic aromatic ring system which contains from 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur, wherein the ring system may contain not more than 2 oxygen atoms and not more than 2 sulfur atoms, and wherein the ring system is fused to the phenyl ring via two carbon atoms, and wherein the ring system may be substituted once or more than once by R 10 , and wherein a substituent on a nitrogen in a heterocyclic ring system may not be halogen;
  • n 0, 1 , 2 or 3;
  • each R 9 or R 10 independently is halogen, C 1-6 alkyl, C 1-6 halogenalkyl, C 3-7 cycloalkyl, C 3- 7 cycloalkyl(Ci -4 alkyl), C 1-6 alkoxy, or C 1-6 halogenalkoxy;
  • each of A3a or A3b is independently a five- to six-membered monocyclic aromatic ring system which may contain from 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur, wherein the ring system may contain not more than 2 oxygen atoms and not more than 2 sulfur atoms, and wherein the ring system may be substituted once or more than once by Rn, and wherein a substituent on a nitrogen in a heterocyclic ring system may not be halogen;
  • each R independently is halogen, C 1-6 alkyl, C 1-6 halogenalkyl, C 3-7 cycloalkyl, C 3 .
  • A4a is a five- to six-membered monocyclic aromatic ring system which contains from 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur, wherein the ring system may contain not more than 2 oxygen atoms and not more than 2 sulfur atoms, and wherein the ring system is substituted once or more than once by R 12 , and wherein a substituent on a nitrogen in a heterocyclic ring system may not be halogen; each R 12 independently is halogen; C 1-6 alkyl; C 1-6 halogenalkyl; C 1-6 all ⁇ oxy; or 6 halogenalkoxy; or a three- to eight-membered monocyclic or bicyclic saturated or unsaturated non-aromatic ring system which may contain from 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur, wherein the saturated or unsaturated non-aromatic ring system may contain not more than 2 oxygen atoms and not more than 2 sulfur atoms, wherein the saturated or unsaturated non-aromatic
  • each R 13 independently is halogen, C 1-6 alkyl, C 1-6 halogenalkyl, C 3 . 7 cycloalkyl, C 3-
  • each R 1 independently is halogen or C 1-6 alkyl, or two R 14 at the same ring atom of the fused unsaturated non-aromatic ring system together are oxo;
  • p is 0 or 1 ;
  • Ri5 is halogen, C 1-6 alkyl, C 1-6 halogenalkyl, C 3 . 7 cycloalkyl, C 1-6 alkoxy, or C 1-6 halogenalkoxy;
  • C is a five- to ten-membered monocyclic or fused polycyclic aromatic ring system which may contain from 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur, wherein the ring system may contain not more than 2 oxygen atoms and not more than 2 sulfur atoms, and wherein the ring system may be substituted once or more than once by Ri 6 , and wherein a substituent on a nitrogen in a heterocyclic ring system may not be halogen; each R 6 independently is d -6 alkyl; C -6 halogenalkyl; C -6 alkoxy; C -6 halogenalkoxy; halogen; cyano; or two R 6 at adjacent ring atoms of the ring system C form together with said ring atoms a fused five- to seven-membered unsaturated non-aromatic ring system which may contain from 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur, wherein the fused unsaturated non-aromatic ring system may contain not
  • Alkyl represents a straight-chain or branched-chain alkyl group, for example, methyl, ethyl, n- or iso-propyl, n-, iso-, sec- or tert-butyl, n-pentyl, n-hexyl;
  • C -6 alkyl preferably represents a straight-chain or branched-chain C -4 alkyl with particular preference given to methyl, ethyl, n- propyl, iso-propyl and tert-butyl.
  • C 2 .6alkyl preferably represents a straight-chain or branched- chain C 2-4 alkyl with particular preference given to ethyl, n-propyl, iso-propyl and tert-butyl.
  • alkyl part of "alkoxy”, “halogenalkyl” and so on shall have the same meaning as described in the above-mentioned definition of “alkyl”, especially regarding linearity and preferential size.
  • C3 -7 cycloalkyl represents a saturated alicyclic moiety having from three to seven carbon atoms. This term refers to groups such as cyclopropyl, cyclobutyl, cyclopentyl and
  • alkylene refers to divalent alkyl group as defined herein, for example methylene, ethylene, n-propylene, / ' so-propylene, n-butylene, sec-butylene, iso- butylene, and terf-butylene.
  • a substituent being substituted "once or more than once", for example as defined for A1 a, is preferably substituted by one to three substituents.
  • Halogen is generally fluorine, chlorine, bromine or iodine; preferably fluorine, chlorine or bromine.
  • Halogenalkyl groups preferably have a chain length of 1 to 4 carbon atoms and are, for example, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 2-fluoroethyl, 2-chloroethyl, pentafluoroethyl, 1 ,1-difluoro- 2,2,2-trichloroethyl, 2,2,2-trichloroethyl, 1 , 1 ,2,2-tetrafluoroethyl, 2,2,3,3-tetrafluoropropyl, 2,2,3,3,3-pentafluoropropyl or 2,2,3,4,4,4-hexafluorobutyl; preferably -CF 3 , -CHF 2 , -CH 2
  • A1b, A3a and/or A3b as a "five- to six- membered monocyclic aromatic ring system which may contain from 1 to 4 heteroatoms" encompasses a C 6 -aromatic hydrocarbon group or a five- to six-membered heterocyclic aromatic ring system.
  • C as a "five- to ten-membered monocyclic or fused polycyclic aromatic ring system which may contain from 1 to 4 heteroatoms" encompasses a C 6 - or C 10 -aromatic hydrocarbon group or a five- to ten-membered heterocyclic aromatic ring system.
  • Polycyclic means preferably bicyclic.
  • fused polycyclic aromatic ring system refers to an aromatic sustituent which consists of multiple, e.g. two, aromatic rings that are fused together.
  • R 12 as a "three- to eight-membered monocyclic or bicyclic saturated or unsaturated non-aromatic ring system which may contain from 1 to 4 heteroatoms" encompasses three- to eight membered monocyclic or bicyclic non- aromatic hydrocarbon groups and non-aromatic heterocyclic ring systems of the same sizes.
  • two R 12 or two R 16 as a "fused five- to seven- membered unsaturated non-aromatic ring system” encompasses five- to seven-membered non-aromatic hydrocarbon and heterocyclic groups which comprise at least one double- bond, which is shared with the aromatic ring system they are fused to.
  • a C 6 - or do-aromatic hydrocarbon group is typically phenyl or naphthyl, especially phenyl.
  • five- to six-membered heterocyclic aromatic ring systems consist of 5 to 6 ring atoms of which 1-3 ring atoms are hetero atoms.
  • heterocyclic ring systems are: imidazo[2,1-b]thiazole, pyrrole, pyrroline, pyrrolidine, pyrazole, pyrazoline, pyrazolidine, imidazole, imidazoline, imidazolidine, triazole, triazoline, triazolidine, tetrazole, furane, dihydrofurane, tetrahydrofurane, furazane
  • heterocycles are: imidazo[2,1-b]thiazole, oxazole, isoxazole, thiazole, isothiazole, triazole, pyrrole, furane, tetrahydrofurane, pyridine, pyrimidine, imidazole or pyrazole.
  • the compounds of formula I exist in optically active form or in form of mixtures of optical isomers, e.g. in form of racemic mixtures or diastereomeric mixtures.
  • further asymmetrical carbon atom(s) may be present in the compounds of formula I and their salts.
  • all optical isomers and their mixtures, including the racemic mixtures, are embraced by the invention.
  • the term “isomers” refers to different compounds that have the same molecular formula but differ in arrangement and configuration of the atoms.
  • an optical isomer or “a stereoisomer” refers to any of the various stereo isomeric configurations which may exist for a given compound of the invention and includes geometric isomers. It is understood that a substituent may be attached at a chiral center of a carbon atom. Therefore, the invention includes enantiomers, diastereomers or racemates of the compound. "Enantiomers” are a pair of stereoisomers that are non- superimposable mirror images of each other.
  • a 1 : 1 mixture of a pair of enantiomers is a "racemic" mixture.
  • the term is used to designate a racemic mixture where appropriate.
  • "Diastereoisomers” are stereoisomers that have at least two asymmetric atoms, but which are not mirror-images of each other.
  • the absolute stereochemistry is specified according to the Cahn- Ingold- Prelog R-S system. When a compound is a pure enantiomer the stereochemistry at each chiral carbon may be specified by either R or S. Resolved compounds whose absolute stereochemistry
  • the compounds described herein contain one or more asymmetric centers and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R)- or (S)-.
  • the invention is meant to include all such possible isomers, including racemic mixtures, optically pure forms and intermediate mixtures.
  • Optically active (R)- and (S)- isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituent may be E or Z configuration. If the compound contains a disubstituted cycloalkyl, the cycloalkyl substituent may have a cis- or trans-configuration.
  • any asymmetric atom (e.g. carbon or the like) of the compound(s) of the invention can be present in racemic or enantiomerically enriched, for example the ( ?)-, (S)- or (Reconfiguration.
  • each asymmetric atom has at least 50 %
  • a compound of the invention can be in the form of one of the possible isomers, rotamers, atropisomers, tautomers or mixtures thereof, for example, as substantially pure geometric (cis or trans) isomers, diastereomers, optical isomers
  • Any resulting mixtures of isomers can be separated on the basis of the physicochemical differences of the constituents, into the pure or substantially pure geometric or optical isomers, diastereomers, racemates, for example, by chromatography and/or fractional crystallization.
  • any resulting racemates of final products or intermediates can be resolved into the optical antipodes by known methods, e.g., by separation of the diastereomeric salts thereof, obtained with an optically active acid or base, and liberating the optically active acidic or basic compound.
  • a basic moiety may thus be employed to resolve the compounds of the invention into their optical antipodes, e.g., by fractional crystallization of a salt formed with an optically active acid, e.g., tartaric acid, dibenzoyl tartaric acid, diacetyl tartaric acid, di-0,0'-p-toluoyl tartaric acid, mandelic acid, malic acid or camphor-10-sulfonic acid.
  • Racemic products can also be resolved by chiral chromatography, e.g., high pressure liquid chromatography (HPLC) using a chiral adsorbent.
  • HPLC high pressure liquid chromatography
  • compounds of formula I may occur in various tautomeric forms. All tautomeric forms of the compounds of formula I are embraced by the invention.
  • Compounds of formula I may exist in free form or as a salt. In this specification, unless otherwise indicated, language such as "compound of formula I" is to be understood as embracing the compounds in any form, for example free or acid addition salt form. Salts which are unsuitable for pharmaceutical uses but which can be employed, for example, for the isolation or purification of free compounds of formula I, such as picrates or perchlorates, are also included. For therapeutic use, only pharmaceutically acceptable salts or free compounds are employed (where applicable in the form of pharmaceutical preparations), and are therefore preferred. Salts are preferably physiologically acceptable salts, formed by the addition of an acid.
  • the term "pharmaceutically acceptable salts” refers to salts that retain the biological effectiveness and properties of the compounds of this invention and, which typically are not biologically or otherwise undesirable.
  • the compounds of the invention may be capable of forming acid salts by virtue of the presence of suitable groups, such as amino groups.
  • Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids, e.g., acetate, aspartate, benzoate, besylate, bromide/hydrobromide, bicarbonate/carbonate, bisulfate/sulfate, camphorsulfornate, chloride/hydrochloride, chlortheophyllonate, citrate, ethandisulfonate, fumarate, gluceptate, gluconate, glucuronate, hippurate, , hydroiodide/iodide, isethionate, lactate, lactobionate, laurylsulfate, malate, maleate, malonate, mandelate, mesylate, methylsulphate, naphthoate, napsylate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate/hydrogen
  • Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.
  • Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid,
  • the pharmaceutically acceptable salts of the invention can be synthesized from a parent compound by conventional chemical methods. Generally, such salts can be prepared by reacting free base forms of these compounds with a stoichiometric amount of the appropriate acid. Such reactions are typically carried out in water or in an organic solvent, or in a mixture of the two. Generally, non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred, where practicable.
  • the invention includes all pharmaceutically acceptable isotopically-labeled compounds of the invention, i.e. compounds of formula (I), wherein (1) one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature, and/or (2) the isotopic ratio of one or more atoms is different from the naturally occurring ratio.
  • compounds of formula (I) wherein (1) one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature, and/or (2) the isotopic ratio of one or more atoms is different from the naturally occurring ratio.
  • isotopes suitable for inclusion in the compounds of the invention comprises isotopes of hydrogen, such as 2 H and 3 H, carbon, such as 11 C, 13 C and 14 C, chlorine, such as 36 CI, fluorine, such as 18 F, iodine, such as 123 l and 125 l, nitrogen, such as 13 N and 15 N, oxygen, such as 15 0, 17 0 and 18 0, phosphorus, such as 32 P, and sulfur, such as 35 S.
  • hydrogen such as 2 H and 3 H
  • carbon such as 11 C, 13 C and 14 C
  • chlorine such as 36 CI
  • fluorine such as 18 F
  • iodine such as 123 l and 125 l
  • nitrogen such as 13 N and 15 N
  • oxygen such as 15 0, 17 0 and 18 0, phosphorus, such as 32 P
  • sulfur such as 35 S.
  • isotopically-labeled compounds of formula (I), for example, those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies.
  • the radioactive isotopes tritium, i.e. 3 H, and carbon-14, i.e. 14 C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.
  • substitution with heavier isotopes such as deuterium, i.e. 2 H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances.
  • Isotopically-labeled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and Preparations using an appropriate isotopically-labeled reagents in place of the non-labeled reagent previously employed.
  • solvates in accordance with the invention include those wherein the solvent of crystallization may be isotopically substituted, e.g. D 2 0, d 6 -acetone, d 6 -DMSO.
  • Compounds of the invention i.e. compounds of formula (I) that contain groups capable of acting as donors and/or acceptors for hydrogen bonds may be capable of forming co-crystals with suitable co-crystal formers.
  • These co-crystals may be prepared from compounds of formula (I) by known co-crystal forming procedures. Such procedures include grinding, heating, co-subliming, co-melting, or contacting in solution compounds of formula I with the co-crystal former under crystallization conditions and isolating co-crystals thereby formed.
  • Suitable co-crystal formers include those described in WO 2004/078163.
  • the invention further provides co-crystals comprising a compound of formula (I).
  • the invention also provides pro-drugs of the compounds of the invention that converts in vivo to the compounds of the invention.
  • a pro-drug is an active or inactive compound that is modified chemically through in vivo physiological action, such as hydrolysis, metabolism and the like, into a compound of this invention following administration of the prodrug to a subject.
  • the suitability and techniques involved in making and using pro-drugs are well known by those skilled in the art.
  • Prodrugs can be conceptually divided into two non-exclusive categories, bioprecursor prodrugs and carrier prodrugs. See The Practice of Medicinal Chemistry, Ch. 31-32 (Ed. Wermuth, Academic Press, San Diego, Calif., 2001).
  • bioprecursor prodrugs are compounds, which are inactive or have low activity compared to the corresponding active drug compound, that contain one or more protective groups and are converted to an active form by metabolism or solvolysis. Both the active drug form and any released metabolic products should have acceptably low toxicity.
  • Carrier prodrugs are drug compounds that contain a transport moiety, e.g., that improve uptake and/or localized delivery to a site(s) of action. Desirably for such a carrier prodrug, the linkage between the drug moiety and the transport moiety is a covending bond, the prodrug is inactive or less active than the drug compound, and any released transport moiety is acceptably non-toxic.
  • Carrier prodrugs can, for example, be used to improve one or more of the following properties: increased lipophilicity, increased duration of
  • lipophilicity can be increased by esterification of hydroxyl groups with lipophilic carboxylic acids (e.g., a carboxylic acid having at least one lipophilic moiety).
  • Exemplary prodrugs are, e.g., O-acyl derivatives of alcohols.
  • Preferred are pharmaceutically acceptable ester derivatives convertible by solvolysis under physiological conditions to the parent carboxylic acid, e.g., lower alkyl esters, cycloalkyl esters, lower alkenyl esters, benzyl esters, mono- or di-substituted lower alkyl esters, such as the co-(amino, mono- or di-lower alkylamino, carboxy, lower alkoxycarbonyl)-lower alkyl esters, the a-(lower alkanoyloxy, lower alkoxycarbonyl or di-lower alkylaminocarbonyl)-lower alkyl esters, such as the pivaloyloxymethyl ester and the like conventionally used in the art.
  • amines have been masked as arylcarbonyloxymethyl substituted derivatives which are cleaved by esterases in vivo releasing the free drug and formaldehyde (Bundgaard, J. Med. Chem. 2503 (1989)).
  • drugs containing an acidic NH group such as imidazole, imide, indole and the like, have been masked with N-acyloxymethyl groups (Bundgaard, Design of Prodrugs, Elsevier (1985)). Hydroxy groups have been masked as esters and ethers.
  • EP 039,051 (Sloan and Little) discloses Mannich-base hydroxamic acid prodrugs, their preparation and use.
  • the compounds of the invention can also be obtained in the form of their hydrates, or include other solvents used for their crystallization.
  • Preferred substituents, preferred ranges of numerical values or preferred ranges of the radicals present in compounds of the formula I, IA, IB and the corresponding intermediate compounds are defined below.
  • the definition of the substituents applies to the end-products as well as to the corresponding intermediates.
  • the definitions of the substituents may be combined at will, e.g. preferred substituents R 1 and particularly preferred substituents R 2 .
  • the invention relates to one or more than one of the compounds of the formula I mentioned in the Examples hereinafter, in free form or in salt form.
  • One class of compounds of the invention are compounds of formula IA
  • R ⁇ R 2 , R 3 , R 4l R 5 , R 6 , A, B and C are as defined under formula (I).
  • One class of compounds of the invention are compounds of formula IB
  • R ⁇ R 2 , R 3 , R 4 , R 5 , Re, A, B and C are as defined under formula (I).
  • C - alkyl for example, methyl, ethyl or n- propyl. In one class of compounds of the invention, is methyl.
  • R 2 , R 3 , R 5 and R 6 are each independently selected from hydrogen, halogen, and C -4 alkyl. In one class of compounds of the invention, R2, R3, R5 and R 6 are each hydrogen.
  • R is hydrogen or C -4 alkyl. In one class of compounds of the invention, R is hydrogen. ln one class of compounds of the invention, A is a ring system selected from A1 , A2, A3 or
  • A1a is a five- to six-membered monocyclic aromatic ring system which contains from 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur, wherein the ring system may contain not more than 2 oxygen atoms and not more than 2 sulfur atoms, and wherein the ring system may be substituted once or more than once by R 7 , and wherein a substituent on a nitrogen in a heterocyclic ring system may not be halogen;
  • A1 b is a five- to six-membered monocyclic aromatic ring system which may contain from 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur, wherein the ring system may contain not more than 2 oxygen atoms and not more than 2 sulfur atoms, and wherein the ring system is fused to ring system A1 a via carbon and/or nitrogen atoms, and wherein the ring system may be substituted once or more than once by R 8 , and wherein a substituent on a nitrogen in a heterocyclic ring system may not be halogen;
  • each R 7 or R 8 independently is halogen, C h alky!, C 1-6 halogenalkyl, C 3-7 cycloalkyl, C 3- 7 cycloalkyl(C -4 alkyl), C -6 alkoxy, or C 1-6 halogenalkoxy;
  • A2a is a six-membered monocyclic aromatic ring system which contains from 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur, wherein the ring system may contain not more than 2 oxygen atoms and not more than 2 sulfur atoms, and wherein the ring system is fused to the phenyl ring via two carbon atoms, and wherein the ring system may be substituted once or more than once by R 0 , and wherein a substituent on a nitrogen in a heterocyclic ring system may not be halogen;
  • n 0, 1 , 2 or 3;
  • each R 9 or R 10 independently is halogen, C 1-6 alkyl, C ⁇ halogenalkyl, C 3-7 cycloalkyl, C 3- 7 cycloalkyl(C 1 4 alkyl), C 1 6 alkoxy, or C 1 6 halogenalkoxy;
  • each of A3a or A3b is independently a five- to six-membered monocyclic aromatic ring system which may contain from 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur, wherein the ring system may contain not more than 2 oxygen atoms and not more than 2 sulfur atoms, and wherein the ring system may be substituted once or more than once by Ru, and wherein a substituent on a nitrogen in a heterocyclic ring system may not be halogen;
  • each Ru independently is halogen, C 1-6 alkyl, C 1-6 halogenalkyl, C 3-7 cycloalkyl, C 3 .
  • A4a is a five- to six-membered monocyclic aromatic ring system which contains from 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur, wherein the ring system may contain not more than 2 oxygen atoms and not more than 2 sulfur atoms, and wherein the ring system is substituted once or more than once by R 12 , and wherein a substituent on a nitrogen in a heterocyclic ring system may not be halogen;
  • each R 12 independently is halogen; C 1-6 alkyl; Ci -6 halogenalkyl; C 1-6 alkoxy; or d.
  • ehalogenalkoxy or a three- to eight-membered monocyclic or bicyclic saturated or unsaturated non-aromatic ring system which may contain from 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur, wherein the saturated or unsaturated non-aromatic ring system may contain not more than 2 oxygen atoms and not more than 2 sulfur atoms, wherein the saturated or unsaturated non-aromatic ring system may be attached directly to the ring system A4a or via a C 1-4 alkylene group, and wherein the saturated or unsaturated non-aromatic ring system may be substituted once or more than once by Ri 3 , and wherein a substituent on a nitrogen in a heterocyclic saturated or unsaturated non-aromatic ring system may not be halogen; or two R 12 at adjacent ring atoms of the ring system A4a form together with said ring atoms a fused five- to seven-membered unsaturated non-aromatic ring system which may
  • each R 13 independently is halogen, C 1-6 alkyl, C 1-6 halogenalkyl, C 3-7 cycloalkyl, C 3 .
  • each Ru independently is halogen or Ci -6 alkyl, or two R 4 at the same ring atom of the fused unsaturated non-aromatic ring system together are oxo.
  • A is A1
  • A1a is a five- to six-membered monocyclic aromatic ring system which contains from 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur, wherein the ring system may contain not more than 2 oxygen atoms and not more than 2 sulfur atoms, and wherein the ring system may be substituted once or more than once by R 7 , and wherein a substituent on a nitrogen in a heterocyclic ring system may not be halogen;
  • A1b is a five- to six-membered monocyclic aromatic ring system which may contain from 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur, wherein the ring system may contain not more than 2 oxygen atoms and not more than 2 sulfur atoms, and wherein the ring system is fused to ring system A1 a via carbon and/or nitrogen atoms, and wherein the ring system may be substituted once or more than once by R 8 , and wherein a substituent on a nitrogen in a heterocyclic ring system may not be halogen;
  • each R 7 or R 8 independently is halogen, C h alky!, C 1-6 halogenalkyl, C 3 . 7 cycloalkyl, C 3 .
  • each R 7 or R 8 independently is halogen, C 1-4 alkyl or C 1-4 halogenalkyl.
  • A is A2
  • A2a is a six-membered monocyclic aromatic ring system which contains from 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur, wherein the ring system may contain not more than 2 oxygen atoms and not more than 2 sulfur atoms, and wherein the ring system is fused to the phenyl ring via two carbon atoms, and wherein the ring system may be substituted once or more than once by Ri 0 , and wherein a substituent on a nitrogen in a heterocyclic ring system may not be halogen;
  • n 0, 1 , 2 or 3; each R 9 or R 0 independently is halogen, C 1-6 alkyl, C 1-6 halogenalkyl, C 3-7 cycloalkyl, C 3 . 7 cycloalkyl(Ci -4 alkyl), C 1-6 alkoxy, or C 1-6 halogenalkoxy.
  • n is 0 and each R 10 independently is halogen, C -4 alkyl or C 1-4 halogenalkyl.
  • A is A2
  • A2a is a five-membered monocyclic aromatic ring system which contains from 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur, wherein the ring system may contain not more than 2 oxygen atoms and not more than 2 sulfur atoms, and wherein the ring system is fused to the phenyl ring via two carbon atoms, and wherein the ring system may be substituted once or more than once by R 0 , and wherein a substituent on a nitrogen in a heterocyclic ring system may not be halogen;
  • n 0, 1 , 2 or 3;
  • each R 9 or R 10 independently is halogen, C -6 alkyl, C 1-6 halogenalkyl, C 3-7 cycloalkyl, C 3- 7 cycloalkyl(C - alkyl), C 1-6 alkoxy, or C 1-6 halogenalkoxy.
  • n is 0 and each R 10 independently is halogen, C 1-4 alkyl or C ⁇ halogenalkyl.
  • A is A2
  • A2a is a five-membered monocyclic aromatic ring system which contains from 2 to 3 hetero atoms selected from nitrogen, oxygen and sulfur, wherein the ring system may contain not more than 2 oxygen atoms and not more than 2 sulfur atoms, and wherein the ring system is fused to the phenyl ring via two carbon atoms, and wherein the ring system may be substituted once or more than once by R 0 , and wherein a substituent on a nitrogen in a heterocyclic ring system may not be halogen; n is 0, 1 , 2 or 3;
  • each R 9 or R 10 independently is halogen, C 1-6 alkyl, Ci -6 halogenalkyl, C 3 -7cycloalkyl, C 3- 7 cycloalkyl(Ci. 4 alkyl), C -6 alkoxy, or Ci -6 halogenalkoxy.
  • n is 0 and each R 10 independently is halogen, C 1-4 alkyl or C ⁇ halogenalkyl.
  • A is A2
  • A2a is a five-membered monocyclic aromatic ring system which contains from 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur, wherein the ring system may contain not more than 2 oxygen atoms and not more than 2 sulfur atoms, and wherein the ring system is fused to the phenyl ring via two carbon atoms, and wherein the ring system is substituted two or three times by R 10 , and wherein a substituent on a nitrogen in a heterocyclic ring system may not be halogen;
  • n 0, 1 , 2 or 3;
  • each R 9 or R 10 independently is halogen, C 1-6 alkyl, Ci -6 halogenalkyl, C 3-7 cycloalkyl, C 3- 7 cycloalkyl(C 1-4 alkyl), d -6 alkoxy, or C 1-6 halogenalkoxy.
  • n is 0 and each R 10 independently is halogen, C 1-4 alkyl or C 1-4 halogenalkyl.
  • A is A3
  • each of A3a or A3b is independently a five- to six-membered monocyclic aromatic ring system which may contain from 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur, wherein the ring system may contain not more than 2 oxygen atoms and not more than 2 sulfur atoms, and wherein the ring system may be substituted once or more than once by Rn, and wherein a substituent on a nitrogen in a heterocyclic ring system may not be halogen; each Rn independently is halogen, C h alky!, C 1-6 halogenalkyl, C 3 - 7 cycloalkyl, C 3 .
  • each Rn independently is halogen, C 1-4 alkyl or C 1-4 halogenalkyl.
  • A is A3
  • A3a is phenyl which may be substituted once or more than once by Rn;
  • A3b is a five- to six-membered monocyclic aromatic ring system which may contain from 1 to
  • hetero atoms selected from nitrogen, oxygen and sulfur wherein the ring system may contain not more than 2 oxygen atoms and not more than 2 sulfur atoms, and wherein the ring system may be substituted once or more than once by Rn, and wherein a substituent on a nitrogen in a heterocyclic ring system may not be halogen;
  • each Rn independently is halogen, C 1-6 alkyl, C 1-6 halogenalkyl, C 3 . 7 cycloalkyl, C 3-
  • each Rn independently is halogen, C -4 alkyl or C 1-4 halogenalkyl.
  • A3a is unsubstituted and each Rn independently is halogen, C 1- alkyl or Ci.
  • A is A3 which is biphenyl which may be substituted once or more than once by Rn.
  • each Rn independently is halogen, C ⁇ alkyl or C 1- halogenalkyl.
  • A is A3 which is unsubstituted biphenyl.
  • A is A3
  • A3a is phenyl which may be substituted once or more than once by R ;
  • A3b is a five- to six-membered monocyclic aromatic ring system which contains from 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur, wherein the ring system may contain not more than 2 oxygen atoms and not more than 2 sulfur atoms, and wherein the ring system may be substituted once or more than once by Rn, and wherein a substituent on a nitrogen in a heterocyclic ring system may not be halogen;
  • each Rn independently is halogen, C 1-6 alkyl, C -6 halogenalkyl, C 3-7 cycloalkyl, C 3- 7 cycloalkyl(C 1- alkyl), C 1-6 alkoxy, or C 1-6 halogenalkoxy.
  • each R independently is halogen, Ci. 4 alkyl or C -4 halogenalkyl.
  • A3a is unsubstituted and each Rn independently is halogen, C 1-4 alkyl or d.
  • A is A4
  • A4a is a five- to six-membered monocyclic aromatic ring system which contains from 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur, wherein the ring system may contain not more than 2 oxygen atoms and not more than 2 sulfur atoms, and wherein the ring system is substituted once or more than once by Ri 2 , and wherein a substituent on a nitrogen in a heterocyclic ring system may not be halogen;
  • each R 12 independently is halogen; C 1-6 alkyl; C 1-6 halogenalkyl; C 1-6 alkoxy; or Ci_
  • ehalogenalkoxy or a three- to eight-membered monocyclic or bicyclic saturated or unsaturated non-aromatic ring system which may contain from 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur, wherein the saturated or unsaturated non-aromatic ring system may contain not more than 2 oxygen atoms and not more than 2 sulfur atoms, wherein the saturated or unsaturated non-aromatic ring system may be attached directly to the ring system A4a or via a C -4 alkylene group, and wherein the saturated or unsaturated non-aromatic ring system may be substituted once or more than once by Ri 3 , and wherein a substituent on a nitrogen in a heterocyclic saturated or unsaturated non-aromatic ring system may not be halogen; or two Ri 2 at adjacent ring atoms of the ring system A4a form together with said ring atoms a fused five- to seven-mem bered unsaturated non-aromatic ring system which
  • each R 3 independently is halogen, C -6 alkyl, C -6 halogenalkyl, C 3-7 cycloalkyl, C 3 .
  • each R 14 independently is halogen or C 1-6 alkyl, or two R 14 at the same ring atom of the fused unsaturated non-aromatic ring system together are oxo.
  • A is A4
  • A4a is a five- to six-membered monocyclic aromatic ring system which contains from 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur, wherein the ring system may contain not more than 2 oxygen atoms and not more than 2 sulfur atoms, and wherein the ring system is substituted once or more than once by R 12 , and wherein a substituent on a nitrogen in a heterocyclic ring system may not be halogen; each R 12 independently is halogen; C -6 alkyl; C 1-6 halogenalkyl; C ⁇ alkoxy; or C -6 halogenalkoxy.
  • A4a is a five-membered monocyclic aromatic ring system and each R 12 independently is halogen, C 1-4 alkyl, C 1-4 halogenalkyl, or C ⁇ alkoxy. In one embodiment of said class, A4a is a six-membered monocyclic aromatic ring system and each R 12 independently is halogen, C 1-4 alkyl, C 1-4 halogenalkyl or C 1-4 alkoxy.
  • p 0.
  • p is 1.
  • p is 1 and Ri 5 is halogen or C 1- alkyl.
  • C is a five- to ten-membered monocyclic or fused polycyclic aromatic ring system which may contain from 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur, wherein the ring system may contain not more than 2 oxygen atoms and not more than 2 sulfur atoms, and wherein the ring system may be substituted once or more than once by Ri 6 , and wherein a substituent on a nitrogen in a heterocyclic ring system may not be halogen;
  • each Ri 6 independently is C 1-6 alkyl; C 1-6 halogenalkyl; C 1-6 alkoxy; C 1-6 halogenalkoxy; halogen; cyano; or two R 16 at adjacent ring atoms of the ring system C form together with said ring atoms a fused five- to seven-membered unsaturated non-aromatic ring system which may contain from 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur, wherein the fused unsaturated non-aromatic ring system may contain not more than 2 oxygen atoms and not more than 2 sulfur atoms, and wherein the fused unsaturated non-aromatic ring system may in turn be substituted once or more than once by R 17 , and wherein a substituent on a nitrogen in a heterocyclic fused unsaturated non-aromatic ring system may not be halogen; each R 17 independently is halogen or C 1-6 alkyl, or two R 17 at the same ring atom of the fused unsatur
  • C is phenyl, which may be substituted once or more than once by R 16 .
  • each R 16 independently is C 1-6 alkyl; C 1-6 halogenalkyl; C -6 alkoxy; C 1-6 halogenalkoxy; halogen or cyano.
  • C is a five- to six-membered monocyclic aromatic ring system which may contain from 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur, and wherein the ring system may be substituted once or more than once by R 16 .
  • each R 16 independently is halogen, C - alkyl, 4 halogenalkyl, or C M alkoxy.
  • C is pyridyl, for example 2-, 3- or 4-pyridyl, and each R 16 independently is halogen, C 1- alkyl, C 1- halogenalkyl, or C 1- alkoxy.
  • C is unsubstituted 2-pyridyl.
  • C is pyrrolyl, for example 1-, 2- or 3-pyrrolyl, and each R 16 independently is halogen, C 1-4 alkyl or C 1-4 halogenalkyl. In one embodiment of said class, C is 1-methyl-1H-pyrrol-2-yl.
  • C is an eight- to ten-membered bicyclic aromatic ring system which contains from 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur, and wherein the ring system may be substituted once or more than once by R 16 .
  • C is C1
  • Ri 6a is C 1- alkyl, for example methyl.
  • One class of compounds of the invention are compounds of formula IA
  • Ri is C 1-4 alkyl and R 2 , R3, R 4 , R 5 and R 6 are each hydrogen;
  • A1 a is a five- to six-membered monocyclic aromatic ring system which contains from 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur, wherein the ring system may contain not more than 2 oxygen atoms and not more than 2 sulfur atoms, and wherein the ring system may be substituted once or more than once by R 7 , and wherein a substituent on a nitrogen in a heterocyclic ring system may not be halogen;
  • A1 b is a five- to six-membered monocyclic aromatic ring system which may contain from 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur, wherein the ring system may contain not more than 2 oxygen atoms and not more than 2 sulfur atoms, and wherein the ring system is fused to ring system A1a via carbon and/or nitrogen atoms, and wherein the ring system may be substituted once or more than once by R 8 , and wherein a substituent on a nitrogen in a heterocyclic ring system may not be halogen;
  • each R 7 or R 8 independently is halogen, Ci. 4 alkyl or C ⁇ halogenalkyl;
  • B is phenyl
  • C is a five- to six-membered monocyclic aromatic ring system which may contain from 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur, and wherein the ring system may be substituted once or more than once by Ri 6 ;
  • each R 16 independently is halogen, C 1-4 alkyl or C ⁇ halogenalkyl.
  • One class of compounds of the invention are compounds of formula IA
  • R 2 , R3, R4, R5 and R 6 are each hydrogen;
  • A2a is a five- or six-membered monocyclic aromatic ring system which contains from 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur, wherein the ring system may contain not more than 2 oxygen atoms and not more than 2 sulfur atoms, and wherein the ring system is fused to the phenyl ring via two carbon atoms, and wherein the ring system may be substituted once or more than once by R 10 , and wherein a substituent on a nitrogen in a heterocyclic ring system may not be halogen;
  • n 0, 1 , 2 or 3;
  • each R 9 or R 10 independently is halogen, C 1-4 alkyl or C 1- halogenalkyl
  • B is phenyl
  • C is a five- to six-membered monocyclic aromatic ring system which may contain from 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur, and wherein the ring system may be substituted once or more than once by R 6 ;
  • each R 16 independently is halogen, C 1-4 alkyl or C ⁇ halogenalkyl.
  • One class of compounds of the invention are compounds of formula IA
  • R is d. 4 alkyl and R 2 , R3, R , R5 and R 6 are each hydrogen;
  • A2a is a five-membered monocyclic aromatic ring system which contains from 2 to 3 hetero atoms selected from nitrogen, oxygen and sulfur, wherein the ring system may contain not more than 2 oxygen atoms and not more than 2 sulfur atoms, and wherein the ring system is fused to the phenyl ring via two carbon atoms, and wherein the ring system may be substituted once or more than once by R 10 , and wherein a substituent on a nitrogen in a heterocyclic ring system may not be halogen;
  • n 0, 1 , 2 or 3;
  • each R 9 or Ri 0 independently is halogen, Ci. 4 alkyl or Ci. 4 halogenalkyl;
  • B is phenyl
  • C is a five- to six-membered monocyclic aromatic ring system which may contain from 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur, and wherein the ring system may be substituted once or more than once by R 16 ;
  • each R 16 independently is halogen, C 1- alkyl or C 1-4 halogenalkyl.
  • One class of compounds of the invention are compounds of formula IA
  • R 1 is Ci -4 alkyl and R 2 , R3, R , R5 and R 6 are each hydrogen;
  • A is A3
  • A3a is phenyl which may be substituted once or more than once by R ;
  • A3b is a five- to six-membered monocyclic aromatic ring system which may contain from 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur, wherein the ring system may contain not more than 2 oxygen atoms and not more than 2 sulfur atoms, and wherein the ring system may be substituted once or more than once by Rn, and wherein a substituent on a nitrogen in a heterocyclic ring system may not be halogen;
  • each Rn independently is halogen, C 1-4 alkyl or d ⁇ halogenalkyl
  • B is phenyl
  • C is a five- to six-membered monocyclic aromatic ring system which may contain from 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur, and wherein the ring system may be substituted once or more than once by R 16 ;
  • each R 16 independently is halogen, C 1-4 alkyl or C 1-4 halogenalkyl.
  • One class of compounds of the invention are compounds of formula IA
  • R 2 , R3, R 4 , R 5 and R 6 are each hydrogen;
  • A4a is a five- to six-membered monocyclic aromatic ring system which contains from 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur, wherein the ring system may contain not more than 2 oxygen atoms and not more than 2 sulfur atoms, and wherein the ring system is substituted once or more than once by R 12 , and wherein a substituent on a nitrogen in a heterocyclic ring system may not be halogen;
  • each Ri2 independently is halogen, or C 1-4 alkoxy
  • B is phenyl
  • C is a five- to six-membered monocyclic aromatic ring system which may contain from 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur, and wherein the ring system may be substituted once or more than once by R 16 ;
  • each Ri6 independently is halogen
  • One class of compounds of the invention are compounds of formula IB
  • R is Ci -4 alkyl and R 2 , R 3 , R 4 , Rs and R 6 are each hydrogen;
  • A1 a is a five- to six-membered monocyclic aromatic ring system which contains from 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur, wherein the ring system may contain not more than 2 oxygen atoms and not more than 2 sulfur atoms, and wherein the ring system may be substituted once or more than once by R 7 , and wherein a substituent on a nitrogen in a heterocyclic ring system may not be halogen;
  • A1 b is a five- to six-membered monocyclic aromatic ring system which may contain from 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur, wherein the ring system may contain not more than 2 oxygen atoms and not more than 2 sulfur atoms, and wherein the ring system is fused to ring system A1 a via carbon and/or nitrogen atoms, and wherein the ring system may be substituted once or more than once by R 8 , and wherein a substituent on a nitrogen in a heterocyclic ring system may not be halogen; each R 7 or R 8 independently is halogen, C 1-4 alkyl or C 1-4 halogenalkyl;
  • B is phenyl
  • C is a five- to six-membered monocyclic aromatic ring system which may contain from 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur, and wherein the ring system may be substituted once or more than once by R 6 ;
  • each R 6 independently is halogen, C 1-4 alkyl or C 1-4 halogenalkyl.
  • One class of compounds of the invention are compounds of formula IB
  • R 2 , R 3 , R 4 , R 5 and R 6 are each hydrogen;
  • A2a is a five- or six-membered monocyclic aromatic ring system which contains from 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur, wherein the ring system may contain not more than 2 oxygen atoms and not more than 2 sulfur atoms, and wherein the ring system is fused to the phenyl ring via two carbon atoms, and wherein the ring system may be substituted once or more than once by R 10 , and wherein a substituent on a nitrogen in a heterocyclic ring system may not be halogen;
  • n 0, 1 , 2 or 3;
  • each R 9 or Ri 0 independently is halogen, C ⁇ alkyl or C halogenalkyl
  • B is phenyl
  • C is a five- to six-membered monocyclic aromatic ring system which may contain from 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur, and wherein the ring system may be substituted once or more than once by R 16 ;
  • each R 16 independently is halogen, C 1-4 alkyl or C -4 halogenalkyl.
  • ne class of compounds of the invention are compounds of formula IB
  • Ri is C -4 alkyl and R 2 , R3, R4, R5 and R 6 are each hydrogen;
  • A2a is a five-membered monocyclic aromatic ring system which contains from 2 to 3 hetero atoms selected from nitrogen, oxygen and sulfur, wherein the ring system may contain not more than 2 oxygen atoms and not more than 2 sulfur atoms, and wherein the ring system is fused to the phenyl ring via two carbon atoms, and wherein the ring system may be substituted once or more than once by R 0 , and wherein a substituent on a nitrogen in a heterocyclic ring system may not be halogen;
  • n 0, 1 , 2 or 3;
  • each R 9 or R 10 independently is halogen, C -4 alkyl or
  • B is phenyl
  • C is a five- to six-membered monocyclic aromatic ring system which may contain from 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur, and wherein the ring system may be substituted once or more than once by R 6 ;
  • each R 16 independently is halogen, C 1- alkyl or C 1-4 halogenalkyl.
  • One class of compounds of the invention are compounds of formula IB
  • R 2 , R3, R 4 , R5 and R 6 are each hydrogen;
  • A3a is phenyl which may be substituted once or more than once by Rn ;
  • A3b is a five- to six-membered monocyclic aromatic ring system which may contain from 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur, wherein the ring system may contain not more than 2 oxygen atoms and not more than 2 sulfur atoms, and wherein the ring system may be substituted once or more than once by Rn , and wherein a substituent on a nitrogen in a heterocyclic ring system may not be halogen;
  • each R11 independently is halogen, C 1-4 alkyl or C 1-4 halogenalkyl
  • B is phenyl
  • C is a five- to six-membered monocyclic aromatic ring system which may contain from 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur, and wherein the ring system may be substituted once or more than once by R 16 ;
  • each R16 independently is halogen, C 1-4 alkyl or n, are compounds of formula IB
  • Ri is C 1-4 alkyl and R 2 , R3, R 4 , R5 and R 6 are each hydrogen;
  • A is A4
  • A4a is a five- to six-membered monocyclic aromatic ring system which contains from 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur, wherein the ring system may contain not more than 2 oxygen atoms and not more than 2 sulfur atoms, and wherein the ring system is substituted once or more than once by Ri 2 , and wherein a substituent on a nitrogen in a heterocyclic ring system may not be halogen;
  • each R 12 independently is halogen, C 1-4 alkyl, C 1-4 halogenalkyl or alkoxy;
  • B is phenyl
  • C is a five- to six-membered monocyclic aromatic ring system which may contain from 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur, and wherein the ring system may be substituted once or more than once by R 16 ;
  • each R 6 independently is halogen, C 1-4 alkyl, C -4 halogenalkyl or C 1-4 alkoxy.
  • the invention provides a compound selected from
  • the invention also provides a process for the production of compounds of the formula I.
  • Compounds of the formula I are obtainable according to the following process as described in scheme 1 :
  • Step 1 A compound of formula III, in which R 2 , R 3 , R 4 , R 5 , R 6 and B are as defined under formula I, and R a is C ⁇ alkyl, preferably tert-butyl, may be obtained by reacting a compound of formula II, in which R 2 , R 3 , R 4 , R 5 , Re and B are as defined under formula I, and R a is as defined under formula III, in a first step with methanesulfonyl chloride in the presence of a base, such as triethylamine, in the presence of a suitable solvent, e.g. dichlormethan. The resulting product may then be reacted with sodium cyanide in the presence of a suitable solvent, e.g. dimethylformamide.
  • a base such as triethylamine
  • Step 2 A compound of formula IV, in which R 2 , R 3 , R , R5, Re and B are as defined under formula I, and R a is as defined under formula III, may be obtained by reacting the compound of formula III with a compound of formula V, in which Ri is as defined under formula I, and X c is iodide, in the presence of sodium hydride in the presence of a suitable solvent, e.g. dry tetrahydrofurane.
  • a suitable solvent e.g. dry tetrahydrofurane.
  • Step 3 A compound of formula VI, in which R 1 f R 2 , R 3 , R4, R5, Re and B are as defined under formula I, and R a is as defined under formula III, may be obtained from the compound of formula IV by reduction with e.g. hydrogen/Raney nickel.
  • Step 4 A compound of formula VII, in which Ri, R 2 , R 3 , R4, R5, R 6 , B and C are as defined under formula I, and R a is as defined under formula III, may be obtained by reacting the compound of formula VI with an acid or acid derivative of formula VIII, in which C is defined under formula I, and X is hydroxyl or halogen under suitable reaction conditions as described in the Examples. E.g., when X is halogen in the presence of a suitable base and solvent.
  • Step 5 A compound of formula IX, in which R ⁇ R 2 , R 3 , R , R5, Re, B and C are as defined under formula I, may be obtained by reacting the compound of formula VII with hydrochloric acid in a suitable solvent, e.g. dichlormethane and dioxane.
  • Step 6 A compound of formula I, may be obtained by reacting the compound of formula IX with an acid or acid derivative of formula X, in which A is defined under formula I, and X is hydroxyl or halogen as described in step 4.
  • Step 7 A compound of formula XI, in which R 2 , R 3 , R 4 , R 5 , R 6 and B are as defined under formula I, may be obtained from a compound of formula IV as described in step 5.
  • Step 8 A compound of formula XII, in which Ri, R 2 , R 3 , R 4 , R 5 , R 6 and B are as defined under formula I, may be obtained by reacting the compound of formula XI with a compound of formula X as described in step 6.
  • Step 9 A compound of formula XIII, in which Ri, R 2 , R 3 , R 4 , R 5 , R 6 , A and B are as defined under formula I, may be obtained from the compound of formula XII by reduction as described in step 3.
  • Step 10 A compound of formula I, may be obtained by reacting the compound of formula XIII with a compound of formula VIII as described in step 4.
  • the reactions can be effected according to conventional methods, for example as described in the Examples.
  • Acid addition salts may be produced from the free bases in known manner, and vice-versa.
  • the starting materials of the formulae II, V, VIII and X are known or may be prepared according to conventional procedures starting from known compounds, for example as described in the Examples. In some cases, an intermediate of scheme 1 may be known. In such a situation, said intermediate could be used as an alternative starting point for the process according to scheme 1.
  • the invention also provides a process for the production of compounds of the formula I, in which R 1 t R 2 , R3, R4, R 5 , R 6 , A, B and C are as defined under formula I, which comprises
  • the invention also provides a process for the production of compounds of the formula I, in which Ri , R 2 , R3, R4, R5, Re, A, B and C are as defined under formula I, which comprises
  • A is as defined under formula I, and X is halogen, in the presence of a suitable base and a suitable solvent.
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the invention and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition can be formulated for particular routes of administration such as oral administration, parenteral administration, and rectal administration, etc.
  • the pharmaceutical compositions of the invention can be made up in a solid form including capsules, tablets, pills, granules, powders or suppositories, or in a liquid form including solutions, suspensions or emulsions.
  • compositions can be subjected to conventional pharmaceutical operations such as sterilization and/or can contain conventional inert diluents, lubricating agents, or buffering agents, as well as adjuvants, such as preservatives, stabilizers, wetting agents, emulsifers and buffers etc.
  • the pharmaceutical compositions are tablets and gelatin capsules comprising the active ingredient together with
  • diluents e.g., lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine
  • lubricants e.g., silica, talcum, stearic acid, its magnesium or calcium salt and/or polyethyleneglycol
  • binders e.g., magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone; if desired
  • disintegrants e.g., starches, agar, alginic acid or its sodium salt, or effervescent mixtures; and/or
  • Tablets may be either film coated or enteric coated according to methods known in the art.
  • compositions for oral administration include an effective amount of a compound of the invention in the form of tablets, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsion, hard or soft capsules, or syrups or elixirs.
  • Compositions intended for oral use are prepared according to any method known in the art for the manufacture of pharmaceutical compositions and such compositions can contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with nontoxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets.
  • excipients are, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example, starch, gelatin or acacia; and lubricating agents, for example magnesium stearate, stearic acid or talc.
  • the tablets are uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • a time delay material such as glyceryl monostearate or glyceryl distearate can be employed.
  • Formulations for oral use can be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example, peanut oil, liquid paraffin or olive oil.
  • an inert solid diluent for example, calcium carbonate, calcium phosphate or kaolin
  • water or an oil medium for example, peanut oil, liquid paraffin or olive oil.
  • compositions are aqueous isotonic solutions or suspensions, and suppositories are advantageously prepared from fatty emulsions or suspensions.
  • Said compositions may be sterilized and/or contain adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure and/or buffers. In addition, they may also contain other therapeutically valuable substances.
  • Said compositions are prepared according to conventional mixing, granulating or coating methods, respectively, and contain about 0.1-75%, or contain about 1-50%, of the active ingredient.
  • compositions for transdermal application include an effective amount of a compound of the invention with carrier.
  • Carriers include absorbable pharmacologically acceptable solvents to assist passage through the skin of the host.
  • transdermal devices are in the form of a bandage comprising a backing member, a reservoir containing the compound optionally with carriers, optionally a rate controlling barrier to deliver the compound of the skin of the host at a controlled and predetermined rate over a prolonged period of time, and means to secure the device to the skin.
  • compositions for topical application include aqueous solutions, suspensions, ointments, creams, gels or sprayable formulations, e.g., for delivery by aerosol or the like.
  • topical delivery systems will in particular be appropriate for dermal application, e.g., for the treatment of skin cancer, e.g., for prophylactic use in sun creams, lotions, sprays and the like. They are thus particularly suited for use in topical, including cosmetic, formulations well-known in the art.
  • Such may contain solubilizers, stabilizers, tonicity enhancing agents, buffers and preservatives.
  • a topical application may also pertain to an inhalation or to an intranasal application. They are conveniently delivered in the form of a dry powder (either alone, as a mixture, for example a dry blend with lactose, or a mixed component particle, for example with phospholipids) from a dry powder inhaler or an aerosol spray presentation from a pressurised container, pump, spray, atomizer or nebuliser, with or without the use of a suitable propellant.
  • a dry powder either alone, as a mixture, for example a dry blend with lactose, or a mixed component particle, for example with phospholipids
  • the invention further provides anhydrous pharmaceutical compositions and dosage forms comprising the compounds of the invention as active ingredients, since water may facilitate the degradation of certain compounds.
  • Anhydrous pharmaceutical compositions and dosage forms of the invention can be prepared using anhydrous or low moisture containing ingredients and low moisture or low humidity conditions.
  • An anhydrous pharmaceutical composition may be prepared and stored such that its anhydrous nature is maintained.
  • anhydrous compositions are preferably packaged using materials known to prevent exposure to water such that they can be included in suitable formulary kits. Examples of suitable packaging include, but are not limited to, hermetically sealed foils, plastics, unit dose containers (e. g., vials), blister packs, and strip packs.
  • compositions and dosage forms that comprise one or more agents that reduce the rate by which the compound of the invention as an active ingredient will decompose.
  • agents which are referred to herein as “stabilizers,” include, but are not limited to, antioxidants such as ascorbic acid, pH buffers, or salt buffers, etc.
  • the term "pharmaceutically acceptable carrier” includes any and all solvents, dispersion media, coatings, surfactants, antioxidants, preservatives (e.g., antibacterial agents, antifungal agents), isotonic agents, absorption delaying agents, salts, preservatives, drugs, drug stabilizers, binders, excipients, disintegration agents, lubricants, sweetening agents, flavoring agents, dyes, such like materials and combinations thereof, as would be known to one of ordinary skill in the art (see, for example, Remington's Pharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990, pp. 1289- 1329). Except insofar as any conventional carrier is incompatible with the active ingredient, its use in the therapeutic or pharmaceutical compositions is contemplated.
  • the compounds of formula I in free form or in pharmaceutically acceptable salt form exhibit valuable pharmacological properties, e.g. orexin receptor modulating properties, e.g. as indicated in in-vitro and in-vivo tests as provided in the next sections and are therefore indicated for therapy.
  • pharmacological properties e.g. orexin receptor modulating properties, e.g. as indicated in in-vitro and in-vivo tests as provided in the next sections and are therefore indicated for therapy.
  • Preferred compounds of the invention show an inhibition of calcium accumulation in recombinant cells expressing at least one of hOxI R or hOx2R at 10 ⁇ of test compound of at least 10%.
  • compounds of the invention which are described in Tables 1 to 4 as showing an inhibition of calcium accumulation in recombinant cells expressing at least one of hOx1 R or hOx2R at 10 ⁇ of test compound of lower than 10%, are excluded.
  • Further preferred compounds of the invention show a Ki value for said calcium accumulation in recombinant cells expressing at least one of hOxl R or hOx2R of at least 1 ⁇ .
  • Further preferred compounds of the invention show a Ki value for said calcium accumulation in recombinant cells expressing at least one of hOxl R or hOx2R of at least 500 nM.
  • Further preferred compounds of the invention show a Ki value for said calcium accumulation in recombinant cells expressing at least one of hOxl R or hOx2R of at least 100 nM.
  • Further preferred compounds of the invention show a Ki value for said calcium accumulation in recombinant cells expressing at least one of hOxI R or hOx2R of at least 50 nM.
  • Compounds of the invention may be useful in the treatment of an indication selected from: i) sleep disorders;
  • psychiatric, neurological and neurodegenerative disorders such as depression; anxiety; addictions, obsessive compulsive disorder; affective neurosis; depressive neurosis; anxiety neurosis; dysthymic disorder; mood disorder; sexual dysfunction; psychosexual dysfunction; sex disorder; schizophrenia; manic depression; delirium; dementia; severe mental retardation and dyskinesias such as Huntington's disease and Tourette syndrome; Parkinson's disease; ischemic or haemorrhagic stroke; migraine; and neurodegenerative disorder including nosological entities such as disinhibition-dementia-parkinsonism-amyotrophy complex;
  • cardiovascular diseases diabetes; asthma; Cushing's syndrome/disease; basophil adenoma; prolactinoma; hyperprolactinemia; hypopituitarism; hypophysis tumour/adenoma; hypothalamic diseases; Froehlich's syndrome; hypophysis diseases, hypothalamic hypogonadism; Kallman's syndrome (anosmia, hyposmia); functional or psychogenic amenorrhea; hypopituitarism; hypothalamic hypothyroidism; hypothalamic-adrenal dysfunction; idiopathic hyperprolactinemia; hypothalamic disorders of growth hormone deficiency; idiopathic growth deficiency; dwarfism; gigantism; acromegaly; heart and lung diseases, acute and congestive heart failure; hypotension; hypertension; urinary retention; osteoporosis; angina pectoris; myocardial infarction; subarachnoid haemorrhage
  • hyperalgesia pain
  • pain enhanced or exaggerated sensitivity to pain such as hyperalgesia, causalgia, and allodynia; acute pain; burn pain; atypical facial pain; neuropathic pain; back pain; complex regional pain syndrome I and II; arthritic pain; sports injury pain; pain related to infection e.g. HIV, post-chemotherapy pain; post-stroke pain; post-operative pain; neuralgia; conditions associated with visceral pain such as irritable bowel syndrome, migraine and angina; and
  • Compounds of the invention may be especially useful in the treatment of an indication selected from: sleep disorders, eating disorders, substance-related disorders and Alzheimers disease.
  • Eating disorders may be defined as comprising metabolic dysfunction; dysregulated appetite control; compulsive obesities; emeto-bulimia or anorexia nervosa.
  • pathologically modified food intake may result from disturbed appetite (attraction or aversion for food); altered energy balance (intake vs expenditure); disturbed perception of food quality (high fat or carbohydrates, high palatability); disturbed food availability (unrestricted diet or deprivation) or disrupted water balance.
  • insomnias include insomnias, narcolepsy and other disorders of excessive sleepiness, sleep-related dystonias; restless leg syndrome; sleep apneas; jet-lag syndrome; shift-work syndrome, delayed or advanced sleep phase syndrome.
  • Insomnias are defined as comprising sleep disorders associated with aging; intermittent treatment of chronic insomnia; situational transient insomnia (new environment, noise) or short-term insomnia due to stress; grief; pain or illness.
  • Substance-related disorders include substance abuse, substance dependence and substance withdrawal disorders, e.g. nicotine withdrawal or narcotics withdrawal.
  • the invention provides the use of a compound of formula (I) in free form or in pharmaceutically acceptable salt form as a medicament.
  • the invention provides the use of a compound of formula (I) in free form or in pharmaceutically acceptable salt form in therapy.
  • the invention provides a method of inhibiting orexin receptor activity in a subject, wherein the method comprises administering to the subject a therapeutically effective amount of a compound of formula I.
  • the invention provides a method of treating a disorder or a disease in a subject mediated by orexin receptors, wherein the method comprises administering to the subject a therapeutically effective amount of a compound of formula I.
  • a disorder or said disease is selected from sleep disorders, eating disorders, substance-related disorders or Alzheimers disease.
  • the invention provides the use of a compound of formula I, for the treatment of a disorder or disease in a subject mediated by orexin receptors.
  • the invention provides the use of a compound of formula I, for the treatment of a disorder or disease in a subject characterized by an abnormal activity of orexin receptors.
  • a disorder or said disease is selected from sleep disorders, eating disorders, substance-related disorders or Alzheimers disease.
  • the therapy is selected from a disease which is ameliorated by modulation, preferably antagonism, of orexin receptors.
  • the disease is selected from the afore-mentioned list, suitably sleep disorders, eating disorders, substance-related disorders or Alzheimers disease.
  • the invention provides a method of treating a disease which is ameliorated by modulation, preferably antagonism, of orexin receptors comprising administration of a therapeutically acceptable amount of a compound of formula (I) in free form or in pharmaceutically acceptable salt form.
  • the disease is selected from the afore-mentioned list, suitably sleep disorders, eating disorders or
  • a therapeutically effective amount of a compound of the invention refers to an amount of the compound of the invention that will elicit the biological or medical response of a subject, for example, reduction or inhibition of an enzyme or a protein activity, or ameliorate symptoms, alleviate conditions, slow or delay disease progression, or prevent a disease, etc.
  • a therapeutically effective amount refers to the amount of the compound of the invention that, when administered to a subject, is effective to (1) at least partially alleviating, inhibiting, preventing and/or ameliorating a condition, or a disorder or a disease (i) mediated by orexin receptors, or (ii) associated with orexin receptor activity, or (iii) characterized by abnormal activity of orexin receptors; or (2) reducing or inhibiting the activity of orexin receptors; or (3) reducing or inhibiting the expression of orexin receptors.
  • a therapeutically effective amount refers to the amount of the compound of the invention that, when administered to a cell, or a tissue, or a non-cellular biological material, or a medium, is effective to at least partially reducing or inhibiting the activity of orexin receptors; or at least partially reducing or inhibiting the expression of orexin receptors.
  • the term "subject" refers to an animal.
  • the animal is a mammal.
  • a subject also refers to for example, primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds and the like.
  • the subject is a human.
  • the term “inhibition” or “inhibiting” refers to the reduction or suppression of a given condition, symptom, or disorder, or disease, or a significant decrease in the baseline activity of a biological activity or process.
  • treating refers in one embodiment, to ameliorating the disease or disorder (i.e., slowing or arresting or reducing the development of the disease or at least one of the clinical symptoms thereof).
  • treating refers to alleviating or ameliorating at least one physical parameter including those which may not be discernible by the patient.
  • treating or “treatment” refers to modulating the disease or disorder, either physically, (e.g., stabilization of a discernible symptom), physiologically, (e.g., stabilization of a physical parameter), or both.
  • treating refers to preventing or delaying the onset or development or progression of the disease or disorder.
  • the pharmaceutical composition or combination of the invention can be in unit dosage of about 1-1000 mg of active ingredient(s) for a subject of about 50-70 kg, or about 1-500 mg or about 1-250 mg or about 1-150 mg or about 0.5-100 mg, or about 1-50 mg of active ingredients.
  • the therapeutically effective dosage of a compound, the pharmaceutical composition, or the combinations thereof is dependent on the species of the subject, the body weight, age and individual condition, the disorder or disease or the severity thereof being treated. A physician, clinician or veterinarian of ordinary skill can readily determine the effective amount of each of the active ingredients necessary to prevent, treat or inhibit the progress of the disorder or disease.
  • the above-cited dosage properties are demonstrable in vitro and in vivo tests using advantageously mammals, e.g., mice, rats, dogs, monkeys or isolated organs, tissues and preparations thereof.
  • the compounds of the invention can be applied in vitro in the form of solutions, e.g., preferably aqueous solutions, and in vivo either enterally, parenterally, advantageously intravenously, e.g., as a suspension or in aqueous solution.
  • the dosage in vitro may range between about 10 3 molar and 10 "9 molar concentrations.
  • a therapeutically effective amount in vivo may range depending on the route of administration, between about 0.1-500 mg/kg, or between about 1-100 mg/kg.
  • the activity of a compound according to the invention can be assessed by in vitro & in vivo methods described herein.
  • the compound of the invention may be administered either simultaneously with, or before or after, at least one other therapeutic agent.
  • the compound of the invention may be administered separately, by the same or different route of administration, or together in the same pharmaceutical composition.
  • Agilent 1100 series, Agilent 1100 DAD, Micromass ZMD; column Waters XBridge C18 2.5 pm; 3 x 30 mm; Agilent 1100 oven: temperature 50°C; binary gradient formed with: A: water + acetonitrile (5 %) + TFA (0.05 %) and B: acetonitrile + TFA (0.05 %); 0 - 1.7 min (linear gradient from 90 % A : 10 % B to 5 % A : 95 % B) at 1.4 ml/min; 1.7 - 2.4 min (isocratic elution with 5 % A : 95 % B) at 1.6 ml/min; 2.4 - 2.45 min (linear gradient from 5 % A : 95 % B to 90 % A : 10 % B) at 2.4 ml/min;
  • Lithium hydroxide (143 mg, 5.96 mmol) was added to a solution of 3-methyl-3H- benzotriazole-4-carboxylic acid methyl ester (380 mg, 1.99 mmol) in methanol (6.5 ml). The mixture was stirred at 60 °C overnight. The solvent was evaporated and the residue was acidified to pH 1 with 1 N HCI solution (6.6 ml). The crystals which fell out of solution were filtered and dried to deliver 130 mg of the title compound (91 %).
  • 6-Amino-4-methyl-nicotinonitrile (1.7 g, 12.8 mmol) was suspended in 4N sodium hydroxid solution and stirred 5 h at 100°C to obtain a clear solution.
  • the reaction mixture was cooled in an icebath and acidified by addition of 4N hydrochloric acid.
  • the precipitate was filtered and washed with little water.
  • the residue was dissolved in MeOH, the solvent evaporated at reduced pressure and the product dried at high vacuum to yield the title compound 1.74 g (90%) as colorless solid.
  • 6-Amino-4-methyl-nicotinic acid (1.7 g, 11.2 mmol) was dissolved in MeOH (23 ml) and cone, sulfuric acid (0.30 ml, 5.6 mmol) was added dropwise. The reaction was heated (bath temperature 85°C) over night. Then, the mixture was diluted with EtOAc, washed with NaHC0 3 - and NaCI-soln., dried (Na 2 S0 ), filtered and concentrated. The residue was crystallized from DCM(MeOH)/diethylether/hexane to give the title compound as yellowish crystals (735 mg, 40%).
  • the reaction mixture was extracted with DCM, the combined organic layers were dried over sodium sulfate, and the solvents were evaporated at reduced pressure.
  • the crude product was purified by chromatography on silica (Flashmaster, hexanes to hexanes/EtOAc 7/3 over 40 min), followed by preparative HPLC (water sunfire C18, 5 ⁇ ; solvent: A water + 0.05 % TFA / B acetonitrile + 0.05 % TFA; gradient: 15-35% B over 16 min; flow 50 ml/min) to give the product as colorless solid.
  • 6-Methyl-furo[3,2-b]pyridine-5-carbonitrile (290 mg, 1.8 mmol) was dissolved in EtOH (12 ml) and potassium hydroxide (1.03 g, 18 mmol) in water (3.3 ml) was added. The reaction was heated at reflux temperature for 20 h. The solvents were evaporated at reduced pressure and the residue was dissolved in water (6.5 ml) and acidified with acetic acid (1.5 ml). The aqueous solution was extracted with EtOAc, the organic layer dried over sodium sulfate and the solvent was evaporated at reduced pressure to give the crude product as brown oil (215 mg, 66%, ⁇ 50% purity) which was used without further purification for the next steps.
  • the HCI salt was dissolved in DCM and washed with sat. NaHC0 3 and NaCI-solution, dried (Na 2 S0 4 ), filtered and concentrated.
  • the title compound (5.01 g, 95 %) was obtained as a yellow oil.
  • 6-Methyl-imidazo[2, 1 -b]thiazole-5-carboxylic acid ((S)-3-methylamino-4-phenyl-butyl)-amide (250 mg, 0.55 mmol), 1 H-indazole-3-carboxylic acid (108 mg, 0.66 mmol), HOBt (102 mg, 0.66 mmol), EDC x HCI (159 mg, 0.83 mmol), and triethylamine (0.46ml, 3.32 mmol) were dissolved in DCM (10 ml) and stirred at rt for 20 h.
  • Examples 1.9 to 1.102 were prepared or can be prepared in analogy to the methods described for Examples 1.1 to 1.8 using the appropriate starting materials or intermediates.
  • Example 1.23 f S)-N.1 -dimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamidoM ⁇ henylbutan-2-yl)-1H-indole-2-carboxamide

Abstract

The invention relates to compound of the formula (I): in which the substituents are as defined in the specification; in free form or in salt form; to its preparation, to its use as medicament and to medicaments comprising it.

Description

4-Aryl-butane-1.3-diamides
The invention relates to 4-aryl-butane-1 , 3-diamides, to their preparation, to their use as medicaments and to medicaments comprising them.
Orexins (orexin A OX-A and orexin B/OX-B), which are also known as hypocretins, are neuropeptides. Orexin A is a 33 amino acid peptide and orexin B is a 28 amino acid peptide (Sakurai T. et al., Cell, 1998, 92, 573-585). Orexins are produced in discrete neurons of the lateral hypothalamus and bind to G-protein-coupled receptors, the orexin receptors (also known as hypocretin receptors): known are the orexin-1 receptor (OX1R) and the orexin-2 receptor (OX2R). The orexin-1 receptor has some selectivity for OX-A, whereas the orexin-2 receptor binds OX-A and OX-B with similar affinity. Orexins regulate states of sleep and wakefulness, opening potentially novel therapeutic approaches for narcolepsy as well as insomnia and other sleep disorders (Chemelli R.M. et al., Cell, 1999, 98, 437-45 1).
Furthermore, orexins were found to stimulate food consumption in rats suggesting a physiological role for these peptides as mediators in the central feedback mechanism that regulates feeding behavior (Sakurai T. et al., Cell, 1998, 92, 573-585). Still furthermore, orexins were shown to play a role in brain reward function/motivation suggesting usefulness to treat substance-related disorders (Harris A.C. et al, Nature, 2005, 437, 556-559). Still furthermore, it has been shown that amyloid beta levels inversely correlate with orexin levels in rodents and humans (brain and/or CSF), and that an orexin receptor antagonist reduces both amyloid beta levels and amyloid plaque load in Alzheimer's transgenic mice, thus suggesting usefulness in the treatment of Alzheimers disease (Kang J.E. et al, Science 2009, 326, 1005-1007).
Orexin receptors may have numerous implications in disorders such as
i) sleep disorders, e.g. sleep apnea, narcolepsy, insomnia, parasomnia, jet lag syndrome, disturbed biological and circadian rhythms; sleep disturbances associated with diseases such as neurological disorders, neuropathic pain and restless leg syndrome;
ii) eating disorders, e.g. appetite and taste disorders;
iii) substance-related disorders, e.g. substance abuse, substance dependence and substance withdrawal disorders, such as nicotine withdrawal or narcotics withdrawal;
iv) Alzheimers disease;
v) psychiatric, neurological and neurodegenerative disorders, e.g. depression; anxiety;
addictions, obsessive compulsive disorder; affective neurosis; depressive neurosis; anxiety neurosis; dysthymic disorder; mood disorder; sexual dysfunction; psychosexual dysfunction; sex disorder; schizophrenia; manic depression; delirium; dementia; severe mental retardation and dyskinesias such as Huntington's disease and Tourette syndrome; Parkinson's disease; ischemic or hemorrhagic stroke; migraine; and neurodegenerative disorders including nosological entities such as disinhibition-dementia-parkinsonism-amyotrophy complex;
pallido-ponto-nigral degeneration epilepsy; seizure disorders;
vi) cardiovascular diseases, diabetes; asthma; Cushing's syndrome/disease; basophile adenoma; prolactinoma; hyperprolactinemia; hypopituitarism; hypophysis tumor/adenoma; hypothalamic diseases; Froehlich's syndrome; hypophysis diseases, hypothalamic hypogonadism; Kallman's syndrome (anosmia, hyposmia); functional or psychogenic amenorrhea; hypopituitarism; hypothalamic hypothyroidism; hypothalamic-adrenal dysfunction; idiopathic hyperprolactinemia; hypothalamic disorders of growth hormone deficiency; idiopathic growth deficiency; dwarfism; gigantism; acromegaly; heart and lung diseases, acute and congestive heart failure; hypotension; hypertension; urinary retention; osteoporosis; angina pectoris; myocardial infarction; subarachnoid hemorrhage; ulcers;
allergies; benign prostatic hypertrophy; chronic renal failure; renal disease; impaired glucose tolerance; vomiting and nausea; inflammatory bowel disease; gastric dyskinesia; gastric ulcers; urinary bladder incontinence e.g. urge incontinence; hyperalgesia; pain; enhanced or exaggerated sensitivity to pain such as hyperalgesia, causalgia, and allodynia; acute pain; burn pain; atypical facial pain; neuropathic pain; back pain; complex regional pain syndrome I and II; arthritic pain; sports injury pain; pain related to infection e.g. HIV, post-chemotherapy pain; post-stroke pain; post-operative pain; neuralgia; conditions associated with visceral pain such as irritable bowel syndrome, migraine and angina; and
vii) other diseases related to general orexin system dysfunction.
Orexin receptor antagonists, are considered to be useful in the treatment of a wide range of disorders, in particular sleep disorders, eating disorders and substance-related disorders.
Therefore, there is a need to provide new orexin receptor antagonists that are good drug candidates. In particular, preferred compounds should bind potently to the orexin receptors (either as OX1 R or OX2R subtype selective antagonists or as dual OX1 R/OX2R antagonists) whilst showing little affinity for other receptors. They should be well absorbed from the gastrointestinal tract, be sufficiently metabolically stable and possess favorable
pharmacokinetic properties. When targeted against receptors in the central nervous system they should cross the blood brain barrier freely and when targeted selectively against receptors in the peripheral nervous system they should not cross the blood brain barrier. They should be non-toxic and demonstrate few side-effects. Furthermore, the ideal drug candidate will be able to exist in a physical form that is stable, non-hygroscopic and easily formulated.
The compounds of the invention are orexin receptor antagonists and are therefore potentially useful in the treatment of a wide range of disorders, particularly sleep disorders, eating disorders, substance-related disorders and Alzheimers disease.
In a first aspect, the invention relates to a compound of the formula I
Figure imgf000004_0001
(I)
wherein
Ri is C1-6alkyl, C -6halogenalkyl, C3.7cycloalkyl or C3-7cycloalkyl(C - alkyl);
R2, R3, R5 and R6 are each independently selected from hydrogen, halogen, hydroxyl, C^.
6alkyl, C1-6halogenalkyl, C3-7cycloalkyl, C3.7cycloalkyl(Ci-4alkyl), C1-6alkoxy, or d.
ehalogenalkoxy;
or R2 and R3 together are oxo;
or R2 and R3 together with the carbon atom to which they are bound form a C3.7cycloalkyl; or R5 and R6 together are oxo;
or R5 and R6 together with the carbon atom to which they are bound form a C3.7cycloalkyl; R4 is hydrogen or C1-6alkyl;
A is a group A1 , A2, A3 or A4
Figure imgf000004_0002
A1 A2 A3 A4 wherein
A1a is a five- to six-membered monocyclic aromatic ring system which contains from 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur, wherein the ring system may contain not more than 2 oxygen atoms and not more than 2 sulfur atoms, and wherein the ring system may be substituted once or more than once by R7, and wherein a substituent on a nitrogen in a heterocyclic ring system may not be halogen;
A1 b is a five- to six-membered monocyclic aromatic ring system which may contain from 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur, wherein the ring system may contain not more than 2 oxygen atoms and not more than 2 sulfur atoms, and wherein the ring system is fused to ring system A1a via carbon and/or nitrogen atoms, and wherein the ring system may be substituted once or more than once by R8, and wherein a substituent on a nitrogen in a heterocyclic ring system may not be halogen;
each R7 or R8 independently is halogen, C1-6alkyl, d.6halogenalkyl, C3-7cycloalkyl, C3.
7cycloalkyl(Ci-4alkyl), Ci-6alkoxy, or C1-6halogenalkoxy;
A2a is a five- to six-membered monocyclic aromatic ring system which contains from 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur, wherein the ring system may contain not more than 2 oxygen atoms and not more than 2 sulfur atoms, and wherein the ring system is fused to the phenyl ring via two carbon atoms, and wherein the ring system may be substituted once or more than once by R10, and wherein a substituent on a nitrogen in a heterocyclic ring system may not be halogen;
n is 0, 1 , 2 or 3;
each R9 or R10 independently is halogen, C1-6alkyl, C1-6halogenalkyl, C3-7cycloalkyl, C3- 7cycloalkyl(Ci-4alkyl), C1-6alkoxy, or C1-6halogenalkoxy;
each of A3a or A3b is independently a five- to six-membered monocyclic aromatic ring system which may contain from 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur, wherein the ring system may contain not more than 2 oxygen atoms and not more than 2 sulfur atoms, and wherein the ring system may be substituted once or more than once by Rn, and wherein a substituent on a nitrogen in a heterocyclic ring system may not be halogen;
each R independently is halogen, C1-6alkyl, C1-6halogenalkyl, C3-7cycloalkyl, C3.
7cycloalkyl(C1-4alkyl), C1-6alkoxy, or C1-6halogenalkoxy;
A4a is a five- to six-membered monocyclic aromatic ring system which contains from 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur, wherein the ring system may contain not more than 2 oxygen atoms and not more than 2 sulfur atoms, and wherein the ring system is substituted once or more than once by R12, and wherein a substituent on a nitrogen in a heterocyclic ring system may not be halogen; each R12 independently is halogen; C1-6alkyl; C1-6halogenalkyl; C1-6all<oxy; or 6halogenalkoxy; or a three- to eight-membered monocyclic or bicyclic saturated or unsaturated non-aromatic ring system which may contain from 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur, wherein the saturated or unsaturated non-aromatic ring system may contain not more than 2 oxygen atoms and not more than 2 sulfur atoms, wherein the saturated or unsaturated non-aromatic ring system may be attached directly to the ring system A4a or via a C1-4alkylene group, and wherein the saturated or unsaturated non-aromatic ring system may be substituted once or more than once by R13, and wherein a substituent on a nitrogen in a heterocyclic saturated or unsaturated non-aromatic ring system may not be halogen; or two R12 at adjacent ring atoms of the ring system A4a form together with said ring atoms a fused five- to seven-mem bered unsaturated non-aromatic ring system which may contain from 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur, wherein the fused unsaturated non-aromatic ring system may contain not more than 2 oxygen atoms and not more than 2 sulfur atoms, and wherein the fused unsaturated non- aromatic ring system may in turn be substituted once or more than once by R14, and wherein a substituent on a nitrogen in a heterocyclic fused unsaturated non-aromatic ring system may not be halogen;
each R13 independently is halogen, C1-6alkyl, C1-6halogenalkyl, C3.7cycloalkyl, C3-
7cycloalkyl(C1- alkyl), C1-6alkoxy, or C1-6halogenalkoxy; or two R13 at the same ring atom of the saturated or unsaturated non-aromatic ring system together are oxo;
each R1 independently is halogen or C1-6alkyl, or two R14 at the same ring atom of the fused unsaturated non-aromatic ring system together are oxo;
B is
Figure imgf000006_0001
p is 0 or 1 ;
Ri5 is halogen, C1-6alkyl, C1-6halogenalkyl, C3.7cycloalkyl, C1-6alkoxy, or C1-6halogenalkoxy; and
C is a five- to ten-membered monocyclic or fused polycyclic aromatic ring system which may contain from 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur, wherein the ring system may contain not more than 2 oxygen atoms and not more than 2 sulfur atoms, and wherein the ring system may be substituted once or more than once by Ri6, and wherein a substituent on a nitrogen in a heterocyclic ring system may not be halogen; each R 6 independently is d-6alkyl; C -6halogenalkyl; C -6alkoxy; C -6halogenalkoxy; halogen; cyano; or two R 6 at adjacent ring atoms of the ring system C form together with said ring atoms a fused five- to seven-membered unsaturated non-aromatic ring system which may contain from 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur, wherein the fused unsaturated non-aromatic ring system may contain not more than 2 oxygen atoms and not more than 2 sulfur atoms, and wherein the fused unsaturated non-aromatic ring system may in turn be substituted once or more than once by Ri7, and wherein a substituent on a nitrogen in a heterocyclic fused unsaturated non-aromatic ring system may not be halogen; each R 7 independently is halogen or C -6alkyl, or two R17 at the same ring atom of the fused unsaturated non-aromatic ring system together are oxo;
and provided that the compounds
1-methyl-1 H-benzoimidazole-2-carboxylic acid {(S)-3-[(1 H-indole-4-carbonyl)-methyl-amino]- 4-phenyl-butyl}-amide;
1 H-indole-5-carboxylic acid {(S)-1 -benzyl-3-[(pyridine-2-carbonyl)-amino]-propyl}-methyl- amide;
1 H-indole-4-carboxylic acid {(S)-1-benzyl-3-[(pyridine-2-carbonyl)-amino]-propyl}-methyl- amide;
pyridine-2-carboxylic acid {(S)-3-[(benzofuran-5-carbonyl)-methyl-amino]-4-phenyl-butyl}- amide;
1-methyl-1 H-indole-7-carboxylic acid {(S)-1-benzyl-3-[(pyridine-2-carbonyl)-amino]-propyl}- methyl-amide;
1 H-indole-7-carboxylic acid {(S)-1 -benzyl-3-[(pyridine-2-carbonyl)-amino]-propyl}-methyl- amide;
1-methyl-1 H-indole-4-carboxylic acid {(S)-1-benzyl-3-[(pyridine-2-carbonyl)-amino]-propyl}- methyl-amide;
1 H-indole-6-carboxylic acid {(S)-1-benzyl-3-[(pyridine-2-carbonyl)-amino]-propyl}-methyl- amide;
1-methyl-1 H-benzoimidazole-2-carboxylic acid {(S)-3-[(1 H-indole-5-carbonyl)-methyl-amino]- 4-phenyl-butyl}-amide;
1-methyl-1 H-indole-5-carboxylic acid {(S)-1-benzyl-3-[(pyridine-2-carbonyl)-amino]-propyl}- methyl-amide and
1 -methyl-1 H-indole-6-carboxylic acid {(S)-1 -benzyl-3-[(pyridine-2-carbonyl)-amino]-propyl}- methyl-amide are excluded;
in free form or in salt form. Unless indicated otherwise, the expressions used in this invention have the following meaning:
"Alkyl" represents a straight-chain or branched-chain alkyl group, for example, methyl, ethyl, n- or iso-propyl, n-, iso-, sec- or tert-butyl, n-pentyl, n-hexyl; C -6alkyl preferably represents a straight-chain or branched-chain C -4alkyl with particular preference given to methyl, ethyl, n- propyl, iso-propyl and tert-butyl. C2.6alkyl preferably represents a straight-chain or branched- chain C2-4alkyl with particular preference given to ethyl, n-propyl, iso-propyl and tert-butyl.
Each alkyl part of "alkoxy", "halogenalkyl" and so on shall have the same meaning as described in the above-mentioned definition of "alkyl", especially regarding linearity and preferential size.
"C3-7cycloalkyl" represents a saturated alicyclic moiety having from three to seven carbon atoms. This term refers to groups such as cyclopropyl, cyclobutyl, cyclopentyl and
cyclohexyl.
As used herein, the term "alkylene" refers to divalent alkyl group as defined herein, for example methylene, ethylene, n-propylene, /'so-propylene, n-butylene, sec-butylene, iso- butylene, and terf-butylene.
A substituent being substituted "once or more than once", for example as defined for A1 a, is preferably substituted by one to three substituents.
Halogen is generally fluorine, chlorine, bromine or iodine; preferably fluorine, chlorine or bromine. Halogenalkyl groups preferably have a chain length of 1 to 4 carbon atoms and are, for example, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 2-fluoroethyl, 2-chloroethyl, pentafluoroethyl, 1 ,1-difluoro- 2,2,2-trichloroethyl, 2,2,2-trichloroethyl, 1 , 1 ,2,2-tetrafluoroethyl, 2,2,3,3-tetrafluoropropyl, 2,2,3,3,3-pentafluoropropyl or 2,2,3,4,4,4-hexafluorobutyl; preferably -CF3, -CHF2, -CH2F, - CHF-CH3, -CF2CH3, or -CH2CF3. ln the context of the invention, the definition of A1b, A3a and/or A3b as a "five- to six- membered monocyclic aromatic ring system which may contain from 1 to 4 heteroatoms" encompasses a C6-aromatic hydrocarbon group or a five- to six-membered heterocyclic aromatic ring system.
In the context of the invention, the definition of C as a "five- to ten-membered monocyclic or fused polycyclic aromatic ring system which may contain from 1 to 4 heteroatoms" encompasses a C6- or C10-aromatic hydrocarbon group or a five- to ten-membered heterocyclic aromatic ring system. "Polycyclic" means preferably bicyclic.
The term "fused polycyclic aromatic ring system" refers to an aromatic sustituent which consists of multiple, e.g. two, aromatic rings that are fused together.
In the context of the invention, the definition of R12 as a "three- to eight-membered monocyclic or bicyclic saturated or unsaturated non-aromatic ring system which may contain from 1 to 4 heteroatoms" encompasses three- to eight membered monocyclic or bicyclic non- aromatic hydrocarbon groups and non-aromatic heterocyclic ring systems of the same sizes.
In the context of the invention, the definition of two R12 or two R16 as a "fused five- to seven- membered unsaturated non-aromatic ring system" encompasses five- to seven-membered non-aromatic hydrocarbon and heterocyclic groups which comprise at least one double- bond, which is shared with the aromatic ring system they are fused to.
A C6- or do-aromatic hydrocarbon group is typically phenyl or naphthyl, especially phenyl.
Preferably, but also depending on substituent definition, "five- to six-membered heterocyclic aromatic ring systems" consist of 5 to 6 ring atoms of which 1-3 ring atoms are hetero atoms.
Examples of heterocyclic ring systems are: imidazo[2,1-b]thiazole, pyrrole, pyrroline, pyrrolidine, pyrazole, pyrazoline, pyrazolidine, imidazole, imidazoline, imidazolidine, triazole, triazoline, triazolidine, tetrazole, furane, dihydrofurane, tetrahydrofurane, furazane
(oxadiazole), dioxolane, thiophene, dihydrothiophene, tetrahydrothiophene, oxazole, oxazoline, oxazolidine, isoxazole, isoxazoline, isoxazolidine, thiazole, thiazoline, thiazolidine, isothiazole, isothiazoline, isothiazolidine, thiadiazole, thiadiazoline, thiadiazolidine, pyridine, piperidine, pyridazine, pyrazine, piperazine, triazine, pyrane, tetrahydropyrane, thiopyrane, tetrahydrothiopyrane, oxazine, thiazine, dioxine, morpholine, purine, pteridine, and the corresponding benz-annelated heterocycles, e.g. indole, isoindole, coumarin, isoquinoline, quinoline and the like. Preferred heterocycles are: imidazo[2,1-b]thiazole, oxazole, isoxazole, thiazole, isothiazole, triazole, pyrrole, furane, tetrahydrofurane, pyridine, pyrimidine, imidazole or pyrazole.
The compounds of formula I exist in optically active form or in form of mixtures of optical isomers, e.g. in form of racemic mixtures or diastereomeric mixtures. In particular, further asymmetrical carbon atom(s) may be present in the compounds of formula I and their salts. Unless otherwise specified, all optical isomers and their mixtures, including the racemic mixtures, are embraced by the invention.
As used herein, the term "isomers" refers to different compounds that have the same molecular formula but differ in arrangement and configuration of the atoms. Also as used herein, the term "an optical isomer" or "a stereoisomer" refers to any of the various stereo isomeric configurations which may exist for a given compound of the invention and includes geometric isomers. It is understood that a substituent may be attached at a chiral center of a carbon atom. Therefore, the invention includes enantiomers, diastereomers or racemates of the compound. "Enantiomers" are a pair of stereoisomers that are non- superimposable mirror images of each other. A 1 : 1 mixture of a pair of enantiomers is a "racemic" mixture. The term is used to designate a racemic mixture where appropriate. "Diastereoisomers" are stereoisomers that have at least two asymmetric atoms, but which are not mirror-images of each other. The absolute stereochemistry is specified according to the Cahn- Ingold- Prelog R-S system. When a compound is a pure enantiomer the stereochemistry at each chiral carbon may be specified by either R or S. Resolved compounds whose absolute
configuration is unknown can be designated (+) or (-) depending on the direction (dextro- or levorotatory) which they rotate plane polarized light at the wavelength of the sodium D line. The compounds described herein contain one or more asymmetric centers and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R)- or (S)-. The invention is meant to include all such possible isomers, including racemic mixtures, optically pure forms and intermediate mixtures. Optically active (R)- and (S)- isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituent may be E or Z configuration. If the compound contains a disubstituted cycloalkyl, the cycloalkyl substituent may have a cis- or trans-configuration.
Any asymmetric atom (e.g. carbon or the like) of the compound(s) of the invention can be present in racemic or enantiomerically enriched, for example the ( ?)-, (S)- or (Reconfiguration. In certain embodiments, each asymmetric atom has at least 50 %
enantiomeric excess, at least 60 % enantiomeric excess, at least 70 % enantiomeric excess, at least 80 % enantiomeric excess, at least 90 % enantiomeric excess, at least 95 % enantiomeric excess, or at least 99 % enantiomeric excess in the ( ?)- or (S)- configuration. Substituents at atoms with unsaturated bonds may, if possible, be present in cis- {∑)- or trans- (£)- form.
Accordingly, as used herein a compound of the invention can be in the form of one of the possible isomers, rotamers, atropisomers, tautomers or mixtures thereof, for example, as substantially pure geometric (cis or trans) isomers, diastereomers, optical isomers
(antipodes), racemates or mixtures thereof.
Any resulting mixtures of isomers can be separated on the basis of the physicochemical differences of the constituents, into the pure or substantially pure geometric or optical isomers, diastereomers, racemates, for example, by chromatography and/or fractional crystallization.
Any resulting racemates of final products or intermediates can be resolved into the optical antipodes by known methods, e.g., by separation of the diastereomeric salts thereof, obtained with an optically active acid or base, and liberating the optically active acidic or basic compound. In particular, a basic moiety may thus be employed to resolve the compounds of the invention into their optical antipodes, e.g., by fractional crystallization of a salt formed with an optically active acid, e.g., tartaric acid, dibenzoyl tartaric acid, diacetyl tartaric acid, di-0,0'-p-toluoyl tartaric acid, mandelic acid, malic acid or camphor-10-sulfonic acid. Racemic products can also be resolved by chiral chromatography, e.g., high pressure liquid chromatography (HPLC) using a chiral adsorbent.
Depending on substituent definition, compounds of formula I may occur in various tautomeric forms. All tautomeric forms of the compounds of formula I are embraced by the invention. Compounds of formula I may exist in free form or as a salt. In this specification, unless otherwise indicated, language such as "compound of formula I" is to be understood as embracing the compounds in any form, for example free or acid addition salt form. Salts which are unsuitable for pharmaceutical uses but which can be employed, for example, for the isolation or purification of free compounds of formula I, such as picrates or perchlorates, are also included. For therapeutic use, only pharmaceutically acceptable salts or free compounds are employed (where applicable in the form of pharmaceutical preparations), and are therefore preferred. Salts are preferably physiologically acceptable salts, formed by the addition of an acid.
As used herein, the term "pharmaceutically acceptable salts" refers to salts that retain the biological effectiveness and properties of the compounds of this invention and, which typically are not biologically or otherwise undesirable. The compounds of the invention may be capable of forming acid salts by virtue of the presence of suitable groups, such as amino groups.
Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids, e.g., acetate, aspartate, benzoate, besylate, bromide/hydrobromide, bicarbonate/carbonate, bisulfate/sulfate, camphorsulfornate, chloride/hydrochloride, chlortheophyllonate, citrate, ethandisulfonate, fumarate, gluceptate, gluconate, glucuronate, hippurate, , hydroiodide/iodide, isethionate, lactate, lactobionate, laurylsulfate, malate, maleate, malonate, mandelate, mesylate, methylsulphate, naphthoate, napsylate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate/hydrogen
phosphate/dihydrogen phosphate, polygalacturonate, propionate, stearate, succinate, subsalicylate, tartrate, tosylate and trifluoroacetate salts. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid,
methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, sulfosalicylic acid, and the like. The pharmaceutically acceptable salts of the invention can be synthesized from a parent compound by conventional chemical methods. Generally, such salts can be prepared by reacting free base forms of these compounds with a stoichiometric amount of the appropriate acid. Such reactions are typically carried out in water or in an organic solvent, or in a mixture of the two. Generally, non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred, where practicable. Lists of additional suitable salts can be found, e.g., in "Remington's Pharmaceutical Sciences", 20th ed., Mack Publishing Company, Easton, Pa., (1985); and in "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).
The invention includes all pharmaceutically acceptable isotopically-labeled compounds of the invention, i.e. compounds of formula (I), wherein (1) one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature, and/or (2) the isotopic ratio of one or more atoms is different from the naturally occurring ratio.
Examples of isotopes suitable for inclusion in the compounds of the invention comprises isotopes of hydrogen, such as 2H and 3H, carbon, such as 11C, 13C and 14C, chlorine, such as 36CI, fluorine, such as 18F, iodine, such as 123l and 125l, nitrogen, such as 13N and 15N, oxygen, such as 150, 170 and 180, phosphorus, such as 32P, and sulfur, such as 35S.
Certain isotopically-labeled compounds of formula (I), for example, those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies. The radioactive isotopes tritium, i.e. 3H, and carbon-14, i.e. 14C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.
Substitution with heavier isotopes such as deuterium, i.e. 2H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances.
Substitution with positron emitting isotopes, such as 11C, 18F, 150 and 13N, can be useful in Positron Emission Tomography (PET) studies for examining substrate receptor occupancy. Isotopically-labeled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and Preparations using an appropriate isotopically-labeled reagents in place of the non-labeled reagent previously employed.
Pharmaceutically acceptable solvates in accordance with the invention include those wherein the solvent of crystallization may be isotopically substituted, e.g. D20, d6-acetone, d6-DMSO.
Compounds of the invention, i.e. compounds of formula (I) that contain groups capable of acting as donors and/or acceptors for hydrogen bonds may be capable of forming co-crystals with suitable co-crystal formers. These co-crystals may be prepared from compounds of formula (I) by known co-crystal forming procedures. Such procedures include grinding, heating, co-subliming, co-melting, or contacting in solution compounds of formula I with the co-crystal former under crystallization conditions and isolating co-crystals thereby formed. Suitable co-crystal formers include those described in WO 2004/078163. Hence the invention further provides co-crystals comprising a compound of formula (I).
Compounds of the invention are either obtained in the free form, as a salt thereof, or as prodrug derivatives thereof.
The invention also provides pro-drugs of the compounds of the invention that converts in vivo to the compounds of the invention. A pro-drug is an active or inactive compound that is modified chemically through in vivo physiological action, such as hydrolysis, metabolism and the like, into a compound of this invention following administration of the prodrug to a subject. The suitability and techniques involved in making and using pro-drugs are well known by those skilled in the art. Prodrugs can be conceptually divided into two non-exclusive categories, bioprecursor prodrugs and carrier prodrugs. See The Practice of Medicinal Chemistry, Ch. 31-32 (Ed. Wermuth, Academic Press, San Diego, Calif., 2001). Generally, bioprecursor prodrugs are compounds, which are inactive or have low activity compared to the corresponding active drug compound, that contain one or more protective groups and are converted to an active form by metabolism or solvolysis. Both the active drug form and any released metabolic products should have acceptably low toxicity. Carrier prodrugs are drug compounds that contain a transport moiety, e.g., that improve uptake and/or localized delivery to a site(s) of action. Desirably for such a carrier prodrug, the linkage between the drug moiety and the transport moiety is a covaient bond, the prodrug is inactive or less active than the drug compound, and any released transport moiety is acceptably non-toxic. For prodrugs where the transport moiety is intended to enhance uptake, typically the release of the transport moiety should be rapid. In other cases, it is desirable to utilize a moiety that provides slow release, e.g., certain polymers or other moieties, such as cyclodextrins. Carrier prodrugs can, for example, be used to improve one or more of the following properties: increased lipophilicity, increased duration of
pharmacological effects, increased site-specificity, decreased toxicity and adverse reactions, and/or improvement in drug formulation (e.g., stability, water solubility, suppression of an undesirable organoleptic or physiochemical property). For example, lipophilicity can be increased by esterification of hydroxyl groups with lipophilic carboxylic acids (e.g., a carboxylic acid having at least one lipophilic moiety).
Exemplary prodrugs are, e.g., O-acyl derivatives of alcohols. Preferred are pharmaceutically acceptable ester derivatives convertible by solvolysis under physiological conditions to the parent carboxylic acid, e.g., lower alkyl esters, cycloalkyl esters, lower alkenyl esters, benzyl esters, mono- or di-substituted lower alkyl esters, such as the co-(amino, mono- or di-lower alkylamino, carboxy, lower alkoxycarbonyl)-lower alkyl esters, the a-(lower alkanoyloxy, lower alkoxycarbonyl or di-lower alkylaminocarbonyl)-lower alkyl esters, such as the pivaloyloxymethyl ester and the like conventionally used in the art. In addition, amines have been masked as arylcarbonyloxymethyl substituted derivatives which are cleaved by esterases in vivo releasing the free drug and formaldehyde (Bundgaard, J. Med. Chem. 2503 (1989)). Moreover, drugs containing an acidic NH group, such as imidazole, imide, indole and the like, have been masked with N-acyloxymethyl groups (Bundgaard, Design of Prodrugs, Elsevier (1985)). Hydroxy groups have been masked as esters and ethers. EP 039,051 (Sloan and Little) discloses Mannich-base hydroxamic acid prodrugs, their preparation and use.
Furthermore, the compounds of the invention, including their salts, can also be obtained in the form of their hydrates, or include other solvents used for their crystallization. Preferred substituents, preferred ranges of numerical values or preferred ranges of the radicals present in compounds of the formula I, IA, IB and the corresponding intermediate compounds are defined below. The definition of the substituents applies to the end-products as well as to the corresponding intermediates. The definitions of the substituents may be combined at will, e.g. preferred substituents R1 and particularly preferred substituents R2.
In especially preferred embodiments, the invention relates to one or more than one of the compounds of the formula I mentioned in the Examples hereinafter, in free form or in salt form.
One class of compounds of the invention, are compounds of formula IA
Figure imgf000016_0001
wherein R^ R2, R3, R4l R5, R6, A, B and C are as defined under formula (I). One class of compounds of the invention, are compounds of formula IB
Figure imgf000016_0002
wherein R^ R2, R3, R4, R5, Re, A, B and C are as defined under formula (I).
In one class of compounds of the invention, is C - alkyl, for example, methyl, ethyl or n- propyl. In one class of compounds of the invention, is methyl.
In one class of compounds of the invention, R2, R3, R5 and R6 are each independently selected from hydrogen, halogen, and C -4alkyl. In one class of compounds of the invention, R2, R3, R5 and R6 are each hydrogen.
In one class of compounds of the invention, R is hydrogen or C -4alkyl. In one class of compounds of the invention, R is hydrogen. ln one class of compounds of the invention, A is a ring system selected from A1 , A2, A3 or
Figure imgf000017_0001
A1 A2 A3 A4 wherein
A1a is a five- to six-membered monocyclic aromatic ring system which contains from 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur, wherein the ring system may contain not more than 2 oxygen atoms and not more than 2 sulfur atoms, and wherein the ring system may be substituted once or more than once by R7, and wherein a substituent on a nitrogen in a heterocyclic ring system may not be halogen;
A1 b is a five- to six-membered monocyclic aromatic ring system which may contain from 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur, wherein the ring system may contain not more than 2 oxygen atoms and not more than 2 sulfur atoms, and wherein the ring system is fused to ring system A1 a via carbon and/or nitrogen atoms, and wherein the ring system may be substituted once or more than once by R8, and wherein a substituent on a nitrogen in a heterocyclic ring system may not be halogen;
each R7 or R8 independently is halogen, Chalky!, C1-6halogenalkyl, C3-7cycloalkyl, C3- 7cycloalkyl(C -4alkyl), C -6alkoxy, or C1-6halogenalkoxy;
A2a is a six-membered monocyclic aromatic ring system which contains from 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur, wherein the ring system may contain not more than 2 oxygen atoms and not more than 2 sulfur atoms, and wherein the ring system is fused to the phenyl ring via two carbon atoms, and wherein the ring system may be substituted once or more than once by R 0, and wherein a substituent on a nitrogen in a heterocyclic ring system may not be halogen;
n is 0, 1 , 2 or 3;
each R9 or R10 independently is halogen, C1-6alkyl, C^halogenalkyl, C3-7cycloalkyl, C3- 7cycloalkyl(C1 4alkyl), C1 6alkoxy, or C1 6halogenalkoxy;
each of A3a or A3b is independently a five- to six-membered monocyclic aromatic ring system which may contain from 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur, wherein the ring system may contain not more than 2 oxygen atoms and not more than 2 sulfur atoms, and wherein the ring system may be substituted once or more than once by Ru, and wherein a substituent on a nitrogen in a heterocyclic ring system may not be halogen;
each Ru independently is halogen, C1-6alkyl, C1-6halogenalkyl, C3-7cycloalkyl, C3.
7cycloalkyl(C1-4alkyl), C1-6alkoxy, or C1-6halogenalkoxy;
A4a is a five- to six-membered monocyclic aromatic ring system which contains from 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur, wherein the ring system may contain not more than 2 oxygen atoms and not more than 2 sulfur atoms, and wherein the ring system is substituted once or more than once by R12, and wherein a substituent on a nitrogen in a heterocyclic ring system may not be halogen;
each R12 independently is halogen; C1-6alkyl; Ci-6halogenalkyl; C1-6alkoxy; or d.
ehalogenalkoxy; or a three- to eight-membered monocyclic or bicyclic saturated or unsaturated non-aromatic ring system which may contain from 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur, wherein the saturated or unsaturated non-aromatic ring system may contain not more than 2 oxygen atoms and not more than 2 sulfur atoms, wherein the saturated or unsaturated non-aromatic ring system may be attached directly to the ring system A4a or via a C1-4alkylene group, and wherein the saturated or unsaturated non-aromatic ring system may be substituted once or more than once by Ri3, and wherein a substituent on a nitrogen in a heterocyclic saturated or unsaturated non-aromatic ring system may not be halogen; or two R12 at adjacent ring atoms of the ring system A4a form together with said ring atoms a fused five- to seven-membered unsaturated non-aromatic ring system which may contain from 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur, wherein the fused unsaturated non-aromatic ring system may contain not more than 2 oxygen atoms and not more than 2 sulfur atoms, and wherein the fused unsaturated non- aromatic ring system may in turn be substituted once or more than once by R14, and wherein a substituent on a nitrogen in a heterocyclic fused unsaturated non-aromatic ring system may not be halogen;
each R13 independently is halogen, C1-6alkyl, C1-6halogenalkyl, C3-7cycloalkyl, C3.
7cycloalkyl(C1.4alkyl), C1-6alkoxy, or C1-6halogenalkoxy; or two Ri3 at the same ring atom of the saturated or unsaturated non-aromatic ring system together are oxo;
each Ru independently is halogen or Ci-6alkyl, or two R 4 at the same ring atom of the fused unsaturated non-aromatic ring system together are oxo.
In one class of compounds of the invention, A is A1
Figure imgf000019_0001
A1
wherein
A1a is a five- to six-membered monocyclic aromatic ring system which contains from 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur, wherein the ring system may contain not more than 2 oxygen atoms and not more than 2 sulfur atoms, and wherein the ring system may be substituted once or more than once by R7, and wherein a substituent on a nitrogen in a heterocyclic ring system may not be halogen;
A1b is a five- to six-membered monocyclic aromatic ring system which may contain from 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur, wherein the ring system may contain not more than 2 oxygen atoms and not more than 2 sulfur atoms, and wherein the ring system is fused to ring system A1 a via carbon and/or nitrogen atoms, and wherein the ring system may be substituted once or more than once by R8, and wherein a substituent on a nitrogen in a heterocyclic ring system may not be halogen;
each R7 or R8 independently is halogen, Chalky!, C1-6halogenalkyl, C3.7cycloalkyl, C3.
7cycloalkyl(C1.4alkyl), C1-6alkoxy, or C1-6halogenalkoxy. In one embodiment of said class, each R7 or R8 independently is halogen, C1-4alkyl or C1-4halogenalkyl.
In one class of compounds of the invention, A is A2
Figure imgf000019_0002
A2
wherein
A2a is a six-membered monocyclic aromatic ring system which contains from 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur, wherein the ring system may contain not more than 2 oxygen atoms and not more than 2 sulfur atoms, and wherein the ring system is fused to the phenyl ring via two carbon atoms, and wherein the ring system may be substituted once or more than once by Ri0, and wherein a substituent on a nitrogen in a heterocyclic ring system may not be halogen;
n is 0, 1 , 2 or 3; each R9 or R 0 independently is halogen, C1-6alkyl, C1-6halogenalkyl, C3-7cycloalkyl, C3. 7cycloalkyl(Ci-4alkyl), C1-6alkoxy, or C1-6halogenalkoxy. In one embodiment of said class, n is 0 and each R10 independently is halogen, C -4alkyl or C1-4halogenalkyl.
In one class of compounds of the invention, A is A2
Figure imgf000020_0001
A2
wherein
A2a is a five-membered monocyclic aromatic ring system which contains from 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur, wherein the ring system may contain not more than 2 oxygen atoms and not more than 2 sulfur atoms, and wherein the ring system is fused to the phenyl ring via two carbon atoms, and wherein the ring system may be substituted once or more than once by R 0, and wherein a substituent on a nitrogen in a heterocyclic ring system may not be halogen;
n is 0, 1 , 2 or 3;
each R9 or R10 independently is halogen, C -6alkyl, C1-6halogenalkyl, C3-7cycloalkyl, C3- 7cycloalkyl(C - alkyl), C1-6alkoxy, or C1-6halogenalkoxy. In one embodiment of said class, n is 0 and each R10 independently is halogen, C1-4alkyl or C^halogenalkyl.
In one class of compounds of the invention, A is A2
Figure imgf000020_0002
A2
wherein
A2a is a five-membered monocyclic aromatic ring system which contains from 2 to 3 hetero atoms selected from nitrogen, oxygen and sulfur, wherein the ring system may contain not more than 2 oxygen atoms and not more than 2 sulfur atoms, and wherein the ring system is fused to the phenyl ring via two carbon atoms, and wherein the ring system may be substituted once or more than once by R 0, and wherein a substituent on a nitrogen in a heterocyclic ring system may not be halogen; n is 0, 1 , 2 or 3;
each R9 or R10 independently is halogen, C1-6alkyl, Ci-6halogenalkyl, C3-7cycloalkyl, C3- 7cycloalkyl(Ci.4alkyl), C -6alkoxy, or Ci-6halogenalkoxy. In one embodiment of said class, n is 0 and each R10 independently is halogen, C1-4alkyl or C^halogenalkyl.
In one class of compounds of the invention, A is A2
Figure imgf000021_0001
A2
wherein
A2a is a five-membered monocyclic aromatic ring system which contains from 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur, wherein the ring system may contain not more than 2 oxygen atoms and not more than 2 sulfur atoms, and wherein the ring system is fused to the phenyl ring via two carbon atoms, and wherein the ring system is substituted two or three times by R10, and wherein a substituent on a nitrogen in a heterocyclic ring system may not be halogen;
n is 0, 1 , 2 or 3;
each R9 or R10 independently is halogen, C1-6alkyl, Ci-6halogenalkyl, C3-7cycloalkyl, C3- 7cycloalkyl(C1-4alkyl), d-6alkoxy, or C1-6halogenalkoxy. In one embodiment of said class, n is 0 and each R10 independently is halogen, C1-4alkyl or C1-4halogenalkyl.
In one class of compounds of the invention, A is A3
Figure imgf000021_0002
A3
wherein
each of A3a or A3b is independently a five- to six-membered monocyclic aromatic ring system which may contain from 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur, wherein the ring system may contain not more than 2 oxygen atoms and not more than 2 sulfur atoms, and wherein the ring system may be substituted once or more than once by Rn, and wherein a substituent on a nitrogen in a heterocyclic ring system may not be halogen; each Rn independently is halogen, Chalky!, C1-6halogenalkyl, C3-7cycloalkyl, C3.
7cycloalkyl(C -4alkyl), d-6alkoxy, or C -6halogenalkoxy. In one embodiment of said class, each Rn independently is halogen, C1-4alkyl or C1-4halogenalkyl.
In one class of compounds of the invention, A is A3
Figure imgf000022_0001
A3
wherein
A3a is phenyl which may be substituted once or more than once by Rn;
A3b is a five- to six-membered monocyclic aromatic ring system which may contain from 1 to
4 hetero atoms selected from nitrogen, oxygen and sulfur, wherein the ring system may contain not more than 2 oxygen atoms and not more than 2 sulfur atoms, and wherein the ring system may be substituted once or more than once by Rn, and wherein a substituent on a nitrogen in a heterocyclic ring system may not be halogen;
each Rn independently is halogen, C1-6alkyl, C1-6halogenalkyl, C3.7cycloalkyl, C3-
7cycloalkyl(C1-4alkyl), C^eal oxy, or C^ehalogenalkoxy. In one embodiment of said class, each Rn independently is halogen, C -4alkyl or C1-4halogenalkyl. In one embodiment of said class, A3a is unsubstituted and each Rn independently is halogen, C1- alkyl or Ci.
4halogenalkyl.
In one class of compounds of the invention, A is A3 which is biphenyl which may be substituted once or more than once by Rn. In one embodiment of said class, each Rn independently is halogen, C^alkyl or C1- halogenalkyl. In one embodiment of said class, A is A3 which is unsubstituted biphenyl.
In one class of compounds of the invention, A is A3
Figure imgf000022_0002
A3
wherein
A3a is phenyl which may be substituted once or more than once by R ; A3b is a five- to six-membered monocyclic aromatic ring system which contains from 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur, wherein the ring system may contain not more than 2 oxygen atoms and not more than 2 sulfur atoms, and wherein the ring system may be substituted once or more than once by Rn, and wherein a substituent on a nitrogen in a heterocyclic ring system may not be halogen;
each Rn independently is halogen, C1-6alkyl, C -6halogenalkyl, C3-7cycloalkyl, C3- 7cycloalkyl(C1- alkyl), C1-6alkoxy, or C1-6halogenalkoxy. In one embodiment of said class, each R independently is halogen, Ci.4alkyl or C -4halogenalkyl. In one embodiment of said class, A3a is unsubstituted and each Rn independently is halogen, C1-4alkyl or d.
4halogenalkyl.
In one class of compounds of the invention, A is A4
Figure imgf000023_0001
A4
wherein
A4a is a five- to six-membered monocyclic aromatic ring system which contains from 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur, wherein the ring system may contain not more than 2 oxygen atoms and not more than 2 sulfur atoms, and wherein the ring system is substituted once or more than once by Ri2, and wherein a substituent on a nitrogen in a heterocyclic ring system may not be halogen;
each R12 independently is halogen; C1-6alkyl; C1-6halogenalkyl; C1-6alkoxy; or Ci_
ehalogenalkoxy; or a three- to eight-membered monocyclic or bicyclic saturated or unsaturated non-aromatic ring system which may contain from 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur, wherein the saturated or unsaturated non-aromatic ring system may contain not more than 2 oxygen atoms and not more than 2 sulfur atoms, wherein the saturated or unsaturated non-aromatic ring system may be attached directly to the ring system A4a or via a C -4alkylene group, and wherein the saturated or unsaturated non-aromatic ring system may be substituted once or more than once by Ri3, and wherein a substituent on a nitrogen in a heterocyclic saturated or unsaturated non-aromatic ring system may not be halogen; or two Ri2 at adjacent ring atoms of the ring system A4a form together with said ring atoms a fused five- to seven-mem bered unsaturated non-aromatic ring system which may contain from 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur, wherein the fused unsaturated non-aromatic ring system may contain not more than 2 oxygen atoms and not more than 2 sulfur atoms, and wherein the fused unsaturated non- aromatic ring system may in turn be substituted once or more than once by Ri4, and wherein a substituent on a nitrogen in a heterocyclic fused unsaturated non-aromatic ring system may not be halogen;
each R 3 independently is halogen, C -6alkyl, C -6halogenalkyl, C3-7cycloalkyl, C3.
7cycloalkyl(C -4alkyl), C1-6alkoxy, or C -6halogenalkoxy; or two R13 at the same ring atom of the saturated or unsaturated non-aromatic ring system together are oxo;
each R14 independently is halogen or C1-6alkyl, or two R14 at the same ring atom of the fused unsaturated non-aromatic ring system together are oxo.
In one class of compounds of the invention, A is A4
Figure imgf000024_0001
A4
wherein
A4a is a five- to six-membered monocyclic aromatic ring system which contains from 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur, wherein the ring system may contain not more than 2 oxygen atoms and not more than 2 sulfur atoms, and wherein the ring system is substituted once or more than once by R12, and wherein a substituent on a nitrogen in a heterocyclic ring system may not be halogen; each R12 independently is halogen; C -6alkyl; C1-6halogenalkyl; C^alkoxy; or C -6halogenalkoxy. In one embodiment of said class, A4a is a five-membered monocyclic aromatic ring system and each R12 independently is halogen, C1-4alkyl, C1-4halogenalkyl, or C^alkoxy. In one embodiment of said class, A4a is a six-membered monocyclic aromatic ring system and each R12 independently is halogen, C1-4alkyl, C1-4halogenalkyl or C1-4alkoxy.
In one class of compounds of the invention, p is 0.
In one class of compounds of the invention, p is 1.
In one class of compounds of the invention, p is 1 and Ri5 is halogen or C1- alkyl.
In one class of compounds of the invention, C is a five- to ten-membered monocyclic or fused polycyclic aromatic ring system which may contain from 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur, wherein the ring system may contain not more than 2 oxygen atoms and not more than 2 sulfur atoms, and wherein the ring system may be substituted once or more than once by Ri6, and wherein a substituent on a nitrogen in a heterocyclic ring system may not be halogen;
each Ri6 independently is C1-6alkyl; C1-6halogenalkyl; C1-6alkoxy; C1-6halogenalkoxy; halogen; cyano; or two R16 at adjacent ring atoms of the ring system C form together with said ring atoms a fused five- to seven-membered unsaturated non-aromatic ring system which may contain from 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur, wherein the fused unsaturated non-aromatic ring system may contain not more than 2 oxygen atoms and not more than 2 sulfur atoms, and wherein the fused unsaturated non-aromatic ring system may in turn be substituted once or more than once by R17, and wherein a substituent on a nitrogen in a heterocyclic fused unsaturated non-aromatic ring system may not be halogen; each R17 independently is halogen or C1-6alkyl, or two R17 at the same ring atom of the fused unsaturated non-aromatic ring system together are oxo.
In one class of compounds of the invention, C is phenyl, which may be substituted once or more than once by R16. In one embodiment of said class, each R16 independently is C1-6alkyl; C1-6halogenalkyl; C -6alkoxy; C1-6halogenalkoxy; halogen or cyano.
In one class of compounds of the invention, C is a five- to six-membered monocyclic aromatic ring system which may contain from 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur, and wherein the ring system may be substituted once or more than once by R16. In one embodiment of said class, each R16 independently is halogen, C - alkyl, 4halogenalkyl, or CMalkoxy. In one embodiment of said class, C is pyridyl, for example 2-, 3- or 4-pyridyl, and each R16 independently is halogen, C1- alkyl, C1- halogenalkyl, or C1- alkoxy. In one embodiment of said class, C is unsubstituted 2-pyridyl. In one embodiment of said class, C is pyrrolyl, for example 1-, 2- or 3-pyrrolyl, and each R16 independently is halogen, C1-4alkyl or C1-4halogenalkyl. In one embodiment of said class, C is 1-methyl-1H-pyrrol-2-yl.
In one class of compounds of the invention, C is an eight- to ten-membered bicyclic aromatic ring system which contains from 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur, and wherein the ring system may be substituted once or more than once by R16. In a subclass of said class, C is C1
Figure imgf000026_0001
wherein Ri6a is C1- alkyl, for example methyl.
One class of compounds of the invention, are compounds of formula IA
Figure imgf000026_0002
wherein Ri is C1-4alkyl and R2, R3, R4, R5 and R6 are each hydrogen;
Figure imgf000026_0003
A1
wherein
A1 a is a five- to six-membered monocyclic aromatic ring system which contains from 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur, wherein the ring system may contain not more than 2 oxygen atoms and not more than 2 sulfur atoms, and wherein the ring system may be substituted once or more than once by R7, and wherein a substituent on a nitrogen in a heterocyclic ring system may not be halogen;
A1 b is a five- to six-membered monocyclic aromatic ring system which may contain from 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur, wherein the ring system may contain not more than 2 oxygen atoms and not more than 2 sulfur atoms, and wherein the ring system is fused to ring system A1a via carbon and/or nitrogen atoms, and wherein the ring system may be substituted once or more than once by R8, and wherein a substituent on a nitrogen in a heterocyclic ring system may not be halogen;
each R7 or R8 independently is halogen, Ci.4alkyl or C^halogenalkyl;
B is phenyl; C is a five- to six-membered monocyclic aromatic ring system which may contain from 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur, and wherein the ring system may be substituted once or more than once by Ri6; and
each R16 independently is halogen, C1-4alkyl or C^halogenalkyl.
One class of compounds of the invention, are compounds of formula IA
Figure imgf000027_0001
(IA)
wherein is C -4alkyl and R2, R3, R4, R5 and R6 are each hydrogen;
Figure imgf000027_0002
A2
wherein
A2a is a five- or six-membered monocyclic aromatic ring system which contains from 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur, wherein the ring system may contain not more than 2 oxygen atoms and not more than 2 sulfur atoms, and wherein the ring system is fused to the phenyl ring via two carbon atoms, and wherein the ring system may be substituted once or more than once by R10, and wherein a substituent on a nitrogen in a heterocyclic ring system may not be halogen;
n is 0, 1 , 2 or 3;
each R9 or R10 independently is halogen, C1-4alkyl or C1- halogenalkyl;
B is phenyl;
C is a five- to six-membered monocyclic aromatic ring system which may contain from 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur, and wherein the ring system may be substituted once or more than once by R 6; and
each R16 independently is halogen, C1-4alkyl or C^halogenalkyl.
One class of compounds of the invention, are compounds of formula IA
Figure imgf000028_0001
wherein R is d.4alkyl and R2, R3, R , R5 and R6 are each hydrogen;
Figure imgf000028_0002
A2 J
wherein
A2a is a five-membered monocyclic aromatic ring system which contains from 2 to 3 hetero atoms selected from nitrogen, oxygen and sulfur, wherein the ring system may contain not more than 2 oxygen atoms and not more than 2 sulfur atoms, and wherein the ring system is fused to the phenyl ring via two carbon atoms, and wherein the ring system may be substituted once or more than once by R10, and wherein a substituent on a nitrogen in a heterocyclic ring system may not be halogen;
n is 0, 1 , 2 or 3;
each R9 or Ri0 independently is halogen, Ci.4alkyl or Ci.4halogenalkyl;
B is phenyl;
C is a five- to six-membered monocyclic aromatic ring system which may contain from 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur, and wherein the ring system may be substituted once or more than once by R16; and
each R16 independently is halogen, C1- alkyl or C1-4halogenalkyl.
One class of compounds of the invention, are compounds of formula IA
(IA)
Figure imgf000028_0003
wherein R1 is Ci-4alkyl and R2, R3, R , R5 and R6 are each hydrogen;
A is A3
Figure imgf000029_0001
A3 i
wherein
A3a is phenyl which may be substituted once or more than once by R ;
A3b is a five- to six-membered monocyclic aromatic ring system which may contain from 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur, wherein the ring system may contain not more than 2 oxygen atoms and not more than 2 sulfur atoms, and wherein the ring system may be substituted once or more than once by Rn, and wherein a substituent on a nitrogen in a heterocyclic ring system may not be halogen;
each Rn independently is halogen, C1-4alkyl or d^halogenalkyl;
B is phenyl;
C is a five- to six-membered monocyclic aromatic ring system which may contain from 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur, and wherein the ring system may be substituted once or more than once by R16; and
each R16 independently is halogen, C1-4alkyl or C1-4halogenalkyl.
One class of compounds of the invention, are compounds of formula IA
Figure imgf000029_0002
wherein is C1-4alkyl and R2, R3, R4, R5 and R6 are each hydrogen;
Figure imgf000029_0003
A4 J
A4a is a five- to six-membered monocyclic aromatic ring system which contains from 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur, wherein the ring system may contain not more than 2 oxygen atoms and not more than 2 sulfur atoms, and wherein the ring system is substituted once or more than once by R12, and wherein a substituent on a nitrogen in a heterocyclic ring system may not be halogen;
each Ri2 independently is halogen,
Figure imgf000030_0001
or C1-4 alkoxy;
B is phenyl;
C is a five- to six-membered monocyclic aromatic ring system which may contain from 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur, and wherein the ring system may be substituted once or more than once by R16; and
each Ri6 independently is halogen,
Figure imgf000030_0002
One class of compounds of the invention, are compounds of formula IB
Figure imgf000030_0003
wherein R is Ci-4alkyl and R2, R3, R4, Rs and R6 are each hydrogen;
Figure imgf000030_0004
A1
wherein
A1 a is a five- to six-membered monocyclic aromatic ring system which contains from 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur, wherein the ring system may contain not more than 2 oxygen atoms and not more than 2 sulfur atoms, and wherein the ring system may be substituted once or more than once by R7, and wherein a substituent on a nitrogen in a heterocyclic ring system may not be halogen;
A1 b is a five- to six-membered monocyclic aromatic ring system which may contain from 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur, wherein the ring system may contain not more than 2 oxygen atoms and not more than 2 sulfur atoms, and wherein the ring system is fused to ring system A1 a via carbon and/or nitrogen atoms, and wherein the ring system may be substituted once or more than once by R8, and wherein a substituent on a nitrogen in a heterocyclic ring system may not be halogen; each R7 or R8 independently is halogen, C1-4alkyl or C1-4halogenalkyl;
B is phenyl;
C is a five- to six-membered monocyclic aromatic ring system which may contain from 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur, and wherein the ring system may be substituted once or more than once by R 6; and
each R 6 independently is halogen, C1-4alkyl or C1-4halogenalkyl.
One class of compounds of the invention, are compounds of formula IB
Figure imgf000031_0001
wherein is C1-4alkyl and R2, R3, R4, R5 and R6 are each hydrogen;
Figure imgf000031_0002
A2
wherein
A2a is a five- or six-membered monocyclic aromatic ring system which contains from 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur, wherein the ring system may contain not more than 2 oxygen atoms and not more than 2 sulfur atoms, and wherein the ring system is fused to the phenyl ring via two carbon atoms, and wherein the ring system may be substituted once or more than once by R10, and wherein a substituent on a nitrogen in a heterocyclic ring system may not be halogen;
n is 0, 1 , 2 or 3;
each R9 or Ri0 independently is halogen, C^alkyl or C halogenalkyl;
B is phenyl;
C is a five- to six-membered monocyclic aromatic ring system which may contain from 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur, and wherein the ring system may be substituted once or more than once by R16; and
each R16 independently is halogen, C1-4alkyl or C -4halogenalkyl. ne class of compounds of the invention, are compounds of formula IB
Figure imgf000032_0001
wherein Ri is C -4alkyl and R2, R3, R4, R5 and R6 are each hydrogen;
Figure imgf000032_0002
A2
wherein
A2a is a five-membered monocyclic aromatic ring system which contains from 2 to 3 hetero atoms selected from nitrogen, oxygen and sulfur, wherein the ring system may contain not more than 2 oxygen atoms and not more than 2 sulfur atoms, and wherein the ring system is fused to the phenyl ring via two carbon atoms, and wherein the ring system may be substituted once or more than once by R 0, and wherein a substituent on a nitrogen in a heterocyclic ring system may not be halogen;
n is 0, 1 , 2 or 3;
each R9 or R10 independently is halogen, C -4alkyl or
Figure imgf000032_0003
B is phenyl;
C is a five- to six-membered monocyclic aromatic ring system which may contain from 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur, and wherein the ring system may be substituted once or more than once by R 6; and
each R16 independently is halogen, C1- alkyl or C1-4halogenalkyl.
One class of compounds of the invention, are compounds of formula IB
Figure imgf000033_0001
wherein is C1-4alkyl and R2, R3, R4, R5 and R6 are each hydrogen;
Figure imgf000033_0002
A3
wherein
A3a is phenyl which may be substituted once or more than once by Rn ;
A3b is a five- to six-membered monocyclic aromatic ring system which may contain from 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur, wherein the ring system may contain not more than 2 oxygen atoms and not more than 2 sulfur atoms, and wherein the ring system may be substituted once or more than once by Rn , and wherein a substituent on a nitrogen in a heterocyclic ring system may not be halogen;
each R11 independently is halogen, C1-4alkyl or C1-4halogenalkyl;
B is phenyl;
C is a five- to six-membered monocyclic aromatic ring system which may contain from 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur, and wherein the ring system may be substituted once or more than once by R16; and
each R16 independently is halogen, C1-4alkyl or
Figure imgf000033_0003
n, are compounds of formula IB
Figure imgf000033_0004
wherein Ri is C1-4alkyl and R2, R3, R4, R5 and R6 are each hydrogen;
A is A4
Figure imgf000034_0001
A4
A4a is a five- to six-membered monocyclic aromatic ring system which contains from 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur, wherein the ring system may contain not more than 2 oxygen atoms and not more than 2 sulfur atoms, and wherein the ring system is substituted once or more than once by Ri2, and wherein a substituent on a nitrogen in a heterocyclic ring system may not be halogen;
each R12 independently is halogen, C1-4alkyl, C1-4halogenalkyl or alkoxy;
B is phenyl;
C is a five- to six-membered monocyclic aromatic ring system which may contain from 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur, and wherein the ring system may be substituted once or more than once by R16; and
each R 6 independently is halogen, C1-4alkyl, C -4halogenalkyl or C1-4alkoxy.
In one embodiment, the invention provides a compound selected from
N,1-dimethyl-N-(1-phenyl-4-(picolinamido)butan-2-yl)-1 H-benzo[d]imidazole-2-carboxamide;
N-methyl-N-(4-(1-methyl-1H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)imidazo[1 ,2- a] pyridine-6-carboxamide;
6-methyl-N-(3-(N-methyl-1 H-indazole-3-carboxamido)-4-phenylbutyl)imidazo[2, 1 -b]thiazole- 5-carboxamide;
N-methyl-N-(4-(1-methyl-1H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)isoquinoline-1- carboxamide;
N,1-dimethyl-N-(4-(1-methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)-1H-pyrrolo[2,3- b] pyridine-3-carboxamide;
N,1-dimethyl-N-(4-(1-methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)-1H-indazole-3- carboxamide;
, 1 , 5-trimethyl-N-(4-( 1 -methyl- 1 H-pyrrole-2-carboxamido)- 1 -phenylbutan-2-yl)- 1 H-indazole- 3-carboxamide;
2-methoxy-N-methyl-N-(4-(1 -methyl- 1 H-pyrrole-2-carboxamido)-1 -phenylbutan-2- yl)quinoline-4-carboxamide;
5-fluoro-N-methyl-N-(4-(1-methyl-1H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)-1 H-indole- 2-carboxamide; N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)quinazoline-4- carboxamide;
N-methyl-N-(4-(1-methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)imidazo[1 ,5- a] pyridine-6-carboxamide;
N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)-1 H-pyrrolo[2,3- b] pyridine-3-carboxamide;
N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1 -phenylbutan-2-yl)-1 H-indazole-3- carboxamide;
6-methyl-N-(3-(N-methyl-1H-pyrrolo[2,3-b]pyridine-3-carboxamido)-4- phenylbutyl)imidazo[2, 1 -b]thiazole-5-carboxamide;
N,2-dimethyl-N-(4-(1-methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)pyrazolo[1 ,5- a]pyridine-3-carboxamide;
N,4,7-trimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1 -phenylbutan-2-yl)pyrazolo[5, 1 - c] [ 1 ,2,4]triazi ne-3-carboxam ide ;
5-methoxy-N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1 -phenylbutan-2- yl)pyrazolo[1 ,5-a]pyridine-3-carboxamide;
N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)imidazo[1 , 2- a]pyridine-7-carboxamide;
N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)benzo[d]isoxazole-3- carboxamide;
N,1-dimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)-1 H- pyrazolo[3,4-b]pyridine-3-carboxamide;
N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)furo[2,3-c]pyridine-5- carboxamide;
1-methyl-N-(3-(N-methylbenzofuran-3-carboxamido)-4-phenylbutyl)-1 H-pyrrole-2- carboxamide;
N,1-dimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)-1 H-indole-2- carboxamide;
N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1 -phenylbutan-2-yl)-1 H- benzo[d]imidazole-2-carboxamide;
5-fluoro-N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)-1 H- indazole-3-carboxamide;
5-methoxy-N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1 -phenylbutan-2-yl)-1 H- indazole-3-carboxamide; 6-fluoro-N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1 -phenylbutan-2-yl)-1 H- indazole-3-carboxamide;
N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)quinoline-2- carboxamide;
N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)cinnoline-4- carboxamide;
N,2,7-trimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)pyrazolo[1 , 5- a]pyrimidine-6-carboxamide;
N,2,7-trimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)imidazo[1 ,2- a]pyridine-3-carboxamide;
N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)-1 ,6-naphthyridine- 2-carboxamide;
N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1 -phenylbutan-2-yl)pyrazolo[1 ,5- a]pyridine-3-carboxamide;
N, 1-dimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)-1 H-indole-3- carboxamide;
5,7-difluoro-N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1 -phenylbutan-2-yl)-1 H- indole-2-carboxamide;
N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1 -phenylbutan-2-yl)-1 H-indole-3- carboxamide;
N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1 -phenylbutan-2-yl)quinoline-3- carboxamide;
N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)quinoline-4- carboxamide;
N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1 -phenylbutan-2-yl)quinoxaline-2- carboxamide;
N,5-dimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1 -phenylbutan-2-yl)-1 H-indole-2- carboxamide;
N-(3-(N,3-dimethylbenzofuran-2-carboxamido)-4-phenylbutyl)-1 -methyl-1 H-pyrrole-2- carboxamide;
N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)isoquinoline-3- carboxamide;
N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)-[1 ,2,4]triazolo[1 ,5- a]pyrimidine-2-carboxamide; N,2,8-trimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)'imidazo[1 ,2- a]pyridine-3-carboxamide;
N,5,7-trimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)pyrazolo[1 , 5- a] pyrimidine-2-carboxamide;
N,5-dimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)-1 H-indazole-3- carboxamide;
N-methyl-N-(4-(1-methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)-1 H-pyrrolo[2,3- b] pyridine-4-carboxamide;
5- methoxy-N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)-1 H- indole-2-carboxamide;
6- chloro-N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1 -phenylbutan-2- yl)imidazo[1 ,2-a]pyridine-2-carboxamide;
N,2-dimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1 -phenylbutan-2-yl)-1 ,6- naphthyridine-3-carboxamide;
N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1 -phenylbutan-2-yl)imidazo[1 ,2- a]pyridine-3-carboxamide;
N,7-dimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)imidazo[1 , 2- a]pyridine-6-carboxamide;
N,2-dimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)quinoline-4- carboxamide;
2-chloro-N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1 -phenylbutan-2-yl)quinoline-4- carboxamide;
N,8-dimethyl-N-(4-(1-methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)imidazo[1 ,2- a] pyridine-2-carboxamide;
N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)furo[3,2-b]pyridine- 5-carboxamide;
N , 1 , 3-trimethyl-N-(4-( 1 -methyl- 1 H-pyrrole-2-carboxamido)- 1 -phenylbutan-2-yl)-1 H-thieno[2, 3- c] pyrazole-5-carboxam'ide;
5-chloro-N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1 -phenyl butan-2- yl)imidazo[1 ,2-a]pyridine-2-carboxamide;
N,6-dimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1 -phenylbutan-2-yl)furo[2,3- b] pyri d ine-5-carboxami de ;
N,2-dimethyl-N-(4-(1-methyl-1 H-pyrrole-2-carboxam'ido)-1-phenylbutan-2-yl)imidazo[1 ,2- a]pyridine-3-carboxamide; N-methyl-N-(4-(1-methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)imidazo[1 ,2- a]pyridine-8-carboxamide;
N-methyl-N-(4-(1-methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)imidazo[1 ,2- a] pyridine-5-carboxamide;
N,6-dimethyl-N-(4-(1-methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)imidazo[2,1- b] thiazole-5-carboxamide;
N-methyl-N-(4-(1-methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)imidazo[2,1- b]thiazole-6-carboxamide;
N,2,3-trimethyl-N-(4-(1-methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)imidazo[2,1- b]thiazole-6-carboxamide;
N-methyl-N-(4-(1-methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)-1 ,8-naphthyridine-
4- carboxamide;
7-methoxy-N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1 -phenylbutan-2- yl)isoquinoline-4-carboxamide;
N-methy l-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)furo[2,3-b]pyridine-
5- carboxamide;
N,6-dimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)furo[3,2- b]pyridine-5-carboxamide;
6- bromo-N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1 -phenylbutan-2- yl)imidazo[1 ,2-a]pyridine-7-carboxamide;
N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)imidazo[2,1- b]thiazole-5-carboxamide;
N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)isoquinoline-4- carboxamide;
N,2,6-trimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)imidazo[2,1- b][1 ,3,4]thiadiazole-5-carboxamide;
N,4-dimethyl-N-(4-(1-methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)-4H-furo[3,2- b]pyrrole-5-carboxamide;
N,2-dimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)imidazo[2,1- b][1 ,3,4]thiadiazole-6-carboxamide;
N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)imidazo[1 ,2- a]pyrimidine-2-carboxamide;
N, ,5-trimethyl-N-(4-( -methyl-1 H-benzo[d]imidazole-2-carboxamido)-1-phenylbutan-2-yl)- 1 H-indazole-3-carboxamide; 1-methyl-N-(3-(N-methylbenzofuran-3-carboxamido)-4-phenylbutyl)-1 H-benzo[d]imidazole-2- carboxamide;
N-(4-(1-ethyl-3-methyl-1 H-pyrazole-5-carboxamido)-1-phenylbutan-2-yl)-N-methylfuro[2,3- c]pyridine-5-carboxamide;
1-ethyl-3-methyl-N-(3-(N-methylbenzofuran-3-carboxamido)-4-phenylbutyl)-1H-pyrazole-5- carboxamide;
N-(4-(1-ethyl-3-methyl-1 H-pyrazole-5-carboxamido)-1-phenylbutan-2-yl)-N,1 ,5-trimethyl-1 H- indazole-3-carboxamide;
N-(4-(1-ethyl-3-methyl-1 H-pyrazole-5-carboxamido)-1-phenylbutan-2-yl)-N-methylfuro[2,3- b]pyridine-5-carboxamide;
N -dimethyl-N-(4-(1-methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)-1 H-pyrrolo[2,3- b]pyridine-4-carboxamide;
N-(4-(1-ethyl-3-methyl-1 H-pyrazole-5-carboxamido)-1-phenylbutan-2-yl)-N- methylisoquinoline-1 -carboxamide;
N-(4-(1-ethyl-3-methyl-1 H-pyrazole-5-carboxamido)-1-phenylbutan-2-yl)-N ,3-trimethyl-1 H- thieno[2,3-c]pyrazole-5-carboxamide;
N-(4-(1-ethyl-3-methyl-1 H-pyrazole-5-carboxamido)-1-phenylbutan-2-yl)-N- methylisoquinoline-4-carboxamide;
N-(4-(1-ethyl-3-methyl-1 H-pyrazole-5-carboxamido)-1-phenylbutan-2-yl)-N,2- dimethylpyrazolo[1 ,5-a]pyridine-3-carboxamide;
N-(4-(1 -ethyl-3-methyl-1 H-pyrazole-5-carboxamido)-1 -phenylbutan-2-yl)-N- methyrimidazo[1 ,2-a]pyridine-5-carboxamide;
6-methyl-N-(3-(N-methylbenzofuran-3-carboxamido)-4-p enylbutyl)picolinamide;
N, 1 ,5-trimethyl-N-(4-(6-methylpicolinamido)-1 -phenylbutan-2-yl)-1 H-indazole-3-carboxamide;
N,2-dimethyl-N-(4-(6-methylpicolinamido)-1-phenylbutan-2-yl)pyrazolo[1 ,5-a]pyridine-3- carboxamide;
6-methoxy-N-(3-(N-methylbenzofuran-3-carboxamido)-4-phenylbutyl)picolinamide;
N-(4-(6-methoxypicolinamido)-1-phenylbutan-2-yl)-N ,5-trimethyl-1 H-in
carboxamide;
N-(4-(6-methoxypicolinamido)-1-phenylbutan-2-yl)-N,2-dimethylpyrazolo[1 ,5-a]pyrid'ine-3- carboxamide;
5-(4-fluorophenyl)-N,2-dimethyl-N-(4-(1-methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2- yl)thiazole-4-carboxamide; N,5,7-trimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)pyrazolo[1 , 5- a]pyrimidine-3-carboxamide;
N , 3-dimethyl-N-(4-( 1 -methyl-1 H-pyrrole-2-carboxamido)- 1 -pheny lbutan-2-yl)-5- phenylisoxazole-4-carboxamide;
N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)imidazo[1 , 2- a]pyridine-2-carboxamide;
N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)pyrazolo[1 , 5- a]pyrimidine-3-carboxamide;
3-bromo-5-chloro-N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1 -phenylbutan-2- yl)imidazo[1 ,2-a]pyridine-2-carboxamide;
N-(4-(1 -ethyl-3-methyl-1 H-pyrazole-5-carboxamido)-1 -phenylbutan-2-yl)-N,6- dimethylfuro[2,3-b]pyridine-5-carboxamide;
1-methyl-N-(4-phenyl-3-(N,5,6-trimethylbenzofuran-3-carboxamido)butyl)-1H-pyrrole-2- carboxamide;
N-(4-phenyl-3-(N,2,3-trimethylbenzofuran-6-carboxamido)butyl)picolinamide;
1- methyl-N-(3-(N-methylbenzofuran-5-carboxamido)-4-phenylbutyl)-1 H-pyrrole-2- carboxamide;
6-methyl-N-(3-(N-methyl-1 H-indole-5-carboxamido)-4-phenylbutyl)imidazo[2, 1 -b]thiazole-5- carboxamide;
N-(3-(N, 1 -dimethyl-1 H-indole-4-carboxamido)-4-phenylbutyl)-1 -methyl-1 H-benzo[d]imidazole-
2- carboxamide;
5-(4-fluorophenyl)-2-methyl-N-(3-(N-methylbenzofuran-4-carboxamido)-4- phenylbutyl)thiazole-4-carboxamide;
N,2-dimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)-2H-indazole-4- carboxamide;
N, 1-dimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)-1 H- benzo[d][1 ,2,3]triazole-7-carboxamide;
N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)benzo[d]oxazole-6- carboxamide;
N,2-dimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2- yl)benzo[d]oxazole-6-carboxamide;
N,2-dimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2- yl)benzo[d]oxazole-5-carboxamide; N,3-dimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1 -phenylbutari-2- yl)benzo[d]isoxazole-6-carboxamide;
N,3-dimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1 -phenylbutan-2- yl)benzo[d]isoxazole-5-carboxamide;
N -dimethyl-N-(1-phenyM-(picolinamido)butan-2-yl)-1 H-indole-7-carboxamide;
N-methyl-N-( 1 -phenyl-4-(picolinamido)butan-2-yl)-1 H-indole-7-carboxamide;
N, 1 -dimethyl-N-(1 -phenyl-4-(picolinamido)butan-2-yl)-1 H-indole-4-carboxamide;
1-methyl-N-(3-(N-methyl-1 H-indole-4-carboxamido)-4-phenylbutyl)-1 H-benzo[d]imidazole-2- carboxamide;
1 -methyl-N-(3-(N-methyl-1 H-indole-5-carboxamido)-4-phenylbutyl)-1 H-benzo[d]imidazole-2- carboxamide;
N-methyl-N-(1-phenyl-4-(picolinamido)butan-2-yl)quinoxaline-6-carboxamide;
N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)benzo[d]oxazole-5- carboxamide;
N-(3-(N,2-dimethylbenzofuran-5-carboxamido)-4-phenylbutyl)-1 -methyl-1 H-pyrrole-2- carboxamide;
N-methyl-N-(1-phenyl-4-(picolinamido)butan-2-yl)-1H-indole-4-carboxamide;
N, 1 -dimethyl-N-(1 -phenyl-4-(picolinamido)butan-2-yl)-1 H-indole-5-carboxamide;
N, 1 -dimethyl-N-(1 -phenyl-4-(picolinamido)butan-2-yl)-1 H-indole-6-carboxamide;
N-(3-(N-methylbenzofuran-5-carboxamido)-4-phenylbutyl)picolinamide;
N-methyl-N-(1-phenyl-4-(picolinamido)butan-2-yl)-1 H-indole-6-carboxamide;
N-methyl-N-(1-phenyl-4-(picolinamido)butan-2-yl)-1 H-indole-5-carboxamide;
N-(3-(N-methylbenzofuran-4-carboxamido)-4-phenylbutyl)picolinamide;
1-methyl-N-(3-(N-methylbenzofuran-4-carboxamido)-4-phenylbutyl)-1 H-pyrrole-2- carboxamide;
1-methyl-N-(3-(N-methylbenzofuran-4-carboxamido)-4-phenylbutyl)-1 H-benzo[d]imidazole-2- carboxamide;
N,1-dimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)-1 H-indole-5- carboxamide;
N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1 -phenylbutan-2-yl)-1 H-indole-5- carboxamide;
N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1 -phenylbutan-2-yl)quinoline-6- carboxamide; N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)-1H-indole-4- carboxamide;
N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1 -phenylbutan-2-yl)quinoxaline-6- carboxamide;
6-methyl-N-(3-(N-methylquinoxaline-6-carboxamido)-4-phenylbutyl)imidazo[2,1-b]thiazole-5- carboxamide;
6-methyl-N-(3-(N-methyl-1 H-indole-4-carboxamido)-4-phenylbutyl)imidazo[2, 1 -b]thiazole-5- carboxamide;
6-methyl-N-(3-(N-methylquinoline-6-carboxamido)-4-phenylbutyl)imidazo[2,1-b]thiazole-5- carboxamide;
N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1 -phenylbutan-2- yl)benzo[c][1 ,2,5]thiadiazole-5-carboxamide;
N-(3-(3-bromo-N-methylbenzofuran-5-carboxamido)-4-phenylbutyl)-1-methyl-1 H-pyrrole-2- carboxamide;
N,2-dimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2- yl)benzo[d]thiazole-5-carboxamide;
N-(3-(N , 3-dimethylbenzofuran-5-carboxamido)-4-phenylbutyl)- 1 -methyl- 1 H-pyrrole-2- carboxamide;
1-methyl-N-(3-(N-methylbenzofuran-6-carboxamido)-4-phenylbutyl)-1 H-pyrrole-2- carboxamide;
N, 1 -dimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1 -phenylbutan-2-yl)-1 H- benzo[d][ 1 , 2, 3]triazole-5-carboxamide;
N,1-dimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)-1 H-indazole-5- carboxamide;
N,2-dimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1 -phenylbutan-2-yl)-2H- benzo[d][1 ,2,3]triazole-4-carboxamide;
N, 1-dimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)-1H- benzo[d][ 1 , 2, 3]triazole-4-carboxamide;
N, 1 -dimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1 -phenylbutan-2-yl)-1 H-indazole-4- carboxamide;
N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1 -phenylbutan-2-yl)-1 H- benzo[d][1 ,2,3]triazole-5-carboxamide;
N,2-dimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)-1 H- benzo[d]imidazole-5-carboxamide; N-methyl-N-(4-(1-methyl-1H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)-1H-indazole-5- carboxamide;
N-methyl-N-(4-(1-methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)-1H- benzo[d]imidazole-5-carboxamide;
N-methyl-N-(4-(1 -methyl- 1 H-pyrrole-2-carboxamido)-1 -phenylbutan-2-yl)benzo[d]thiazole-6- carboxamide;
N-methyl-N-(4-(1-methyl-1H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)quinoline-8- carboxamide;
N-methyl-N-(4-(1-methyl-1H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)benzo[d]oxazole-4- carboxamide;
N,2-dimethyl-N-(4-(1-methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2- yl)benzo[d]oxazole-4-carboxamide;
N-methyl-N-(4-(1-methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)benzo[d]thiazole-5- carboxamide;
N-methyl-N-(4-(1-methyl-1H-pyrrole-2-carboxamido)-1-phenylbutan-2- yl)benzo[c][1,2,5]oxadiazole-5-carboxamide;
N-methyl-N-(4-(1-methyl-1H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)quinoline-5- carboxamide;
6-chloro-N-methyl-N-(4-(1-methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)quinoline-8- carboxamide;
N,2,4-trimethyl-N-(4-(1-methyl-1H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)quinoline-8- carboxamide;
NI2,5-trimethyl-N-(4-(1-methyl-1H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)quinoline-8- carboxamide;
5,6-dimethoxy-N-methyl-N-(4-(1 -methyl- 1 H-pyrrole-2-carboxamido)-1 -phenylbutan-2- yl)quinoline-8-carboxamide;
6-bromo-N,2-dimethyl-N-(4-(1-methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2- yl)quinoline-8-carboxamide;
6-methoxy-N-methyl-N-(4-(1 -methyl- 1 H-pyrrole-2-carboxamido)-1 -phenylbutan-2- yl)quinoline-8-carboxamide;
6-methoxy-N,2-dimethyl-N-(4-(1-methyl-1H-pyrrole-2-carboxamido)-1-phenylbutan-2- yl)quinoline-8-carboxamide;
N,6-dimethyl-N-(4-(1-methyl-1H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)quinoline-8- carboxamide; N-(3-(5-fluoro-N-methylbenzofuran-6-carboxamido)-4-phenylbutyl)-1-methyl-1H-pyrrole-2- carboxamide;
N-(3-(N,5-dimethylbenzofuran-6-carboxamido)-4-phenylbutyl)-1 -methyl-1 H-pyrrole-2- carboxamide;
N,1-dimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)-1H-indole-4- carboxamide;
N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1 -phenylbutan-2-yl)benzo[d]oxazole-7- carboxamide;
N,2-dimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2- yl)benzo[d]oxazole-7-carboxamide;
N,2-dimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)quinoline-8- carboxamide;
N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)quinoxaline-5- carboxamide;
N, 1 ,2-trimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1 -phenylbutan-2-yl)-1 H-indole-4- carboxamide;
N,1 ,3-trimethyl-N-(4-(1-methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)-1 H-indole-4- carboxamide;
N,1 ,5-trimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)-1 H-indole-4- carboxamide;
N,1 ,7-trimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)-1H-indole-4- carboxamide;
N-(4-(1-ethyl-3-methyl-1 H-pyrazole-5-carboxamido)-1-phenylbutan-2-yl)-N- methylbenzo[d]oxazole-5-carboxamide;
4-chloro-N, 1-dimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)-1 H- indole-5-carboxamide;
6-chloro-N, 1 -dimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1 -phenylbutan-2-yl)-1 H- indole-5-carboxamide;
N,1 ,6-trimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)-1 H-indole-4- carboxamide;
1-methyl-N-(3-(N-methyl-3-(5-methyloxazol-2-yl)benzamido)-4-phenylbutyl)-1 H-pyrrole-2- carboxamide;
1-methyl-N-(3-(N-methyl-3-(1 H-pyrrol-1-yl)benzamido)-4-phenylbutyl)-1H-pyrrole-2- carboxamide; N-(3-(N-methylbiphenyl-2-ylcarboxamido)-4-phenylbutyl)picolinamide;
5-(2-fluorophenyl)-N,2-dimethyl-N-(4-(1-methyl-1 H-benzo[d]imidazole-2-carboxamido)-1- phenylbutan-2-yl)thiazole-4-carboxamide;
N-(3-(3-(3,5-dimethyl-1 H-pyrazol-1 -yl)-N-methylbenzamido)-4-phenylbutyl)-1-methyl-1 H- pyrrole-2-carboxamide;
1 -methyl-N-(3-(N-methyl-3-(5-methyl-1 ,2,4-oxadiazol-3-yl)benzamido)-4-phenylbutyl)-1 H- py rrole-2-carboxam ide ;
1-methyl-N-(3-(N-methyl-3-(1 H-tetrazol-1-yl)benzamido)-4-phenylbutyl)-1 H-pyrrole-2- carboxamide;
1 -methyl-N-(3-(N-methyl-3-(5-methyl-1 ,3,4-oxadiazol-2-yl)benzamido)-4-phenylbutyl)-1 H- pyrrole-2-carboxamide;
1- methyl-N-(3-(N-methyl-3-(1-methyl-1 H-pyrazol-5-yl)benzamido)-4-phenylbutyl)-1 H-pyrrole-
2- carboxamide;
1- methyl-N-(3-(N-methyl-3-(oxazol-5-yl)benzamido)-4-phenylbutyl)-1 H-pyrrole-2- carboxamide;
1 -methyl-N-(3-(N-methyl-3-(1 -methyl- 1 H-pyrazol-3-yl)benzamido)-4-phenylbutyl)-1 H-pyrrole-
2- carboxamide;
1- methyl-N-(3-(N-methyl-3-(1 H-pyrazol-3-yl)benzamido)-4-phenylbutyl)-1 H-pyrrole-2- carboxamide;
1 -methyl-N-(3-(N-methyl-3-(1 H-tetrazol-5-yl)benzamido)-4-phenylbutyl)-1 H-pyrrole-2- carboxamide;
1 -methyl-N-(3-(N-methyl-3-(5-methyl-1 H-pyrazol-1 -yl)benzamido)-4-phenylbutyl)-1 H-pyrrole-
2- carboxamide;
1- methyl-N-(3-(N-methyl-3-(3-methyl-1 H-pyrazol-1 -yl)benzamido)-4-phenylbutyl)-1 H-pyrrole-
2- carboxamide;
1-methyl-N-(3-(N-methyl-3-(pyridin-2-yl)benzamido)-4-phenylbutyl)-1 H-pyrrole-2- carboxamide;
1-methyl-N-(3-(N-methyl-3-(pyrimidin-2-yl)benzamido)-4-phenylbutyl)-1 H-pyrrole-2- carboxamide;
N,5-dimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1 -phenylbutan-2-yl)-3- phenylisoxazole-4-carboxamide;
1 -methyl-N-(3-(N-methyl-3-(1 H-pyrazol-1 -yl)benzamido)-4-phenylbutyl)-1 H-pyrrole-2- carboxamide; N-(3-(N,5-dimethyl-2-(2H-1 ,2,3-triazol-2-yl)benzamido)-4-phenylbutyl)-1-methyl-1 H-pyrrole-2- carboxamide;
N-(3-(N,5-dimethyl-2-(pyrimidin-2-yl)benzamido)-4-phenylbutyl)-1-methyl-1 H-pyrrole-2- carboxamide;
5- (2-fluorophenyl)-N,2-dimethyl-N-(1-phenyl-4-(picolinamido)butan-2-yl)thiazole-4- carboxamide;
N-(3-(N,5-dimethyl-2-(2H-1 ,2,3-triazol-2-yl)benzamido)-4-phenylbutyl)-1-ethy^
pyrazole-5-carboxamide;
N-(3-(3-(1 H-imidazol-1-yl)-N-methylbenzamido)-4-phenylbutyl)-1-methyl-1 H-pyrrole-^^ carboxamide;
2-methoxy-N-methyl-N-(4-(1-methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2- yl)isonicotinamide;
2-chloro-6-methoxy-N-methyl-N-(4-(1 -methyl- 1 H-pyrrole-2-carboxamido)-1 -phenylbutan-2- yl)isonicotinamide;
2-chloro-N,6-dimethyl-N-(4-(1-methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2- yl)isonicotinamide;
6- methoxy-N-methyl-N-(1-phenyl-4-(picolinamido)butan-2-yl)picolinamide;
6-methoxy-N-methyl-N-(4-(1-methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2- yl)nicotinamide;
3.5- difluoro-N-methyl-N-(4-(1 -methyl- 1 H-pyrrole-2-carboxamido)-1 -phenylbutan-2- yl)picolinamide;
2.6- dichloro-N-methyl-N-(4-(1-methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2- yl)isonicotinamide;
N,2-dimethyl-N-(4-(1-methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)isonicotinamide; 2,6-difluoro-N-methyl-N-(4-(1 -methyl- 1 H-pyrrole-2-carboxamido)-1 -phenylbutan-2- yl)isonicotinamide;
6-methoxy-N-methyl-N-(4-(1-methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2- yl)picolinamide;
4,6-dimethoxy-N-methyl-N-(4-(1-methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2- yl)pyrimidine-2-carboxamide;
4-methoxy-N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1 -phenylbutan-2- yl)picolinamide;
N,6-dimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1 -phenylbutan-2-yl)picolinamide; N-methyl-N-(4-(1-methyl-1H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)-1 ,4,5,6- tetrahydrocyclopenta[c]pyrazole-3-carboxamide;
N,2-dimethyl-N-(4-(1-methyl-1H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)-4,5,6,7- tetrahydro-2H-indazole-3-carboxamide;
N-methyl-N-(4-(1-methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)-4,5,6,7-tetrahydro- 2H-indazole-3-carboxamide;
N,3,5-trimethyl-N-(4-(1-methyl-1H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)isoxazole-4- carboxamide;
2-ethoxy-N,6-dimethyl-N-(4-(1-methyl-1H-pyrrole-2-carboxamido)-1-phenylbutan-2- yl)isonicotinamide;
2-methoxy-N-methyl-N-(4-(1 -methyl- 1 H-pyrrole-2-carboxamido)-1 -phenylbutan-2- yl)nicotinamide;
2,6-dimethoxy-N-methyl-N-(4-(1-methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2- yl)isonicotinamide;
2-methoxy-N-methyl-N-(4-(1-methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2- y I) py ri m id i ne-4-ca rboxam ide;
N,2-dimethyl-N-(4-(1-methyl-1H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)nicotinamide; 4-methoxy-N-methyl-N-(4-(1 -methyl- 1 H-pyrrole-2-carboxamido)-1 -phenylbutan-2- yl)nicotinamide;
2-ethyl-N,6-dimethyl-N-(4-(1-methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2- yl)isonicotinamide;
4,6-dichloro-N-methyl-N-(4-(1-methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2- yl)picolinamide;
4-methoxy-N-methyl-N-(4-(1-methyl-1H-pyrrole-2-carboxamido)-1-phenylbutan-2- yl)pyrimidine-2-carboxamide;
4,6-dimethoxy-N-methyl-N-(4-(1-methyl-1H-pyrrole-2-carboxamido)-1-phenylbutan-2- yl)picolinamide;
6-methoxy-N,4-dimethyl-N-(4-(1-methyl-1H-pyrrole-2-carboxamido)-1-phenylbutan-2- yl)picolinamide;
N,2,6-trimethyl-N-(4-(1-methyl-1H-pyrrole-2-carboxamido)-1-phenylbutan-2- yl)isonicotinamide;
N,2,5-trimethyl-N-(4-(1-methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2- yl)isonicotinamide; 2-methoxy-N,5-dimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2- yl)isonicotinamide;
N-(3-(2-methoxy-N,6-dimethylisonicotinamido)-4-phenylbutyl)-1-methyl-1 H- benzo[d]imidazole-2-carboxamide;
2-isopropyl-N,6-dimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2- yl)isonicotinamide;
N,2,5-trimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1 -phenylbutan-2-yl)nicotinamide;
5- chloro-2-methoxy-N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1 -phenylbutan-2- yl)nicotinamide;
2-ethyl-N-(4-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1-phenylbutan-2-yl)-N,6- dimethylisonicotinamide;
N-(4-(1-ethyl-3-methyl-1 H-pyrazole-5-carboxamido)-1-phenylbutan-2-yl)-2-methoxy-N,6- dimethylisonicotinamide;
2-ethoxy-N-(4-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1-phenylbutan-2-yl)-N,6- dimethylisonicotinamide;
N-(4-(1-ethyl-3-methyl-1 H-pyrazole-5-carboxamido)-1-phenylbutan-2-yl)-2,6-dimethoxy-N- methylisonicotinamide;
N-(4-(1-ethyl-3-methyl-1 H-pyrazole-5-carboxamido)-1-phenylbutan-2-yl)-4,6-dimethoxy-N- methylpyrimidine-2-carboxamide;
6- methoxy-N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1 -phenylbutan-2-yl)pyrazine- 2-carboxamide;
5-methoxy-N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1 -phenylbutan-2- yl)nicotinamide;
2-ethoxy-N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)pyrimidine- 4-carboxamide;
2-isopropoxy-N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1 -phenylbutan-2- yl)pyrimidine-4-carboxamide;
2-methoxy-N,6-dimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2- yl)isonicotinamide;
2,6-dimethoxy-N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2- yl)pyrimidine-4-carboxamide;
N,2-dimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)-6-(pyrrolidin-1- yl)isonicotinamide;
N-(3-(2-methoxy-N,6-dimethylisonicotinamido)-4-phenylbutyl)-6-methylpicolinamide; N-(3-(2,6-dimethoxy-N-methylisonicotinamido)-4-phenylbutyl)-6-methylpicolina
2-methoxy-N-methyl-N-(4-(6-methylpicolinamido)-1-phenylbutan-2-yl)pyrimidine-4- carboxamide;
2-methoxy-N-(4-(6-methoxypicolinamido)-1-phenylbutan-2-yl)-N-methylpyrimidine-4- carboxamide;
N-(3-(2-methoxy-N-methylpyrimidine-4-carboxamido)-4-phenylbutyl)-1-methyl-1H- benzo[d]imidazole-2-carboxamide;
N,2-dimethyl-N-(4-(6-methylpicolinamido)-1-phenylbutan-2-yl)pyrimidine-4-carboxam N-(4-(6-methoxypicolinamido)-1-phenylbutan-2-yl)-N,2-dimethylpyrimidine-4-carboxam N-(3-(N,2-dimethylpyrimidine-4-carboxamido)-4-phenylbutyl)-1-methyl-1 H-benzo[d]imi 2-carboxamide;
6-methoxy-N-(3-(2-methoxy-N,6-dimethylisonicotinamido)-4-phenylbutyl)picolinam
N-(3-(2,6-dimethoxy-N-methylisonicotinamido)-4-phenylbutyl)-6-methoxypicolinami
1 -ethyl-N,3-dimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1 -phenylbutan-2-yl)-1 H- pyrazole-5-carboxamide; and
N,1 ,3,5-tetramethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)-1 H- pyrazole-4-carboxamide.
In a further aspect, the invention also provides a process for the production of compounds of the formula I. Compounds of the formula I are obtainable according to the following process as described in scheme 1 :
Scheme 1 :
Figure imgf000050_0001
Figure imgf000050_0002
Figure imgf000050_0003
The process steps are described in more detail below:
Step 1: A compound of formula III, in which R2, R3, R4, R5, R6 and B are as defined under formula I, and Ra is C^alkyl, preferably tert-butyl, may be obtained by reacting a compound of formula II, in which R2, R3, R4, R5, Re and B are as defined under formula I, and Ra is as defined under formula III, in a first step with methanesulfonyl chloride in the presence of a base, such as triethylamine, in the presence of a suitable solvent, e.g. dichlormethan. The resulting product may then be reacted with sodium cyanide in the presence of a suitable solvent, e.g. dimethylformamide.
Step 2: A compound of formula IV, in which R2, R3, R , R5, Re and B are as defined under formula I, and Ra is as defined under formula III, may be obtained by reacting the compound of formula III with a compound of formula V, in which Ri is as defined under formula I, and Xc is iodide, in the presence of sodium hydride in the presence of a suitable solvent, e.g. dry tetrahydrofurane.
Step 3: A compound of formula VI, in which R1 f R2, R3, R4, R5, Re and B are as defined under formula I, and Ra is as defined under formula III, may be obtained from the compound of formula IV by reduction with e.g. hydrogen/Raney nickel.
Step 4: A compound of formula VII, in which Ri, R2, R3, R4, R5, R6, B and C are as defined under formula I, and Ra is as defined under formula III, may be obtained by reacting the compound of formula VI with an acid or acid derivative of formula VIII, in which C is defined under formula I, and X is hydroxyl or halogen under suitable reaction conditions as described in the Examples. E.g., when X is halogen in the presence of a suitable base and solvent. Step 5: A compound of formula IX, in which R^ R2, R3, R , R5, Re, B and C are as defined under formula I, may be obtained by reacting the compound of formula VII with hydrochloric acid in a suitable solvent, e.g. dichlormethane and dioxane.
Step 6: A compound of formula I, may be obtained by reacting the compound of formula IX with an acid or acid derivative of formula X, in which A is defined under formula I, and X is hydroxyl or halogen as described in step 4.
Step 7: A compound of formula XI, in which R2, R3, R4, R5, R6 and B are as defined under formula I, may be obtained from a compound of formula IV as described in step 5.
Step 8: A compound of formula XII, in which Ri, R2, R3, R4, R5, R6 and B are as defined under formula I, may be obtained by reacting the compound of formula XI with a compound of formula X as described in step 6.
Step 9: A compound of formula XIII, in which Ri, R2, R3, R4, R5, R6, A and B are as defined under formula I, may be obtained from the compound of formula XII by reduction as described in step 3.
Step 10: A compound of formula I, may be obtained by reacting the compound of formula XIII with a compound of formula VIII as described in step 4.
Further compounds of formula I may be obtainable from compounds of formula I - prepared as described according to scheme 1 - by reduction, oxidation and/or other functionalization of resulting compounds and/or by cleavage of any protecting group(s) optionally present, and of recovering the so obtainable compound of the formula I.
The reactions can be effected according to conventional methods, for example as described in the Examples.
The work-up of the reaction mixtures and the purification of the compounds thus obtainable may be carried out in accordance with known procedures.
Acid addition salts may be produced from the free bases in known manner, and vice-versa.
Compounds of the formula I can also be prepared by further conventional processes, e. g. as described in the Examples, which processes are further aspects of the invention.
The starting materials of the formulae II, V, VIII and X are known or may be prepared according to conventional procedures starting from known compounds, for example as described in the Examples. In some cases, an intermediate of scheme 1 may be known. In such a situation, said intermediate could be used as an alternative starting point for the process according to scheme 1.
In a further aspect, the invention also provides a process for the production of compounds of the formula I, in which R1 t R2, R3, R4, R5, R6, A, B and C are as defined under formula I, which comprises
reacting a compound of the formula XIII
Figure imgf000052_0001
In which Ri, R2, R3, R4, R5, R6, A and B are as defined under formula I, with a compound of the formula VIII
Figure imgf000052_0002
(VIII), in which C is as defined under formula I, and X is halogen, in the presence of a suitable base and a suitable solvent.
In a further aspect, the invention also provides a process for the production of compounds of the formula I, in which Ri , R2, R3, R4, R5, Re, A, B and C are as defined under formula I, which comprises
reacting a compound of the formula IX
Figure imgf000053_0001
In which Ri , R2, R3, R , R5, Re, B and C are as defined under formula I, with a compound of the formula X
Figure imgf000053_0002
in which A is as defined under formula I, and X is halogen, in the presence of a suitable base and a suitable solvent.
In another aspect, the invention provides a pharmaceutical composition comprising a compound of the invention and a pharmaceutically acceptable carrier. The pharmaceutical composition can be formulated for particular routes of administration such as oral administration, parenteral administration, and rectal administration, etc. In addition, the pharmaceutical compositions of the invention can be made up in a solid form including capsules, tablets, pills, granules, powders or suppositories, or in a liquid form including solutions, suspensions or emulsions. The pharmaceutical compositions can be subjected to conventional pharmaceutical operations such as sterilization and/or can contain conventional inert diluents, lubricating agents, or buffering agents, as well as adjuvants, such as preservatives, stabilizers, wetting agents, emulsifers and buffers etc.
Typically, the pharmaceutical compositions are tablets and gelatin capsules comprising the active ingredient together with
a) diluents, e.g., lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine; b) lubricants, e.g., silica, talcum, stearic acid, its magnesium or calcium salt and/or polyethyleneglycol; for tablets also
c) binders, e.g., magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone; if desired
d) disintegrants, e.g., starches, agar, alginic acid or its sodium salt, or effervescent mixtures; and/or
e) absorbents, colorants, flavors and sweeteners.
Tablets may be either film coated or enteric coated according to methods known in the art.
Suitable compositions for oral administration include an effective amount of a compound of the invention in the form of tablets, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsion, hard or soft capsules, or syrups or elixirs. Compositions intended for oral use are prepared according to any method known in the art for the manufacture of pharmaceutical compositions and such compositions can contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with nontoxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients are, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example, starch, gelatin or acacia; and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets are uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate can be employed. Formulations for oral use can be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example, peanut oil, liquid paraffin or olive oil.
Certain injectable compositions are aqueous isotonic solutions or suspensions, and suppositories are advantageously prepared from fatty emulsions or suspensions. Said compositions may be sterilized and/or contain adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure and/or buffers. In addition, they may also contain other therapeutically valuable substances. Said compositions are prepared according to conventional mixing, granulating or coating methods, respectively, and contain about 0.1-75%, or contain about 1-50%, of the active ingredient.
Suitable compositions for transdermal application include an effective amount of a compound of the invention with carrier. Carriers include absorbable pharmacologically acceptable solvents to assist passage through the skin of the host. For example, transdermal devices are in the form of a bandage comprising a backing member, a reservoir containing the compound optionally with carriers, optionally a rate controlling barrier to deliver the compound of the skin of the host at a controlled and predetermined rate over a prolonged period of time, and means to secure the device to the skin.
Suitable compositions for topical application, e.g., to the skin and eyes, include aqueous solutions, suspensions, ointments, creams, gels or sprayable formulations, e.g., for delivery by aerosol or the like. Such topical delivery systems will in particular be appropriate for dermal application, e.g., for the treatment of skin cancer, e.g., for prophylactic use in sun creams, lotions, sprays and the like. They are thus particularly suited for use in topical, including cosmetic, formulations well-known in the art. Such may contain solubilizers, stabilizers, tonicity enhancing agents, buffers and preservatives.
As used herein a topical application may also pertain to an inhalation or to an intranasal application. They are conveniently delivered in the form of a dry powder (either alone, as a mixture, for example a dry blend with lactose, or a mixed component particle, for example with phospholipids) from a dry powder inhaler or an aerosol spray presentation from a pressurised container, pump, spray, atomizer or nebuliser, with or without the use of a suitable propellant.
The invention further provides anhydrous pharmaceutical compositions and dosage forms comprising the compounds of the invention as active ingredients, since water may facilitate the degradation of certain compounds. Anhydrous pharmaceutical compositions and dosage forms of the invention can be prepared using anhydrous or low moisture containing ingredients and low moisture or low humidity conditions. An anhydrous pharmaceutical composition may be prepared and stored such that its anhydrous nature is maintained. Accordingly, anhydrous compositions are preferably packaged using materials known to prevent exposure to water such that they can be included in suitable formulary kits. Examples of suitable packaging include, but are not limited to, hermetically sealed foils, plastics, unit dose containers (e. g., vials), blister packs, and strip packs.
The invention further provides pharmaceutical compositions and dosage forms that comprise one or more agents that reduce the rate by which the compound of the invention as an active ingredient will decompose. Such agents, which are referred to herein as "stabilizers," include, but are not limited to, antioxidants such as ascorbic acid, pH buffers, or salt buffers, etc.
As used herein, the term "pharmaceutically acceptable carrier" includes any and all solvents, dispersion media, coatings, surfactants, antioxidants, preservatives (e.g., antibacterial agents, antifungal agents), isotonic agents, absorption delaying agents, salts, preservatives, drugs, drug stabilizers, binders, excipients, disintegration agents, lubricants, sweetening agents, flavoring agents, dyes, such like materials and combinations thereof, as would be known to one of ordinary skill in the art (see, for example, Remington's Pharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990, pp. 1289- 1329). Except insofar as any conventional carrier is incompatible with the active ingredient, its use in the therapeutic or pharmaceutical compositions is contemplated.
The compounds of formula I in free form or in pharmaceutically acceptable salt form, exhibit valuable pharmacological properties, e.g. orexin receptor modulating properties, e.g. as indicated in in-vitro and in-vivo tests as provided in the next sections and are therefore indicated for therapy.
Preferred compounds of the invention show an inhibition of calcium accumulation in recombinant cells expressing at least one of hOxI R or hOx2R at 10 μΜ of test compound of at least 10%. In one embodiment of the invention, compounds of the invention, which are described in Tables 1 to 4 as showing an inhibition of calcium accumulation in recombinant cells expressing at least one of hOx1 R or hOx2R at 10 μΜ of test compound of lower than 10%, are excluded.
Further preferred compounds of the invention show a Ki value for said calcium accumulation in recombinant cells expressing at least one of hOxl R or hOx2R of at least 1 μΜ.
Further preferred compounds of the invention show a Ki value for said calcium accumulation in recombinant cells expressing at least one of hOxl R or hOx2R of at least 500 nM.
Further preferred compounds of the invention show a Ki value for said calcium accumulation in recombinant cells expressing at least one of hOxl R or hOx2R of at least 100 nM.
Further preferred compounds of the invention show a Ki value for said calcium accumulation in recombinant cells expressing at least one of hOxI R or hOx2R of at least 50 nM.
Compounds of the invention may be useful in the treatment of an indication selected from: i) sleep disorders;
ii) eating disorders;
iii) substance-related disorders;
iv) Alzheimers disease;
v) psychiatric, neurological and neurodegenerative disorders, such as depression; anxiety; addictions, obsessive compulsive disorder; affective neurosis; depressive neurosis; anxiety neurosis; dysthymic disorder; mood disorder; sexual dysfunction; psychosexual dysfunction; sex disorder; schizophrenia; manic depression; delirium; dementia; severe mental retardation and dyskinesias such as Huntington's disease and Tourette syndrome; Parkinson's disease; ischemic or haemorrhagic stroke; migraine; and neurodegenerative disorder including nosological entities such as disinhibition-dementia-parkinsonism-amyotrophy complex;
pallido-ponto-nigral degeneration epilepsy; seizure disorders;
vi) cardiovascular diseases, diabetes; asthma; Cushing's syndrome/disease; basophil adenoma; prolactinoma; hyperprolactinemia; hypopituitarism; hypophysis tumour/adenoma; hypothalamic diseases; Froehlich's syndrome; hypophysis diseases, hypothalamic hypogonadism; Kallman's syndrome (anosmia, hyposmia); functional or psychogenic amenorrhea; hypopituitarism; hypothalamic hypothyroidism; hypothalamic-adrenal dysfunction; idiopathic hyperprolactinemia; hypothalamic disorders of growth hormone deficiency; idiopathic growth deficiency; dwarfism; gigantism; acromegaly; heart and lung diseases, acute and congestive heart failure; hypotension; hypertension; urinary retention; osteoporosis; angina pectoris; myocardial infarction; subarachnoid haemorrhage; ulcers; allergies; benign prostatic hypertrophy; chronic renal failure; renal disease; impaired glucose tolerance; vomiting and nausea; inflammatory bowel disease; gastric dyskinesia; gastric ulcers; urinary bladder incontinence e.g. urge incontinence; hyperalgesia; pain; enhanced or exaggerated sensitivity to pain such as hyperalgesia, causalgia, and allodynia; acute pain; burn pain; atypical facial pain; neuropathic pain; back pain; complex regional pain syndrome I and II; arthritic pain; sports injury pain; pain related to infection e.g. HIV, post-chemotherapy pain; post-stroke pain; post-operative pain; neuralgia; conditions associated with visceral pain such as irritable bowel syndrome, migraine and angina; and
vii) other diseases related to general orexin system dysfunction.
Compounds of the invention may be especially useful in the treatment of an indication selected from: sleep disorders, eating disorders, substance-related disorders and Alzheimers disease.
"Eating disorders" may be defined as comprising metabolic dysfunction; dysregulated appetite control; compulsive obesities; emeto-bulimia or anorexia nervosa. This
pathologically modified food intake may result from disturbed appetite (attraction or aversion for food); altered energy balance (intake vs expenditure); disturbed perception of food quality (high fat or carbohydrates, high palatability); disturbed food availability (unrestricted diet or deprivation) or disrupted water balance.
"Sleep disorders" include insomnias, narcolepsy and other disorders of excessive sleepiness, sleep-related dystonias; restless leg syndrome; sleep apneas; jet-lag syndrome; shift-work syndrome, delayed or advanced sleep phase syndrome. Insomnias are defined as comprising sleep disorders associated with aging; intermittent treatment of chronic insomnia; situational transient insomnia (new environment, noise) or short-term insomnia due to stress; grief; pain or illness.
"Substance-related disorders" include substance abuse, substance dependence and substance withdrawal disorders, e.g. nicotine withdrawal or narcotics withdrawal.
Thus, as a further embodiment, the invention provides the use of a compound of formula (I) in free form or in pharmaceutically acceptable salt form as a medicament. As a further embodiment, the invention provides the use of a compound of formula (I) in free form or in pharmaceutically acceptable salt form in therapy.
In one embodiment, the invention provides a method of inhibiting orexin receptor activity in a subject, wherein the method comprises administering to the subject a therapeutically effective amount of a compound of formula I.
In a further embodiment, the invention provides a method of treating a disorder or a disease in a subject mediated by orexin receptors, wherein the method comprises administering to the subject a therapeutically effective amount of a compound of formula I. Preferably said disorder or said disease is selected from sleep disorders, eating disorders, substance-related disorders or Alzheimers disease.
In yet a further embodiment, the invention provides the use of a compound of formula I, for the treatment of a disorder or disease in a subject mediated by orexin receptors.
In yet a further embodiment, the invention provides the use of a compound of formula I, for the treatment of a disorder or disease in a subject characterized by an abnormal activity of orexin receptors. Preferably said disorder or said disease is selected from sleep disorders, eating disorders, substance-related disorders or Alzheimers disease.
In a further embodiment, the therapy is selected from a disease which is ameliorated by modulation, preferably antagonism, of orexin receptors. In another embodiment, the disease is selected from the afore-mentioned list, suitably sleep disorders, eating disorders, substance-related disorders or Alzheimers disease.
In another embodiment, the invention provides a method of treating a disease which is ameliorated by modulation, preferably antagonism, of orexin receptors comprising administration of a therapeutically acceptable amount of a compound of formula (I) in free form or in pharmaceutically acceptable salt form. In a further embodiment, the disease is selected from the afore-mentioned list, suitably sleep disorders, eating disorders or
Alzheimers disease. The term "a therapeutically effective amount" of a compound of the invention refers to an amount of the compound of the invention that will elicit the biological or medical response of a subject, for example, reduction or inhibition of an enzyme or a protein activity, or ameliorate symptoms, alleviate conditions, slow or delay disease progression, or prevent a disease, etc. In one non-limiting embodiment, the term "a therapeutically effective amount" refers to the amount of the compound of the invention that, when administered to a subject, is effective to (1) at least partially alleviating, inhibiting, preventing and/or ameliorating a condition, or a disorder or a disease (i) mediated by orexin receptors, or (ii) associated with orexin receptor activity, or (iii) characterized by abnormal activity of orexin receptors; or (2) reducing or inhibiting the activity of orexin receptors; or (3) reducing or inhibiting the expression of orexin receptors. In another non-limiting embodiment, the term "a therapeutically effective amount" refers to the amount of the compound of the invention that, when administered to a cell, or a tissue, or a non-cellular biological material, or a medium, is effective to at least partially reducing or inhibiting the activity of orexin receptors; or at least partially reducing or inhibiting the expression of orexin receptors.
As used herein, the term "subject" refers to an animal. Preferably, the animal is a mammal. A subject also refers to for example, primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds and the like. In a preferred embodiment, the subject is a human.
As used herein, the term "inhibition" or "inhibiting" refers to the reduction or suppression of a given condition, symptom, or disorder, or disease, or a significant decrease in the baseline activity of a biological activity or process.
As used herein, the term "treating" or "treatment" of any disease or disorder refers in one embodiment, to ameliorating the disease or disorder (i.e., slowing or arresting or reducing the development of the disease or at least one of the clinical symptoms thereof). In another embodiment "treating" or "treatment" refers to alleviating or ameliorating at least one physical parameter including those which may not be discernible by the patient. In yet another embodiment, "treating" or "treatment" refers to modulating the disease or disorder, either physically, (e.g., stabilization of a discernible symptom), physiologically, (e.g., stabilization of a physical parameter), or both. In yet another embodiment, "treating" or "treatment" refers to preventing or delaying the onset or development or progression of the disease or disorder. The pharmaceutical composition or combination of the invention can be in unit dosage of about 1-1000 mg of active ingredient(s) for a subject of about 50-70 kg, or about 1-500 mg or about 1-250 mg or about 1-150 mg or about 0.5-100 mg, or about 1-50 mg of active ingredients. The therapeutically effective dosage of a compound, the pharmaceutical composition, or the combinations thereof, is dependent on the species of the subject, the body weight, age and individual condition, the disorder or disease or the severity thereof being treated. A physician, clinician or veterinarian of ordinary skill can readily determine the effective amount of each of the active ingredients necessary to prevent, treat or inhibit the progress of the disorder or disease.
The above-cited dosage properties are demonstrable in vitro and in vivo tests using advantageously mammals, e.g., mice, rats, dogs, monkeys or isolated organs, tissues and preparations thereof. The compounds of the invention can be applied in vitro in the form of solutions, e.g., preferably aqueous solutions, and in vivo either enterally, parenterally, advantageously intravenously, e.g., as a suspension or in aqueous solution. The dosage in vitro may range between about 103 molar and 10"9 molar concentrations. A therapeutically effective amount in vivo may range depending on the route of administration, between about 0.1-500 mg/kg, or between about 1-100 mg/kg.
The activity of a compound according to the invention can be assessed by in vitro & in vivo methods described herein.
The compound of the invention may be administered either simultaneously with, or before or after, at least one other therapeutic agent. The compound of the invention may be administered separately, by the same or different route of administration, or together in the same pharmaceutical composition.
The following Examples illustrate the invention, but do not limit it.
Abbreviations:
AcOH acetic acid
DCM dichloromethane
DIPEA diisopropyl ethylamine
DMA dimethylacetamide DMF dimethylformamide
DMSO dimethylsulfoxide
EDC 1 -(3-dimethylaminopropyl)-3-ethylcarbodiimide
ESIMS electrospray ionization mass spectrometry
EtOAc ethyl acetate
Et20 diethyl ether
EtOH ethanol
FA formic acid
h hour(s)
HATU 2-(7-aza-1H-benzotriazole-1-yl)-1 ,1,3,3-tetramethyluronium hexafluorophosphate Hex hexane
HOBt 1-hydroxybenzotriazole trihydrate
HPLC high pressure liquid chromatography
min minute(s)
NMP N-methylpyrrolidone
NMR nuclear magnetic resonance spectrometry
quant, quantitative
rt room temperature
THF tetrahydrofurane
TFA trifluoroacetic acid
T3P propane phosphonic acid anhydride
UPLC ultra performance liquid chromatography
LCMS/HPLC conditions (% = percent by volume)
Method A (RtA = retention time A)
Agilent 1100 series, LC-MSD; column Zorbax SB-C18 1.8 m; 3 x 30 mm; gradient: A water + 0.05 % TFA / B acetonitrile + 0.05 % TFA; 0 - 3.25 min 70A : 30B - OA : 100B; 3.25 - 4.0 min OA : 100B; 4.0 - 4.25 min OA : 100B - 70A : 30 B; flow 0.7 ml/min; column temperature 35 °C.
Method B (RtB = retention time B)
Agilent 1100 series, LC-MSD; column Zorbax SB-C18 1.8 pm; 3 x 30 mm; gradient: A water + 0.05 % TFA / B acetonitrile + 0.05 % TFA; 0 - 3.25 min 90A : 10B - OA : 100B; 3.25 - 4.0 min OA : 100B; 4.0 - 4.25 min OA : 100B - 90A : 10 B; flow 0.7 ml/min; column temperature 35 °C. Method C (Rtc = retention time C)
Agilent 1100 series, LC-MSD; column Zorbax SB-C18 1.8 pm; 3 x 30 mm; gradient: A water + 0.05 % TFA / B acetonitrile + 0.05 % TFA; 0 - 3.25 min 60A : 40B - OA : 100B; 3.25 - 4.0 min OA : 100B; 4.0 - 4.25 min OA : 100B - 60A : 40 B; flow 0.7 ml/min; column temperature 35 °C.
Method D (RtD = retention time D)
Agilent 1100 series, LC-MSD; column Zorbax SB-C18 1.8 μιτι; 3 x 30 mm; gradient: A water + 0.05 % TFA / B acetonitrile + 0.05 % TFA; 0 - 3.25 min 100A : 0B - OA : 100B; 3.25 - 4.0 min OA : 100B; 4.0 - 4.25 min OA : 100B - 100A : 0 B; flow 0.7 ml/min; column temperature 35 °C.
Method E (RtE = retention time E)
Waters Alliance 2690, LC-MSD; column Waters Sunfire C18 2.5 pm; 2.1 x 50 mm; gradient: A 90 % water + 10 % acetonitrile + 0.04% TFA / B 10 % water + 90 % acetonitrile + 0.04% TFA; 0 - 2.0 min 10A : 90B, flow 0.4 ml/min; 2.0 - 5.0 min 95A : 5B, flow 0.4 ml/min; 5.0 - 6.0 min 10A : 90B, flow 0.4 ml/min; column temperature 50 °C.
Method F (RtF = retention time F)
Waters Acquity UPLC / ZQ2000, column Waters RP Acquity HSS T3 1.8 pm; 2.1 x 50 mm; gradient: A water + 0.05% FA + 3.75 mM ammonium acetate / B acetonitrile + 0.4% FA; 0 - 2.15 min 2A : 98B, flow 1.2 ml/min; 1.7 - 2.20 min 98A : 2B, flow .2 ml/min; column temperature 50 °C.
Method G (Rtc = retention time G)
Agilent 1100 series, LC-MSD; column Zorbax SB-C18 1.8 pm; 3 x 30 mm; gradient: A water + 0.05 % TFA / B acetonitrile + 0.05 % TFA; 0 - 3.25 min 50A : 50B - OA : 100B; 3.25 - 4.0 min OA : 100B; 4.0 - 4.25 min OA : 100B - 50A : 50 B; flow 0.7 ml/min; column temperature 35 °C.
Method H (RtH = retention time H)
Agilent 1100 series, Agilent 1100 DAD, Micromass ZMD; column Waters XBridge C18 2.5 pm; 3 x 30 mm; Agilent 1100 oven: temperature = 50°C; binary gradient formed with: A: water + acetonitrile (5 %) + TFA (0.05 %) and B: acetonitrile + TFA (0.05 %); 0 - 1.7 min (linear gradient from 90 % A : 10 % B to 5 % A : 95 % B) at 1.4 ml/min; 1.7 - 2.4 min (isocratic elution with 5 % A : 95 % B) at 1.6 ml/min; 2.4 - 2.45 min (linear gradient from 5 % A : 95 % B to 90 % A : 10 % B) at 2.4 ml/min;
Method I (Rt, = retention time I) Waters Acquity, UPLC; column Acquity UPLC BEH C18 1.7 pm; 2.1 x 50 mm; gradient: A 95 % water + 5% acetonitrile + 0.05 % FA / B acetonitrile + 0.05 % FA; 0 - 2.0 min 95A : 5B - OA : 100B; 2.0 - 3.0 min OA : 100B; 3.0 - 3.1 min OA : 100B - 95A : 5 B; 3.1 - 3.5 min 95A : 5B; flow 0.6 ml/min; column temperature 35 °C.
Method J (Rtj = retention time J)
Waters UPLC Acquity-SQD: column Acquity HSS T3 1.8 m 2.1 x 50 mm; A 0.05% formic acid + 0.05 % ammonium acetate in water / B 0.04% formic acid in acetonitrile; 0 - 1.40 min 98A : 2B - 2A : 98B, 1.40 - 2.15 min 2A : 98B, 2.15 - 2.20 min 98A : 2B; flow 1.2ml/min; column temperature 50°C.
1 H-NMR instruments: Varian Mercury (400 MHz); Bruker Advance (600 MHz).
Building block A1: 1-Methyl-1H-benzotriazole-4-carboxylic acid / 2-Methyl-2H- benzotriazole-4-carboxylic acid / 3-Methyl-3H-benzotriazole-4-carboxylic acid
Figure imgf000064_0001
a) 1 -Methyl- 1 H-benzotriazole-4-carboxylic acid methyl ester / 2-Methyl-2H-benzotriazole-4- carboxylic acid methyl ester / 3-Methyl-3H-benzotriazole-4-carboxylic acid methyl ester
Figure imgf000064_0002
Sodium hydride (241 mg, 8.04 mmol, 80% suspension in oil) was added to a cooled solution (0 °C) of 3H-benzotriazole-4-carboxylic acid methyl ester (949 mg , 5.36 mmol) and methyl iodide (2.281 g, 16.06 mmol) in DMF (4 ml). The resulting mixture was stirred at 0 °C for 90 min. A saturated solution of NH4CI was added and the resulting mixture was extracted with tert-butyl methyl ether. The organic layer was washed with sat. NH4CI and brine, dried (MgS04), filtered and concentrated. The desired products were obtained after flash chromatography (DCM:MeOH, 97:3). 1 -Methyl- 1 H-benzotriazole-4-carboxylic acid methyl ester (188 mg, 18 %): [LCMS RtF = 0.66 min; [M+H]+ = 192.1]; 2-Methyl-2H-benzotriazole-4- carboxylic acid methyl ester (242 mg, 24 %): [1 H-NMR (DMSO, 600 MHz) 8.25 (d, 1 H), 8.10 (d, 1 H), 7.56 (t, 1 H), 4.56 (s, 3H), 3.93 (s, 3H); LCMS RtF = 0.76 min; [M+H]+ = 192.1]; 3- Methyl-3H-benzotriazole-4-carboxylic acid methyl ester (382 mg, 37 %): [1 H-NMR (DMSO, 600 MHz) 8.35 (d, 1 H), 8.10 (d, 1 H), 7.51 (t, 1 H), 4.46 (s, 3H). 3.96 (s, 3H); LCMS RtF = 0.84 min; [M+H]+ = 192.4] b) 3-Methyl-3H-benzotriazole-4-carboxylic acid
Figure imgf000065_0001
Lithium hydroxide (143 mg, 5.96 mmol) was added to a solution of 3-methyl-3H- benzotriazole-4-carboxylic acid methyl ester (380 mg, 1.99 mmol) in methanol (6.5 ml). The mixture was stirred at 60 °C overnight. The solvent was evaporated and the residue was acidified to pH 1 with 1 N HCI solution (6.6 ml). The crystals which fell out of solution were filtered and dried to deliver 130 mg of the title compound (91 %). [1 H-NMR (DMSO, 400 MHz) 13.2 (s, 1 H), 8.12 (d, 1 H), 7.96 (d, 1 H), 7.64 (t, 1 H), 4.34 (s, 3H); LCMS RtF = 0.54 min;
[M+H + = 178.1].
Figure imgf000065_0002
1 -Methyl- 1 H-benzotriazole-4-carboxylic acid was prepared in the same manner. [LCMS RtF = 0.51 min [M+H]+ = 178.1]
Figure imgf000065_0003
2-Methyl-2H-benzotriazole-4-carboxylic acid was prepared in the same manner. [LCMS RtF = 0.59 min; [M+H]+ = 178.1]
Building block A2: 7-Methyl-imidazon .2-a1pyridine-6-carboxylic acid
Figure imgf000066_0001
Copper(ll)cyanide (2.87 g, 32 mmol) was added to the solution of 5-bromo-4-methyl-pyridin- 2-ylamine (3.0 g, 16.0 mmol) in DMA (12 ml) and the reaction was stirred under an atmosphere of argon at 170°C for 24 h. After cooling to rt the reaction mixture was added to the solution of ethylenediamine (60 ml) in water (240 ml) and stirred for 15 min. Then, the mixture was diluted with EtOAc, washed with water and NaCI-soln., dried (Na2S04), filtered and concentrated. The crude product was purified by chromatography (Flashmaster, Hex:EtOAc 4: 1 to 1 :9 over 40 min; Hex:EtOAc 1 :9 for 10 min) followed by crystallization from DCM(MeOH)/diethylether/hexane to yield 1.73 g (81 %) of the title compound as yellowish crystals. [1 H-NMR (DMSO, 600 MHz) 8.23 (s, 1H), 6.91 (s, 2H), 6.35 (s, 1H), 2.25 (s, 3H); LCMS RtD = 1.959 min; [M+H]+ = 134.0]. -Atnino-4-tnethyl-nicotinic acid
Figure imgf000066_0002
6-Amino-4-methyl-nicotinonitrile (1.7 g, 12.8 mmol) was suspended in 4N sodium hydroxid solution and stirred 5 h at 100°C to obtain a clear solution. The reaction mixture was cooled in an icebath and acidified by addition of 4N hydrochloric acid. The precipitate was filtered and washed with little water. The residue was dissolved in MeOH, the solvent evaporated at reduced pressure and the product dried at high vacuum to yield the title compound 1.74 g (90%) as colorless solid. [1 H-NMR (DMSO, 600 MHz) 12.17 (s, 1 H), 8.45 (s, 1 H), 6.56 (2H), 6.23 (s, 1 H), 2.38 (s, 3H); LCMS RtD = 1.910 min; [M+H]+ = 153.0]. -Amino-4-methyl-nicotinic acid methyl ester
Figure imgf000067_0001
6-Amino-4-methyl-nicotinic acid (1.7 g, 11.2 mmol) was dissolved in MeOH (23 ml) and cone, sulfuric acid (0.30 ml, 5.6 mmol) was added dropwise. The reaction was heated (bath temperature 85°C) over night. Then, the mixture was diluted with EtOAc, washed with NaHC03- and NaCI-soln., dried (Na2S0 ), filtered and concentrated. The residue was crystallized from DCM(MeOH)/diethylether/hexane to give the title compound as yellowish crystals (735 mg, 40%). [1 H-NMR (DMSO, 600 MHz) 8.46 (s, 1 H), 6.65 (2H), 6.25 (s, 1 H), 3.73 (s, 3H), 2.37 (s, 3H); LCMS RtD = 2.355 min; [M+H]* = 167.0]. d 7-Methyl-imidazof1 ,2-alpyridine-6-carboxylic acid methyl ester
Figure imgf000067_0002
The solution of 6-amino-4-methyl-nicotinic acid methyl ester (072 g, 4.3 mmol),
chioroacetaidehyde (55% in water, 2.3 ml, 19.5 mmol), and sodium bicarbonate (0.62 g, 7.4 mmol) in ethanol (25 ml) was heated (bath temperature 90°C) for 1.5 h. The mixture was diluted with EtOAc, washed with NaHC03- and NaCI-soln., dried (Na2S04), filtered and concentrated. The crude product was purified by chromatography (Flashmaster, Hex: EtOAc 1 :1 to EtOAc over 30 min; EtOAc for 20 min) to yield the title compound as off-white solid (700 mg, 85%). [1H-NMR (DMSO, 600 MHz) 9.24 (s, 1 H), 8.01 (s, 1H), 7.59 (s, 1 H), 7.45 (s, 1H), 3.85 (s, 3H), 2.54 (s, 3H); LCMS RtD = 2.378 min; [M+Hf = 191.0]. 7-Methyl-imidazof1 ,2-alpyridine-6-carboxylic acid
Figure imgf000067_0003
The solution of 7-methyl-imidazo[1 ,2-a]pyridine-6-carboxylic acid methyl ester (0.69 g, 3.6 mmol) and 4 N aqueous sodium hydroxide (2.27 ml, 9.1 mmol) in MeOH (30 ml) was stirred at rt for 2 h, followed by 1 h at 50°C. The MeOH was evaporated at reduced pressure and EtOAc was added. The mixture was extracted with 0.5 N aqueous sodium hydroxide. The aqueous layer was acidified with 1 N hydrochloric acid. The solvents were evaporated at reduced pressure and the residue re-suspended in EtOH and evaporated several times to remove remaining water. The residue was stirred in DCM:MeOH 1 :1 (60 ml) and the insoluble part (NaCI) filtered off. The filtrate was concentrated at reduced pressure and titurated by addition of Et20. The product was filtered and washed with little Et20 to obtain the title compound as off-white crystals (450 mg, 70%). [1 H-NMR (DMSO, 600 MHz) 9.48 (s, 1 H), 8.33 (s, 1 H), 8.16 (s, 1 H), 7.84 (s, 1 H), 2.71 (s, 3H); LCMS RtD = 2.033 min; [M+Hf = 177.0].
Building block A3: 6-Methyl-furor2.3-blpyridine-5-carboxylic acid
Figure imgf000068_0001
[3424-43-9]
1) Cul, EtOH, EtjN, 68h, 70°C
2) KjCC 24h, 70-C
3) DARCO, MeOH, reflux, 2h
4) MeOH, H2S04, reflux, 18h
3%
Figure imgf000068_0002
a) 6-Hvdroxy-5-iodo-2-methyl-nicotinic acid ethyl ester
Figure imgf000068_0003
To the solution of 6-hydroxy-2-methyl-nicotinic acid ethyl ester (7.5 g, 41.4 mmol) in MeOH (180 ml) was added N-iodo-succinimide (13.97 g, 62 mmol) and the reaction was stirred at 50°C. After 2h concentrated hydrochloric acid (0.126 mml, 4.1 mmol) was added followed by another portion of N-iodo-succinimide (2.5 g, 11.1 mmol) and stirring was continued for another hour, when a third portion of N-iodo-succinimide (2.5 g, 11.1 mmol) was added. After 2 h the reactions mixture was cooled to rt and poured into ice-water (300 ml). The precipitate was filtered and washed with water. The filter cake was dissolved in DCM, the sulution washed with aqueous sodium thiosulfate, and dried over sodium sulfate. Evaporation of the solvent at reduced pressure gave the title compound as colorless solid (12.2 g, 96%). [1H- NMR (DMSO, 600 MHz) 12.41 (s, 1H), 8.36 (s, 1H), 4.21 (q, 2H), 3.33 (s, 3H), 1.27 (t, 1 H).] b) 6-Hvdroxy-2-methyl-5-trimethylsilanylethvnyl-nicotinic acid ethyl ester
Figure imgf000069_0001
To the solution of 6-hydroxy-5-iodo-2-methyl-nicotinic acid ethyl ester (12 g, 39.1 mmol) in THF (93 mml) and chloroform (185 ml) under argon atmosphere were added
trimethylsilylacetylene (5.37 g, 47.7 mmol), dichlorobis-(triphenylphosphine)palladium(ll) (0.823 g, 1.17 mmol), and copper(l) iodide (0.112 g, 0.59 mmol). After addition of triethylamine (18.9 ml, 121 mmol) the reaction mixture was stirred at 50°C for 20 h. The mixture was cooled to rt and diluted with EtOAc. Washing with 10% aqueous citric acid, brine, aqueous sodium bicarbonate and again brine, drying over sodium sulfate and evaporation of the solvents at reduced pressure gave the crude product. Chromatography on silicagel (Flashmaster, hexanes/EtOAc 7/3 to hexanes/EtOAc 3/7 over 40 min, then 20 min hexanes/EtOAc 3/7) gave the product as off-white solid (7.27 g, 67%). [1H-NMR (DMSO, 600 MHz) 12.48 (s, 1 H), 7.95 (s, 1H), 4.20 (q, 2H), 2.53 (s, 3H), 1.27 (t, 3H), 0.21 (s, 9H).] -Methyl-furof2,3-b1pyridine-5-carboxylic acid methyl ester
Figure imgf000069_0002
To the solution of 6-hydroxy-2-methyl-5-trimethylsilanylethynyl-nicotinic acid ethyl ester (3.6 g, 13.0 mmol) in EtOH (50 ml) under argon atmosphere were added copper(l) iodide (0.124 g, 0.65 mmol) and triethylamine (50 ml) and the suspension was stirred at 70°C for 68 h. Potassium carbonate (dry powder, 1.79 g, 13.0 mmol) was added and stirring continued for 24 h. The mixture was cooled and diluted with MeOH (50 ml). DARCO was added and the mixture stirred for 2 h at reflux temperature. After cooling the mixture was filtered through a glassfilter and the residue washed with MeOH. The solvents were evaporated at reduced pressure to give a black solid (2.9 g, mixture of carboxylic acid and ester). 1.2 g of the crude mixture was dissolved in MeOH (13.7 ml) and concentrated sulfuric acid (0.36 ml) was added with care. The mixture was heated under reflux over night. After cooling to rt the solvents were evaporated under reduced pressure and the residue was purified by chromatography on silica (Flashmaster, gradient hexanes to EtOAc over 20 min, 20 min EtOAc, then 40 min EtOAc/MeOH 95/5) to give the product as yellowish solid (45 mg, 3%). [1 H-NMR (DMSO, 600 MHz) 8.58 (s, 1 H), 8.13 (d, 1 H), 7.07 (d, 1 H), 3.87 (s, 3H), 2.77 (s, 3H).] -Methyl-furor2,3-b1pyridine-5-carboxylic acid (lithium carboxylate)
Figure imgf000070_0001
To the solution 6-methyl-furo[2,3-b]pyridine-5-carboxylic acid methyl ester (43 mg, 0.225 mmol) in MeOH (2 ml) was added 1 N aqueous lithium hydroxide (0.247 ml) and the reaction was stirred at 50°C for 24 h. The solvents were evaporated at reduced pressure and the residue was re-dissolved in MeOH and the solvents were evaporated a few times. The title compound was obtained as yellowish solid (45 mg, quant.). [1H-NMR (DMSO, 600 MHz) 8.11 (s, 1 H), 7.89 (d, 1 H), 6.88 (d, 1 H), 2.67 (s, 3H).]
Building block A4: 6-Methyl-furof2.3-b1pyridine-5-carboxylic acid % I
Figure imgf000070_0002
[934330-61-7]
Figure imgf000070_0003
-Methyl-furor3.2-blpyridine
Figure imgf000070_0004
The solution of 6-bromo-furo[3,2-b]pyridine (500 mg, 2.53 mmol) in DMF (15 ml) were added trimethylboroxin (1.33 ml, 9.6 mmol), tetrakis(triphenylphosphine)palladium(0) (73 mg, 0.063 mmol), and 4 M aqueous sodium carbonate (2.78 ml, 11.1 mmol). The reaction mixture was stirred in the microwave oven at 120°C for 2 h). The mixture was taken into EtOAc, washed with brine, dried over sodium sulfate and the solvents were evaporated at reduced pressure. The crude product was purified by chromatography on silica (Flashmaster, silica pretreated with hexanes containing 1% triethylamine, hexanes to hexanes/EtOAc 1/4 over 20 min) to give the product as colorless oil (240 mg, 71%, contains about 20% furo[3,2-b]pyridine). [1 H- NMR (DMSO, 600 MHz) 8.38 (s, 1 H), 8.21 (s, 1 H), 7.86 (s, 1 H), 7.07 (s, 1 H), 2.42 (s, 3H).] b -Methyl-furor3.2-b1pyridine-5-carbonitrile
Figure imgf000071_0001
The mixture of 6-methyl-furo[3,2-b]pyridine and furo[3,2-b]pyridine obtained above (460 mg, 3.4 mmol) was dissolved in DCM (40 ml) and m-chloroperoxybenzoic acid (715 mg, 4.15 mmol) was added. The mixture was stirred at rt for 24 h. The reaction mixture was then added to a solution of potassium cyanide (2.48 g, 38 mmol) in water (3.6 ml) and a solution of benzoyl chloride (4.25 ml, 36.6 mmol) in DCM (20 ml) was added dropwise to the reaction. The reaction mixture was vigorously stirred at rt for 3 h. The reaction mixture was extracted with DCM, the combined organic layers were dried over sodium sulfate, and the solvents were evaporated at reduced pressure. The crude product was purified by chromatography on silica (Flashmaster, hexanes to hexanes/EtOAc 7/3 over 40 min), followed by preparative HPLC (water sunfire C18, 5μηι; solvent: A water + 0.05 % TFA / B acetonitrile + 0.05 % TFA; gradient: 15-35% B over 16 min; flow 50 ml/min) to give the product as colorless solid. [1 H- NMR (DMSO, 600 MHz) 8.84 (s, 1 H), 8.24 (s, 1 H), 7.24 (s, 1 H), 2.50 (s, 3H).] c -Methyl-furor2.3-blpyridine-5-carboxylic acid
Figure imgf000071_0002
6-Methyl-furo[3,2-b]pyridine-5-carbonitrile (290 mg, 1.8 mmol) was dissolved in EtOH (12 ml) and potassium hydroxide (1.03 g, 18 mmol) in water (3.3 ml) was added. The reaction was heated at reflux temperature for 20 h. The solvents were evaporated at reduced pressure and the residue was dissolved in water (6.5 ml) and acidified with acetic acid (1.5 ml). The aqueous solution was extracted with EtOAc, the organic layer dried over sodium sulfate and the solvent was evaporated at reduced pressure to give the crude product as brown oil (215 mg, 66%, ~50% purity) which was used without further purification for the next steps. [1 H- NMR (DMSO, 600 MHz) 13.05 (br s, 1 H), 8.35 (s, 1 H), 8.03 (s, 1 H), 7.16 (s, 1 H), 2.56 (s, 3H).] Buildin block A5: 6-Methoxy-2-methyl-quinoline-8-carboxylic acid
Figure imgf000072_0001
To the solution of 2-amino-5-methoxy-benzoic acid (500 mg, 2.99 mmol) and 6 N aqueous HCI (7 ml, 42 mmol) in dioxane (6 ml) was added but-2-enal (419 mg, 6.0 mmol) and the mixture was heated for 2h at 120°C in a microwave oven . After cooling to rt the pH was adjusted to 3-4 by addition of 25% aqueous ammonia, and the reaction was extracted with DCM. The combined organic layers were washed with brine, dried over sodium sulfate, and the solvents were evaporated at reduced pressure. The residue was dissolved in
DCM/MeOH 4/1. After addition of diethylether the precipitated product was filtered and dried in vacuum ( light brown solid , 278 mg, 43%). [1H-NMR (DMSO, 600 MHz) 17.07 (s, 1H), 8.49 (d, 1H), 8.08 (s, 1 H), 7.76 (s, 1H), 7.65 (d, 1H), 3.95 (s, 3H), 2.75 (s, 3H).]
Building block A6: 5-Fluoro-benzofuran-6-carboxylic acid
Figure imgf000072_0002
5-Fluoro-benzofuran-6-carboxylic acid was obtained by an analogous reaction sequence as described for building block A3, starting from 2-fluoro-5-hydroxy benzoic acid. [1 H-NMR (DMSO, 600 MHz) 13.27 (br s, 1H), 8.24 (d, 1 H), 8.05 (d, 1H), 7.57 (d, 1 H), 7.04 (d, 1 H); LCMS RtB = 2.656 min; [M+H]+ = 181.0]
Buildin block A7: 5-Methyl-benzofuran-6-carboxylic acid
5-Methyl-benzofuran-6-carboxylic acid was obtained by an analogous reaction sequence as described for building block A3, starting from 2-methyl-5-hydroxy benzoic acid. [1H-NMR (DMSO, 600 MHz) 12.82 (s, 1H), 8.13 (d, 1 H), 8.03 (s, 1 H), 7.55 (s, 1 H), 6.96 (d, 1 H), 2.59 (s, 3H); LCMS RtB = 2.932 min; [M+H]+ = 177.0] Buildin block A8: 2-Ethoxy-pyrimidine-4-carboxylic acid
Figure imgf000073_0001
2-Chloropyrimidine-4-carboxylic acid (150 mg, 0.95 mmol) and sodium ethylate (193 mg, 2.84 mmol) in EtOH (5 ml) were heated at reflux temperature for 16 h. After cooling to rt the mixture was acidified to pH 5 by addition of 1 N aqueous HCI. The solvents were evaporated at reduced pressure and the residue was stirred with water (2 ml). The solid product was filtered and dried in vacuum (brownish solid, 1 13 mg, 71%). [1 H-NMR (DMSO, 400 MHz) 8.81 (d, 1 H), 7.56 (d, 1 H), 4.38 (q, 2H), 1.33 (t, 3H); LCMS Rtj = 0.43 min; [M+H]+ = 169.1]
Buildin block A9: 2-lsopropoxy-pyrimidine-4-carboxylic acid
Figure imgf000073_0002
2-Chloropyrimidine-4-carboxylic acid (100 mg, 0.63 mmol) was dissolved in 1-propanol (3 ml) and sodium hydride (55-65%, 63 mg, 1.58 mmol) was added carefully in portions. The mixture was heated for 1 h at 150°C in a microwave oven. The mixture was poured on ice- water and the mixture was acidified to pH 3. Extraction with DCM, drying over sodium sulfate and evaporation of the solvent under reduced pressure gave the product as a solid (78 mg, 68%). [1 H-NMR (DMSO, 400 MHz) 8.80 (d, 1 H), 7.53 (d, 1 H), 5.24 (hep, 1 H), 1.32 (d, 6H); LCMS RtD = 2.739 min; [M+H]+ = 183.0]
Buildingblock B1 : Pyridine-2-carboxylic acid ((S)-3-methylamino-4-phenyl-butyl)-amide hydrochloride
Figure imgf000074_0001
93 %
a) Methanesulfonic acid (S)-2-tert-butoxycarbonylamino-3-phenyl-propyl ester
Figure imgf000074_0002
To a solution of ((S)-1-hydroxymethyl-2-phenyl-ethyl)-carbamic acid tert-butyl ester (50.9 g, 202.6 mmol) in dry DCM (800 ml) at 0 °C, triethylamine (30.7 g, 303.9 mmol) and
methanesulfonyl chloride (34.8 g, 303.9 mol) were added drop wise. The reaction mixture was stirred at 0 °C for 30 min and at rt for another 30 min. Then, the mixture was diluted with EtOAc, washed with 1 N-HCI-, NaCI-, NaHC03- and NaCI-soln., dried (Na2S04), filtered and concentrated. The crude product was recrystallized from a mixture of DCM-Et20-Hex to yield 65.9 g (99%) of the title compound as white solid. [1 H-NMR (CDCI3, 400 MHz) 7.34-7.30 (m, 2H), 7.27-7.21 (m, 3H), 4.72 (br s, 1H), 4.25-4.23 (m, 1 H), 4.13-4.09 (m, 2H), 3.01 (s, 3H), 2.93 (dd, 1 H), 2.85 (dd, 1 H), 1.42 (s, 9H); LCMS RtA = 2.781 min; [M+Na]+ = 352.0]. -1-Benzyl-2-cvano-ethyl)-carbamic acid tert-butyl ester
Figure imgf000074_0003
To a solution of methanesulfonic acid (S)-2-tert-butoxycarbonylamino-3-phenyl-propyl ester (65.8 g, 199.7 mmol) in dry DMF (500 ml), sodium cyanide (24.5 g, 499.4 mmol) was added. The reaction mixture was heated at 60 °C for 5.h. Then, the mixture was cooled to 0 °C, water was added, the precipitate was filtered off and washed with water. The filtrate was dissolved in EtOAc, washed with NaHC03- and NaCI-soln., dried (Na2S04), filtered and concentrated. The crude product was recrystallized from a mixture of DCM-Et20-Hex to yield 39.3 g (76 %) of the title compound as white solid. [1 H-NMR (CDCI3, 400 MHz) 7.37-7.21 (m, 5H), 4.73 (br d, 1 H), 4.08 (br d, 1 H), 3.01 (dd, 1 H), 2.87 (dd, 1 H), 2.71 (dd, 1 H), 2.42 (dd, 1 H), 1.43 (s, 9H); LCMS RtA = 2.764 min; [M+Na]+ = 283.0]. c ((S)-1-Benzyl-2-cvano-ethyl)-methyl-carbamic acid tert-butyl ester
Figure imgf000075_0001
To a solution of ((S)-1-benzyl-2-cyano-ethyl)-carbamic acid tert-butyl ester (6.2 g, 23.8 mmol) in dry THF (55 ml) at 0 °C, sodium hydride 60 % in mineral oil (2.9 g, 71.4 mmol) was added. Methyl iodide (27.0 g, 191.0 mmol) was added drop wise. The reaction mixture was warmed- up to rt and stirred for 1 h. The reaction mixture was exothermic, a water-bath was added to maintain the temperature at 25 °C. Then, the mixture was diluted with EtOAc, washed with Na2S203-, NaHC03- and NaCI-soln., dried (Na2S0 ), filtered and concentrated. The crude product was purified by chromatography (Flashmaster, Hex to Hex:EtOAc 2:8 over 50 min.) to yield 4.7 g (72 %) of the title compound as yellowish oil. [1 H-NMR (DMSO, 600 MHz, rotamers) 7.29-7.25 (m, 2H), 7.21-7.16 (m, 3H), 4.52 (br s, 1 H), 2.92 (dd, 1 H), 2.83-2.72 (m, 3H), 2.65/2.63 (s, 3H), 1.27/1.18 (s, 9H); LCMS RtA = 3.022 min; [M+Na]+ = 297.0]. -3-Amino-1-benzyl-propyl)-methyl-carbamic acid tert-butyl ester
Figure imgf000075_0002
((S)-1-Benzyl-2-cyano-ethyl)-methyl-carbamic acid tert-butyl ester (4.7 g, 17.3 mmol) and Raney-nickel were dissolved in MeOH-5%NH3 (150 ml) and stirred for 30 h at rt under H2 (1 atm). The reaction mixture was filtered over celite and concentrated. The crude product was purified by chromatography (Flashmaster, DCM to DCM:MeOH-5%NH3 85:15 over 50 min.) to yield 4.4 g (91 %) of the title compound as yellowish oil. [1 H-NMR (DMSO, 600 MHz) 7.26- 7.22 (m, 2H), 7.17-7.14 (m, 3H), 4.32 (d, 1 H), 2.69 (d, 1 H), 2.66 (d, 1 H), 2.57/2.56 (s, 3H), 2.49-2.38 (m, 2H), 1.65-1.40 (m, 4H) 1.26/1.16 (s, 9H); LCMS RtB = 2.847 min; [M+H]+ = 279.2]. e S)-1-Benzyl-3-f(pyridine-2-carbonvn-aminol-propylVmethyl-carbamic acid tert-butyl ester
Figure imgf000076_0001
((S)-3-Amino-1-benzyl-propyl)-methyl-carbamic acid tert-butyl ester (1.5 g, 5.4 mmol), picolinic acid (796 mg, 6.5 mmol), HOBt (990 mg, 6.5 mmol), EDC x HCI (1.5 g, 8.1 mmol), and triethylamine (3.0 ml, 21.5 mmol) were dissolved in DCM (80 ml) and the mixture was stirred at rt for 24 h. Then, the mixture was diluted with EtOAc, washed with NaHC03- and NaCI-soln., dried (Na2S04), filtered and concentrated. The crude product was purified by chromatography (Flashmaster, Hex to Hex:EtOAc 4:6 over 50 min.) to yield 1.9 g (93 %) of the title compound as colorless oil. [1 H-NMR (DMSO, 600 MHz, rotamers) 8.76 (d, 1 H), 8.62 (s, 1H), 8.04-7.97 (m, 2H), 7.59 (br s, 1H), 7.25-7.23 (m, 2H), 7.15-7.13 (m, 3H), 4.31 (br d, 1H), 3.23-3.09 (m, 2H), 2.78-2.64 (m, 2H), 2.64/2.63 (s, 3H), 1.82-1.65 (m, 2H), 1.27/1.03 (s, 9H); LCMS RtA = 3.147 min; [M+H]+ = 384.2]. f Pyridine-2-carboxylic acid ((S)-3-methylamino-4-phenyl-butyl)-amide hydrochloride
Figure imgf000076_0002
To a solution of {(S)-1-benzyl-3-[(pyridine-2-carbonyl)-amino]-propyl}-methyl-carbamic acid tert-butyl ester (1.9 g, 5.0 mmol) in DCM (10 ml), a 4M HCI solution in dioxane (31.5 ml, 126 mmol) was added drop wise. The reaction mixture was stirred at rt for 1 h. Then, the mixture was concentrated, taken-up in DCM and concentrated under high vacuum to yield 1.7 g (quant.) of the title compound as white solid. [1 H-NMR (DMSO, 600 MHz) 9.02-8.79 (m, 3H), 8.63 (d, 1H), 8.00-7.98 (m, 2H), 7.62-7.58 (m, 1 H), 7.28-7.26 (m, 4H), 7.23-7.19 (m, 1H), 3.42-3.30 (m, 3H), 3.12 (dd, 1H), 2.82 (dd, 1 H), 2.60 (t, 3H), 1.84-1.71 (m, 2H); LCMS RtB = 2.465 min; [M+H]+ = 284.2]. Buildinq block B2: 1-Methyl-1H-pyrrole-2-carboxylic acid ((S)-3-methylamino-4-phenyl- butvD-amide:.
Figure imgf000077_0001
Figure imgf000077_0002
a) (S)-1-Benzyl-3-[(1 -methyl- 1 H-pyrrole-2-carbonvn-aminol-propylVmethyl-carbamic acid tert-butyl ester
Figure imgf000077_0003
((S)-3-Amino-1-benzyl-propyl)-methyl-carbamic acid tert-butyl ester (6.9 g, 24.5 mmol), 1- methyl-1 H-pyrrole-2-carboxylic acid (3.76 g, 29.4 mmol), HOBt (5.64 g, 36.8 mmol), and EDC x HCI (5.64 g, 29.4 mmol) and Et3N (10.3 ml, 73.6 mmol) were dissolved in DCM (50 ml) and stirred at rt for 18 h. Then, the mixture was concentrated, redissolved in EtOAc, washed with sat. NaHC03- and NaCI-soln., dried (Na2S04), filtered and concentrated. The crude product was purified by chromatography (Biotage, Hex to Hex:EtOAc 1 :1 over 10 min.) to yield 7.15 g (74 %) of the title compound as white solid. [1 H-NMR (DMSO, 600 MHz) 7.94- 7.85 (m, 1 H), 7.30-7.20 (m, 2H), 7.20-7.13 (m, 3H), 6.88 (s, 1 H), 6.72 (d, 1 H), 5.99 (s, 1 H), 4.42-4.17 m, (1 H), 3.82 (s, 3H), 3.25-2.95 (m, 2H), 2.83-2.77 (m, 2H), 2.63 (s, 3H), 1.80-1.58 (m, 2H), 1.29/1.09 (s, 9H); UPLCMS Rt, = 1.17 min; [M+H]+ = 386.3]. b) 1 -Methyl- 1 H-pyrrole-2-carboxylic acid ((S)-3-methylamino-4-phenyl-butyl)-amide hydrochloride
Figure imgf000078_0001
To a solution of (S)-1-benzyl-3-[(1-methyl-1H-pyrrole-2-carbonyl)-amino]-propyl}-methyl- carbamic acid tert-butyl ester (7.15 g, 18.6 mmol) in DCM (100 ml), a 4M HCI solution in dioxane (116 ml, 464 mmol) was added drop wise. The reaction mixture was stirred at rt for 30 min. Then, the mixture was concentrated, taken-up in DCM, concentrated and dried under high vacuum to yield the title compound as white solid. [1H-NMR (DMSO, 600 MHz) 8.97 (br s, 2H), 8.20 (t, 1H), 7.33-7.24 (m, 5H), 6.89 (s, 1 H), 6.74 (dd, 1H), 6.00 (dd, 1 H), 3.80 (s, 3H), 3.40-3.22 (m, 3H), 3.14 (dd, 1 H), 2.82 (dd, 1H), 2.61 (s, 3H), 1.79-1.64 (m, 2H); LCMS RtB = 2.635 min; [M+H]+ = 286.2]. c 1-Methyl-1H-pyrrole-2-carboxylic acid ((S)-3-methylamino-4-phenyl-butvD-amide
Figure imgf000078_0002
The HCI salt was dissolved in DCM and washed with sat. NaHC03 and NaCI-solution, dried (Na2S04), filtered and concentrated. The title compound (5.01 g, 95 %) was obtained as a yellow oil. [1 H-NMR (DMSO, 600 MHz) 8.09-8.03 (m, 1 H), 7.30-7.22 (m, 2H), 7.22-7.14 (m, 3H), 6.85 (s, 1 H), 6.65 (s, 1 H), 5.97 (s, 1H), 3.60 (s, 3H), 3.36-3.30 (m, 1H), 3.30-3.15 (m, 2H), 2.77-2.53 (m, 3H), 2.30 (s, 3H), 1.55-1.43 (m, 2H); UPLCMS Rt, = 0.58 min; [M+H]+ = 286.2].
Building block B3; 6-Methyl-imidazor2.1-b1thiazole-5-carboxylic acid ((S)-3- meth lamino-4-phenyl-butyl)-amide hydrochloride
Figure imgf000078_0003
a) ((S)-1-Benzyl-3-r(6-methyl-imidazoi2,1-b1thiazole-5-carbonyl)-amino1-propyl)-methyl- carbamic acid tert-butyl ester
Figure imgf000079_0001
((S)-3-Amino-1-benzyl-propyl)-methyl-carbamic acid tert-butyl ester (1.5 g, 5.4 mmol), 6- methylimidazo[2,1-b]thiazole-5-carboxylic acid (1.18 g, 6.5 mmol), HOBt (990 mg, 6.5 mmol), EDC x HCI (1.55 g, 8.1 mmol), and triethylamine (3.0 ml, 21.6 mmol) were dissolved in DCM (50 ml) and the reaction was stirred at rt for 20 h. The mixture was diluted with EtOAc, washed with NaHC03- and NaCI-soln., dried (Na2S04), filtered and concentrated. The crude product was purified by chromatography (Flashmaster, Hex:EtOAc 4:1 to EtOAc over 40 min.) to yield 1.88 g (79 %) of the title compound as glass-like solid. [1 H-NMR (DMSO, 600 MHz, rotamers) 8.08-8.07 (m, 1 H), 7.54/7.47 (br s, 1 H), 7.33 (d, 1 H), 7.28-7.23 (m, 2H), 7.18-7.15 (m, 3H), 4.40/4.28 (br s, 1 H), 3.38-3.18 (m, 2H), 2.80-2.60 (m, 2H), 2.67/2.65 (s, 3H), 2.50/2.49 (s, 9H); LCMS RtA = 2.641 min; [M+H]+ = 443.2]. b) 6-Methyl-imidazo[2.1-blthiazole-5-carboxylic acid ((S)-3-methylamino-4-phenyl-butvD- amide h drochloride
Figure imgf000079_0002
To a solution of {(S)-1-benzyl-3-[(6-methyl-imidazo[2,1-b]thiazole-5-carbonyl)-amino]-propyl}- methyl-carbamic acid tert-butyl ester (1.87 g, 5.2 mmol) in DCM (7 ml), a 4M HCI solution in dioxane (26.4 ml, 106 mmol) was added drop wise. The reaction mixture was stirred at rt for 1 h. Then, the mixture was concentrated, the residue taken-up again in DCM, concentrated and dried under high vacuum to yield 1.98 g (quant.) of the title compound as white solid.
[1 H-NMR (DMSO, 600 MHz) 9.17 (br s, H), 9.05 (br s, H), 8.11 (d, 1 H), 8.04 (br s, 1 H), 7.49 (d, 1 H), 7.30-7.29 (m, 4H), 7.23-7.19 (m, 1 H), 3.45-3.32 (m, 3H), 3.17 (dd, 1 H), 2.82 (dd, 1 H), 1.87-1.75 (m, 2H); LCMS RtB = 2.194 min; [M+H]+ = 343.2].
Building block B4: 1-Methyl-1H-benzoimidazole-2-carboxylic acid f(S)-3-methylamino-
4-phenyl-butyl)-amide hydrochloride
Figure imgf000080_0001
a) {(S)-1-Benzyl-3-[(1-methyl-1H-benzoimidazole-2-carbonyl)-aminol-propyl>-methyl- carb mic acid tert-butyl ester
Figure imgf000080_0002
((S)-3-Amino-1-benzyl-propyl)-methyl-carbamic acid tert-butyl ester (3.4 g, 12.2 mmol), 1- methyl-1H-benzoimidazole-2-carboxylic acid (2.58 g, 14.7 mmol), HOBt (2.24 g, 14.7 mmol), EDC x HCI (3.51 g, 18.3 mmol), and triethylamine (6.8 ml, 48.9 mmol) were dissolved in DCM (150 ml) and the reaction mixtures was stirred at rt for 20 h. The mixture was diluted with EtOAc, washed with NaHC03- and NaCI-soln., dried (Na2S04), filtered and
concentrated. The crude product was purified by chromatography (Flashmaster, Hex to Hex:EtOAc 3:7 over 50 min.) to yield 3.6 g (68 %) of the title compound as amorphous solid.
[1H-NMR (DMSO, 400 MHz, rotamers) 8.93-8.89 (m, 1 H), 7.70 (d, 1 H), 7.66 (d, 1H), 7.37 (dd, 1 H), 7.30 (dd, 1 H), 7.23 (dd, 2H), 7.17-7.15 (m, 3H), 4.33/4.30 (br s, 1H), 4.12/4.10 (s, 3H), 3.32-3.10 (m, 2H), 2.80-2.64 (m, 2H), 2.64/2.63 (s, 3H), 1.83-1.68 (m, 2H), 1.26/1.04 (s, 9H); LCMS RtG = 2.406 min; [M+H]+ = 437.2]. b) 1-Methyl-1 H-benzoimidazole-2-carboxylic acid ((S)-3-methylamino-4-phenyl-butyl)-amide h drochloride
Figure imgf000080_0003
To a solution of {(S)-1-benzyl-3-[(1-methyl-1H-benzoimidazole-2-carbonyl)-amino]-propyl}- methyl-carbamic acid tert-butyl ester (3.6 g, 8.2 mmol) in DCM (20 ml), a 4M HCI solution in dioxane (51.5 ml, 206 mmol) was added drop wise. The reaction mixture was stirred at rt for 1 h. Then, the mixture was concentrated, the residue taken-up again in DCM, concentrated and dried under high vacuum to yield 3.4 g (quant.) of the title compound as white solid. [1H- NMR (DMSO, 400 MHz) 9.14 (t, 1H), 9.05-9.00 (m, 1H), 8.90-8.85 (m, 1H), 7.71 (d, 1H), 7.68 (d, 1H), 7.39 (dd, 1H), 7.32 (dd, 1H), 7.29-7.16 (m, 5H), 4.07 (s, 3H), 3.48-3.26 (m, 4H), 3.13 (dd, 1H), 2.83 (dd, 1H), 2.59 (t, 3H), 1.87-1.72 (m, 2H); LCMS RtB = 2.768 min; [M+H]+ =
337.2].
Building block B5: (S)-1-ethyl-3-methyl-N-(3-(methylamino)-4-phenylbutyl)-1H- razole-5-carboxamide
Figure imgf000081_0001
Obtained in analogy to building block B4. [1H-NMR (DMSO, 400 MHz) 9.15-9.02 (br m, 1H), 9.01-8.90 (brm, 1H), 8.56 (t, 1H), 7.32-7.19 (m, 5H), 6.56 (s, 1H), 4.36 (dd, 1H), 4.33 (dd, 1H), 3.55 (s, 3H), 3.33-3.17 (m, 2H), 3.13 (dd, 1H), 2.81 (dd, 1H), 2.57 (brt, 2H), 2.13 (s, 3H), 1.82-1.65 (m, 2H), 1.22 (t, 3H); LCMS Rtj = 0.61 min; [M+H]+ = 315.2].
Building block B6: 6-Methyl-pyridine-2-carboxylic acid ((S)-3-methylamino-4-phenyl- butvD-amide
Figure imgf000081_0002
Obtained in analogy to building block B4. [1H-NMR (DMSO, 600 MHz) 9.46 (br s, 1H), 9.29 (brs, 1H), 9.08 (s, 1H), 8.00 (t, 1H), 7.94 (d, 1H), 7.57 (d, 1H), 7.29-7.24 (m, 4H), 7.19 (t, 1H), 3.43-3.31 (m, 3H), 3.20 (dd, 1H), 2.85 (dd, 1H), 2.59 (s, 6H), 1.88-1.74 (m, 2H); LCMS Rtj = 0.66 min; [M+H]+ = 298.2].
Building block B7: 6-Methoxy-pyridine-2-carboxylic acid ((S)-3-methylamino-4-phenyl- butvh-amide
Figure imgf000082_0001
Obtained in analogy to building block B4. [1 H-NMR (DMSO, 600 MHz) 9.37 (br s, 1 H), 9.24 (br s, 1 H), 8.83 (t, 1 H), 7.84 (t, 1 H), 7.57 (d, 1 H), 7.27-7.20 (m, 5H), 7.00 (d, 1 H), 3.96 (s, 3H), 3.45-3.33 (m, 3H), 3.18 (dd, 1 H), 2.85 (dd, 1 H), 2.59 (s, 3H), 1.87-1.75 (m, 2H); LCMS Rtj = 0.68 min; [M+H]+ = 314.2].
Buildin block C1 :(S)-N-(4-amino-1 -phenylbutan-2-yl)-3-methoxy-N-methylbenzamide
Figure imgf000082_0002
Obtained in analogy to intermediate c described in Example 2.5. [1 H-NMR (DMSO, 400 MHz, rotamers) 7.35-7.10 (m, 4H), 6.99-6.93 (m, 1 H), 6.92-6.84 (m, 1 H), 6.50/6.26 (d, 1 H), 6.33 (d, 1 H), 5.01-4.90/3.76-3.67 (m, 1 H), 3.68/3.67 (s, 3H), 2.88/2.56 (s, 3H), 2.86- 2.75/2.68-2.61 (m,2H), 2.55-2.30 (m, 2H), 1.78-1.30 (m, 2H); LCMS Rtj = 0.86 min (broad); [M+H]+ = 313.1].
Example 1.1 : (S1-N.1 -dimethyl-N-M -phenyl-4-(picolinamido)butan-2-ylH H- nzordlimidazole-2-carboxamide
Figure imgf000082_0003
Pyridine-2-carboxylic acid ((S)-3-methylamino-4-phenyl-butyl)-amide hydrochloride (150 mg, 0.47 mmol), 1-methyl-1 H-benzoimidazole-2-carboxylic acid (99 mg, 0.56 mmol), HOBt (86 mg, 0.56 mmol), EDC x HCI (135 mg, 0.70 mmol), and triethylamine (0.26ml, 1.88 mmol) were dissolved in DCM (15 ml) and stirred at rt for 20 h. The mixture was diluted with EtOAc, washed with NaHC03- and NaCI-soln., dried (Na2S04), filtered and concentrated. The crude product was purified by chromatography (Flashmaster, Hex:EtOAc 4:1 to EtOAc over 25 min) to yield 130 mg (63%) of the title compound as colorless solid. [1 H-NMR (DMSO, 600 MHz, rotamers) 9.20/8.93 (t, 1 H), 8.65-8.83 (m, 1 Η), 8.04-7.96 (m, 2H), 7.70/7.66 (d, 1 Η), 7.62- 7.58 (m, 1 H), 7.55/7.51 (d, 1 H), 7.33-6.90 (m, 7H), 5.05/4.74 (br s, 1 H), 3.66-3.61/3.48-3.43 (m, 1 H), 3.37-3.23 (m, 5H), 3.11/2.93 (s, 3H), 3.01-2.72 (m, 2H), 2.10-1.77 (m, 2H); LCMS RtA = 2.611 min; [M+H]+ = 442.2].
Example 1.2: (S)-N-methyl-N-f 4-f 1 -methyl-1 H-pyrrole-2-carboxamido)-1 -phenylbutan-2- l)imidazori,2-a1pyridine-6-carboxamide
Figure imgf000083_0001
1 -Methyl-1 H-pyrrole-2-carboxylic acid ((S)-3-methylamino-4-phenyl-butyl)-amide
hydrochloride (150 mg, 0.47 mmol), imidazo[1 ,2-a]pyridine-6-carboxylic acid (91 mg, 0.56 mmol), HOBt (86 mg, 0.56 mmol), EDC x HCI (134 mg, 0.70 mmol), and triethylamine (0.33ml, 2.33 mmol) were dissolved in DCM (15 ml) and stirred at rt for 20 h. The mixture was diluted with EtOAc, washed with NaHC03- and NaCI-soln., dried (Na2S04), filtered and concentrated. The crude product was purified by chromatography (Flashmaster, EtOAc 1 min, then EtOAc to EtOAc: MeOH 9:1 over 30 min) to yield 170 mg (85%) of the title compound as colorless solid. [1H-NMR (DMSO, 600 MHz, rotamers) 8.50-7.03 (m, 10H), 6.86 (s, 1 H), 6.83/6.53 (d, 1 H), 6.72/6.64 (s, 1 H), 5.99 (s, 1 H), 4.85/3.35 (br s, 1 H), 3.81/3.65 (s, 3H), 2.98/2.81 (s, 3H), 3.35-3.30/3.16-2.79 (m, 4H), 1.94-1.74 (m, 2H); LCMS RtB = 2.668 min; [M+H]+ = 430.2].
Example 1.3: (S)-6-methyl-N-(3-(N-methyl-1 H-indazole-3-carboxamido)-4- henylbutyl)imidazor2.1-b1thiazole-5-carboxamide
Figure imgf000083_0002
6-Methyl-imidazo[2, 1 -b]thiazole-5-carboxylic acid ((S)-3-methylamino-4-phenyl-butyl)-amide (250 mg, 0.55 mmol), 1 H-indazole-3-carboxylic acid (108 mg, 0.66 mmol), HOBt (102 mg, 0.66 mmol), EDC x HCI (159 mg, 0.83 mmol), and triethylamine (0.46ml, 3.32 mmol) were dissolved in DCM (10 ml) and stirred at rt for 20 h. The mixture was diluted with EtOAc, washed with NaHC03- and NaCI-soln., dried (Na2S04), filtered and concentrated. The crude product was purified by chromatography (Flashmaster, DCM to DCM:MeOH 95:5 over 40 min) to yield 142 mg (53%) of the title compound as off-white solid. [1 H-NMR (DMSO, 600 MHz, rotamers) 13.42/13.38 (s, 1 H), 8.11/7.93 (d, 1 H), 7.63-7.01 (m, 11 H), 5.12 (br s, 1 H), 3.5-2.86 (m, 4H), 3.1 1/3.02 (s, 3H), 2.55/2.29 (s, 3H), 1.99-1.93 (m, 1 H), 1.89-1.66 (m, 1 H); LCMS RtB = 2.934 min; [M+Hf = 487.2].
Example 1.4: (S)-N-methyl-N-(4-M -methyl-1 H-pyrrole-2-carboxamido)-1 -phenylbutan-2- isoquinoline-1 -carboxamide
Figure imgf000084_0001
To a solution of isoquinoline-1-carboxylic acid (43.3 mg, 0.25 mmol) in DMF (0.45 ml) were added solutions of 1-methyl-1 H-pyrrole-2-carboxylic acid ((S)-3-methylamino-4-phenyl-butyl)- amide (65 mg, 0.23 mmol, in 0.2 ml DMF), HATU (130 mg, 0.34 mmol, in 0.25 ml DMF), and DIPEA (59.7 μΙ, 0.34 mmol) and the reaction was stirred at rt over night. MeOH (1 ml) was added and the mixture was filtered. The filter cake was washed with MeOH (1 ml) and the combined solutions were purified by a preparative HPLC system using Waters ZQ MS detection under the following conditions: Waters SunfireTM C-18 column [150 x 30 mm, 5μπι particle size ]; the gradient was composed of eluent A (water containing 0.79 g/L ammonium carbonate) and eluent B (acetonitrile): 0 - 1.5 min (isocratic elution with 80 % A : 20 % B) at 50 ml/min; 1.5 - 10.0 min (linear gradient from 80 % A : 20 % B to 40 % A : 60 % B) at 50 ml/min; 10.0 - 10.1 min (linear gradient from 40 % A : 60 % B to 0 % A : 100 % B) at 50 ml/min; 10.1 - 14.0 min (isocratic elution with 0 % A : 100 % B) at 50 ml/min; The product was collected by MS detection. The solvent was removed by freeze drying to give the title compound as a colorless powder (54 mg, 53%). [1 H-NMR (DMSO, 600 MHz, rotamers) 8.46/8.34 (d, 1 H), 8.02/7.93 (t, 1 H), 7.97 (dd, 1 H), 7.84/7.77 (d, 1 H), 7.74 (dd, 1 H), 7.49-7.34 (m, 5H), 7.05/7.00 (t, 1 H), 6.88 (d, 1 H), 6.77-6.54 (m, 2H), 6.01/5.99 (dd, 1 H), 5.26 (br s, 1 H), 3.85/3.67 (s, 3H), 3.51-3.12 (m, 2H), 3.08-2.84 (m, 2H), 3.12/2.55 (s, 3H), 1.96-1.85/1.57- 1.50 (m, 2H); LCMS Rtc = 1.681/1.935 min (rotamers); [M+H]+ = 441.2; LCMS RtH =
1.27/1.31 min (rotamers); [M+H]+ = 461.6]; Example 1.5: (SWN.1-dimethyl-N-(4-(1-methyl-1H-pyrrole-2-carboxamidoM- phenylbutan-2-yl)-1H-pyrrolor2.3-blPyridine-3-carboxamide
Figure imgf000085_0001
To a solution of 1 -methyl- 1 H-pyrrole-2-carboxylic acid ((S)-3-methylamino-4-phenyl-butyl)- amide hydrochloride (160 mg, 0.497 mmol), 1-methyl-1 H-pyrrolo[2,3-b]pyridine-3-carboxylic acid (127 mg, 0.597 mmol), HOBt (91 mg, 0.597 mmol) and triethylamine (0.345 ml, 2.486 mmol) in DCM (4 ml) and DMF (2 ml) was added EDC x HCI (143 mg, 0.746 mmol). The reaction was stirred at rt overnight. A saturated solution of Na2C03 was added and the resulting mixture was extracted with tert-butyl methyl ether. The organic layer was washed with sat. Na2C03 and brine, dried (MgS0 ), filtered and concentrated. The crude product was purified by flash chromatography (DCM:MeOH, 97:3) followed by purification on a
preparative chromatography system (HPLC Waters 2767, column: Sunfire 19x150mm 5μιη, Grad: 10 to 90% CH3CN with TFA over 15min) to obtain the title compound 104 mg (47 %).
[1 H-NMR (DMSO, 400 MHz, 120 °C) (8.25 (d, 1 H), 7.80 (d, 1 H), 7.45 (br s, 1 H), 7.41 (s, 1 H), 7.25-7.15 (m 6H), 7.05 (dd, 1 H), 6.78 (br s, 1 H), 6.65 (m, 1 H), 5.85 (br s, 1 H), 4.80 (m, 1 H), 3.80 (s, 3H), 3.70 (s, 3H), 3.40-3.05 (m, 2H), 2.97 (s, 3H), 2.95-2.85 (m, 2H), 2.00-1.75 (m, 2H); LCMS RtF = 1.08 min; [M+H]+ = 444.3].
Example 1.6: (S)-N.1 -dimethyl-N-(4-(1 -methvl-1 H-pyrrole-2-carboxamidoH - phenylbutan-2-vQ-1H-indazole-3-carboxamide
Figure imgf000085_0002
To a solution of 1 -methyl- 1H-pyrrole-2-carboxylic acid ((S)-3-methylamino-4-phenyl-butyl)- amide hydrochloride (160 mg, 0.497 mmol), 1 -methyl- 1 H-indazole-3-carboxylic acid
(107 mg, 0.597 mmol), HOBt (91 mg, 0.597 mmol) and triethylamine (0.345 ml, 2.49 mmol) in DCM (5 ml) was added EDC x HCI (1 14 mg, 0.746 mmol). The reaction was stirred at rt for 18 h. The mixture was diluted with DCM and washed with sat. Na2C03 and brine, dried (MgS04), filtered and concentrated. Purification by flash chromatography (DCM:MeOH, 97:3) gave the title compound (97 mg, 45%). [1H-NMR (DMSO, 600 MHz, rotamers) 7.97 - 7.88 (d, 1 H), 7.68-7.52 (m, 3H), 7.29-7.13 (m, 5H), 7.16-7.11 (m, 1 H), 6.88-6.83 (d, 1 H), 6.74-6.60 (d, 1 H), 6.01-5.95 (dd, 1H), 5.10 (m, 1 H), 3.98/4.07 (s, 3H), 3.81/3.69 (s, 3H), 3.86-2.86 (m, 4H), 3.09/2.98 (s, 3H), 1.96-1.66 (m, 2H); LCMS RtF = 1.24 min; [M+H]+ = 444.4].
Example 1.7: f S)-N.1 ,5-trimethyl-N-(4-(1 -methvl-1 H-pyrrole-2-carboxamido)-1 - phenylbutan-2-yl)-1H-indazole-3-carboxamide
Figure imgf000086_0001
1-Methyl-1 H-pyrrole-2-carboxylic acid ((S)-3-methylamino-4-phenyl-butyl)-amide hydrochloride (100 mg, 0.31 mmol), 1 ,5-dimethyl-1H-indazole-3-carboxylic acid (59 mg, 0.31 mmol), HOBt (71 mg, 0.476 mmol), EDC x HCI (72 mg, 0.37 mmol), and triethylamine (0.108 ml, 0.78 mmol) were dissolved in DCM (5 ml) and stirred at rt for 5 h. The mixture was concentrated, redissolved in EtOAc, washed with sat. NaHCCv and NaCI-soln., dried (Na2S04), filtered and concentrated. The crude product was purified by chromatography (Biotage, DCM to DCM:MeOH 95:5 over 10 min) to yield 131 mg (90 %) of the title compound as white solid. [1 H-NMR (DMSO, 600 MHz, rotamers) 7.93 (d, 1H), 7.53 (dd, 1 H), 7.33-7.28 (m, 3H), 7.26-7.19 (m, 2H), 7.11-7.04 (m, 2H), 6.86 (d, 1 H), 6.67 (d, 1H), 5.98 (d, 1H), 5.10-5.02 (m, 1H), 4.04, 3.95 (2s, 3H), 3.82, 3.70 (2s, 3H), 3.05, 2.98 (2s, 3H), 3.24- 3.16 (m, 1H), 3.00-2.95 (m, 1H), 2.91-2.88 (m, 2H), 2.36 (s, 3H), 1.94-1.63 (m, 2H); UPLCMS Rt, = 1.29 min; [M+H]+ = 458.3].
Example 1.8: (S)-2-methoxy-N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1- phenylbutan-2-yl)quinoline-4-carboxamide
Figure imgf000087_0001
1-Methyl-1H-pyrrole-2-carboxylic acid ((S)-3-methylamino-4-phenyl-butyl)-amide hydrochloride (130 mg, 0.392 mmol), 2-methoxy-quinoline-4-carboxylic acid (90 mg, 0.439 mmol), HATU (167 mg, 0.435 mmol), and diisopropylethylamine (0.29 ml, 1.646 mmol) were dissolved in acetonitrile (1 ml) and stirred at 100 °C for 6 min in the microwave. The mixture was diluted with EtOAc, washed with NaHC03- and NaCI-solution, dried (Na2S04), filtered and concentrated. The crude product was purified by flash chromatography (EtOAc: heptane 2:1 to 3:1) to yield 107 mg (58 %) of the title compound as colorless solid. [1 H-NMR (DMSO, 600 MHz, rotamers) 8.06 - 7.17 (m, 8H), 7.17 - 6.31 (m, 5H), 6.13 - 5.86 (m, 1 H), 5.28 (br s, 1 H), 3.96 (s, 3H), 3.83 (s, 3H), 3.76 - 3.63 (m, 2H), 3.17 - 2.96 (m, 2H), 2.93 -2.69 (m, 1 H), 2.59 - 2.52 (m, 2H), 1.97 - 1.83 (m, 2H); LCMS RtF = 1.35 min; [M+H]+ = 471.3].
Examples 1.9 to 1.102:
Examples 1.9 to 1.102, as mentioned below, were prepared or can be prepared in analogy to the methods described for Examples 1.1 to 1.8 using the appropriate starting materials or intermediates.
Example 1.9: (S)-5-fluoro-N-methyl-N-(4-i1-methyl-1H-pyrrole-2-carboxamido)-1- henylbutan-2-yl)-1H-indole-2-carboxamide
Figure imgf000087_0002
Obtained in analogy to Example 1.4. [LCMS RtH = 1.42 min; [M+H]+ = 447.6]
Example 1.10: (S)-N-methyl-N-(4-f 1 -methyl-1 H-pyrrole-2-carboxamido)-1 -phenylbutan- 2-yl)quinazoline-4-carboxamide
Figure imgf000088_0001
Obtained in analogy to Example 1.4 using NMP as solvent instead of acetonitrile. [LCMS RtF = 1.09/1.14 min (rotamers); [M+H]+ = 442.3]
Example 1.11 : (S)-N-methyl-N-(4-(1-methyl-1H-pyrrole-2-carboxamido)-1-phenylbutan- 2- imidazori.5-alPyridine-6-carboxamide
Figure imgf000088_0002
Obtained in analogy to Example 1.2. [LCMS RtB = 2.689 min; [M+H]+ = 430.2]
Example 1.12: (S)-N-methyl-N-(4-( 1 -methyl-1 H-pyrrole-2-carboxamido)-1 -phenylbutan- -vh-1H-pyrrolor2.3-b1pyridine-3-carboxamide
Figure imgf000088_0003
Obtained in analogy to Example 1.2. [LCMS RtB = 2.837 min; [M+H]+ = 430.2]
Example 1.13: (S)-N-methyl-N-f 4-(1 -methyl-1 H-pyrrole-2-carboxamidoH -phenylbutan- -yl)-1 H-indazole-3-carboxamide
Figure imgf000088_0004
Obtained in analogy to Example 1.2. [LCMS RtB Example 1.14: (S)-6-methyl-N-(3-(N-methyl-1H-pyrrolor2.3-blpyridine-3-carboxamido)-4- henylbutyl)imidazor2.1-b1thiazole-5-carboxamide
Figure imgf000089_0001
Obtained in analogy to Example 1.3. [LCMS RtB = 2.626 min; [M+H]+ = 487.2]
Example 1.15: f S)-N.2-dimethyl-N-(4-( 1 -methyl-1 H-pyrrole-2-carboxamidoH■ phenylbutan-2-yl)pyrazolon.5-a1pyridine-3-carboxamide
Figure imgf000089_0002
Obtained in analogy to Example 1.2. [LCMS RtA = 2.600 min; [M+H]+ = 444.2]
Example 1.16: (S)-N,4.7-trimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1 - phenylbutan-2-yl)pyrazolor5.1-cin.2.41triazine-3-carboxamide
Figure imgf000089_0003
Obtained in analogy to Example 1.2. [LCMS RtA = 2.578 min; [M+H]+ = 460.2]
Example 1.17: (S)-5-methoxy-N-methyl-N-(4-(1 -methyl -1 H-pyrrole-2-carboxamido)-1 - phenylbutan-2-yl)pyrazolori.5-alpyridine-3-carboxamide
Figure imgf000089_0004
Obtained in analogy to Example 1.2. [LCMS RtA = 2.596 min; [M+H]+ = 460.2] Example 1.18: fS)-N-methyl-N-(4-(1-methyl-1H-pyrrole-2-carboxamido)-1-phenylbutan- 2- l)imidazon.2-alPyridine-7-carboxamide
Figure imgf000090_0001
Obtained in analogy to Example 1.2. [LCMS RtB = 2.654 min; [M+H]+ = 430.2]
Example 1.19: (S)-N-methyl-N-(4-(1-methyl-1H-pyrrole-2-carboxamido)-1-phenylbutan- -yl)benzord1isoxazole-3-carboxamide
Figure imgf000090_0002
Obtained in analogy to Example 1.2. [LCMS Rtc = 2.578 min; [M+H]+ = 431.2]
Example 1.20: (S)-N,1 -dimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1 - phenylbutan-2-yl)-1H-pyrazolof3.4-b1pyridine-3-carboxamide
Figure imgf000090_0003
Obtained in analogy to Example 1.2. [LCMS RtA = 2.581 min; [M+H]+ = 445.2]
Example 1.21 : (S)-N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan- 2-yl)furor2.3-clPyridine-5-carboxamide
Figure imgf000090_0004
Obtained in analogy to Example 1.2. [LCMS RtA = 2.321 min; [M+H]+ = 431.2]
Example 1.22: (S)-1-methyl-N-(3-(N-methylbenzofuran-3-carboxamido)-4-phenylbutyl)- 1 H-pyrrole-2-carboxamide
Figure imgf000091_0001
Obtained in analogy to Example 1.2. [UPLCMS Rt, = 1.268 min; [M+H]+ = 430.3]
Example 1.23: f S)-N.1 -dimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamidoM■ henylbutan-2-yl)-1H-indole-2-carboxamide
Figure imgf000091_0002
Obtained in analogy to Example 1.4. [LCMS RtH = 1.45 min; [M+H]+ = 443.6]
Example 1.24: (S)-N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1 -phenylbutan- 2- l)-1H-benzord1imidazole-2-carboxamide
Obtained in analogy to Example 1.4. [LCMS RtH = 1.29 min; [M+H]+ = 430.6]
Example 1.25: (S)-5-fluoro-N-methyl-N-f4-f 1 -methyl-1 H-pyrrole-2-carboxamido)-1 - phenylbutan-2-yl)-1H-indazole-3-carboxamide
Figure imgf000092_0001
Obtained in analogy to Example 1.4. [LCMS RtH = 1.29 min; [M+H]+ = 448.6]
Example 1.26: (S)-5-methoxy-N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1 · phenylbutan-2-yl)-1H-indazole-3-carboxamide
Figure imgf000092_0002
Obtained in analogy to Example 1.4. [LCMS RtH = 1.26 min; [M+H]+ = 460.6]
Example 1.27: f S)-6-fluoro-N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamidoH■ phenylbutan-2-vO-1H-indazole-3-carboxamide
Figure imgf000092_0003
Obtained in analogy to Example 1.4. [LCMS RtH = 1.3 min; [M+H]+ = 448.6]
Example 1.28: (S)-N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1 -phenylbutan- 2- inoline-2-carboxamide
Figure imgf000092_0004
Obtained in analogy to Example 1.4. [LCMS RtH = 1.29 min; [M+H]+ = 441.6] Example 1.29: (S)-N -methyl -N-(4-(1 -methyl-1 H-pyrrole-2-carboxamidoM-phenylbutan- 2-yl)cinnoline-4-carboxamide
Figure imgf000093_0001
Obtained in analogy to Example 1.4. [LCMS RtH = 1.04 / 1.20 min (rotamers); [M+H]+ 442.6]
Example 1.30: (S)-N.2.7-trimethyl-N-(4-M -methyl-1 H-pyrrole-2-carboxamido)-1 - phenylbutan-2-yl)pyrazolon.5-alpyrimidine-6-carboxamide
Figure imgf000093_0002
Obtained in analogy to Example 1.4. [LCMS RtH = 1.18 min; [M+H]+ = 459.6]
Example 1.31 : (S)-N.2.7-trimethyl-N-(4-( 1 -methyl-1 H-pyrrole-2-carboxamido)-1 · phenylbutan-2-yl)imidazoM,2-a1pyridine-3-carboxamide
Figure imgf000093_0003
Obtained in analogy to Example 1.4. [LCMS RtH = 1.02 min; [M+H]+ = 458.6]
Example 1.32: (S)-N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1 -phenylbutan-
2-yl)-1.6-naphthyridine-2-carboxamide
Figure imgf000093_0004
Obtained in analogy to Example 1.4. [LCMS RtH = 0.95 / 1.06 min (rotamers); [M+H]+ = 442.6]
Example 1.33: (S)-N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1 -phenylbutan- 2-yl)pyrazolori.5-alpyridine-3-carboxamide
Figure imgf000094_0001
Obtained in analogy to Example 1.4. [LCMS RtH = 1.19 min; [M+H]+ = 430.6]
Example 1.34: (S)-N.1 -dimethyl-N-(4-( 1 -methyl-1 H-pyrrole-2-carboxamido)-1■ phenylbutan-2-yl)-1H-indole-3-carboxamide
Figure imgf000094_0002
Obtained in analogy to Example 1.4. [LCMS RtH = 1.37 min; [M+H]+ = 443.6]
Example 1.35: (S)-5.7-difluoro-N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamidoM■ phenylbutan-2-yl)-1H-indole-2-carboxamide
Figure imgf000094_0003
Obtained in analogy to Example 1.4. [LCMS RtH = 1.44 min; [M+H]+ = 465.6]
Example 1.36: (S)-N-methvl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1 -phenylbutan- 2-yl)-1 H-indole-3-carboxamide
Figure imgf000095_0001
Obtained in analogy to Example 1.4. [LCMS RtH = 1.28 min; [M+H]+ = 429.6]
Example 1.37: (S)-N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan- -yl)quinoline-3-carboxamide
Figure imgf000095_0002
Obtained in analogy to Example 1.4. [LCMS RtH = 1.13 min; [M+H]+ = 441.6]
Example 1.38: (S)-N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1 -phenylbutan- 2- l)quinoline-4-carboxamide
Figure imgf000095_0003
Obtained in analogy to Example 1.4. [LCMS RtH = 0.99 / 1.12 min (rotamers); [M+H]+ = 441.6]
Example 1.39: (S)-N-methyl-N-(4-f1 -methyl-1 H-pyrrole-2-carboxamidoH-phenylbutan- -yl)quinoxaline-2-carboxamide
Figure imgf000095_0004
Obtained in analogy to Example 1.4. [LCMS RtH = 1.23 min; [M+H]+ = 442.6] Example 1.40: (S)-N.5-dimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1- henylbutan-2-yl)-1H-indole-2-carboxamide
Figure imgf000096_0001
Obtained in analogy to Example 1.4. [LCMS RtH = 1 47 min; [M+H]+ = 443.6]
Example 1.41 : (S)-N-(3-fN.3-dimethylbenzofuran-2-carboxamido)-4-phenylbutyl)-1- meth l-1 H-pyrrole-2-carboxamide
Figure imgf000096_0002
Obtained in analogy to Example 1.4. [LCMS RtH = 1.47 min; [M+H]+ = 444.6]
Example 1.42: f S)-N-methyl-N-f 4-f 1 -methyl-1 H-pyrrole-2-carboxamido)-1 -phenylbutan- 2- l)isoquinoline-3-carboxamide
Figure imgf000096_0003
Obtained in analogy to Example 1.4. [LCMS RtH = 1.24 min; [M+H]+ = 441.6]
Example 1.43: (S)-N-methyl-N-f 4-f 1 -methyl-1 H-pyrrole-2-carboxamidoH-phenylbutan- 2-νΙ)-Γ1.2.41triazoloM .5-alpyrimidine-2-carboxamide
Figure imgf000097_0001
Obtained in analogy to Example 1.4. [LCMS RtH = 1.04 / 1.09 min (rotamers); [M+H]+ 432.6]
Example 1.44: (S)-N.2.8-trimethyl-N-(4-M -methyl-1 H-pyrrole-2-carboxamidoH - henylbutan-2-yl)imidazori.2-alpyridine-3-carboxamide
Figure imgf000097_0002
Obtained in analogy to Example 1.4. [LCMS RtH = 1.01 min; [M+H]+ = 458.6]
Example 1.45: (S)-N.5.7-trimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamidoM - henylbutan-2-yl)pyrazolori.5-a1pyrimidine-2-carboxamide
Figure imgf000097_0003
Obtained in analogy to Example 1.4. [LCMS RtH = 1. 6 min; [M+H]+ = 459.7]
Example 1.46: (S)-N.5-dimethyl-N-(4-M -methyl-1 H-pyrrole-2-carboxamidoM- phenylbutan-2-yl)-1H-indazole-3-carboxamide
Figure imgf000097_0004
Obtained in analogy to Example 1.4. [LCMS RtH = 1.32 min; [M+H]+ = 444.6] Example .47: (S)-N-methyl-N-f 4-f 1 -methyl-1 H-pyrrole-2-carboxamidoH -phenylbutan- 2- l)-1H-pyrrolor2.3-blpyridine-4-carboxamide
Figure imgf000098_0001
Obtained in analogy to Example 1.4. [LCMS RtH = 1.04 min; [M+H]+ = 430.6]
Example 1.48: f S)-5-methoxy-N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1 - phenylbutan-2-yl)-1 H-indole-2-carboxamlde
Figure imgf000098_0002
Obtained in analogy to Example 1.4. [LCMS RtH = 1.37 min; [M+H]+ = 459.6]
Example 1.49: (S)-6-chloro-N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamidoM - henylbutan-2-yl)imidazoM.2-alpyridine-2-carboxamide
Figure imgf000098_0003
Obtained in analogy to Example 1.4. [LCMS RtH = 1.19 min; [M+H]+ = 464.6]
Example 1.50: (S)-N.2-dimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1 - phenylbutan-2-yl)-1.6-naphthyridine-3-carboxamide
Figure imgf000099_0001
Obtained in analogy to Example 1.4. [LCMS RtH = 0.91 / 1.04 min (rotamers); [M+H]+ = 456.6]
Example 1.51 : (S)-N-methyl-N-(4-(1 -methvl-1 H-pyrrole-2-carboxamido)-1-phenylbutan- -yl)imidazori.2-alPyridine-3-carboxamide
Figure imgf000099_0002
Obtained in analogy to Example 1.2. [LCMS RtB = 2.753 min; [M+H]+ = 430.2]
Example 1.52: (S)-N.7-dimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamidoH■ henylbutan-2-vhimidazon.2-alpyridine-6-carboxamid
Figure imgf000099_0003
Obtained in analogy to Example 1.2. [LCMS RtB = 2.630 min (broad, rotamers); [M+H]+ 444.2]
Example 1.53: (S)-N.2-dimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1 - henylbutan-2-yl)quinoline-4-carboxamide
Figure imgf000099_0004
Obtained in analogy to Example 1.8. [LCMS RtB = 0.99/1.14 min rotamers); [M+Hf = 455.3] Example 1.54: (S)-2-chloro-N-methyl-N-(4-(1-methyl-1H-pyrrole-2-carboxamido)-1- phenylbutan-2-yl)quinoline-4-carboxamide
Figure imgf000100_0001
Obtained in analogy to Example 1.8. [LCMS RtB = 1.20/1.32 min rotamers); [M+H]+
Example 1.55: (S)-N.8-dimethyl-N-(4-M -methvl-1 H-pyrrole-2-carboxamido)-1 - phenylbutan-2-yl)imidazon.2-alPyridine-2-carboxamide
Figure imgf000100_0002
Obtained in analogy to Example 1.2. [LCMS RtB = 2.818 min; [M+H]+ = 444.2]
Example 1.56: (S)-N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan- 2- l)furor3.2-blpyridine-5-carboxamide
Figure imgf000100_0003
Obtained in analogy to Example 1.8. [1H-NMR (DMSO, 600 MHz, rotamers) 8.39/8.33 (s, 1 H), 8.09/7.87 (d, 1H), 7.96/7.91 (t, 1 H), 7.33-7.05 (m, 6H), 7.09/6.61 (d, 1 H), 6.87/6.85 (2, 1 H), 6.73-6.71/6.58-6.56 (m, 1 H), 5.99/5.95 (t, 1H), 4.32/3.90 (br s, 1H), 3.82/3.72 (s, 3H), 3.33-2.75 (m, 4H), 2.99/2.75 (s, 3H), 1.92-1.62 (m, 2H); LCMS RtA = 2.455 min; [M+H]+ = 431.2].
Example 1.57: (S)-N.1.3-trimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1 - phenylbutan-2-yl)-1H-thienor2.3-c1pyrazole-5-carboxamide
Figure imgf000101_0001
Obtained in analogy to Example 1.8. [1H-NMR (DMSO, 600 MHz, 120°C) 7.44 (br s, 1H), 7.28-7.16 (m, 5H), 6.96 (s, 1 H), 6.77 (dd, 1 H), 6.62 (dd, 1H), 5.97 (dd, 1 H), 4.74-4.67 (m, 1 H), 3.81 (s, 3H), 3.78 (s, 3H), 3.38-3.29 (m, 1 H), 3.17-3-09 (m, 1 H), 3.05 (s, 3H), 2.94-2.92 (m, 2H), 2.30 (s, 3H), 2.01-1.81 (m, 2H); LCMS RtA = 2.455 min; [M+H]+ = 431.2].
Example 1.58: (S)-5-chloro-N-methyl-N-(4-(1-methyl-1H-pyrrole-2-carboxamido)-1- henylbutan-2-yl)imidazori.2-a1pyridine-2-carboxamide
Figure imgf000101_0002
Obtained in analogy to Example 1.2. [LCMS RtB = 3.143 min; [M+H]+ = 464.2]
Example 1.59: (S)-N.6-dimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1 - phenylbutan-2-yl)furor2.3-blPyridine-5-carboxamide
Figure imgf000101_0003
Obtained in analogy to Example 1.8. [LCMS RtB = 3.257 min; [M+H]+ = 445.2]
Example 1.60: (S)-N.2-dimethyl-N-(4-(1-methyl-1H-pyrrole-2-carboxamido)-1- phenylbutan-2-yl)imidazori,2-a1pyridine-3-carboxamide
Figure imgf000102_0001
Obtained in analogy to Example 1.8. [LCMS RtB = 2.814 min; [M+H]+ = 444.2]
Example 1.61 : (S)-N-methyl-N-(4-(1-methyl-1H-pyrrole-2-carboxamido)-1-phenylbutan- 2- l)imidazori.2-alpyridine-8-carboxamide
Figure imgf000102_0002
Obtained in analogy to Example 1.2. [LCMS RtB = 2.662 min; [M+H]+ = 430.2]
Example 1.62: (S)-N-methyl-N-(4-(1-methyl-1H-pyrrole-2-carboxamido)-1-phenylbutan- 2- l)imidazon.2-alpyridine-5-carboxamide
Obtained in analogy to Example 1.2. [LCMS RtB = 2.690 min; [M+H]+ = 430.2]
Example 1.63: (S)-N,6-dimethyl-N-(4-(1-methyl-1H-pyrrole-2-carboxamido)-1- henylbutan-2-yl)imidazor2.1-b1thiazole-5-carboxamide
Figure imgf000102_0004
Obtained in analogy to Example 1.2. [LCMS RtB = 2.873 min; [M+H]+ = 450.2] Example 1.64: (S)-N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1 -phenylbutan- 2- l)imidazor2.1-b1thiazole-6-carboxamide
Figure imgf000103_0001
Obtained in analogy to Example 1.2. [LCMS RtB = 3.059 min; [M+H]+ = 436.2]
Example 1.65: (S)-N,2.3-trimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1 - phenylbutan-2-yl)imidazor2.1-b1thiazole-6-carboxamide
Figure imgf000103_0002
Obtained in analogy to Example 1.2. [LCMS RtB = 3.226 min; [M+H]+ = 464.2]
Example 1.66: fS)-N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1 -phenylbutan- 2- l)-1.8-naphthyridine-4-carboxamide
Figure imgf000103_0003
Obtained in analogy to Example 1.2. [LCMS RtB = 2.695/2.955 min (rotamers); [M+H]+ = 442.2]
Example 1.67: (S)-7-methoxy-N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1- phenylbutan-2-yl)isoquinoline-4-carboxamide
Figure imgf000104_0001
Obtained in analogy to Example 1.8. [LCMS RtB = 2.761/3.014 min (rotamers); [M+H]+ = 471.2]
Example 1.68: (S)-N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1 -phenylbutan- -yl)furor2.3-blpyridine-5-carboxamide
Figure imgf000104_0002
Obtained in analogy to Example 1.8. [LCMS RtB = 3.157 min; [M+H]+ = 431.2]
Example 1.69: S)-N.6-dimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamidoH · henylbutan-2-yl)furor3.2-blpyridine-5-carboxamide
Figure imgf000104_0003
Obtained in analogy to Example 1.8. [LCMS RtA = 2.608/2.803 min (rotamers); [M+H]+ 445.2]
Example 1.70: (S)-6-bromo-N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1■ phenylbutan-2-yl)imidazof1.2-alpyridine-7-carboxamide
Figure imgf000104_0004
Obtained in analogy to Example 1.2. [LCMS RtB = 2.592/2.844 min (rotamers); [M+H]+ 508.0/510.0] Example 1.71 : S)-N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamidoH -phenylbutan- 2- l)imidazor2.1-b1thiazole-5-carboxamide
Figure imgf000105_0001
Obtained in analogy to Example 1.2. [LCMS RtA = 1.581 min; [M+H]+ = 436.2]
Example 1.72: (S)-N-methyl-N-f 4-f 1 -methyl-1 H-pyrrole-2-carboxamido)-1 -phenylbutan- -yl)isoquinoline-4-carboxamide
Figure imgf000105_0002
Obtained in analogy to Example 1.8. [LCMS RtB = 2.715/2.956 min (rotamers); [M+H]+ 441.2]
Example 1.73: (S)-N.2,6-trimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1 - henylbutan-2-yl)imidazor2.1-bin.3,4 hiadiazole-5-carboxamide
Figure imgf000105_0003
Obtained in analogy to Example 1.2. [LCMS RtA = 2.168 min; [M+H]+ = 465.2]
Example 1.74: (S)-N.4-dimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1■ phenylbutan-2-yl)-4H-furor3.2-b1pyrrole-5-carboxamide
Figure imgf000105_0004
Obtained in analogy to Example 1.2. [LCMS RtA = 2.958 min; [M+H]+ = 433.2]
Example 1.75: (S)-N.2-dimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1■ phenylbutan-2-yl)imidazor2.1-bin.3.41thiadiazole-6-carboxamide
Figure imgf000106_0001
Obtained in analogy to Example 1.8. [LCMS RtA = 2.419 min; [M+H]+ = 451.2]
Example 1.76: (S)-N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1 -phenylbutan- -yl)imidazon.2-alpyrimidine-2-carboxamide
Figure imgf000106_0002
Obtained in analogy to Example 1.2. [LCMS RtB = 2.783 min; [M+H]+ = 431.2]
Example 1.77: (S)-N.1.5-trimethyl-N-(4-(1 -methyl-1 H-benzofdl imidazole-2- carboxamido)-1-phenylbutan-2-yl)-1H-indazole-3-carboxamide
Figure imgf000106_0003
Obtained in analogy to Example 1.2. [LCMS Rtj = 1.22 min; [M+H]+ = 509.2]
Example 1.78: (S)-1-methyl-N-(3-(N-methylbenzofuran-3-carboxamido)-4-phenylbutvH-
1H-benzofd1imidazole-2-carboxamide
Figure imgf000107_0001
Obtained in analogy to Example 1.2. [LCMS Rtj = 1.17 min; [M+H]+ = 481.2]
Example 1.79: (S)-N-f 4- -ethyl-3-methyl-1 H-pyrazole-5-carboxamido)-1 -phenylbutan-2- l)-N-methylfuror2.3-c1pyridine-5-carboxamide
Figure imgf000107_0002
Obtained in analogy to Example 1.2. [LCMS Rtj = 0.94 min; [M+H]+ = 460.4]
Example 1.80: (S)-1-ethyl-3-methyl-N-(3-(N-methylbenzofuran-3-carboxamido)-4- henylbutyl)-1H-pyrazole-5-carboxamide
Figure imgf000107_0003
Obtained in analogy to Example 1.2. [LCMS Rtj = 1.09 min; [M+H]+ = 459.4]
Example 1.81: (S)-N-(4-(1 -ethyl-3-methyl-1 H-pyrazole-5-carboxamido)-1 -phenylbutan-2- l)-N.1.5-trimethyl-1H-indazole-3-carboxamide
Figure imgf000107_0004
Obtained in analogy to Example 1.2. [LCMS Rtj = 1.12 min; [M+H]+ = 487.4] Example 1.82: (S)-N-(4-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1-phenylbutan-2- -N-methylfuror2.3-b1pyridine-5-carboxamide
Figure imgf000108_0001
Obtained in analogy to Example 1.2. [LCMS Rtj = 0.91 min; [M+H]+ = 460.4]
Example 1.83: (S)-N.1 -dimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1 - henylbutan-2-yl)-1H-pyrrolor2.3-blpyridine-4-carboxamide
Figure imgf000108_0002
Obtained in analogy to Example 1.2. [LCMS Rtj = 0.98 min; [M+H]+ = 444.2]
Example 1.84: (S)-N-(4-(1 -ethyl-3-methyl-1 H-pyrazole-5-carboxamido)-1 -phenylbutan-2- l)-N-methylisoquinoline-1-carboxamide
Figure imgf000108_0003
2-Ethyl-5-methyl-2H-pyrazole-3-carboxylic acid ((S)-3-methylamino-4-phenyl-butyl)-amide (60 mg, 0.155 mmol), isoquinoline-1-carboxylic acid (29.5 mg, 0.17 mmol), and DIPEA (0.135 ml, 0.775 mmol) were dissolved in DCM (1 ml. T3P (50% in EtOAc, 0.055 ml, 0.385 mmol) was added and the reaction was stirred over night at rt. The solvents were evaporated under reduced pressure and the residue was purified by preparative HPLC (Waters HPLC 2767, sunfire 19x150mm 5μηι, eluent water and acetonitrile with TFA, grade from 5% to 90% acetonitrile over 15 min). The crude product was dissolved in DCM, filtered through a Varian PL-HC03 MP column (0.18 mmol), and the solvent was evaporated to obtain the product as colorless solid. [1 H-NMR (DMSO, 600 MHz, rotamers) 8.45-8.30 (m, 1 H), 7.96 (d, 1 H), 7.84/7.77 (d, 1 H), 7.74 (dd, 1 H), 7.47-7.31 (m, 5H), 7.06/7.00 (t, 1 H), 7.65 (d)/6.53 (br s) (1 H), 6.69/6.41 (s, 1 H), 5.36 (br s, 1 H), 4.44-4.21 (m, 3H), 3.53-3.24 (m, 2H), 3.11/2.54 (s, 3H), 3.07-2.84 (m, 2H), 2.16/2.15 (s, 3H), 1.97-1.88/1.61-1.55 (m, 2H), 1.28/1.16 (t, 3H); LCMS Rtj = 1.02/1.07 min (rotamers); [M+H]+ = 470.2].
Example 1.85: (S)-N-(4-(1 -ethyl-3-methyl-1 H-pyrazole-5-carboxamido)-1 -phenylbutan-2- l)-N.1.3-trimethyl-1H-thienor2.3-clpyrazole-5-carboxamide
Figure imgf000109_0001
Obtained in analogy to Example 1.84. [LCMS Rtj = 0.98 min; [M+H]+ = 493.2]
Example 1.86: (S)-N-(4-(1 -ethyl-3-methyl-1 H-pyrazole-5-carboxamidoM -phenylbutan-2- l)-N-methylisoquinoline-4-carboxamide
Figure imgf000109_0002
Obtained in analogy to Example 1.84. [LCMS Rtj = 0.96 min; [M+H]+ = 470.2]
Example 1.87: (S)-N-(4-(1 -ethyl-3-methyl-1 H-pyrazole-5-carboxamido)-1 -phenylbutan-2 - l)-N.2-dimethylpyrazolon.5-alpyridine-3-carboxamide
Figure imgf000109_0003
Obtained in analogy to Example 1.84. [LCMS RtB = 0.99 min; [M+H]+ = 473.3] Example 1.88: (S)-N-(4-(1 -ethyl-3-methyl-1 H-pyrazole-5-carboxamido)-1 -phenylbutan-2- -N-methylimidazoM.2-alPyridine-5-carboxamide
Figure imgf000110_0001
Obtained in analogy to Example 1.8. [LCMS Rtj = 0.75 min; [M+H]+ = 459.3]
Example 1.89: (S)-6-methyl-N-(3-(N-methylbenzofuran-3-carboxamido)-4- phenylbutvDpicolinamide
Figure imgf000110_0002
Obtained in analogy to Example 1.2. [LCMS Rtj = 1.12 min; [M+H]+ = 442.2]
Example 1.90: (S)-N.1.5-trimethyl-N-f 4-(6-methylpicolinamido)-1 -phenylbutan-2-ylH H- indazole-3-carboxamide
Figure imgf000110_0003
Obtained in analogy to Example 1.2. [LCMS Rtj = 1.16 min; [M+H]+ = 470.2]
Example 1.91 : (S)-N.2-dimethyl-N-(4-(6-methylpicolinamido)-1-phenylbutan-2- razolori .5-alpyridine-3-carboxamide
Figure imgf000110_0004
Obtained in analogy to Example 1.2. [LCMS Rtj = 1.00 min; [M+H]+ = 456.2] Example 1.92: (S)-6-methoxy-N-(3-(N-methylbenzofuran-3-carboxamido)-4- phenylbutvDpicolinamide
Figure imgf000111_0001
Obtained in analogy to Example 1.2. [LCMS Rtj = 1.15 min; [M+H]+ = 458.1]
Example 1.93: (S)-N-(4-(6-methoxypicolinamido)-1 -phenylbutan-2-yl)-N.1.5-trimethyl- -indazole-3-carboxamide
Figure imgf000111_0002
Obtained in analogy to Example 1.2. [LCMS Rtj = 1.17 min; [M+H]+ = 486.2]
Example 1.94: f S)-N-(4-(6-methoxypicolinamido)-1 -phenylbutan-2-yl)-N.2- d i methyl pyrazolon .5-al pyrid i ne-3-carboxam ide
Figure imgf000111_0003
Obtained in analogy to Example 1.2. [LCMS Rtj = 1.04 min; [M+H]+ = 486.2]
Example 1.95: (S)-5-(4-fluorophenyl)-N.2-dimethyl-N-(4-(1-methyl-1 H-pyrrole-2- carboxamido)-1-phenylbutan-2-yl)thiazole-4-carboxamide
Figure imgf000112_0001
Obtained in analogy to Example 1.8. with acetonitrile as solvent. [LCMS Rtj = 1.22 min; [M+H]+ = 505.2]
Example 1.96: fS)-N,5.7-trimethyl-N-(4-i1-methyl-1H-pyrrole-2-carboxamido)-1- phenylbutan-2-yl)pyrazolori,5-a1pyrimidine-3-carboxamide
Figure imgf000112_0002
Obtained in analogy to Example 1.2. [LCMS RtA = 2.195 min; [M+H]+ = 459.2]
Example 1.97: (S)-N.3-dimethyl-N-(4-(1-methyl-1 H-pyrrole-2-carboxamido)-1- henylbutan-2-yl)-5-phenylisoxazole-4-carboxamide
Figure imgf000112_0003
Obtained in analogy to Example 1.4. [LCMS RtH = 1.45 min; [M+H]+ = 471.6]
Example 1.98: (fS)-N-methyl-N-(4-(1-methyl-1H-pyrrole-2-carboxamido)-1-phenylbutan- 2-yl)imidazof1.2-alpyridine-2-carboxamide
Figure imgf000112_0004
Obtained in analogy to Example 1.4. [LC S RtH = 1.06 min; [M+H]+ = 431.6]
Example 1.99: (S)-N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1 -phenylbutan- -yl)pyrazolori.5-alpyrimidine-3-carboxamide
Figure imgf000113_0001
Obtained in analogy to Example 1.4. [LCMS RtH = 0.096 min; [M+H]+ = 430.6]
Example 1.100: (S)-3-bromo-5-chloro-N-methyl-N-(4-M -methyl-1 H-pyrrole-2- carboxamido)-1-phenylbutan-2- l)imidazori.2-alpyridine-2-carboxamide
Figure imgf000113_0002
Obtained in analogy to Example 1.2. [LCMS RtB = 3.524 min; [M+H]+ = 542.0/544.0]
Example 1.101 : (S)-N-(4-(1 -ethyl-3-methyl-1 H-pyrazole-5-carboxamido)-1 -phenylbutan- 2- l)-N,6-dimethylfuror2.3-b1pyridine-5-carboxamide
Figure imgf000113_0003
Obtained in analogy to Example 1.2. [LCMS Rtj = 0.95 min; [M+H]+ = 474.2]
Example 1.102: ((S)-1 -methyl-N-(4-phenyl-3-(N.5.6-trimethylbenzofuran-3- carboxamido)butyl)-1H-pyrrole-2-carboxamide
Figure imgf000114_0001
Example 2.1 : (S)-N-(4-phenyl-3-(N.2.3-trimethylbenzofuran-6- carboxamido butyl)picolinamide
Figure imgf000114_0002
Pyridine-2-carboxylic acid ((S)-3-methylamino-4-phenyl-butyl)-amide hydrochloride (250 mg, 0.78 mmol), 2,3-dimethyl-benzofuran-6-carboxylic acid (178 mg, 0.94 mmol), HOBt (144 mg, 0.94 mmol), EDC x HCI (225 mg, 1.17 mmol), and triethylamine (0.44 ml, 3.1 mmol) were dissolved in DCM (20 ml) and the reaction was stirred at rt for 20 h. The mixture was diluted with EtOAc, washed with NaHC03- and NaCI-soln., dried (Na2S04), filtered and
concentrated. The crude product was purified by chromatography (Flashmaster, Hex:EtOAc 4:1 to Hex:EtOAc 1 :9 over 30 min; Hex:EtOAc 1 :9 for 10 min) to yield 255 mg (72%) of the title compound as colorless solid. [1 H-NMR (DMSO, 600 MHz, rotamers) 8.93/8.78 (t, 1 H), 8.65/8.56 (dd, 1 H), 8.05-7.94 (m, 2H), 7.60 (dd, 1H), 7.44/6.96 (d, 1H), 7.33-7.23 (m, 4H), 7.04/6.49 (s, 2H), 6.88/6.44 (d, 1H), 4.93/3.78 (br s, 1 H), 3.48-3.11 (m, 2H), 2.98/2.68 (s, 3H), 2.98-2.79 (m, 2H), 2.38/2.31 (s, 3H), 2.12/2.00 (s, 3H), 2.00-1.74 (m, 2H) ; LCMS RtA = 3.113 min; [M+H]+ = 456.2].
Example 2.2: (S)-1 -methyl-N-(3-(N-methylbenzof uran-5-carboxamido)-4-phenylbutyl)- 1 H-pyrrole-2-carboxamide
Figure imgf000115_0001
1-Methyl-1 H-pyrrole-2-carboxylic acid ((S)-3-methylamino-4-phenyl-butyl)-amide
hydrochloride (200 mg, 0.62 mmol), benzofuran-5-carboxylic acid (121 mg, 0.75 mmol), HOBt (114 mg, 0.75 mmol), EDC x HCI (179 mg, 0.93 mmol), and triethylamine (0.35 ml, 2.5 mmol) were dissolved in DCM (12 ml) and the reaction was stirred at rt for 20 h. The mixture was diluted with EtOAc, washed with NaHC03- and NaCI-soln., dried (Na2S04), filtered and concentrated. The crude product was purified by chromatography (Flashmaster, Hex:EtOAc 4:1 to EtOAc over 30 min; EtOAc for 5 min) to yield 220 mg (82%) of the title compound as off-white solid. [1 H-NMR (DMSO, 600 MHz, rotamers) 8.05-7.91 (m, 2H), 7.58/7.17 (d, 1 H), 7.35-7.24 and 7.01-6.95 and 6.74-6.60 (m, 9H), 6.88/6.85 (s, 1 H), 6.01-5.98 (m, 1 H), 4.91/3.72 (br s, 1H), 3.82/3.65 (s, 3H),3.37-2.75 (m, 4H), 2.98/2.70 (s, 3H), 1.92-1.69 (m, 2H); LCMS RtA = 2.856 min; [M+H]+ = 430.2].
Example 2.3: (S)-6-methyl-N-(3-(N-methyl-1 H-indole-5-carboxamido - phenylbutyl)imidazor2.1-blthiazole-5-carboxamide
Figure imgf000115_0002
6-Methyl-imidazo[2, 1 -b]thiazole-5-carboxylic acid ((S)-3-methylamino-4-phenyl-butyl)-amide hydrochloride (250 mg, 0.55 mmol), 1 H-indole-5-carboxylic acid (107 mg, 0.66 mmol), HOBt (102 mg, 0.66 mmol), EDC x HCI (159 mg, 0.83 mmol), and triethylamine (0.46 ml, 3.3 mmol) were dissolved in DCM (10 ml) and the reaction was stirred at rt for 20 h. The mixture was diluted with EtOAc, washed with NaHC03- and NaCI-soln., dried (Na2S04), filtered and concentrated. The crude product was purified by chromatography (Flashmaster, DCM to DCM:MeOH 95:5 over 30 min; DCM:MeOH 95:5 for 10 min) to yield 165 mg (61%) of the title compound as colorless solid. [1 H-NMR (DMSO, 600 MHz, rotamers) 11.24/11.11 (s, 1 H), 8.12/7.95 (d, 1 H), 7.66/7.41 (s, 1H), 7.39-6.58 (m, 10H), 6.42/6.21 (s, 1 H), 4.98/3.91 (br s, 1 H), 3.75-2.75 (m, 4H), 2.99/2.75 (s, 3H), 2.55/2.26 (s, 3H), 1.95-1.64 (m, 2H); LCMS RtB = 2.855 min; [M+H]+ = 486.2]. Example 2.4: (S)-N-(3-(N.1-dimethyl-1H-indole-4-carboxamido)-4-phenylbutyl)-1- methyl-1H-benzord1imidazole-2-carboxamide
Figure imgf000116_0001
1-Methyl-1 H-benzoimidazole-2-carboxylic acid ((S)-3-methylamino-4-phenyl-butyl)-amide hydrochloride (250 mg, 0.61 mmol), 1-methyl-1 H-indole-4-carboxylic acid (128 mg, 0.73 mmol), HOBt (112 mg, 0.73 mmol), EDC x HCI (176 mg, 0.92 mmol), and triethylamine (0.34 ml, 2.4 mmol) were dissolved in DCM (10 ml) and the reaction was stirred at rt over night. The mixture was diluted with EtOAc, washed with NaHC03- and NaCI-soln., dried (Na2S0 ), filtered and concentrated. The crude product was purified by chromatography (Flashmaster, heptane to EtOAc over 25 min; EtOAc for 10 min) to yield 191 mg (63%) of the title compound as off-white solid. [1 H-NMR (DMSO, 600 MHz, rotamers) 9.06/8.82 (br s, 1 H), 7.74-7.67 (m, 2H), 7.42-6.25 (m, 11H), 6.11/5.63 (s, 1H), 5.14/3.65 (br s, 1 H), 4.13/4.00 (s, 3H), 3.75/3.59 (s, 3H), 3.49-3.22 (m, 2H), 3.04/2.59 (s, 3H), 3.00-2.80 (m, 2H), 1.99-1.53 (m, 2H); LCMS RtA = 3.136 min; [M+H]+ = 494.2].
Example 2.5: (S)-5-(4-fluorophenyl)-2-methyl-N-(3-(N-methylbenzofuran-4- carboxamido -4-phenylbutyl)thiazole-4-carboxamide
Figure imgf000116_0002
a) (S)-3-Methylamino-4-phenyl-butyronitrile hydrochloride
Figure imgf000117_0001
To the solution of ((S)-1-benzyl-2-cyano-ethyl)-methyl-carbamic acid tert-butyl ester (2.8 g, 10.2 mmol) in DCM (10 ml) was added 4N HCI in dioxan (63.8 ml, 255 mmol) and the reaction was stirred at rt for 1 h. The solvents were removed under reduced pressure, the residue re-dissolved in DCM, the solvent evaporated under reduced pressure and the product dried under high vacuum to yield the title compound as colorless solid (2.2 g, quant.).
[1 H-NMR (DMSO, 600 MHz) 9.44 (s, 2H), 7.38-7.22 (m, 5H), 3.76 (dd, 1 H), 3.27 (dd, 1 H), 2.99 (dd, 1 H), 2.88-2.82 (m, 2H), 2.62 (s, 3H); LCMS RtD = 2.493 min; [M+H]+ = 175.2]. b Benzofuran-4-carboxylic acid ((S)-1-benzyl-2-cyano-ethyl)-methyl-amide
Figure imgf000117_0002
(S)-3-Methylamino-4-phenyl-butyronitrile hydrochloride (2.2 g, 10.4 mmol), benzofuran-4- carboxylic acid (2.03 g, 12.5 mmol), HOBt (1.9 g, 12.5 mmol), EDC x HCI (3.0 g, 15.7 mmol), and triethylamine (5.82 ml, 41.8 mmol) were dissolved in DCM (50 ml) and the reaction was stirred at rt for 20h. The mixture was diluted with EtOAc, washed with NaHC03- and NaCI- soln., dried (Na2S04), filtered and concentrated. The crude product was purified by chromatography (Flashmaster, Hex to Hex:EtOAc 2:3 over 60 min; Hex:EtOAc 2:3 for 5 min) to yield 2.59 g (78%) of the title compound as yellowish oil. [1 H-NMR (DMSO, 600 MHz, rotamers) 7.97/7.94 (s, 1 H), 7.61/7.58 (d, 1 H), 7.36-6.86 (m, 7H), 6.46/6.16 (s, 1 H), 5.25/4.02 (br s, 1 H), 3.14-2.68 (m, 4H), 3.05/2.61 (s, 3H); LCMS RtA = 2.729 min; [M+H]+ = 319.2]. c Benzofuran-4-carboxylic acid ((S)-3-amino-1-benzyl-propyl)-methyl-amide
Figure imgf000117_0003
Benzofuran-4-carboxylic acid ((S)-1-benzyl-2-cyano-ethyl)-methyl-amide (2.57 g, 8.1 mmol) was dissolved in MeOH/ammonia (5%) and hydrogenated in the presence of Ra-Ni (EtOH, B113 W Degussa, 1.2 g) at rt for 14 h. The catalyst was filtered off and the solvents were removed under reduced pressure. The crude product was purified by chromatography (Flashmaster, DCM to DCM:MeOH (0.5% ammonia) 85:15 over 30 min; DCM:MeOH (0.5% ammonia) 20 min) to yield 2.6 g (quant.) of the title compound as yellowish oil. [1 H-NMR (DMSO, 600 MHz, rotamers) 7.98/7.92 (s, 1 H), 7.58 (d, 1H), 7.34-6.45 (m, 7H), 6.60/5.98 (s, 1H), 5.13/3.65 (br s, 1H), 2.96/2.53 (s, 3H), 2.94-2.83 (m, 2H), 2.73-2.56 (m, 2H), 2.41-1.32 (m, 4H); LCMS RtB = 2.830 min; [M+H]+ = 323.2]. d) (S)-5-(4-fluorophenyl)-2-methyl-N-(3-(N-methylbenzofuran-4-carboxamido)-4- henylbutyl)thiazole-4-carboxamide
Figure imgf000118_0001
Benzofuran-4-carboxylic acid ((S)-3-amino-1-benzyl-propyl)-methyl-amide (200 mg, 0.62 mmol), 5-(4-fluoro-phenyl)-2-methyl-thiazole-4-carboxylic acid (177 mg, 0.74 mmol), HOBt (114 mg, 0.74 mmol), EDC x HCI (178 mg, 0.93 mmol), and triethylamine (0.35 ml, 2.48 mmol) were dissolved in DCM (25 ml) and the reaction was stirred at rt for 20h. The mixture was diluted with EtOAc, washed with NaHC03- and NaCI-soln., dried (Na2S04), filtered and concentrated. The crude product was purified by chromatography (Flashmaster, Hex:EtOAc 4:1 to Hex:EtOAc 3:7 over 25 min; Hex:EtOAc 3:7 for 5 min) to yield 265 mg (79%) of the title compound as colorless solid. [1 H-NMR (DMSO, 600 MHz, rotamers) 8.45/8.16 (s, 1 H), 7.89 (d, 1H), 7.59-7.13 (m, 10 H), 6.93-6.87 (m, 2H), 6.38/5.97 (s, 1H), 5.07/3.62 (br s, 1 H), 3.37- 3.21 (m, 2H), 3.0-2.7 (m, 2H), 2.98/2.57 (s, 3H), 2.69/2.67 (s, 3H), 1.86-1.65 (m, 2H); LCMS RtG = 2.487 min; [M+Hf = 542.2].
Example 2.6: (S)-N.2-dimethyl-N-(4-(1-methyl-1H-pyrrole-2-carboxamido)-1- phenylbutan-2-vH-2H-indazole-4-carboxamide
Figure imgf000118_0002
To a solution of 1-methyl-1H-pyrrole-2-carboxylic acid ((S)-3-methylamino-4-phenyl-butyl)- amide hydrochloride (160 mg, 0.497 mmol), 2-methyl-2H-indazole-4-carboxylic acid (88 mg, 0.497 mmol), HOBt (91 mg, 0.597 mmol) and triethylamine (0.345 ml, 2.489 mmol) in DCM (5 ml) was added EDC x HCI (114 mg, 0.746 mmol). The reaction was stirred at rt for 18 h. The mixture was diluted with DCM and washed with sat. Na2C03 and brine, dried (MgS04), filtered and concentrated. Purification by flash chromatography (DCM:MeOH, 98:2) gave the title compound (109 mg, 50%). [1H-NMR (DMSO, 600 MHz, rotamers) 8.02 (m , 1 H), 7.64 (br s, 1 H), 7.58 ( d, 1H), 7.40-7.30 (m, 5H), 7.22 (m, 1H), 6.88 (m, 1H), 6.68 (m, 1H), 6.76 (br s, 1H), 6.01 (br s, 1H), 5.01 (br s, 1H), 4.08 ( s, 3H), 3.84/3.69 (s, 3H), 3.31-2.81 (m, 4H), 2.62 (s, 3H), 1.92-1.83 ( m, 2H); LCMS RtF = 1.05 min; [M+H]+ = 444.3].
Example 2.7: (S)-N.1 -dimethyl-N-(4-(1 -methvl-1 H-pyrrole-2-carboxamidoH - henylbutan-2-yl)-1 H-benzordlM .2.31triazole-7-carboxamide
Figure imgf000119_0001
To a solution of 1-methyl-1H-pyrrole-2-carboxylic acid ((S)-3-methylamino-4-phenyl-butyl)- amide hydrochloride (160 mg, 0.497 mmol), 3-methyl-3H-benzotriazole-4-carboxylic acid (106 mg, 0.597 mmol), HOBt (91 mg, 0.597 mmol), and triethylamine (0.345 ml, 2.489 mmol) in DCM (5 ml) was added EDC x HCI (143 mg, 0.746 mmol). The reaction was stirred at rt for 18 h. The mixture was diluted with DCM and washed with sat. Na2C03 and brine, dried (MgS04), filtered and concentrated. Purification by flash chromatography (DCM:MeOH, 98:2) gave the title compound (128 mg , 58%). [1 H-NMR (DMSO, 600 MHz, rotamers) 8.20 (m , 1H), 8.04 (m, 1H), 7.39-7.35 (m, 6H) 7.34 (m, 1 H), (6.98 /6.88, br s. 1 H), 6.77 (m, 1 H), 6.01 (m, 1H), 5.10 /4.17 (m, 1H), 3.38 (s, 3H), 3.52 (s, 3H), 3.35 (m, 1 H), 2.90 (m, 2H), 2.77 (s, 3H), 2.07-1.89 (m, 2H); LCMS RtF = 1.08 min; [M+H]+ = 445.3].
Examples 2.8 to 2.81 , as mentioned below, were prepared or can be prepared in analogy to the methods described above using the appropriate starting materials or intermediates.
Example 2.8: (S)-N-Methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2- yl)benzord1oxazole-6-carboxamide
Figure imgf000120_0001
Obtained in analogy to Example 2.2 [LCMS RtF = 1.03 min; [M+H]+ = 431.4]
Example 2.9: (S)-N.2-Dimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1 - henylbutan-2-v0benzord1oxazole-6-carboxamide
Figure imgf000120_0002
Obtained in analogy to Example 2.2. [LCMS RtF = 1.07 min; [M+H]+ = 445.4]
Example 2.10: (S)-N.2-Dimethyl-N-(4- -methyl-1 H-pyrrole-2-carboxamidoH- henylbutan-2-yl)benzo oxazole-5-carboxamide
Figure imgf000120_0003
Obtained in analogy to Example 2.2. [LCMS RtF = 1.08 min; [M+H]+ = 445.4]
Example 2.11 : (S)-N.3-Dimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamidoM- henylbutan-2-yl)benzord1isoxazole-6-carboxamide
Figure imgf000120_0004
Obtained in analogy to Example 2.2. [LCMS RtF = 1.14 min; [M+H]+ = 445.3] Example 2.12: (S)-N.3-Dimethyl-N-(4-(1 -methyl -1 H-pyrrole-2-carboxamido)-1 - phenyl butan-2-yl)benzord1isoxazole-5-carboxamide
Figure imgf000121_0001
Obtained in analogy to Example 2.2. [LCMS RtF = 1.14 min; [M+H]+ = 445.3]
Example 2.13: (S)-N.1-dimethyl-N-(1-phenyl-4-(picolinamido)butan-2-yl)-1H-indole-7- carboxamide
Figure imgf000121_0002
Obtained in analogy to Example 2.1. LCMS RtA = 3.073 min; [M+H]+ = 441.2].
Example 2.14: (S)-N-methyl-N-(1-phenyl-4-(picolinamido)butan-2-yl)-1H-indole-7- carboxamide
Figure imgf000121_0003
Obtained in analogy to Example 2.1. LCMS RtA = 2.928 min; [M+H]+ = 427.2].
Example 2.15: (S)-N,1-dimethyl-N-(1-phenyl-4-(picolinamido)butan-2-yl)-1H-indole-4- carboxamide
Figure imgf000121_0004
Obtained in analogy to Example 2.1. LCMS RtA = 2.788 min; [M+H]+ = 441.2]. Example 2.16: (S)-1-methyl-N-(3-(N-methyl-1 H-indole-4-carboxamido)-4-phenylbutyl)- 1H-benzo d1imidazole-2-carboxamide
Figure imgf000122_0001
Obtained in analogy to Example 2.4. LCMS RtA = 2.824 min; [M+H]+ = 480.2].
Example 2.17: (S)-1-methyl-N-(3-(N-methyl-1H-indole-5-carboxamido)-4-phenylbutyl)- -benzord1imidazole-2-carboxamide
Figure imgf000122_0002
Obtained in analogy to Example 2.4. LCMS RtA = 2.719 min; [M+H]+ = 480.2].
Example 2.18: (S)-N-methyl-N-(1-phenyl-4-(picolinamido)butan-2-yl)quinoxaline-6- carboxamide
Figure imgf000122_0003
Obtained in analogy to Example 2.1. LCMS RtA = 1.775 min; [M+H]+ = 440.2].
Example 2.19: (S)-N-methyl-N-(4-(1-methyl-1H-pyrrole-2-carboxamido)-1-phenylbutan- 2- l)benzordloxazole-5-carboxamide
Figure imgf000122_0004
Obtained in analogy to Example 2.2. LCMS RtA Example 2.20: (S)-N-(3-(N.2-dimethylbenzofuran-5-carboxamido)-4-phenylbutyl)-1- meth l-1 H-pyrrole-2-carboxamide
Figure imgf000123_0001
Obtained in analogy to Example 2.2. LCMS RtA = 3.051 min; [M+H]+ = 444.2].
Example 2.21 : (S)-N-methyl-N-(1-phenyl-4-(picolinamido)butan-2-yl)-1H-indole-4- carboxamide
Figure imgf000123_0002
Obtained in analogy to Example 2.1. LCMS RtA = 2.358 min; [M+H]+ = 427.2].
Example 2.22: fS)-N.1-dimethyl-N-(1-phenyl-4-(picolinamido)butan-2-yl)-1H-indole-5- carboxamide
Figure imgf000123_0003
Obtained in analogy to Example 2.1. LCMS RtA = 2.666 min; [M+H]+ = 441.2].
Example 2.23: (S)-N.1-dimethyl-N-(1-phenyl-4-(picolinamido)butan-2-yl)-1H-indole-6- carboxamide
Figure imgf000123_0004
Obtained in analogy to Example 2.1. LCMS RtA = 2.757 min; [M+H]+ = 441.2].
Example 2.24: (S)-N-(3-(N-methylbenzofuran-5-carboxamido)-4- henylbutvDpicolinamide
Figure imgf000124_0001
Obtained in analogy to Example 2.1. LCMS RtA = 2.686 min; [M+H]+ = 428.2].
Example 2.25: iS)-N-methyl-N-f1-phenyl-4-(picolinamido)butan-2-yl)-1H-indole-6- carboxamide
Figure imgf000124_0002
Obtained in analogy to Example 2.1. LCMS RtA = 2.529 min; [M+H]+ = 427.2].
Example 2.26: (S)-N-methyl-N-(1-phenyl-4-(picolinamido)butan-2-yl)-1H-indole-5- carboxamide
Figure imgf000124_0003
Obtained in analogy to Example 2.1. LCMS RtA = 2.339 min; [M+H]+
Example 2.27: (S)-N-(3-(N-methylbenzofuran-4-carboxamido)-4- phenylbutvDpicolinamide
Figure imgf000125_0001
Obtained in analogy to Example 2.1. LCMS RtA = 2.817 min; [M+H]+ = 428.2].
Example 2.28: (S)-1-methyl-N-(3-(N-methylbenzofuran-4-carboxamido)-4-phenylbutyl)- -pyrrole-2-carboxamide
Figure imgf000125_0002
Obtained in analogy to Example 2.5. LCMS RtA = 2.372 min; [M+H]+ = 430.2].
Example 2.29: (S)-1 -methyl-N-(3-(N-methylbenzofuran-4-carboxamido)-4-phenylbutyl)- -benzord1imidazole-2-carboxamide
Figure imgf000125_0003
Obtained in analogy to Example 2.4. LCMS Rtc = 2.638 min; [M+H]+ = 481.2].
Example 2.30: (S)-N.1-dimethyl-N-(4-(1-methyl-1H-pyrrole-2-carboxamido)-1- phenylbutan-2-yl)-1H-indole-5-carboxamide
Figure imgf000125_0004
Obtained in analogy to Example 2.2. LCMS RtA = 2.885 min; [M+H]+ = 443.2]. Example 2.31 : (S)-N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan- -yl)-1 H-indole-5-carboxamide
Figure imgf000126_0001
Obtained in analogy to Example 2.2. LCMS RtA = 2.572 min; [M+H]+ = 429.2].
Example 2.32: (S)-N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1 -phenylbutan- -yl)quinoline-6-carboxamide
Figure imgf000126_0002
Obtained in analogy to Example 2.2. LCMS RtB = 2.749 min; [M+H]+ = 441.2].
Example 2.33: fS)-N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1 -phenylbutan- 2- l)-1 H-indole-4-carboxamide
Figure imgf000126_0003
Obtained in analogy to Example 2.2. LCMS RtA = 2.659 min; [M+H]+ = 429.2].
Example 2.34; (S)-N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1 -phenylbutan- 2-yl)quinoxaline-6-carboxamide
Figure imgf000126_0004
Obtained in analogy to Example 2.3. LCMS RtB = 3.072 min; [M+H]+ = 442.2].
Example 2.35: (S)-6-methyl-N-(3-(N-methylquinoxaline-6-carboxamido)-4- henylbutyl)imidazor2.1-b1thiazole-5-carboxamide
Figure imgf000127_0001
Obtained in analogy to Example 2.3. LCMS RtB = 2.741 min; [M+H]+ = 499.2].
Example 2.36: (S)-6-methyl-N-(3-(N-methyl-1 H-indole-4-carboxamido)-4- phenylbutyl)imidazo 2.1-b1thiazole-5-carboxamide
Figure imgf000127_0002
Obtained in analogy to Example 2.3. LCMS RtB = 2.953 min; [M+H]+ = 486.2].
Example 2.37; (S)-6-methyl-N-(3-(N-methylquinoline-6-carboxamido)-4- henylbutyl)imidazor2,1-b1thiazole-5-carboxamide
Figure imgf000127_0003
Obtained in analogy to Example 2.3. LCMS RtB = 2.620 min; [M+H]+ = 498.2].
Example 2.38: (S)-N-methyl-N-(4-(1-methyl-1H-pyrrole-2-carboxamido)-1-phenylbutan- 2-yl)benzofciri.2.51thiadiazole-5-carboxamide
Figure imgf000128_0001
Obtained in analogy to Example 2.2. LCMS RtA = 2.676 min; [M+H]+ = 448.2].
Example 2.39: (S)-N-(3-(3-bromo-N-methylbenzofuran-5-carboxamido)-4-phenylbutyl)- 1 -methyl-1 H-pyrrole-2-carboxamide
Figure imgf000128_0002
Obtained in analogy to Example 2.2. LCMS RtA = 3.143 min; [M+H]+ = 508.1/510.2].
Example 2.40: (S)-N,2-dimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamidoH- phenylbutan-2-yl)benzord1thiazole-5-carboxamide
Figure imgf000128_0003
Obtained in analogy to Example 2.2. LCMS RtA = 2.585 min; [M+H]+ = 461.2].
Example 2.41 : (S)-N-(3-(N.3-dimethylbenzofuran-5-carboxamido)-4-phenylbutyl)-1- m thyl-1 H-pyrrole-2-carboxamide
Figure imgf000128_0004
Obtained in analogy to Example 2.2. LCMS RtA = 3.058 min; [M+H]+ = 444.2].
Example 2.42: (S)-1-methyl-N-(3-(N-methylbenzofuran-6-carboxamido)-4-phenylbutyl)- 1 H-pyrrole-2-carboxamide
Figure imgf000129_0001
Obtained in analogy to Example 2.2. LCMS RtA = 2.861 min; [M+H]+ = 430.2].
Example 2.43: (S)-N.1 -dimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1 - phenylbutan-2-yl)-1 H-benzo H .2.31triazole-5-carboxamide
Figure imgf000129_0002
Obtained in analogy to Example 2.7. [LCMS RtF = 0.99 min; [M+H]+ = 445.4].
Example 2.44: (S)-N.1 -dimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamidoH - phenylbutan-2-yl)-1H-indazole-5-carboxamide
Figure imgf000129_0003
Obtained in analogy to Example 2.6. [LCMS RtF = 1.05 min; [M+H]+ = 444.4].
Example 2.45: (S)-N.2-dimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1- henylbutan-2-yl)-2H-benzordiri.2.31triazole-4-carboxamide
Figure imgf000129_0004
Obtained in analogy to Example 2.7. [LCMS RtF = 1.11 min; [M+H]+ = 445.2]. Example 2.46: (S)-N.1 -dimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1■ phenylbutan-2-yl)-1 H-benzo H .2.31triazole-4-carboxamide
Figure imgf000130_0001
Obtained in analogy to Example 2.7. [LCMS RtF = 1.05 min; [M+H]+ = 445.3].
Example 2.47: (S)-N,1 -dimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1■ henylbutan-2-yl)-1H-indazole-4-carboxamide
Figure imgf000130_0002
Obtained in analogy to Example 2.6. [LCMS RtF = 1.11 min; [M+H]+ = 444.3].
Example 2.48: (S)-N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamidoH -phenylbutan- -yl)-1 H-benzordlM .2.31triazole-5-carboxamide
Figure imgf000130_0003
Obtained in analogy to Example 1.4. [LCMS RtH = 1.03 min; [M+H]+ = 431.6]
Example 2.49: (S)-N.2-dimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1- phenylbutan-2-yl)-1H-benzordTimidazole-5-carboxamide
Figure imgf000130_0004
Obtained in analogy to Example 1.4. [LCMS RtH = 0.87 min; [M+H]+ = 444.6] Example 2.50: (S)-N-methyl-N-f 4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1 -phenylbutan- 2-yl)-1 H-indazole-5-carboxamide
Figure imgf000131_0001
Obtained in analogy to Example 1.4. [LCMS RtH = 1.08 min; [M+H]+ = 430.6]
Example 2.51 : (S)-N-methvl-N-(4-(1 -methvl-1 H-pyrrole-2-carboxamidoH-phenylbutan- 2-yl)-1H-benzordlimidazole-5-carboxamide
Figure imgf000131_0002
Obtained in analogy to Example 1.4. [LCMS RtH = 0.88 min; [M+H]+ = 430.6]
Example 2.52: (S)-N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamidoM-phenylbutan- 2- l)benzord1thiazole-6-carboxamide
Figure imgf000131_0003
Obtained in analogy to Example 1.4. [LCMS RtH = 1.16 min; [M+H]+ = 447.6]
Example 2.53: (S)-N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1 -phenylbutan- 2-yl)quinoline-8-carboxamide
Figure imgf000131_0004
Obtained in analogy to Example 1.4. [LCMS RtH = 1.11 min; [M+H]+ = 441.6]
Example 2.54: (S)-N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamidoH -phenylbutan- - l)benzord1oxazole-4-carboxamide
Figure imgf000132_0001
Obtained in analogy to Example 1.2. [LCMS Rtj = 1.00 min; [M+H]+ = 431.2]
Example 2.55: (S)-N.2-dimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1 · phenylbutan-2-yl)benzord1oxazole-4-carboxamide
Figure imgf000132_0002
Obtained in analogy to Example 1.2. [LCMS Rtj = 1.04 min; [M+H]+ = 445.3]
Example 2.56: (S)-N-methyl-N-(4-f 1 -methyl-1 H-pyrrole-2-carboxamido)-1 -phenylbutan- -yl)benzord1thiazole-5-carboxamide
Figure imgf000132_0003
Obtained in analogy to Example 1.2. [LCMS RtB = 3.189 min; [M+H]+ = 447.0]
Example 2.57: (S)-N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamidoM -phenylbutan- 2-yl)benzorciri.2.51oxadiazole-5-carboxamide
Figure imgf000132_0004
Obtained in analogy to Example 1.2. [LCMS RtB = 3.407 min; [M+H]+ = 432.2]
Example 2.58: (S)-N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamidoH -phenylbutan- 2- l)quinoline-5-carboxamide
Figure imgf000133_0001
Obtained in analogy to Example 1.2. [LCMS RtB = 2.657/2.876 min (rotamers); [M+H]+ = 441.2]
Example 2.59: (S)-6-chloro-N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1- phenylbutan-2-yl)quinoline-8-carboxamide
Figure imgf000133_0002
Obtained in analogy to Example 1.2. [LCMS RtB = 3.355/3.771 min (rotamers); [M+H]+ 475.2/477.2]
Example 2.60: (S)-N.2.4-trimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1- henylbutan-2-yl)quinoline-8-carboxamide
Figure imgf000133_0003
Obtained in analogy to Example 1.8. [LCMS RtB = 3.043 min; [M+H]+ = 469.2]
Example 2.61 : (S)-N.2.5-trimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1- phenylbutan-2-yl)quinoline-8-carboxamide
Figure imgf000134_0001
Obtained in analogy to Example 1.8. [LCMS RtB = 3.126 min; [ +H]+ = 469.2]
Example 2.62: (S)-5.6-dimethoxy-N-methyl-N-(4-(1-methyl-1 H-pyrrole-2-carboxamido)- 1- henylbutan-2-yl)quinoline-8-carboxamide
Figure imgf000134_0002
Obtained in analogy to Example 1.8. [LCMS RtB = 3.295 min; [M+H]+ = 501.2]
Example 2.63: (S)-6-bromo-N.2-dimethyl-N-(4- -methyl-1H-pyrrole-2-carboxamido)-1- phenylbutan-2-yl)quinoline-8-carboxamide
Figure imgf000134_0003
Obtained in analogy to Example 1.8. [LCMS RtB = 3.537/3.927 min (rotamers); [M+H]+ = 533.2/535.2]
Example 2.64: (S)-6-methoxy-N-methyl-N-(4-(1-methyl-1 H-pyrrole-2-carboxamidoH- phenylbutan-2-yl)quinoline-8-carboxamide
Figure imgf000135_0001
Obtained in analogy to Example 1.8. [LCMS RtB = 3.099 min; [M+H]+ = 471.2]
Example 2.65: (S)-6-methoxy-N.2-dimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)- 1- henylbutan-2-yl)quinoline-8-carboxamide
Figure imgf000135_0002
Obtained in analogy to Example .8. [LCMS RtB = 3. 54 min; [M+H]+ = 485.2]
Example 2.66: (S)-N.6-dimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamidoH- henylbutan-2-yl)quinoline-8-carboxamide
Figure imgf000135_0003
Obtained in analogy to Example 1.8. [LCMS RtB = 3.120 min; [M+H]+ = 455.2]
Example 2.67: (S)-N-(3-(5-fluoro-N-methylbenzofuran-6-carboxamido)-4-phenylbutyl)-1- methyl- H-pyrrole-2-carboxamide
Figure imgf000135_0004
Obtained in analogy to Example 1.2. [LCMS RtA = 2.901 min; [M+Hf = 448.2]
Example 2.68: (S)-N-(3-(N.5-dimethylbenzofuran-6-carboxamido)-4-phenylbutyl)-1- meth l-1 H-pyrrole-2-carboxamide
Figure imgf000136_0001
Obtained in analogy to Example 1.2. [LCMS RtA = 3.118 min; [M+H]+ = 444.2]
Example 2.69: (S)-N.1 -dimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamidoH■ phenylbutan-2-yl)-1H-indole-4-carboxamide
Figure imgf000136_0002
Obtained in analogy to Example 1.2. [LCMS RtA = 2.949 min; [M+H]+ = 443.2]
Example 2.70: fS)-N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1 -phenylbutan- -yl)benzord1oxazole-7-carboxamide
Figure imgf000136_0003
Obtained in analogy to Example 1.2. [LCMS RtA = 2.319 min; [M+Hf = 431.2]
Example 2.71 : (S)-N.2-dimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1- phenylbutan-2-yl)benzord1oxazole-7-carboxamide
Figure imgf000136_0004
Obtained in analogy to Example 1.2. [LCMS RtA = 2.427 min; [M+H]+ = 445.2]
Example 2.72: (S)-N.2-dimethyl-N-(4- -methyl-1 H-pyrrole-2-carboxamidoH- henylbutan-2-vhauinoline-8-carboxamide
Figure imgf000137_0001
Obtained in analogy to Example 1.8. [LCMS RtB = 3.138 min; [M+H]+ = 455.2]
Example 2.73: (S)-N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamidoM-phenylbutan- 2- l)quinoxaline-5-carboxamide
Figure imgf000137_0002
Obtained in analogy to Example 1.8. [LCMS RtB = 2.938/3.317 min (rotamers); [M+H]+ 442.2]
Example 2.74: (S1-N.1.2-trimethyl-N-(4-M -methyl-1 H-pyrrole-2-carboxamidoH - henylbutan-2-yl)-1H-indole-4-carboxamide
Figure imgf000137_0003
Obtained in analogy to Example 1.2. [LCMS Rtj = 1.15 min; [M+H]+ = 457.2]
Example 2.75: (S)-N.1.3-trimethyl-N-(4-(1-methyl-1H-pyrrole-2-carboxamido)-1- phenylbutan-2-yl)-1H-indole-4-carboxamide
Figure imgf000138_0001
Obtained in analogy to Example 1.2. [LCMS Rtj = 1.16 min; [M+H]+ = 457.2]
Example 2.76: (S)-N.1.5-trimethyl-N-(4-M -methyl-1 H-pyrrole-2-carboxamidoM■ phenylbutan-2-yl)-1H-indole-4-carboxamide
Figure imgf000138_0002
Obtained in analogy to Example 1.2. [LCMS Rtj = 1.17/1.21 min (rotamers); [M+H]+
Example 2.77: (S)-N.1.7-trimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamidoM- henylbutan-2-yl)-1H-indole-4-carboxamide
Figure imgf000138_0003
Obtained in analogy to Example 1.2. [LCMS Rtj = 1.13 min; [M+H]+ = 457.3]
Example 2.78: (S)-N-(4-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1-phenylbutan-2- -N-methylbenzord1oxazole-5-carboxamide
Figure imgf000138_0004
Obtained in analogy to Example 1.8. [LCMS Rtj = 0.92 min; [M+H]+ = 460.2] Example 2.79: (S)-4-chloro-N.1-dimethyl-N-(4-(1-methyl-1H-pyrrole-2-carboxamido)-1- phenylbutan-2-yl)-1H-indole-5-carboxamide
Figure imgf000139_0001
Obtained in analogy to Example 1.8. [LCMS Rt j = 1.18 min; [M+H]+ = 477.1/479.2]
Example 2.80: (S)-6-chloro-N.1-dimethyl-N-(4-(1-methyl-1H-pyrrole-2-carboxamido>-1- henylbutan-2-ylH H-indole-5-carboxamide
Figure imgf000139_0002
Obtained in analogy to Example 1.8. [LCMS Rtj = 1.13 min (br, rotamers); [M+H]+ = 477.2/479.2]
Example 2.81 : (S)-N.1.6-trimethyl-N-(4-(1-methyl-1H-pyrrole-2-carboxamido¾-1- henylbutan-2-yl)-1H-indole-4-carboxamide
Figure imgf000139_0003
Obtained in analogy to 1.8. [LCMS Rtj = 1.13 min; [M+H]+ = 457.2]
Example 3.1 : (S)-1-methyl-N-(3-(N-methyl-3-(5-methyloxazol-2-yl)benzamido)-4- phenylbutylH H-pyrrole-2-carboxamide
Figure imgf000140_0001
1-Methyl-1 H-pyrrole-2-carboxylic acid ((S)-3-methylamino-4-phenyl-butyl)-amide hydrochloride (100 mg, 0.30 mmol), 3-(5-methyl-oxazol-2-yl)-benzoic acid (63 mg, 0.30 mmol), HOBt (56 mg, 0.36 mmol), EDC x HCI (88 mg, 0.45 mmol), and triethylamine (0.11ml, 0.75 mmol) were dissolved in DCM (1 ml) and stirred at rt for 17 h. The mixture was diluted with EtOAc, washed with NaHC03- and NaCI-soln., dried (Na2S04), filtered and concentrated. The crude product was purified by flash chromatography (EtOAc) to yield 112 mg (79%) of the title compound as colorless solid. [1 H-NMR (DMSO, 600 MHz, rotamers) 7.98/7.94 (t, 1H), 7.91/7.69 (d, 1 H), 7.55-7.43 (m, 1 H), 7.39-6.91 (m, 8H), 6.87 (s, 1 H), 6.73/6.61 (d, 1H), 6.00/5.97 (t, 1 H), 4.92/3.71 (br s, 1 H), 3.82/3.69 (s, 3H), 3.39-3.27/3.01-2.92 (two m, 2H), 2.98/2.68 (s, 3H), 2.91-2.72 (m, 2H), 2.41/2.40 (s, 3H), 1.96-1.70 (m, 2H); LCMS RtF = 1.20 min; [M+H]+ = 471.3].
Example 3.2: fS)-1-methyl-N-(3-(N-methyl-3-(1H-pyrrol-1-vnbenzamido)-4-phenylbutvn- 1 H- rrole-2-carboxamide
Figure imgf000140_0002
1 -Methyl-1 H-pyrrole-2-carboxylic acid ((S)-3-methylamino-4-phenyl-butyl)-amide
hydrochloride (150 mg, 0.47 mmol), 3-pyrrol-1-yl-benzoic acid (105 mg, 0.56 mmol), HOBt (86 mg, 0.56 mmol), EDC x HCI (134 mg, 0.70 mmol), and triethylamine (0.33 ml, 2.33 mmol) were dissolved in DCM (15 ml) and the reaction was stirred at rt for 20h. The mixture was diluted with EtOAc, washed with NaHC03- and NaCI-soln., dried (Na2S04), filtered and concentrated. The crude product was purified by chromatography (Flashmaster, Hex:EtOAc 7:3 to Hex: EtOAc 1:9 over 30 min; Hex: EtOAc 1 :9 for 10 min) to yield 150 mg (71%) of the title compound as colorless solid. [1 H-NMR (DMSO, 600 MHz, rotamers) 7.98/7.95 (t, 1 H), 7.59/7.40 (d, 1 H), 7.45-6.55 (m, 12H), 6.28-6.27 (m, 2H), 6.00-5.98 (m, 1 H), 4.90/3.70 (br s, 1 H), 3.82/3.73 (s, 3H), 3.35-3.29 (m, 2H), 2.98-2.78 (m, 2H), 2.99/2.68 (s, 3H), 1.90-1.70 (m, 2H); LCMS RtA = 3.146 min; [M+H]+ = 455.2]. Examples 3.3 to 3.24, as mentioned below, were prepared or can be prepared in analogy to the methods described above using the appropriate starting materials or intermediates.
E -N-(3-(N-methylbiphenyl-2-ylcarboxamido¾-4-phenylbutyl)picolinamide
Figure imgf000141_0001
Obtained in analogy to Example 1.1. [LCMS RtA = 3.314/3.363 min (rotamers); [M+H]+ = 464.2]
Example 3.4: (S)-5-(2-fluorophenyl)-N.2-dimethyl-N-f4- 1-methyl-1H-benzord1imidazole- 2- rboxamidoH-phenylbutan-2-v0thiazole-4-carboxamide
Figure imgf000141_0002
Obtained in analogy to Example 2.4. [LCMS Rtc = 3.018 min; [M+H]+ = 556.2]
Example 3.5: (S)-N-(3- 3-(3.5-dimethyl-1H-pyrazol-1-vn-N-methylbenzamido)-4- henylbutyl)-1 -methyl-1 H-pyrrole-2-carboxamide
Figure imgf000141_0003
Obtained in analogy to Example 3.2. [LCMS RtA = 2.766 min; [M+H]+ = 484.2]
Example 3.6: fS)-1-methyl-N-(3-(N-methyl-3-(5-methyl-1.2.4-oxadiazol-3-yl)benzamido)-
4-phenylbutylHH-pyrrole-2-carboxamide
Figure imgf000142_0001
Obtained in analogy to Example 3.2. [LCMS RtA = 2.740 min; [M+H]+ = 472.2]
Example 3.7: (S)-1 -methyl-N-(3-(N-methyl-3-(1 H-tetrazol-1 -yhbenzamido - henylbutylHH-pyrrole-2-carboxamide
Figure imgf000142_0002
Obtained in analogy to Example 3.2. [LCMS R = 2.243 min; [M+H]+ = 458.2]
Example 3.8: (S)-1 -methyl-N-(3-( N-methyl-3-f 5-methyl-1 ,3.4-oxadiazol-2-yl)benzamido)- 4- henylbutyl)-1H-pyrrole-2-carboxamide
Figure imgf000142_0003
Obtained in analogy to Example 3.2. [LCMS RtA = 2.680 min; [M+H]+ = 472.2]
Example 3.9: fS)-1-methyl-N-(3-(N-methyl-3-(1-methyl-1H-pyrazol-5-yl)benzamido)-4- henylbutyl)-1H-pyrrole-2-carboxamide
Figure imgf000142_0004
Obtained in analogy to Example 3.2. [LCMS RtA = 2.510 min; [M+H]+ = 470.2]
Example 3.10: (S)-1-methyl-N-(3-(N-methyl-3-(oxazol-5-yl)benzamido)-4-phenylbutyl)- 1 H-pyrrole-2-carboxamide
Figure imgf000143_0001
Obtained in analogy to Example 3.2. [LCMS RtA = 2.456 min; [M+H]+ = 457.2]
Example 3.11 : (S)-1 -methyl -N-(3-(N -methyl -3-(1 -methyl -1H-pyrazol -3-vnbenzamido - henylbutyl)-1H-pyrrole-2-carboxamide
Figure imgf000143_0002
Obtained in analogy to Example 3.2. [LCMS RtA = 2.616 min; [M+H]+ = 470.2]
Example 3.12: (S)-1-methyl-N-(3-(N-methyl-3-(1H-pyrazol-3-yl)benzamido)-4- henylbutyl)-1H-pyrrole-2-carboxamide
Figure imgf000143_0003
Obtained in analogy to Example 3.2. [LCMS RtA = 2.285 min; [M+H]+ = 456.2]
Example 3.13: (S)-1-methyl-N-(3- N-methyl-3-f1H-tetrazol-5-vnbenzamido)-4- henylbutyl)-1H-pyrrole-2-carboxamide
Figure imgf000143_0004
Obtained in analogy to Example 3.2. [LCMS RtB = 3.033 min; [M+H]+ = 458.2]
Example 3.14: (S)-1-methyl-N-(3-(N-methyl-3-(5-methyl-1H-pyrazol-1-vnbenzamido)-4- phenylbutyl)-1H-pyrrole-2-carboxamide
Figure imgf000144_0001
Obtained in analogy to Example 1.4. [LCMS RtF = 1.17 min; [M+H]+ = 470.4]
Example 3.15: (S)-1-methyl-N-(3-(N-methyl-3-(3-methyl-1H-pyrazol-1-vhbenzamido)-4- phenylbutvD-1H-pyrrole-2-carboxamide
Figure imgf000144_0002
Obtained in analogy to Example 1.4. [LCMS RtF = 1.23 min; [M+H]+ = 470.4]
Example 3.16: (S)-1-methyl-N-(3-(N-methyl-3-(pyridin-2-yl)benzamido)-4-phenylbutyl)- 1 H- rrole-2-carboxamide
Figure imgf000144_0003
Obtained in analogy to Example 1.4. [LCMS RtF = 1.19 min; [M+H]+ = 467.3]
Example 3.17: (S)-1-methyl-N-(3-(N-methyl-3-(pyrimidin-2-yl)benzamido)-4- henylbutyl)-1H-pyrrole-2-carboxamide
Figure imgf000144_0004
Obtained in analogy to Example 1.4. [LCMS RtF = 1.15 min; [M+H]+ = 468.3]
Example 3.18: (S)-N.5-dimethyl-N-(4-(1-methyl-1 H-pyrrole-2-carboxamido)-1- phenylbutan-2-yl)-3-phenylisoxazole-4-carboxamide
Figure imgf000145_0001
Obtained in analogy to Example 1.4. [LCMS RtH = 1.43 min; [M+H]+ = 471.6]
Example 3.19: fS)-1-methyl-N-(3-(N-methyl-3-(1H-pyrazol-1-vnbenzamido)-4- phenylbutyl)-1H-pyrrole-2-carboxamide
Figure imgf000145_0002
Obtained in analogy to Example 1.4. [LCMS RtH = 1.27 min; [M+H]+ = 456.3]
Example 3.20: (S)-N-(3-(N.5-dimethyl-2-(2H-1.2.3-triazol-2-vnbenzamido)-4- phenylbutyl)-1 -methyl-1 H-pyrrole-2-carboxamide
Figure imgf000145_0003
Obtained in analogy to Example 1.2. [LCMS Rtj = 1.21 min; [M+H]+ = 471.2]
Example 3.21 : (S)-N-(3-(N.5-dimethyl-2-(pyrimidin-2-vnbenzamido)-4-phenylbutyl)-1- methyl-1 H-pyrrole-2-carboxamide
Figure imgf000145_0004
Obtained in analogy to Example 1.84. [LCMS Rt j = 1.19 min; [M+H]+ = 482.2] Example 3.22: (S)-5-(2-fluorophenyl)-N.2-dimethyl-N-(1 -phenyl-4-(picolinamido)butan- 2- l)thiazole-4-carboxamide
Figure imgf000146_0001
Obtained in analogy to Example 1.2. [LCMS Rtc = 2.592 min; [M+H]+ = 503.0]
Example 3.23: (S)-N-(3-(N.5-dimethyl-2-(2H-1.2.3-triazol-2-yl)benzamido)-4- enylbutvh-1 -ethyl-3-methyl-1 H-pyrazole-5-carboxamide
Figure imgf000146_0002
Obtained in analogy to Example 1.84. [LCMS Rt j = 1.19 min; [M+H]+ = 500.3]
Example 3.24: (S)-N-(3-(3-(1H-imidazol-1-yl)-N-methylbenzamido)-4-phenylbutyl)-1- methyl-1 H-pyrrole-2-carboxamide
Figure imgf000146_0003
Obtained in analogy to Example 1.4. [LCMS RtH = 0.94 min; [M+H]+ = 456.6]
Example 4.1 : (S)-2-methoxy-N-methyl-N-(4-(1-methyl-1 H-pyrrole-2-carboxamidoH- phenylbutan-2-yl)isonicotinamide
Figure imgf000147_0001
1-Methyl-1H-pyrrole-2-carboxylic acid ((S)-3-methylamino-4-phenyl-butyl)-amide hydrochloride (100 mg, 0.31 mmol), 2-methoxypyridine-4-carboxylic acid (49 mg, 0.31 mmol), HOBt (71 mg, 0.476 mmol), EDC x HCI (72 mg, 0.37 mmol), and triethylamine (0.108 ml, 0.78 mmol) were dissolved in DCM (5 ml) and stirred at rt for 2 h. The mixture was concentrated, redissolved in EtOAc, washed with sat. NaHC03- and NaCI-soln., dried (Na2S04), filtered and concentrated. The crude product was purified by chromatography (Biotage, DCM to DCM:MeOH 95:5 over 10 min) to yield 84 mg (63 %) of the title compound as white solid. [1 H-NMR (DMSO, 600 MHz) 8.16/7.73 (d, 1 H), 7.93 (t, 1 H), 7.33-7.21, 7.05- 7.01 (2m, 5H), 6.88 (d, 1H), 6.68 (d, 1 H), 6.56/6.11 (d, 1 H), 6.33/5.81 (s, 1H), 6.01-5.98 (m, 1 H), 4.90-4.83/3.58-3.52 (m, 1 H), 3.83/3.76 (s, 3H), 3.81/3.75 (s, 3H), 3.31-3.14 (m, 2H), 3.03-2.90 (m, 1H), 2.96/2.62 (s, 3H), 2.84-2.78 (m, 1 H), 1.89-1.73 (m, 2H); UPLCMS Rt, = 1.09 min; [M+H]+ = 421.3].
Example 4.2: (S)-2-chloro-6-methoxy-N-methyl-N-(4-M-methyl-1 H-pyrrole-2- carboxamido)-1-phenylbutan-2-yl)isonicotinamide
Figure imgf000147_0002
1-Methyl-1 H-pyrrole-2-carboxylic acid ((S)-3-methylamino-4-phenyl-butyl)-amide hydrochloride (100 mg, 0.31 mmol), 2-chloro-6-methoxyisonicotinic acid (58 mg, 0.31 mmol), HOBt (74 mg, 0.466 mmol), EDC x HCI (72 mg, 0.37 mmol), and triethylamine (0.108 ml, 0.78 mmol) were dissolved in DCM (3 ml) and stirred at rt for 16 h. The mixture was concentrated and the crude product was purified by chromatography (Flashmaster, DCM to DCM:EtOAc 1 :1 over 15 min) to yield 108 mg (76 %) of the title compound as white solid. [1 H-NMR (DMSO, 600 MHz) 7.95-7.90 (m, 1 H), 7.33.7.22, 7.10-7.06 (2m, 5H), 6.87 (d, 1 H), 6.70/6.63 (d, 1H), 6.65/6.33 (s, 1 H), 6.06/5.71 (br.s, 1H), 6.00-5.97 (m, 1 H), 4.88-4.81/3.55-3.49 (m, 1H), 3.84/3.71 (s, 3H), 3.80/3.79 (s, 3H), 3.27-3.18/3.05-2.99 (m, 2H), 2.97/2.62 (s, 3H), 2.95-2.90/2.84-2.76 (m, 2H), 1.91-1.75 (m, 2H); LCMS Rtc = 2.466 min; [M+H]+ = 455.2].
Example 4.3: (S)-2-chloro-N.6-dimethyl-N-(4-(1-methyl-1H-pyrrole-2-carboxamido)-1- phenylbutan-2-vhisonicotinamide
Figure imgf000148_0001
1-Methyl-1H-pyrrole-2-carboxylic acid ((S)-3-methylamino-4-phenyl-butyl)-amide hydrochloride (100 mg, 0.31 mmol), 2-chloro-6-methylisonicotinic acid (53 mg, 0.31 mmol), HOBt (74 mg, 0.466 mmol), EDC x HCI (72 mg, 0.37 mmol), and triethylamine (0.108 ml, 0.78 mmol) were dissolved in DCM (3 ml) and stirred at rt for 72 h. The mixture was concentrated and the crude product was purified by chromatography (Flashmaster, DCM to DCM:EtOAc 1 :1 over 15 min) to yield 119 mg (87 %) of the title compound as pink solid. [1 H-NMR (DMSO, 600 MHz) 7.96-7.91 (m, 1 H), 7.35-7.22, 7.10-7.06 (2m, 5H), 6.88 (d, 1 H), 6.88-6.82 (m, 1 H), 6.71/6.63 (d, 1 H), 6.25-6.01 (br. s, 1 H), 6.01-5.97 (m, 1H), 4.87-4.81/3.52-3.46 (m, 1 H), 3.81/3.76 (s, 3H), 3.30-3.22/3.06-3.00 (m, 2H), 2.99/2.63 (s, 3H), 2.85-2.77 (m, 2H), 2.42/2.12 (s, 3H), 1.91-1.76 (m, 2H); LCMS Rtc = 1.763 min; [M+H]+ = 439.0].
Examples 4.4 to 4.59, as mentioned below, were prepared or can be prepared in analogy to the methods described above using the appropriate starting materials or intermediates.
Example 4.4: (S)-6-methoxy-N-methyl-N-(1-phenyl-4-(picolinamido)butan-2- vhpicolinamide
Figure imgf000148_0002
Obtained in analogy to Example 1.1. [LCMS RtA = 2.582 min; [M+H]+ Example 4.5: (S)-6-methoxy-N-methyl-N-(4- -methyl-1 H-pyrrole-2-carboxamido)-1- phenylbutan-2-yl)nicotinamide
Figure imgf000149_0001
Obtained in analogy to Example 4.2. [LCMS RtB = 3.234 min; [M+H]+ = 421.2]
Example 4.6: (S)-3.5-difluoro-N-methyl-N-(4-(1-methyl-1H-pyrrole-2-carboxamido)-1- phenylbutan-2-vQpicolinamide
Figure imgf000149_0002
Obtained in analogy to Example 4.2. [LCMS RtA = 2.629 min; [M+H]+ = 427.2]
Example 4.7: (S)-2.6-dichloro-N-methyl-N-(4-(1-methyl-1H-pyrrole-2-carboxamido)-1- phenylbutan-2-yl)isonicotinamide
Figure imgf000149_0003
Obtained in analogy to Example 4.2. [LCMS Rtc = 2.629 min; [M+H]+ = 459.0/460.0/461.0]
Example 4.8: (S)-N.2-dimethyl-N-f4-(1-methyl-1H-pyrrole-2-carboxamido)-1- henylbutan-2-yl)isonicotinamide
Figure imgf000149_0004
Obtained in analogy to Example 4.2. [LCMS Rtc = 2.578 min; [M+H]+ = 4317.2] Example 4.9: (S)-2.6-difluoro-N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1■ phenylbutan-2-yl)isonicotinamide
Figure imgf000150_0001
Obtained in analogy to Example 4.2. [UPLCMS Rt, = 1.19 min; [M+H]+ = 427.2]
Example 4.10: (S)-6-methoxy-N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1- phenylbutan-2-vQpicolinamide
Figure imgf000150_0002
Obtained in analogy to Example 4.1. [UPLCMS Rt, = 1.17 min; [M+H]+ = 421.3]
Example 4.11: (S)-4.6-dimethoxy-N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)- -phenylbutan-2-yl)pyrimidine-2-carboxamide
Figure imgf000150_0003
Obtained in analogy to Example 4.1. [UPLCMS Rt, = 1.14/1.21 min (rotamers); [M+H]+ = 452.3]
Example 4.12: (S)-4-methoxy-N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1- phenylbutan-2-yl)picolinamide
Figure imgf000151_0001
Obtained in analogy to Example 4.1. [UPLCMS Rt, = 1.06 min; [M+H]+ = 421.3]
Example 4.13: (S)-N.6-dimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1■ phenyl butan-2-vhpicolinamide
Figure imgf000151_0002
Obtained in analogy to Example 1.4. [LCMS RtH = 1.13 min; [M+H]+ = 405.6]
Example 4.14: (S)-N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1 -phenylbutan- -yl)-1.4.5.6-tetrahvdrocvclopentarclpyrazole-3-carboxamide
Figure imgf000151_0003
Obtained in analogy to Example 1.4. [LCMS RtH = 1.21 min; [M+H]+ = 420.6]
Example 4.15: (S)-N,2-dimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1- phenylbutan-2-yl)-4.5.6.7-tetrahvdro-2H-indazole-3-carboxamide
Figure imgf000151_0004
Obtained in analogy to Example 1.4. [LCMS RtH = 1.31 min; [M+H]+ = 448.6] Example 4.16: (S)-N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1 -phenylbutan- -yl)-4.5.6.7-tetrahvdro-2H-indazole-3-carboxamide
Figure imgf000152_0001
Obtained in analogy to Example 1.4. [LCMS RtH = 1 25 min; [M+H]+ = 434.6]
Example 4.17: (S)-N.3.5-trimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamidoH- henylbutan-2-yl)isoxazole-4-carboxamide
Figure imgf000152_0002
Obtained in analogy to Example 1.4. [LCMS RtH = 1.25 min; [M+H]+ = 409.6]
Example 4.18: (S)-2-ethoxy-N.6-dimethyl-N-(4-f 1 -methyl-1 H-pyrrole-2-carboxamido)-1 - henylbutan-2-yl)isonicotinamide
Figure imgf000152_0003
Obtained in analogy to Example 1.2. [LCMS Rtj = 1.09 min; [M+H]+ = 449.4]
Example 4.19: (S)-2-methoxy-N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1 - henylbutan-2-yl)nicotinamide
Figure imgf000152_0004
Obtained in analogy to Example 1.2. [LCMS Rtj = 1.03 min (broad); [M+H]+ Example 4.20: (S)-2.6-dimethoxy-N-methyl-N-f4-(1-methyl-1H-pyrrole-2-carboxamido)- 1-phenylbutan-2-yl)isonicotinamide
Figure imgf000153_0001
(S)-1-methyl-N-(3-(methylamino)-4-phenylbutyl)-1 H-pyrrole-2-carboxamide hydrochloride (287 mg, 0.84 mmol), 2,6-dimethoxyisonicotinic acid (155 mg, 0.84 mmol), HOBt (194 mg, 1.27 mmol), EDC x HCI (195 mg, 1.02 mmol), and triethylamine (0.30 ml, 2.1 mmol) were dissolved in DCM (10 ml) and stirred at rt for 18 h. The mixture was concentrated and the crude product was purified by chromatography (Biotage Isolera, DCM to DCM:MeOH 95:5) to yield 289 mg (74%) of the title compound as white solid. [1 H-NMR (DMSO, 400 MHz, rotamers) 7.93/7.91 (t, 1 H) 7.43-7.20 (m, 4H), 7.08-7.04 (m, 1 H), 6.87 (d, 1 H), 6.70/6.61 (m, 1 H), 6.00-5.96 (m, 1 H), 5.88/5.51 (s, 1 H), 4.92-4.81/3.62-3.55 (br s, 1 H), 3.82/3.74 (s, 6H), 3.81/3.78 (s, 3H), 3.27-3.10/3.01-2.95 (m, 2H), 2.95/2.60 (s, 3H), 2.91/2.80 (br d, 2H), 1.87/1.69 (m, 2H); LCMS Rtj = 1.06 min (broad); [M+H]+ = 451.2].
Example 4.21 : (S)-2-methoxy-N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1 - henyl butan-2-yl)pyrimidine-4-carboxamide
Figure imgf000153_0002
(S)-1-methyl-N-(3-(methylamino)-4-phenylbutyl)-1 H-pyrrole-2-carboxamide hydrochloride (100 mg, 0.31 mmol), 2-methoxypyrimidine-4-carboxylic acid (48 mg, 0.31 mmol), HOBt (74 mg, 0.47 mmol) and triethylamine (79 mg, 0.78 mmol) were dissolved in DCM (3 ml). Then, EDC x HCI (72 mg, 0.37 mmol) was added and the mixture stirred at rt for 72 h. The mixture was concentrated and the crude product was purified by chromatography (Biotage Isolera, DCM to DCM:MeOH 96:4) to yield 97 mg (74%) of the title compound as white foam. [1 H- NMR (DMSO, 600 MHz, rotamers) 8.68/8.40 (d, 1 H), 7.97-7.91 (m, 1 H), 7.32-7.20/7.04-7.00 (m, 5H), 6.87 (s, 1 H), 6.83/6.04 (d, 1 H), 6.71/6.65 (br s, 1 H), 5.99 (br s, 1 H), 4.85-4.75/3.75- 3.68 (m, 1 H), 3.89/3.85 (s, 3H), 3.81/3.79 (s, 3H), 3.32-3.07 (m, 2H), 2.98/2.73 (s, 3H), 2.95- 2.75 (m, 2H), 1.92-1.67 (m, 2H); LCMS Rtj = 0.91 min (broad); [M+H]+ = 422.3].
Example 4.22: (S)-N,2-dimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamidoH - henylbutan-2-yl)nicotinamide
Figure imgf000154_0001
Obtained in analogy to Example 1.2. [LCMS Rtj = 0.86 min; [M+H]+ = 405.3]
Example 4.23: (S)-4-methoxy-N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1- phenylbutan-2-yl)nicotinamide
Figure imgf000154_0002
Obtained in analogy to Example 1.2. [LCMS RtB = 2.584/2.745 min (rotamers); [M+H]+ = 421.2]
Example 4.24: (S)-2-ethyl-N.6-dimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamidoH- henylbutan-2-yl)isonicotinamide
Figure imgf000154_0003
Obtained in analogy to Example 1.2. [LCMS Rtj = 0.86 min; [M+H]+ = 433.2]
Example 4.25: (S)-4.6-dichloro-N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1- phenylbutan-2-yl)picolinamide
Figure imgf000155_0001
Obtained in analogy to Example 1.2. [LCMS RtA = 3.098 min; [M+H]+ = 459.0/461.0]
Example 4.26: (S)-4-methoxy-N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamidoM■ henylbutan-2-yl)pyrimidine-2-carboxamide
Figure imgf000155_0002
Obtained in analogy to Example 1.2. [LCMS Rtj = 1.04 min; [M+H]+ = 448.2]
Example 4.27: (S)-4.6-dimethoxy-N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)- -phenylbutan-2-yl)picolinamide
Figure imgf000155_0003
Obtained in analogy to Example 1.2. [LCMS RtA = 2.792 min; [M+H]+ = 451.2]
Example 4.28: (S)-6-methoxy-N.4-dimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)- 1 -phenylbutan-2-yl)picolinamide
Figure imgf000155_0004
Obtained in analogy to Example 1.2. [LCMS RtA = 2.905 min; [M+H]+ = 435.2] Example 4.29: (S)-N.2.6-trimethyl-N-(4-H -methyl-1 H-pyrrole-2-carboxamidoH - henylbutan-2-yl)isonicotinamide
Figure imgf000156_0001
Obtained in analogy to Example 1.8. [LCMS Rtj = 0.77 min; [M+H]+ = 419.2]
Example 4.30: (S)-N.2.5-trimethyl-N-(4- -methyl-1 H-pyrrole-2-carboxamidoH - henylbutan-2-vDisonicotinamide
Figure imgf000156_0002
Obtained in analogy to Example 1.8. [LCMS Rtj = 0.77/0.88 min (rotamers); [M+H]+ = 419.2]
Example 4.31: (S)-2-methoxy-N.5-dimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)- -phenylbutan-2-yl)isonicotinamide
Figure imgf000156_0003
Obtained in analogy to Example 1.2. [LCMS Rtj = 1.05 min; [M+H]+ = 435.3]
Example 4.32: (S)-N-(3-f2-methoxy-N.6-dimethylisonicotinamido)-4-phenylbutyl)-1 - methyl-1 H-benzordlimidazole-2-carboxamide
Figure imgf000157_0001
Obtained in analogy to Example 1.2. [LCMS Rtj = 1.12 min; [M+H]+ = 486.2]
Example 4.33: (S)-2-isopropyl-N.6-dimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)- 1- henylbutan-2-yl)isonicotinamide
Figure imgf000157_0002
Obtained in analogy to Example 1.8. [LCMS Rtj = 0.96 min; [M+H]+ = 447.4]
Example 4.34: (S)-N.2.5-trimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1 - phenylbutan-2-yl)nicotinamide
Figure imgf000157_0003
Obtained in analogy to Example 1.8. [LCMS Rtj = 1.03/1.05 min (rotamers); [M+H]+
Example 4.35: (S)-5-chloro-2-methoxy-N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2- carboxamidoH -phenyl butan-2-yl)nicotinamide
Figure imgf000157_0004
Obtained in analogy to Example 1.8. [LCMS Rtj = 1.10/1.15 min (rotamers); [M+H]+ = 455.3/457.3]
Example 4.36; (S)-2-ethyl-N-(4-(1 -ethyl-3-methyl-1 H-pyrazole-5-carboxamido)-1 - henylbutan-2-yl)-N.6-dimethylisonicotinamide
Figure imgf000158_0001
Obtained in analogy to Example 1.2. [LCMS Rtj = 0.85 min; [M+H]+ = 462.4]
Example 4.37: (S)-N-(4-(1 -ethyl-3-methyl-1 H-pyrazole-5-carboxamido)-1 -phenylbutan-2- l)-2-methoxy-N.6-dimethylisonicotinamide
Figure imgf000158_0002
Obtained in analogy to Example 1.2. [LCMS Rtj = 1.00 min; [M+H]+ = 464.2]
Example 4.38: (S)-2-ethoxy-N-(4-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1- henylbutan-2-yl)-N,6-dimethylisonicotinamide
Figure imgf000158_0003
Obtained in analogy to Example 1.2. [LCMS Rtj = 1.08 min; [M+H]+ = 478.4]
Example 4.39: (S)-N-(4- 1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1-phenylbutan-2- yl)-2.6-dimethoxy-N-methylisonicotinamide
Figure imgf000159_0001
Obtained in analogy to Example 1.2. [LCMS Rtj = 1.05 min; [M+H]+ = 480.4]
Example 4.40: (S)-N-(4-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1-phenylbutan-2- l)-4.6-dimethoxy-N-methylpyrimidine-2-carboxamide
Figure imgf000159_0002
Obtained in analogy to Example 1.2. [LCMS Rtj = 0.99/1.06 min (rotamers); [M+H]+ = 481.4]
Example 4.41 : (S)-6-methoxy-N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1- phenylbutan-2-yl)pyrazine-2-carboxamide
Figure imgf000159_0003
Obtained in analogy to Example 1.2. [LCMS Rtj = 0.95 min; [M+H]+ = 422.3]
Example 4.42: (S)-5-methoxy-N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1- phenylbutan-2-yl)nicotinamide
Figure imgf000159_0004
Obtained in analogy to Example 1.2. [LCMS Rtj = 0.89 min; [M+H]+ = 421.3] Example 4.43: (S)-2-ethoxy-N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1 - henylbutan-2-yl)pyrimidine-4-carboxamide
Figure imgf000160_0001
Obtained in analogy to Example 1.2. [LCMS Rtj = 21.01/1.03 min (rotamers); [M+H]+ = 436.3]
Example 4.44: (S)-2-isopropoxy-N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1 - henylbutan-2-yl)pyrimidine-4-carboxamide
Figure imgf000160_0002
Obtained in analogy to Example 1.2. [LCMS Rtj = 1.04 min; [M+H]+ = 450.2]
Example 4.45: (S)-2-methoxy-N.6-dimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)- 1- henylbutan-2-yl)isonicotinamide
Figure imgf000160_0003
Obtained in analogy to Example 1.2. [LCMS Rtj = 1.16 min; [M+H]+ = 435.3]
Example 4.46: (S)-2.6-dimethoxy-N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)- 1-phenylbutan-2-vhpyrimidine-4-carboxamide
Figure imgf000161_0001
Obtained in analogy to Example 1.2. [LCMS Rtj = 1.00 min; [M+H]+ = 452.3]
Example 4.47: (S)-N.2-dimethyl-N-(4-(1 -methyl-1 H-pyrrole-2 -carboxamidoH- henylbutan-2-yl¾-6-(pyrrolidin-1-yl)isonicotinamide
Figure imgf000161_0002
Obtained in analogy to Example 1.2. [LCMS Rtj = 0.79 min; [M+H]+ = 474.3]
Example 4.48: (S)-N-(3-(2-methoxy-N.6-dimethylisonicotinamido)-4-phenylbutyl)-6- methylpicolinamide
Figure imgf000161_0003
Obtained in analogy to Example 1.2. [LCMS Rtj = 1.05 min; [M+H]+ = 447.2]
Example 4.49: (S)-N-(3-(2.6-dimethoxy-N-methylisonicotinamido)-4-phenylbutyl)-6- methylpicolinamide
Figure imgf000161_0004
Obtained in analogy to Example 1.2. [LCMS Rtj = 1.09 min; [M+H]+ = 463.2]
Example 4.50: (S)-2-methoxy-N-methyl-N-(4-(6-methylpicolinamido)-1 -phenylbutan-2- l)pyrimidine-4-carboxamide
Figure imgf000162_0001
Obtained in analogy to Example 1.2. [LCMS Rtj = 0.95 min; [M+H]+ = 434.2]
Example 4.51 : fS)-2-methoxy-N-(4-(6-methoxypicolinamido)-1-phenylbutan-2-vn-N- meth lpyrimidine-4-carboxamide
Figure imgf000162_0002
Obtained in analogy to Example 1.2. [LCMS Rtj = 0.97 min; [M+H]+ = 450.2]
Example 4.52: (S)-N-(3-(2-methoxy-N-methylpyrimidine-4-carboxamido)-4-phenylbutyl)- 1 -meth l-1 H-benzofdtimidazole-2-carboxamide
Figure imgf000162_0003
Obtained in analogy to Example 1.2. [LCMS Rtj = 1.01 min; [M+H]+ = 473.2]
Example 4.53: (S)-N.2-dimethyl-N-(4-(6-methylpicolinamido)-1-phenylbutan-2- yl)pyrimidine-4-carboxamide
Figure imgf000163_0001
Obtained in analogy to Example 1.2. [LCMS Rtj = 0.91 min; [M+H]+ = 418.1]
Example 4.54: (S)-N-(4-(6-methoxypicolinamido)-1 -phenylbutan-2-yl)-N.2- dimeth lpyrimidine-4-carboxamide
Figure imgf000163_0002
Obtained in analogy to Example 1.2. [LCMS Rtj = 0.93 min; [M+H]+ = 434.1]
Example 4.55: (S)-N-f 3-(N.2-dimethylpyrimidine-4-carboxamido)-4-phenylbutyl)-1 - meth l-1H-benzord1imidazole-2-carboxamide
Figure imgf000163_0003
Obtained in analogy to Example 1.2. [LCMS Rtj = 0.98 min; [M+H]+ = 457.2]
Example 4.56: fS)-6-methoxy-N-(3-(2-methoxy-N.6-dimethylisonicot'inamido)-4- henylbutvDpicolinamide
Figure imgf000163_0004
Obtained in analogy to Example 1.2. [LCMS Rtj = 1.07 min; [M+H]+ = 463.2] Example 4.57: fS)-N-(3-f2.6-dimethoxy-N-methylisonicotinamido)-4-phenylbutyl)-6- meth xypicolinamide
Figure imgf000164_0001
Obtained in analogy to Example 1.2. [LCMS Rtj = 1.11 min; [M+H]+ = 479.1]
Example 4.58: fS -1-ethyl-N.3-dimethyl-N-(4-(1-methyl-1H-pyrrole-2-carboxamido)-1- henylbutan-2-yl)-1H-pyrazole-5-carboxamide
Figure imgf000164_0002
Obtained in analogy to Example 1.2. [LCMS Rtj = 1.01 min; [M+H]+ = 422.3]
Example 4.59: (S)-N,1,3,5-tetramethyl-N-(4-(1-methyl-1H-pyrrole-2-carboxamido)-1- henylbutan-2-yl)-1H-pyrazole-4-carboxamide
Figure imgf000164_0003
Obtained in analogy to Example 1.2. [LCMS Rtj = 0.93 min; [M+H]+ = 422.3] Radioligand binding assay I
For crude cell membrane preparations, cells (CHO, Chinese hamster ovary or HEK, human embryonic kidney) expressing human orexin 1 or human orexin 2 receptors, were washed with HEPES (10 mM, pH 7.5), scraped off the culture plates with the same buffer, and centrifuged at 4°C for 5 min at 2500 x g. The cell pellet was either stored at -80°C or used directly. Before the experiments, cell membranes were re-suspended in binding assay buffer (10 mM HEPES, 0.5% (w/v) bovine serum albumin, pH 7.5) by homogenisation with a Polytron homogeniser at 50 Hz for 20 s. Cell membranes were also used as made available by commercial providers.
In initial saturation experiments (to calculate Bmax), cell homogenates (150 μΙ) were incubated with 25- 300 pM of the radioligand ([125l)orexin A, 50μΙ), 8 concentrations in triplicates in the presence or absence Orexin A (1 μΜ, 50μΙ) to define non specific binding. Bound radioactivity was measured, and data were analysed with the program XLFIT or Graphpad Prism. Protein concentration was determined according to the Bradford / BioRad Protein Assay Kit.
In competition experiments, cell homogenates (150μΙ) were incubated in assay buffer (10 mM HEPES, pH 7.5, 0.5 % (w/v) bovine serum albumin, 5 mM MgCI2, 1 mMCaCI2, and tween 0.05%) for 1 h at room temperature with about 100 pM of the radioligand ([125l]orexin A, 2100 Ci/mmole, 50 μΙ), and with various concentrations of compounds of the invention (50 μΙ) in triplicates; non-specific binding was determined in the presence of Orexin A (1 μΜ). Reactions were terminated by vacuum filtration, 3 washes of ice cold wash buffer (Tris-HCI pH 7.4 / 10 mM, with NaCI 154 mM). Competition data is expressed in Tables 1-4 as Kd [μΜ].
Radioligand binding assay II
For crude cell membrane preparations, cells (CHO, Chinese hamster ovary or HEK, human embryonic kidney) expressing human orexin 1 or human orexin 2 receptors, were washed with HEPES (10 mM, pH 7.5), scraped off the culture plates with the same buffer, and centrifuged at 4°C for 5 min at 2500 x g. The cell pellet was either stored at -80°C or used directly. Before the experiments, cell membranes were re-suspended in binding assay buffer (10 mM HEPES, 0.5% (w/v) bovine serum albumin, pH 7.5) by homogenisation with a Polytron homogeniser at 50 Hz for 20 s. Cell membranes were also used as made available by commercial providers.
In initial saturation experiments (to calculate Kd and Bmax), cell homogenates (150 μΙ) were incubated with 0.1 to 15 nM of the radioligand ([3H]-SB649868, 50μΙ), 8 concentrations in triplicates in the presence or absence of almorexant (10 μΜ, 50μΙ) to define non specific binding. Bound radioactivity was measured, and data were analysed with the program XLFIT or Graphpad Prism. Protein concentration was determined according to the Bradford / BioRad Protein Assay Kit.
In competition experiments, cell homogenates (150μΙ) were incubated in assay buffer (10 mM HEPES, pH 7.5, 0.5 % (w/v) bovine serum albumin, 5 mM MgCI2, 1 mMCaCI2, and tween 0.05%) for 1 h at room temperature with about 1 nM of the radioligand [3H]-SB649868, 66 Ci/mmole, 50 μΙ), and with various concentrations of compounds of the invention (50 μΙ) in triplicates; non-specific binding was determined in the presence of almorexant (10 μΜ). Reactions were terminated by vacuum filtration, 3 washes of ice cold wash buffer (Tris-HCI pH 7.4 / 10 mM, with NaC1 154 mM). Competition data is expressed in Tables 1-4 as Kd [μΜ].
Calcium accumulation in cells (FLIPR):
Cells expressing human orexin 1 or human orexin 2 receptors, were seeded at 8,000 cells/well in 384 well black-walled clear bottom, poly-D-lysine coated plates. After 24 h, the medium was removed and cells were washed once with phosphate buffered saline and serum-deprived overnight in assay buffer (130 mM NaCI, 5.4 mM KCI, 1.8 mM CaCI2, 0.8 mM MgS04, 0.9 mM NaH2P04, 25 mM glucose, 20 mM HEPES, pH 7.4) containing bovine serum albumin (1 % w/v).
On the day of the experiment, the cells seeded in black plates were treated with assay buffer containing the Ca2+ sensitive fluorescent dye Fluo4-AM (2 μΜ), and probenecid (0.1 mM). After 1 h plates were washed twice with, and resuspended in, assay buffer containing probenecid (0.1 mM) using a multi plate washer. The plates were placed into a FLIPR II (Fluorometric Imaging Plate Reader, Molecular Devices, Sunnyvale, CA, USA) and baseline fluorescence (fluorescence light units, FLU) was measured (5 measurements, 2 S each; laser excitation 488nm at 0.6-1 W, CCD camera exposure 0.4 s) before addition of buffer alone (basal) or containing test compounds (either compound of formula I alone, agonist alone or agonist in the presence of various concentrations of compounds of formula I).
Fluorescence measurements were then continued every 1 S for 120 S followed by every 4 S for 240 S.
The measurements were typically made in two sequences:
In the first round, compounds of formula I were tested alone, to confirm that they do not display any/any significant agonist activity. Compounds of formula I were tested usually in a concentration range from 10"9 M to 10"5 M.
In the second round, performed one hour later (to allow for equilibration), Orexin A was tested either in the absence (calibration curves, Orexin A agonist controls) or in the presence of compounds of formula I to determine antagonism.
Inhibition data is expressed in Table 2 as K<j [μΜ], converted by the Cheng and Prusoff correction (Kd = IC5o/1 +(L/EC5o)), where IC50 is the 50% inhibition value determined in concentration response inhibition curves, EC50 is the half maximal activation concentration determined for orexin A in concentration response curves and L is the concentration of orexin A used in inhibition experiments performed in with a submaximal concentration of orexin A in the presence of up to 8 increasing concentrations of compound of formula I.
Inhibition data is also expressed in Tables 1-4 as % inhibition value measured at a
concentration of 10 μΜ of compound of formula I.
Table 1 :
FLIPR FLIPR Binding I Binding I Binding II Binding II
No hOxI R hOx2R hOxI R hOx2R hOxI R hOx2R
Kd [μΜ] Kd [μΜ] Kd [μΜ] Kd [μΜ] Kd [μΜ] Kd [μΜ]
1.1 15 a 38 a n.d. n.d. n.d. n.d.
1.2 0.375 0.012 0.056 0.023 n.d. n.d.
1.3 0.392 0.018 0.062 0.014 n.d. n.d.
1.4 2.571 0.010 1.554 0.046 1.478 0.039
1.5 0.388 0.010 0.108 0.019 n.d. n.d.
1.6 0.895 0.037 0.342 0.044 n.d. n.d.
1.7 0.386 0.009 0.174 0.020 n.d. n.d.
1.8 0.042 0.000 0.028 0.005 n.d. n.d.
1.9 1.447 0.694 n.d. n.d. n.d. n.d.
1.10 28 a 0.056 2.563 0.059 n.d. n.d.
1.1 1 0.710 0.287 n.d. n.d. n.d. n.d.
1.12 0.896 0.015 0.132 0.034 n.d. n.d.
1.13 1.852 0.012 0.81 1 0.019 n.d. n.d.
1.14 26 a 0.442 n.d. n.d. n.d. n.d.
1.15 1.647 0.055 0.844 0.062 n.d. n.d.
1.16 0.589 0.520 n.d. n.d. n.d. n.d.
1.17 2.481 0.428 n.d. n.d. n.d. n.d.
1.18 34 a 0.469 n.d. n.d. n.d. n.d.
1.19 2.976 0.054 2.933 0.462 n.d. n.d.
1.20 32 a 0.185 n.d. n.d. n.d. n.d.
1.21 1.047 0.164 n.d. n.d. n.d. n.d.
1.22 0.204 0.010 0.536 0.054 n.d. n.d.
1.23 0.068 0.015 0.098 0.070 n.d. n.d. FLIPR FLIPR Binding I Binding I Binding II Binding II hOxI R hOx2R hOxI R hOx2R hOxI R hOx2R
Kd [μΜ] Kd [μΜ] Kd [μΜ] Kd [μΜ] Kd [μΜ] Kd [μΜ]
40 a 1.742 n.d. n.d. n.d. n.d.
1.290 0.042 1.299 0.124 n.d. n.d.
0.571 0.251 0.230 0.278 n.d. n.d.
1.812 0.046 1.324 0.166 n.d. n.d.
2.269 0.712 n.d. n.d. n.d. n.d.
0.945 0.021 0.509 0.039 n.d. n.d.
1.183 0.332 0.639 0.353 n.d. n.d.
1.757 0.294 0.359 0.324 n.d. n.d.
2.795 0.573 n.d. n.d. n.d. n.d.
50 a 0.538 0.286 0.236 n.d. n.d.
0.819 0.018 0.672 0.038 n.d. n.d.
1.447 0.955 n.d. n.d. n.d. n.d.
0.215 0.002 0.152 0.006 n.d. n.d.
0.857 1.177 n.d. n.d. n.d. n.d.
0.514 0.002 0.284 0.015 n.d. n.d.
1.343 1.131 n.d. n.d. n.d. n.d.
2.829 2.008 n.d. n.d. n.d. n.d.
0.058 0.026 0.143 0.140 n.d. n.d.
0.428 0.228 0.300 0.211 n.d. n.d.
40 a 32 a n.d. n.d. n.d. n.d.
0.857 0.485 n.d. n.d. n.d. n.d.
2.114 0.738 n.d. n.d. n.d. n.d.
0.931 0.009 0.706 0.033 n.d. n.d.
27 a 0.380 n.d. n.d. n.d. n.d.
2.234 2.200 n.d. n.d. n.d. n.d.
41 a 1.720 n.d. n.d. n.d. n.d.
28 a 1.560 n.d. n.d. n.d. n.d.
0.868 0.198 n.d. n.d. n.d. n.d.
0.053 0.002 0.033 0.012 n.d. n.d.
0.261 0.003 0.140 0.019 n.d. n.d. FLIPR FLIPR Binding I Binding I Binding II Binding II hOxI R hOx2R hOxI R hOx2R hOxI R hOx2R
Kd [μΜ] Kd [μΜ] Kd [μΜ] Kd [μΜ] Kd [μΜ] Kd [μΜ]
0.038 0.001 0.022 0.004 n.d. n.d.
32 a 20 a n.d. n.d. n.d. n.d.
16a 0.411 n.d. n.d. n.d. n.d.
0.018 0.011 0.01 1 0.025 n.d. n.d.
1.661 0.585 n.d. n.d. n.d. n.d.
0.036 0.001 n.d. n.d. 0.015 0.004
31 a 0.032 2.253 0.067 n.d. n.d.
14 a 0.493 n.d. n.d. n.d. n.d.
0.649 0.010 0.126 0.022 n.d. n.d.
20 a 0.548 n.d. n.d. n.d. n.d.
35 a 2.244 n.d. n.d. n.d. n.d.
44 a 40 a n.d. n.d. n.d. n.d.
0.690 0.002 0.209 0.011 n.d. n.d.
0.330 0.060 2.032 0.192 n.d. n.d.
0.256 0.012 n.d. n.d. 0.064 0.030
34 a 0.043 n.d. n.d. 2.676 0.106
1.232 0.070 1.903 0.112 n.d. n.d.
25 a 0.731 n.d. n.d. n.d. n.d.
0.671 0.012 0.775 0.048 1.120 0.043
17 a 1.150 n.d. n.d. n.d. n.d.
0.479 0.024 0.377 0.052 n.d. n.d.
293 1.180 n.d. n.d. n.d. n.d.
2.728 0.121 n.d. n.d. n.d. n.d.
0.046 0.006 n.d. n.d. 0.014 0.004
0.022 0.005 n.d. n.d. 0.099 0.1 10
1.486 0.011 n.d. n.d. 0.166 0.026
0.786 0.001 n.d. n.d. 0.330 0.007
1.586 0.001 n.d. n.d. 0.625 0.012
0.351 0.010 n.d. n.d. 0.118 0.028
0.554 0.048 0.231 0.052 n.d. n.d. FLIPR FLIPR Binding I Binding I Binding II Binding II
No hOxI R hOx2R hOxI R hOx2R hOxI R hOx2R
Kd [μΜ] Kd [μΜ] Kd [μΜ] Kd [μΜ] Kd [μΜ] Kd [μΜ]
1.84 0.776 0.000 n.d. n.d. 0.163 0.003
1.85 0.003 0.002 n.d. n.d. 0.004 0.007
1.86 3.143 0.005 n.d. n.d. 0.770 0.028
1.87 34 a 0.008 n.d. n.d. 0.461 0.024
1.88 3.151 0.026 n.d. n.d. 0.585 0.064
1.89 39 a 0.124 n.d. n.d. n.d. n.d.
1.90 0.146 0.018 n.d. n.d. 0.065 0.020
1.91 2.667 0.014 n.d. n.d. 1.281 0.053
1.92 1.380 0.009 n.d. n.d. 1.467 0.032
1.93 0.208 0.001 n.d. n.d. 0.135 0.003
1.94 1.629 0.004 n.d. n.d. 0.454 0.015
1.95 0.334 0.597 n.d. n.d. n.d. n.d.
1.96 26 a 29 a n.d. n.d. n.d. n.d.
1.97 13 a 38 a n.d. n.d. n.d. n.d.
1.98 25 a 32 a n.d. n.d. n.d. n.d.
1.99 18a 27 a n.d. n.d. n.d. n.d.
1.100 1.350 1.377 n.d. n.d. n.d. n.d.
1.101 0.044 0.002 n.d. n.d. 0.037 0.020
1.102 0.856 0.407 n.d. n.d. n.d. n.d. n.d. = not determined
a % inhibition value measured at a concentration of 10 μΜ of compound of formula I.
Table 2:
FLIPR FLIPR Binding I Binding I Binding II Binding II
No hOxI R hOx2R hOxI R hOx2R hOxI R hOx2R
Kd [μΜ] Kd [μΜ] Kd [μΜ] Kd [μΜ] Kd [μΜ] Kd [μΜ]
2.1 0.154 0.056 0.947 4.557 n.d. n.d.
2.2 0.223 0.002 0.113 0.008 n.d. 0.009
2.3 0.065 0.006 0.027 0.016 n.d. n.d. FLIPR FLIPR Binding I Binding I Binding II Binding II hOxI R hOx2R hOxI R hOx2R hOxI R hOx2R
Kd [μΜ] Kd [μΜ] Kd [μΜ] Kd [μΜ] Kd [μΜ] Kd [μΜ]
0.003 0.013 0.007 0.025 n.d. n.d.
1.560 0.564 n.d. n.d. n.d. n.d.
0.057 0.001 0.044 0.014 n.d. n.d.
0.967 0.011 0.794 0.027 n.d. n.d.
0.878 0.015 0.147 0.024 n.d. n.d.
1.269 0.274 n.d. n.d. n.d. n.d.
<10a 1.509 n.d. n.d. n.d. n.d.
0.551 0.271 n.d. n.d. n.d. n.d.
0.423 0.031 0.121 0.047 n.d. n.d.
37 a 0.565 0.853 0.468 n.d. n.d.
0.035 0.162 0.086 0.590 n.d. n.d.
0.193 0.221 0.125 0.619 n.d. n.d.
0.048 0.003 0.017 0.010 n.d. n.d.
0.012 0.013 0.006 0.023 n.d. n.d.
45 a 1.548 n.d. n.d. n.d. n.d.
1.116 0.022 0.320 0.014 n.d. n.d.
3.101 0.380 n.d. n.d. n.d. n.d.
0.022 0.016 0.021 0.052 n.d. n.d.
0.050 0.809 0.030 1.333 n.d. n.d.
0.237 0.394 n.d. n.d. n.d. n.d.
0.413 0.123 0.163 0.168 n.d. n.d.
1.005 1.070 0.540 6.859 n.d. n.d.
0.016 0.040 0.007 0.041 n.d. n.d.
0.864 0.171 0.195 0.174 n.d. n.d.
1.140 0.014 0.837 0.030 n.d. n.d.
0.207 0.018 0.174 0.026 n.d. n.d.
0.915 0.725 n.d. n.d. n.d. n.d.
0.089 0.003 0.040 0.009 n.d. n.d.
2.082 0.497 n.d. n.d. n.d. n.d.
0.237 0.029 0.250 0.058 n.d. n.d. FLIPR FLIPR Binding I Binding I Binding II Binding II hOxI R hOx2R hOxI R hOx2R hOxI R hOx2R
Kd [μΜ] Kd [μΜ] Kd [μΜ] Kd [μΜ] Kd [μΜ] Kd [μΜ]
20 a 1.837 n.d. n.d. n.d. n.d.
0.633 0.704 n.d. n.d. n.d. n.d.
0.178 0.006 0.064 0.014 n.d. n.d.
0.355 0.538 n.d. n.d. n.d. n.d.
0.397 0.006 0.107 0.013 n.d. n.d.
0.297 0.047 0.359 0.075 n.d. n.d.
24 a 33 a n.d. n.d. n.d. n.d.
0.175 0.033 0.237 0.063 n.d. n.d.
0.022 0.002 0.031 0.008 n.d. n.d.
1.576 0.230 n.d. n.d. n.d. n.d.
1.733 0.471 n.d. n.d. n.d. n.d.
1.700 0.044 0.793 0.033 n.d. n.d.
1.286 0.644 n.d. n.d. n.d. n.d.
1.113 0.161 n.d. n.d. n.d. n.d.
2.239 0.266 0.238 0.170 n.d. n.d.
1.157 0.156 0.257 0.130 n.d. n.d.
35 a 1.297 n.d. n.d. n.d. n.d.
1.195 0.156 0.135 0.098 n.d. n.d.
0.285 0.004 0.074 0.011 n.d. n.d.
53 a 0.646 n.d. n.d. n.d. n.d.
5.964 0.129 n.d. n.d. n.d. n.d.
3.976 0.094 1.439 0.075 n.d. n.d.
0.423 0.057 0.271 0.085 n.d. n.d.
0.174 0.010 0.176 0.030 n.d. n.d.
0.105 0.001 0.073 0.006 n.d. n.d.
0.323 0.001 0.179 0.006 n.d. n.d.
25 a 0.253 n.d. n.d. n.d. n.d.
1.067 0.088 n.d. n.d. 0.517 0.181
0.518 43 a n.d. n.d. n.d. n.d.
0.091 0.001 n.d. n.d. 0.108 0.009 FLIPR FLIPR Binding I Binding I Binding II Binding II
No hOxI R hOx2R hOxI R hOx2R hOxI R hOx2R
Kd [μΜ] Kd [μΜ] Kd [μΜ] Kd [μΜ] Kd [μΜ] Kd [μΜ]
2.64 1.402 0.003 n.d. n.d. 0.388 0.006
2.65 1.000 0.011 n.d. n.d. 0.298 0.023
2.66 1.402 0.004 n.d. n.d. 0.535 0.015
2.67 0.040 0.001 0.036 0.004 n.d. n.d.
2.68 0.039 0.000 0.038 0.006 n.d. n.d.
2.69 0.265 0.019 0.281 0.051 n.d. n.d.
2.70 0.986 0.007 0.318 0.020 n.d. n.d.
2.71 0.466 0.004 0.133 0.016 n.d. n.d.
2.72 2.080 0.281 n.d. n.d. n.d. n.d.
2.73 3.226 0.015 0.680 0.040 0.966 0.041
2.74 0.371 0.034 0.216 0.114 n.d. n.d.
2.75 0.859 0.065 0.419 0.065 n.d. n.d.
2.76 20 a 0.113 n.d. n.d. n.d. n.d.
2.77 1.155 0.400 n.d. n.d. n.d. n.d.
2.78 38 a 0.005 n.d. n.d. 0.560 0.048
2.79 0.583 0.119 n.d. n.d. 1.656 0.660
2.80 0.459 0.030 n.d. n.d. 0.316 0.107
2.81 0.028 0.000 n.d. n.d. 0.013 0.003 n.d. = not determined
% inhibition value measured at a concentration of 10 μΜ of compound of formula I.
Table 3:
FLIPR FLIPR Binding I Binding I Binding II Binding II
No hOxI R hOx2R hOxI R hOx2R hOxI R hOx2R
Kd [μΜ] Kd [μΜ] Kd [μΜ] Kd [μΜ] Kd [μΜ] Kd [μΜ]
3.1 0.177 0.014 0.074 0.030 n.d. n.d.
3.2 0.457 0.080 0.430 0.183 n.d. n.d.
3.3 15 a 37 a 10.013 4.017 n.d. n.d.
3.4 22 a 0.679 n.d. n.d. n.d. n.d.
3.5 2.382 33 a n.d. n.d. n.d. n.d. FLIPR FLIPR Binding I Binding I Binding II Binding II
No hOxI R hOx2R hOxI R hOx2R hOxI R hOx2R
Kd [μΜ] Kd [μΜ] Kd [μΜ] Kd [μΜ] Kd [μΜ] Kd [μΜ]
3.6 0.942 0.105 n.d. n.d. n.d. n.d.
3.7 0.744 0.665 n.d. n.d. n.d. n.d.
3.8 2.100 0.430 n.d. n.d. n.d. n.d.
3.9 36 a 1.004 n.d. n.d. n.d. n.d.
3.10 2.045 0.213 n.d. n.d. n.d. n.d.
3.11 1.351 0.555 n.d. n.d. n.d. n.d.
3.12 0.292 0.123 n.d. n.d. n.d. n.d.
3.13 3.344 0.020 0.989 0.228 n.d. n.d.
3.14 1.353 0.173 n.d. n.d. n.d. n.d.
3.15 1.052 0.500 n.d. n.d. n.d. n.d.
3.16 0.385 0.076 0.178 0.209 n.d. n.d.
3.17 0.487 0.103 0.203 0.152 n.d. n.d.
3.18 35 a 0.900 n.d. n.d. n.d. n.d.
3.19 0.356 0.025 0.1 19 0.052 n.d. n.d.
3.20 3.994 0.013 0.562 0.015 0.265 0.008
3.21 2.089 0.019 n.d. n.d. 1.394 0.049
3.22 <10 a 21 a n.d. n.d. n.d. n.d.
3.23 3.052 0.007 n.d. n.d. 1.070 0.022
3.24 25 a 29 a n.d. n.d. n.d. n.d. n.d. = not determined
a % inhibition value measured at a concentration of 10 μΜ of compound of formula I.
Table 4:
FLIPR FLIPR Binding I Binding I Binding II Binding II
No hOxI R hOx2R hOxI R hOx2R hOxI R hOx2R
Kd [μΜ] Kd [μΜ] Kd [μΜ] Kd [μΜ] Kd [μΜ] Kd [μΜ]
4.1 0.380 0.016 0.062 0.018 n.d. n.d.
4.2 0.052 0.001 0.036 0.004 n.d. n.d.
4.3 0.044 0.003 0.017 0.007 n.d. n.d.
4.4 <10a 0.840 n.d. n.d. n.d. n.d. FLIPR FLIPR Binding I Binding I Binding II Binding II hOxI R hOx2R hOxI R hOx2R hOxI R hOx2R
Kd [μΜ] Kd [μΜ] Kd [μΜ] Kd [μΜ] Kd [μΜ] Kd [μΜ]
21 a 0.974 n.d. n.d. n.d. n.d.
<10 a 50 a n.d. n.d. n.d. n.d.
0.049 0.002 0.029 0.005 n.d. n.d.
1.912 0.154 n.d. n.d. n.d. n.d.
1.040 0.063 0.503 0.167 n.d. n.d.
19a 0.225 n.d. n.d. n.d. n.d.
2.391 0.009 0.595 0.006 0.692 0.005
1.192 0.083 1.504 0.027 n.d. n.d.
42 a 1.085 n.d. n.d. n.d. n.d.
35 a 2.238 n.d. n.d. n.d. n.d.
25 a 0.640 n.d. n.d. n.d. n.d.
26 a 0.860 n.d. n.d. n.d. n.d.
17 a 2.200 n.d. n.d. n.d. n.d.
0.271 0.001 0.067 0.008 0.055 0.004
37 a 0.517 n.d. n.d. n.d. n.d.
0.080 0.001 0.034 0.002 0.032 0.002
2.200 0.009 0.903 0.011 n.d. n.d.
32 a 0.674 n.d. n.d. n.d. n.d.
19a 1.394 n.d. n.d. n.d. n.d.
0.576 0.024 0.100 0.040 n.d. n.d.
1.319 0.026 0.399 0.035 1.482 0.051
16 a 0.050 n.d. n.d. 7.534 0.029
2.420 0.015 0.757 0.043 0.857 0.014
2.054 0.036 n.d. n.d. 1.525 0.042
0.306 0.022 n.d. n.d. 0.094 0.055
1.739 0.008 n.d. n.d. 0.269 0.038
0.294 0.002 n.d. n.d. 0.056 0.008
0.043 0.020 n.d. n.d. 0.018 0.019
32 a 0.124 n.d. n.d. n.d. n.d.
20 a 2.188 n.d. n.d. n.d. n.d. FLIPR FLIPR Binding I Binding I Binding II Binding II
No hOxI R hOx2R hOxI R hOx2R hOxI R hOx2R
Kd [μΜ] Kd [μΜ] Kd [μΜ] Kd [μΜ] Kd [μΜ] Kd [μΜ]
4.35 0.192 0.002 n.d. n.d. 0.287 0.030
4.36 0.373 0.050 n.d. n.d. 0.080 0.071
4.37 0.1 16 0.003 n.d. n.d. 0.036 0.013
4.38 0.220 0.003 n.d. n.d. 0.099 0.019
4.39 0.170 0.002 n.d. n.d. 0.040 0.006
4.40 10 a 0.154 n.d. n.d. n.d. n.d.
4.41 <10 a 0.426 n.d. n.d. n.d. n.d.
4.42 263 0.607 n.d. n.d. n.d. n.d.
4.43 1.342 0.174 n.d. n.d. n.d. n.d.
4.44 19 a 0.359 n.d. n.d. n.d. n.d.
4.45 0.243 0.001 0.053 0.004 n.d. n.d.
4.46 1.697 0.023 0.302 0.019 n.d. n.d.
4.47 0.075 0.006 0.050 0.026 n.d. n.d.
4.48 0.785 0.016 n.d. n.d. 0.183 0.026
4.49 0.286 0.010 0.101 0.009 0.094 0.012
4.50 14 a 0.073 n.d. n.d. 5.858 0.151
4.51 34 a 0.017 n.d. n.d. 2.809 0.039
4.52 4.105 0.442 n.d. n.d. n.d. n.d.
4.53 <10 a 43 a n.d. n.d. n.d. n.d.
4.54 <10 a 0.783 n.d. n.d. n.d. n.d.
4.55 28 a 35 a n.d. n.d. n.d. n.d.
4.56 1.244 0.005 n.d. n.d. 0.433 0.008
4.57 0.418 0.001 n.d. n.d. 0.162 0.005
4.58 31 a 0.851 n.d. n.d. n.d. n.d.
4.59 14 a 43 a n.d. n.d. n.d. n.d. n.d. = not determined
% inhibition value measured at a concentration of 10 μΜ of compound of formula I. The following are further embodiments of the invention: Embodiment 1. A compound of the formula I
Figure imgf000177_0001
(I)
wherein
R is C1-6alkyl, C1-6halogenalkyl, C3-7cycloalkyl or C3-7cycloalkyl(C1-4alkyl);
R2> R3> R5 and R6 are each independently selected from hydrogen, halogen, hydroxyl, d.
6alkyl, C1-6halogenalkyl, C3.7cycloalkyl, C3-7cycloalkyl(C1-4alkyl), C1-6alkoxy, or
shalogenalkoxy;
or R2 and R3 together are oxo;
or R2 and R3 together with the carbon atom to which they are bound form a C3-7cycloalkyl; or R5 and R6 together are oxo;
or R5 and R6 together with the carbon atom to which they are bound form a C3-7cycloalkyl; R4 is hydrogen or C1-6alkyl;
A is a group A1 , A2, A3 or A4
Figure imgf000177_0002
A1 A2 A3 A4 wherein
A1 a is a five- to six-membered monocyclic aromatic ring system which contains from 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur, wherein the ring system may contain not more than 2 oxygen atoms and not more than 2 sulfur atoms, and wherein the ring system may be substituted once or more than once by R7, and wherein a substituent on a nitrogen in a heterocyclic ring system may not be halogen;
A1 b is a five- to six-membered monocyclic aromatic ring system which may contain from 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur, wherein the ring system may contain not more than 2 oxygen atoms and not more than 2 sulfur atoms, and wherein the ring system is fused to ring system A1 a via carbon and/or nitrogen atoms, and wherein the ring system may be substituted once or more than once by R8, and wherein a substituent on a nitrogen in a heterocyclic ring system may not be halogen;
each R7 or R8 independently is halogen, C1-6alkyl, C1-6halogenalkyl, C3.7cycloalkyl, C3- 7cycloalkyl(C1-4alkyl), C1-6alkoxy, or CLehalogenalkoxy;
A2a is a five- to six-membered monocyclic aromatic ring system which contains from 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur, wherein the ring system may contain not more than 2 oxygen atoms and not more than 2 sulfur atoms, and wherein the ring system is fused to the phenyl ring via two carbon atoms, and wherein the ring system may be substituted once or more than once by R10, and wherein a substituent on a nitrogen in a heterocyclic ring system may not be halogen;
n is 0, 1 , 2 or 3;
each R9 or R10 independently is halogen, d.6alkyl, CLehalogenalkyl, C3-7cycloalkyl, C3- 7cycloalkyl(C1-4alkyl), C1-6alkoxy, or C1-6halogenalkoxy;
each of A3a or A3b is independently a five- to six-membered monocyclic aromatic ring system which may contain from 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur, wherein the ring system may contain not more than 2 oxygen atoms and not more than 2 sulfur atoms, and wherein the ring system may be substituted once or more than once by Rn, and wherein a substituent on a nitrogen in a heterocyclic ring system may not be halogen;
each Rn independently is halogen, C1-6alkyl, C1-6halogenalkyl, C3.7cycloalkyl, C3.
7cycloalkyl(C1-4alkyl), C^alkoxy, or C1-6halogenalkoxy;
A4a is a five- to six-membered monocyclic aromatic ring system which contains from 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur, wherein the ring system may contain not more than 2 oxygen atoms and not more than 2 sulfur atoms, and wherein the ring system is substituted once or more than once by R12, and wherein a substituent on a nitrogen in a heterocyclic ring system may not be halogen;
each R12 independently is halogen; d.6alkyl; C1-6halogenalkyl; C1-6alkoxy; or
6halogenalkoxy; or a three- to eight-membered monocyclic or bicyclic saturated or unsaturated non-aromatic ring system which may contain from 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur, wherein the saturated or unsaturated non-aromatic ring system may contain not more than 2 oxygen atoms and not more than 2 sulfur atoms, wherein the saturated or unsaturated non-aromatic ring system may be attached directly to the ring system A4a or via a C1-4alkylene group, and wherein the saturated or unsaturated non-aromatic ring system may be substituted once or more than once by R13, and wherein a substituent on a nitrogen in a heterocyclic saturated or unsaturated non-aromatic ring system may not be halogen; or two R12 at adjacent ring atoms of the ring system A4a form together with said ring atoms a fused five- to seven-membered unsaturated non-aromatic ring system which may contain from 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur, wherein the fused unsaturated non-aromatic ring system may contain not more than 2 oxygen atoms and not more than 2 sulfur atoms, and wherein the fused unsaturated non- aromatic ring system may in turn be substituted once or more than once by R14, and wherein a substituent on a nitrogen in a heterocyclic fused unsaturated non-aromatic ring system may not be halogen;
each R13 independently is halogen, C1-6alkyl, C^ehalogenalkyl, C3-7cycloalkyl, C3-
7cycloalkyl(C1- alkyl), C -6alkoxy, or d-6halogenalkoxy; or two R13 at the same ring atom of the saturated or unsaturated non-aromatic ring system together are oxo;
each Ri4 independently is halogen or Ci-6alkyl, or two Ri4 at the same ring atom of the fused unsaturated non-aromatic ring system together are oxo;
B is
Figure imgf000179_0001
p is 0 or 1 ;
Ri5 is halogen, C1-6alkyl, C^halogenalkyl, C3.7cycloalkyl, C1-6alkoxy, or Ci-6halogenalkoxy; and
C is a five- to ten-membered monocyclic or fused polycyclic aromatic ring system which may contain from 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur, wherein the ring system may contain not more than 2 oxygen atoms and not more than 2 sulfur atoms, and wherein the ring system may be substituted once or more than once by R16, and wherein a substituent on a nitrogen in a heterocyclic ring system may not be halogen;
each R16 independently is C -6alkyl; Ci-6halogenalkyl; C1-6alkoxy; C -6halogenalkoxy; halogen; cyano; or two Ri6 at adjacent ring atoms of the ring system C form together with said ring atoms a fused five- to seven-membered unsaturated non-aromatic ring system which may contain from 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur, wherein the fused unsaturated non-aromatic ring system may contain not more than 2 oxygen atoms and not more than 2 sulfur atoms, and wherein the fused unsaturated non-aromatic ring system may in turn be substituted once or more than once by Ri7, and wherein a substituent on a nitrogen in a heterocyclic fused unsaturated non-aromatic ring system may not be halogen; each R17 independently is halogen or C1-6alkyl, or two R17 at the same ring atom of the fused unsaturated non-aromatic ring system together are oxo;
and provided that the compounds
1 -methyl-1 H-benzoimidazole-2-carboxylic acid {(S)-3-[(1 H-indole-4-carbonyl)-methyl-amino]- 4-phenyl-butyl}-amide;
1 H-indole-5-carboxylic acid {(S)-1-benzyl-3-[(pyridine-2-carbonyl)-amino]-propyl}-methyl- amide;
1 H-indole-4-carboxylic acid {(S)-1-benzyl-3-[(pyridine-2-carbonyl)-amino]-propyl}-methyl- amide;
pyridine-2-carboxylic acid {(S)-3-[(benzofuran-5-carbonyl)-methyl-amino]-4-phenyl-butyl}- amide;
1 -methyl-1 H-indole-7-carboxylic acid {(S)-1-benzyl-3-[(pyridine-2-carbonyl)-amino]-propyl}- methyl-amide;
1 H-indole-7-carboxylic acid {(S)-1 -benzyl-3-[(pyridine-2-carbonyl)-amino]-propyl}-methyl- amide;
1 -methyl-1 H-indole-4-carboxylic acid {(S)-1 -benzyl-3-[(pyridine-2-carbonyl)-amino]-propyl}- methyl-amide;
1 H-indole-6-carboxylic acid {(S)-1-benzyl-3-[(pyridine-2-carbonyl)-amino]-propyl}-methyl- amide;
1 -methyl-1 H-benzoimidazole-2-carboxylic acid {(S)-3-[(1 H-indole-5-carbonyl)-methyl-amino]- 4-phenyl-butyl}-amide;
1 -methyl-1 H-indole-5-carboxylic acid {(S)-1-benzyl-3-[(pyridine-2-carbonyl)-amino]-propyl}- methyl-amide and
1 -methyl- 1 H-indole-6-carboxylic acid {(S)-1-benzyl-3-[(pyridine-2-carbonyl)-amino]-propyl}- methyl-amide are excluded;
in free form or in salt form.
Embodiment 2: A compound of formula I according to embodiment 1 in free form or in salt form, wherein said compound is a compound of formula IA
(IA)
Figure imgf000180_0001
wherein Ri, R2, R3, R4, R5, R6, A, B and C are as defined according to claim 1. Embodiment 3: A compound of formula I in free form or in salt form, wherein said compound is a compound of formula IB
Figure imgf000181_0001
wherein R2, R3, R4, R5, R6, A, B and C are as defined according to embodiment 1.
Embodiment 4: A compound of formula I according to embodiment 1 in free form or in salt form, wherein is C1-4alkyl and R2, R3, R4, R5 and R6 are each hydrogen.
Embodiment 5. A compound of formula I according to embodiment 1 in free form or in salt form, wherein A is a ring system selected from A1 , A2, A3 or A4
Figure imgf000181_0002
A1 A2 A3 A4 wherein
A1a is a five- to six-membered monocyclic aromatic ring system which contains from 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur, wherein the ring system may contain not more than 2 oxygen atoms and not more than 2 sulfur atoms, and wherein the ring system may be substituted once or more than once by R7, and wherein a substituent on a nitrogen in a heterocyclic ring system may not be halogen;
A1 b is a five- to six-membered monocyclic aromatic ring system which may contain from 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur, wherein the ring system may contain not more than 2 oxygen atoms and not more than 2 sulfur atoms, and wherein the ring system is fused to ring system A1 a via carbon and/or nitrogen atoms, and wherein the ring system may be substituted once or more than once by R8, and wherein a substituent on a nitrogen in a heterocyclic ring system may not be halogen;
each R7 or R8 independently is halogen, C1-6alkyl, C^halogenalkyl, C3-7cycloalkyl, C3- 7cycloalkyl(C -4alkyl), C -6alkoxy, or C -6halogenalkoxy; A2a is a six-membered monocyclic aromatic ring system which contains from 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur, wherein the ring system may contain not more than 2 oxygen atoms and not more than 2 sulfur atoms, and wherein the ring system is fused to the phenyl ring via two carbon atoms, and wherein the ring system may be substituted once or more than once by Ri0, and wherein a substituent on a nitrogen in a heterocyclic ring system may not be halogen;
n is 0, 1 , 2 or 3;
each Rg or Ri0 independently is halogen, Ci-6alkyl, Ci-6halogenalkyl, C3-7cycloalkyl, C3.
7cycloalkyl(Ci-4alkyl), C1-6alkoxy, or C^halogenalkoxy;
each of A3a or A3b is independently a five- to six-membered monocyclic aromatic ring system which may contain from 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur, wherein the ring system may contain not more than 2 oxygen atoms and not more than 2 sulfur atoms, and wherein the ring system may be substituted once or more than once by Rii, and wherein a substituent on a nitrogen in a heterocyclic ring system may not be halogen;
each Rn independently is halogen, C -6alkyl, C1-6halogenalkyl, C3-7cycloalkyl, C3- 7cycloalkyl(C1-4alkyl), C1-6alkoxy, or C1-6halogenalkoxy;
A4a is a five- to six-membered monocyclic aromatic ring system which contains from 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur, wherein the ring system may contain not more than 2 oxygen atoms and not more than 2 sulfur atoms, and wherein the ring system is substituted once or more than once by R12, and wherein a substituent on a nitrogen in a heterocyclic ring system may not be halogen;
each R12 independently is halogen; Ci-6alkyl; C1-6halogenalkyl; C1-6alkoxy; or Ci.
ehalogenalkoxy; or a three- to eight-membered monocyclic or bicyclic saturated or unsaturated non-aromatic ring system which may contain from 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur, wherein the saturated or unsaturated non-aromatic ring system may contain not more than 2 oxygen atoms and not more than 2 sulfur atoms, wherein the saturated or unsaturated non-aromatic ring system may be attached directly to the ring system A4a or via a C^alkylene group, and wherein the saturated or unsaturated non-aromatic ring system may be substituted once or more than once by R13, and wherein a substituent on a nitrogen in a heterocyclic saturated or unsaturated non-aromatic ring system may not be halogen; or two R12 at adjacent ring atoms of the ring system A4a form together with said ring atoms a fused five- to seven-membered unsaturated non-aromatic ring system which may contain from 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur, wherein the fused unsaturated non-aromatic ring system may contain not more than 2 oxygen atoms and not more than 2 sulfur atoms, and wherein the fused unsaturated non- aromatic ring system may in turn be substituted once or more than once by R14, and wherein a substituent on a nitrogen in a heterocyclic fused unsaturated non-aromatic ring system may not be halogen;
each R13 independently is halogen, d.6alkyl, C1-6halogenalkyl, C3-7cycloalkyl, C3.
7cycloalkyl(C1-4alkyl), C1-6alkoxy, or C1-6halogenalkoxy; or two R13 at the same ring atom of the saturated or unsaturated non-aromatic ring system together are oxo;
each RH independently is halogen or C1-6alkyl, or two R14 at the same ring atom of the fused unsaturated non-aromatic ring system together are oxo.
Embodiment 6: A compound of formula I according to embodiment 1 in free form or in salt form, wherein p is 0.
Embodiment 7: A compound of formula I according to embodiment 1 in free form or in salt form, wherein C is a five- to six-membered monocyclic aromatic ring system which may contain from 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur, and wherein the ring system may be substituted once or more than once by R16; and each Ri6 independently is halogen, C1-4alkyl, C1-4halogenalkyl, or C1-4alkoxy.
Embodiment 8: A compound of formula I according to embodiment 1 in free form or in salt form, wherein said compound is selected from the group consisting of
N,1-dimethyl-N-(1-phenyl-4-(picolinamido)butan-2-yl)-1 H-benzo[d]imidazole-2-carboxamide; N-methyl-N-(4-(1-methyl-1H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)imidazo[1 ,2- a] pyridine-6-carboxamide;
6-methyl-N-(3-(N-methyl-1 H-indazole-3-carboxamido)-4-phenylbutyl)imidazo[2, 1 -b]thiazole- 5-carboxamide;
N-methyl-N-(4-(1-methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)isoquinoline-1- carboxamide;
N, 1 -dimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1 -phenylbutan-2-yl)-1 H-pyrrolo[2,3- b] pyridine-3-carboxamide;
N, 1-dimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)-1 H-indazole- 3- carboxamide; N, 1 ,5-trimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1 -phenylbutan-2-yl)-1 H-indazole- 3-carboxamide;
2-methoxy-N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1 -phenylbutan-2- yl)quinoline-4-carboxamide;
5- fluoro-N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1 -phenylbutan-2-yl)-1 H-indole- 2-carboxamide;
N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1 -phenylbutan-2-yl)quinazoline-4- carboxamide;
N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1 -phenylbutan-2-yl)imidazo[1 ,5- aJpyridine-6-carboxamide;
N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)-1H-pyrrolo[2, 3- b] pyridine-3-carboxamide;
N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1 -phenylbutan-2-yl)-1 H-indazole-3- carboxamide;
6- methyl-N-(3-(N-methyl-1H-pyrrolo[2,3-b]pyridine-3-carboxamido)-4- phenylbutyl)imidazo[2, 1 -b]thiazole-5-carboxamide;
N,2-dimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)pyrazolo[1 , 5- a]pyridine-3-carboxamide;
N,4,7-trimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)pyrazolo[5,1- c] [1 ,2,4]triazine-3-carboxamide;
5-methoxy-N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1 -phenylbutan-2- yl)pyrazolo[1 ,5-a]pyridine-3-carboxamide;
N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)imidazo[1 , 2- a]pyridine-7-carboxamide;
N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)benzo[d]isoxazole-3- carboxamide;
N, 1 -dimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1 -phenylbutan-2-yl)-1 H- pyrazolo[3,4-b]pyridine-3-carboxamide;
N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1 -phenylbutan-2-yl)furo[2,3-c]pyridine-5- carboxamide;
1-methyl-N-(3-(N-methylbenzofuran-3-carboxamido)-4-phenylbutyl)-1H-pyrrole-2- carboxamide;
N, 1 -dimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1 -phenylbutan-2-yl)-1 H-indole-2- carboxamide; N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)-1H- benzo[d]imidazole-2-carboxamide;
5-fluoro-N-methyl-N-(4-(1-methyl-1H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)-1 H- indazole-3-carboxamide;
5- methoxy-N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1 -phenylbutan-2-yl)-1 H- indazole-3-carboxamide;
6- fluoro-N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1 -phenylbutan-2-yl)-1 H- indazole-3-carboxamide;
N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1 -phenylbutan-2-yl)quinoline-2- carboxamide;
N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)cinnoline-4- carboxamide;
N,2,7-trimethyl-N-(4-(1-methyl-1H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)pyrazolo[1 ,5- a]pyrimidine-6-carboxamide;
N,2,7-trimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)imidazo[1 ,2- a]pyridine-3-carboxamide;
N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)-1 ,6-naphthyridine- 2-carboxamide;
N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1 -phenylbutan-2-yl)pyrazolo[1 ,5- a]pyridine-3-carboxamide;
N, 1 -dimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1 -phenylbutan-2-yl)-1 H-indole-3- carboxamide;
5,7-difluoro-N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)-1 H- indole-2-carboxamide;
N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1 -phenylbutan-2-yl)-1 H-indole-3- carboxamide;
N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)quinoline-3- carboxamide;
N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1 -phenylbutan-2-yl)quinoline-4- carboxamide;
N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)quinoxaline-2- carboxamide;
N,5-dimethyl-N-(4-(1-methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)-1 H-indole-2- carboxamide; N-(3-(N,3-dimethylbenzofuran-2-carboxamido)-4-phenylbutyl)-1 -methyl-1 H-pyrrole-2- carboxamide;
N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)isoquinoline-3- carboxamide;
N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)-[1 ,2,4]triazolo[1 , 5- a] pyri m id i ne-2-carboxa mide ;
N,2,8-trimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)imidazo[1 , 2- a] pyrid i ne-3-ca rboxa m ide ;
N,5,7-trimethyl-N-(4-(1-methyl-1H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)pyrazolo[1 ,5- a] pyrimidine-2-carboxamide;
N, 5-dimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)-1 H-indazole-3- carboxamide;
N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)-1H-pyrrolo[2, 3- b] pyridine-4-carboxamide;
5- methoxy-N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1 -phenylbutan-2-yl)-1H- indole-2-carboxamide;
6- chloro-N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1 -phenyl butan-2- yl)imidazo[1 ,2-a]pyridine-2-carboxamide;
N,2-dimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)-1 , 6- naphthyridine-3-carboxamide;
N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)imidazo[1 , 2- a]pyridine-3-carboxamide;
N,7-dimethyl-N-(4-(1-methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)imidazo[1 ,2- a]pyridine-6-carboxamide;
N,2-dimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)quinoline-4- carboxamide;
2-chloro-N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1 -phenylbutan-2-yl)quinoline-4- carboxamide;
N,8-dimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)imidazo[1 , 2- a]pyridine-2-carboxamide;
N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)furo[3,2-b]pyridine- 5-carboxamide;
N, 1 ,3-trimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1 -phenylbutan-2-yl)-1 H-thieno[2,3- c] pyrazole-5-carboxamide; 5-chloro-N-methyl-N-(4-( 1 -methyl- 1 H-pyrrole-2-carboxamido)- 1 -phenyl butan-2- yl)imidazo[1 ,2-a]pyridine-2-carboxamide;
N,6-dimethyl-N-(4-(1-methyl-1H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)furo[2,3- b]pyridine-5-carboxamide;
N,2-dimethyl-N-(4-(1-methyl-1H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)imidazo[1 ,2- a] py rid i ne-3-carboxam ide ;
N-methyl-N-(4-( 1 -methyl- 1 H-pyrrole-2-carboxamido)- 1 -phenylbutan-2-y l)im idazo[ 1 , 2- a]pyridine-8-carboxamide;
N-methyl-N-(4-(1-methyl-1H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)imidazo[1 ,2- a] pyridine-5-carboxamide;
N,6-dimethyl-N-(4-(1-methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)imidazo[2,1- b] thiazole-5-carboxamide;
N-methyl-N-(4-(1-methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)imidazo[2,1- b]thiazole-6-carboxamide;
N,2,3-trimethyl-N-(4-(1-methyl-1H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)imidazo[2,1- b]th i azole-6-carboxam ide ;
N-methyl-N-(4-(1-methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)-1 ,8-naphthyridine-
4- carboxamide;
7-methoxy-N-methyl-N-(4-(1-methyl-1H-pyrrole-2-carboxamido)-1-phenylbutan-2- yl)isoquinoline-4-carboxamide;
N-methyl-N-(4-(1-methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)furo[2,3-b]pyridine-
5- carboxamide;
N,6-dimethyl-N-(4-(1-methyl-1H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)furo[3,2- b]pyridine-5-carboxamide;
6- bromo-N-methyl-N-(4-(1-methyl-1H-pyrrole-2-carboxamido)-1-phenylbutan-2- yl)imidazo[1 ,2-a]pyridine-7-carboxamide;
N-methyl-N-(4-(1-methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)imidazo[2,1- b]thiazole-5-carboxamide;
N-methyl-N-(4-(1-methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)isoquinoline-4- carboxamide;
N,2,6-trimethyl-N-(4-(1-methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)imidazo[2,1- b][1 ,3,4]thiadiazole-5-carboxamide;
N,4-dimethyl-N-(4-(1-methyl-1H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)-4H-furo[3,2- b]pyrrole-5-carboxamide; N,2-dimethyl-N-(4-(1-methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)imidazo[2,1- b] [1 ,3,4]thiadiazole-6-carboxamide;
N-methyl-N-(4-(1-methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)imidazo[1 ,2- a] pyrimidine-2-carboxamide;
N ,5-trimethyl-N-(4-(1-methyl-1 H-benzo[d]imidazole-2-carboxamido)-1-phenylbutan-2-yl)- 1 H-indazole-3-carboxamide;
1-methyl-N-(3-(N-methylbenzofuran-3-carboxamido)-4-phenylbutyl)-1 H-benzo[d]imidazole-2- carboxamide;
N-(4-(1 -ethyl-3-methyl-1 H-pyrazole-5-carboxamido)-1 -phenylbutan-2-yl)-N-methylfuro[2,3- c] pyridine-5-carboxamide;
1-ethyl-3-methyl-N-(3-(N-methylbenzofuran-3-carboxamido)-4-phenylbutyl)-1 H-pyrazole-5- carboxamide;
N-(4-(1 -ethyl-3-methyl-1 H-pyrazole-5-carboxamido)-1 -phenylbutan-2-yl)-N, 1 ,5-trimethyl-1 H- indazole-3-carboxamide;
N-(4-(1-ethyl-3-methyl-1 H-pyrazole-5-carboxamido)-1-phenylbutan-2-yl)-N-methylfuro[2,3- b] pyridine-5-carboxamide;
N -dimethyl-N-(4-(1-methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)-1 H-pyrrolo[2,3- b] py ridi ne-4-carboxam ide ;
N-(4-(1 -ethyl-3-methyl-1 H-pyrazole-5-carboxamido)-1 -phenylbutan-2-yl)-N- methylisoquinoline-1 -carboxamide;
N-(4-(1 -ethyl-3-methyl-1 H-pyrazole-5-carboxamido)-1 -phenylbutan-2-yl)-N, 1 ,3-trimethyl-1 H- th ieno[2 , 3-c] py razole-5-carboxam ide ;
N-(4-(1-ethyl-3-methyl-1 H-pyrazole-5-carboxamido)-1-phenylbutan-2-yl)-N- methylisoquinoline-4-carboxamide;
N-(4-(1 -ethyl-3-methyl-1 H-pyrazole-5-carboxamido)-1 -phenylbutan-2-yl)-N,2- dimethylpyrazolo[1 ,5-a]pyridine-3-carboxamide;
N-(4-(1-ethyl-3-methyl-1 H-pyrazole-5-carboxamido)-1-phenylbutan-2-yl)-N- methylimidazo[1 ,2-a]pyridine-5-carboxamide;
6-methyl-N-(3-(N-methylbenzofuran-3-carboxamido)-4-phenylbutyl)picolinamide;
N, 1 ,5-trimethyl-N-(4-(6-methylpicolinamido)-1 -phenylbutan-2-yl)-1 H-indazole-3-carboxamide;
N>2-dimethyl-N-(4-(6-methylpicolinamido)-1-phenylbutan-2-yl)pyrazolo[1 ,5-a]pyridine-3- carboxamide;
6-methoxy-N-(3-(N-methylbenzofuran-3-carboxamido)-4-phenylbutyl)picolinamide; N-(4-(6-methoxypicolinamido)-1-phenylbutan-2-yl)-N ,5-trimethyl-1 H-indazole-3- carboxamide;
N-(4-(6-methoxypicolinamido)-1-phenylbutan-2-yl)-N,2-dimethylpyrazolo[1 ,5-a]pyridine-3- carboxamide;
5- (4-fluorophenyl)-N,2-dimethyl-N-(4-(1-methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2- yl)thiazole-4-carboxamide;
N,5J-trimethyl-N-(4-(1-methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)pyrazolo[1 ,5- a] pyri mid i ne-3-carboxamide ;
N,3-dimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1 -phenylbutan-2-yl)-5- phenylisoxazole-4-carboxamide;
N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)imidazo[1 , 2- a]pyridine-2-carboxamide;
N-methyl-N-(4-(1-methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)pyrazolo[1 ,5- a]pyrimidine-3-carboxamide;
3-bromo-5-chloro-N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1 -phenylbutan-2- yl)imidazo[1 ,2-a]pyridine-2-carboxamide;
N-(4-(1 -ethyl-3-methyl-1 H-pyrazole-5-carboxamido)-1 -phenylbutan-2-yl)-N,6- dimethylfuro[2,3-b]pyridine-5-carboxamide;
1-methyl-N-(4-phenyl-3-(N,5,6-trimethylbenzofuran-3-carboxamido)butyl)-1 H-pyrrole-2- carboxamide;
N-(4-phenyl-3-(N,2,3-trimethylbenzofuran-6-carboxamido)butyl)picolinamide;
1- methyl-N-(3-(N-methylbenzofuran-5-carboxamido)-4-phenylbutyl)-1 H-pyrrole-2- carboxamide;
6- methyl-N-(3-(N-methyl-1 H-indole-5-carboxamido)-4-phenylbutyl)imidazo[2, 1 -b]thiazole-5- carboxamide;
N-(3-(N,1-dimethyl-1 H-indole-4-carboxamido)-4-phenylbutyl)-1-methyl-1 H-benzo[d]imidazole-
2- carboxamide;
5-(4-fluorophenyl)-2-methyl-N-(3-(N-methylbenzofuran-4-carboxamido)-4- phenylbutyl)thiazole-4-carboxamide;
N, 2-dimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)-2H-indazole-4- carboxamide;
N,1-dimethyl-N-(4-(1-methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)-1 H- benzo[d][1 ,2,3]triazole-7-carboxamide; N-methyl-N-(4-(1-methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)benzo[d]oxazole-6- carboxamide;
N,2-dimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1 -phenylbutan-2- yl)benzo[d]oxazole-6-carboxamide;
N,2-dimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1 -phenylbutan-2- yl)benzo[d]oxazole-5-carboxamide;
N,3-dimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2- yl)benzo[d]isoxazole-6-carboxamide;
N,3-dimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2- yl)benzo[d]isoxazole-5-carboxamide;
N, 1 -dimethyl-N-(1 -phenyl-4-(picolinamido)butan-2-yl)-1 H-indole-7-carboxamide;
N-methyl-N-(1-phenyl-4-(picolinamido)butan-2-yl)-1H-indole-7-carboxamide;
N,1-dimethyl-N-(1-phenyl-4-(picolinamido)butan-2-yl)-1H-indole-4-carboxamide;
1 -methyl-N-(3-(N-methyl-1 H-indole-4-carboxamido)-4-phenylbutyl)-1 H-benzo[d]imidazole-2- carboxamide;
1 -methyl-N-(3-(N-methyl-1 H-indole-5-carboxamido)-4-phenylbutyl)-1 H-benzo[d]imidazole-2- carboxamide;
N-methyl-N-(1-phenyl-4-(picolinamido)butan-2-yl)quinoxaline-6-carboxamide;
N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)benzo[d]oxazole-5- carboxamide;
N-(3-(N,2-dimethylbenzofuran-5-carboxamido)-4-phenylbutyl)-1 -methyl-1 H-pyrrole-2- carboxamide;
N-methyl-N-(1-phenyl-4-(picolinamido)butan-2-yl)-1H-indole-4-carboxamide;
N,1-dimethyl-N-(1-phenyl-4-(picolinamido)butan-2-yl)-1H-indole-5-carboxamide;
N,1-dimethyl-N-(1-phenyl-4-(picolinamido)butan-2-yl)-1H-indole-6-carboxamide;
N-(3-(N-methylbenzofuran-5-carboxamido)-4-phenylbutyl)picolinamide;
N-methyl-N-(1 -phenyl-4-(picolinamido)butan-2-yl)-1 H-indole-6-carboxamide;
N-methyl-N-(1-phenyl-4-(picolinamido)butan-2-yl)-1H-indole-5-carboxamide;
N-(3-(N-methylbenzofuran-4-carboxamido)-4-phenylbutyl)picolinamide;
1-methyl-N-(3-(N-methylbenzofuran-4-carboxamido)-4-phenylbutyl)-1 H-pyrrole-2- carboxamide;
1-methyl-N-(3-(N-methylbenzofuran-4-carboxamido)-4-phenylbutyl)-1H-benzo[d]imidazole-2- carboxamide; N -dimethyl-N-(4-( 1 -methyl- 1 H-p^
carboxamide;
N-methyl-N-(4-(1 -methyl- 1 H-pyrrole-2-carboxamido)-1 -phenylbutan-2-yl)-1 H-indole-5- carboxamide;
N-methyl-N-(4-(1-methyl-1H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)quinoline-6- carboxamide;
N-methyl-N-(4-(1-methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)-1H-indole-4- carboxamide;
N-methyl-N-(4-(1-methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)quinoxaline-6- carboxamide;
6-methyl-N-(3-(N-methylquinoxaline-6-carboxamido)-4-phenylbutyl)imidazo[2,1-b]thiazole-5- carboxamide;
6-methyl-N-(3-(N-methyl-1 H-indole-4-carboxamido)-4-phenylbutyl)imidazo[2,1-b]thiazole-5- carboxamide;
6-methyl-N-(3-(N-methylquinoline-6-carboxamido)-4-phenylbutyl)imidazo[2,1-b]thiazole-5- carboxamide;
N-methyl-N-(4-(1-methyl-1H-pyrrole-2-carboxamido)-1-phenylbutan-2- yl)benzo[c][1,2,5]thiadiazole-5-carboxamide;
N-(3-(3-bromo-N-methylbenzof uran-5-carboxamido)-4-phenylbutyl)- 1 -methyl- 1 H-pyrrole-2- carboxamide;
N,2-dimethyl-N-(4-(1-methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2- yl)benzo[d]thiazole-5-carboxamide;
N-(3-(N,3-dimethylbenzofuran-5-carboxamido)-4-phenylbutyl)-1-methyl-1 H-pyrrole-2- carboxamide;
1-methyl-N-(3-(N-methylbenzofuran-6-carboxamido)-4-phenylbutyl)-1H-pyrrole-2- carboxamide;
N,1-dimethyl-N-(4-(1-methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)-1H- benzo[d][ 1 , 2, 3]triazole-5-carboxamide;
N,1-dimethyl-N-(4-(1-methyl-1H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)-1 H-indazole-5- carboxamide;
N,2-dimethyl-N-(4-(1-methyl-1H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)-2H- benzo[d][1 ,2,3]triazole-4-carboxamide;
N, 1 -dimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1 -phenylbutan-2-yl)-1 H- benzo[d][1 ,2,3]triazole-4-carboxamide; N, 1 -dimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1 -phenylbutan-2-yl)-1 H-indazole-4- carboxamide;
N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1 -phenylbutan-2-yl)-1 H- benzo[d][1 ,2,3]triazole-5-carboxamide;
N,2-dimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1 -phenylbutan-2-yl)-1 H- benzo[d]imidazole-5-carboxamide;
N-methyl-N-(4-( 1 -methyl-1 H-pyrrole-2-carboxamido)- 1 -phenylbutan-2-y I)- 1 H-indazole-5- carboxamide;
N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1 -phenylbutan-2-yl)-1 H- benzo[d]imidazole-5-carboxamide;
N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1 -phenylbutan-2-yl)benzo[d]thiazole-6- carboxamide;
N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1 -phenylbutan-2-yl)quinoline-8- carboxamide;
N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)benzo[d]oxazole-4- carboxamide;
N,2-dimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2- yl)benzo[d]oxazole-4-carboxamide;
N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)benzo[d]thiazole-5- carboxamide;
N-methyl-N-(4-( 1 -methyl- 1 H-pyrrole-2-carboxamido)- 1 -phenylbutan-2- yl)benzo[c][1 ,2,5]oxadiazole-5-carboxamide;
N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)quinoline-5- carboxamide;
6-chloro-N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1 -phenylbutan-2-yl)quinoline-8- carboxamide;
N,2,4-trimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1 -phenylbutan-2-yl)quinoline-8- carboxamide;
N,2,5-trimethyl-N-(4-(1-methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)quinoline-8- carboxamide;
5,6-dimethoxy-N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2- yl)quinoline-8-carboxamide;
6-bromo-N,2-dimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1 -phenylbutan-2- yl)quinoline-8-carboxamide; 6-methoxy-N-methyl-N-(4-(1-methyl-1H-pyrrole-2-carboxamido)-1-phenylbutan-2- yl)quinoline-8-carboxamide;
6-methoxy-N,2-dimethyl-N-(4-(1-methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2- yl)quinoline-8-carboxamide;
N,6-dimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1 -phenylbutan-2-yl)quinoline-8- carboxamide;
N-(3-(5-fluoro-N-methylbenzofuran-6-carboxamido)-4-phenylbutyl)-1 -methyl-1 H-pyrrole-2- carboxamide;
N-(3-(N,5-dimethylbenzofuran-6-carboxamido)-4-phenylbutyl)-1 -methyl-1 H-pyrrole-2- carboxamide;
N, 1 -dimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1 -phenylbutan-2-yl)-1 H-indole-4- carboxamide;
N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)benzo[d]oxazole-7- carboxamide;
N,2-dimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2- yl)benzo[d]oxazole-7-carboxamide;
N,2-dimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)quinoline-8- carboxamide;
N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1 -phenylbutan-2-yl)quinoxaline-5- carboxamide;
N,1 ,2-trimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)-1 H-indole-4- carboxamide;
N,1 ,3-trimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)-1 H-indole-4- carboxamide;
N,1 ,5-trimethyl-N-(4-(1-methyl-1H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)-1 H-indole-4- carboxamide;
N,1 ,7-trimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)-1 H-indole-4- carboxamide;
N-(4-(1 -ethyl-3-methyl-1 H-pyrazole-5-carboxamido)-1 -phenylbutan-2-yl)-N- methylbenzo[d]oxazole-5-carboxamide;
4-chloro-N, 1 -dimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1 -phenylbutan-2-yl)-1 H- indole-5-carboxamide;
6-chloro-N, 1 -dimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1 -phenylbutan-2-yl)-1 H- i ndole-5-carboxam ide ; N , 1 ,6-trimethyl-N-(4-( 1 -methyl- 1 H-pyrrole-2-carboxamido)- 1 -phenylbutan-2-yl)- 1 H-indole-4- carboxamide;
1-methyl-N-(3-(N-methyl-3-(5-methyloxazol-2-yl)benzamido)-4-phenylbutyl)-1 H-pyrrole-2- carboxamide;
1 -methyl-N-(3-(N-methyl-3-(1 H-pyrrol-1 -yl)benzamido)-4-phenylbutyl)-1 H-pyrrole-2- carboxamide;
N-(3-(N-methylbiphenyl-2-ylcarboxamido)-4-phenylbutyl)picolinamide;
5-(2-fluorophenyl)-N,2-dimethyl-N-(4-(1 -methyl-1 H-benzo[d]imidazole-2-carboxamido)-1- phenylbutan-2-yl)thiazole-4-carboxamide;
N-(3-(3-(3,5-dimethyl-1 H-pyrazol-1-yl)-N-methylbenzamido)-4-phenylbutyl)-1-methyl-1 H- pyrrole-2-carboxamide;
1 -methyl-N-(3-(N-methyl-3-(5-methyl-1 ,2,4-oxadiazol-3-yl)benzamido)-4-phenylbutyl)-1 H- pyrrole-2-carboxamide;
1- methyl-N-(3-(N-methyl-3-(1 H-tetrazol-1-yl)benzamido)-4-phenylbutyl)-1 H-pyrrole-2- carboxamide;
1 -methyl-N-(3-(N-methyl-3-(5-methyl-1 ,3,4-oxadiazol-2-yl)benzamido)-4-phenylbutyl)-1 H- pyrrole-2-carboxamide;
1 -methyl-N-(3-(N-methyl-3-(1 -methyl-1 H-pyrazol-5-yl)benzamido)-4-phenylbutyl)-1 H-pyrrole-
2- carboxamide;
1- methyl-N-(3-(N-methyl-3-(oxazol-5-yl)benzamido)-4-phenylbutyl)-1 H-pyrrole-2- carboxamide;
1 -methyl-N-(3-(N-methyl-3-(1 -methyl-1 H-pyrazol-3-yl)benzamido)-4-phenylbutyl)-1 H-pyrrole-
2- carboxamide;
1 -methyl-N-(3-(N-methyl-3-(1 H-pyrazol-3-yl)benzamido)-4-phenylbutyl)-1 H-pyrrole-2- carboxamide;
1 -methyl-N-(3-(N-methyl-3-(1 H-tetrazol-5-yl)benzamido)-4-phenylbutyl)-1 H-pyrrole-2- carboxamide;
1 -methyl-N-(3-(N-methyl-3-(5-methyl-1 H-pyrazol-1 -yl)benzamido)-4-phenylbutyl)-1 H-pyrrole- 2-carboxamide;
1 -methyl-N-(3-(N-methyl-3-(3-methyl-1 H-pyrazol-1 -yl)benzamido)-4-phenylbutyl)-1 H-pyrrole- 2-carboxamide;
1-methyl-N-(3-(N-methyl-3-(pyridin-2-yl)benzamido)-4-phenylbutyl)-1 H-pyrrole-2- carboxamide; 1-methyl-N-(3-(N-methyl-3-(pyrimidin-2-yl)benzamido)-4-phenylbutyl)-1 H-pyrrole-2- carboxamide;
N,5-dimethyl-N-(4-(1-methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)-3- phenylisoxazole-4-carboxamide;
1- methyl-N-(3-(N-methyl-3-(1 H-pyrazol-1-yl)benzamido)-4-phenylbutyl)-1H-pyrrole-2- carboxamide;
N-(3-(N,5-dimethyl-2-(2H-1 ,2,3-triazol-2-yl)benzamido)-4-phenylbutyl)-1-methyl-1 H-pyrrole-2- carboxamide;
N-(3-(N,5-dimethyl-2-(pyrimidin-2-yl)benzamido)-4-phenylbutyl)-1-methyl-1 H-pyrrole-2- carboxamide;
5- (2-fluorophenyl)-N,2-dimethyl-N-(1-phenyl-4-(picolinamido)butan-2-yl)thiazole-4- carboxamide;
N-(3-(N,5-dimethyl-2-(2H-1 ,2,3-triazol-2-yl)benzamido)-4-phenylbutyl)-1 -ethyl-3-methyl-1 H- pyrazole-5-carboxamide;
N-(3-(3-(1H-imidazol-1-yl)-N-methylbenzamido)-4-phenylbutyl)-1-methyl-1H-pyrrole-2- carboxamide;
2- methoxy-N-methyl-N-(4-(1 -methyl- 1 H-pyrrole-2-carboxamido)-1 -phenylbutan-2- yl)isonicotinamide;
2-chloro-6-methoxy-N-methyl-N-(4-(1-methyl-1H-pyrrole-2-carboxamido)-1-phenylbutan-2- yl)isonicotinamide;
2-chloro-N,6-dimethyl-N-(4-(1-methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2- yl)isonicotinamide;
6- methoxy-N-methyl-N-(1-phenyl-4-(picorinamido)butan-2-yl)picolinamide;
6-methoxy-N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1 -phenylbutan-2- yl)nicotinamide;
3.5- difluoro-N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2- yl)picolinamide;
2.6- dichloro-N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2- yl)isonicotinamide;
N,2-dimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)isonicotinamide; 2,6-difluoro-N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1 -phenylbutan-2- yl)isonicotinamide;
6-methoxy-N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1 -phenylbutan-2- yl)picolinamide; 4,6-dimethoxy-N-methyl-N-(4-(1-methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2- yl)pyrimidine-2-carboxamide;
4-methoxy-N-methyl-N-(4-(1-methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2- yl)picolinamide;
N,6-dimethyl-N-(4-(1-methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)picolinamid N-methyl-N-(4-(1-methyl-1H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)-1 , 4,5,6- tetrahydrocyclopenta[c]pyrazole-3-carboxamide;
N,2-dimethyl-N-(4-(1-methyl-1H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)-4,5,6,7- tetrahydro-2H-indazole-3-carboxamide;
N-methyl-N-(4-(1-methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)-4,5,6,7-tetrahydro- 2H-indazole-3-carboxamide;
N,3,5-trimethyl-N-(4-(1-methyl-1H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)isoxazole-4- carboxamide;
2-ethoxy-N,6-dimethyl-N-(4-(1-methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2- yl)isonicotinamide;
2-methoxy-N-methyl-N-(4-( 1 -methyl-1 H-pyrrole-2-carboxamido)-1 -phenylbutan-2- yl)nicotinamide;
2,6-dimethoxy-N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2- yl)isonicotinamide;
2-methoxy-N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1 -phenylbutan-2- yl)pyrimidine-4-carboxamide;
N,2-dimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)nicotinamide; 4-methoxy-N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1 -phenylbutan-2- yl)nicotinamide;
2-ethyl-N,6-dimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1 -phenylbutan-2- yl)isonicotinamide;
4,6-dichloro-N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2- yl)picolinamide;
4-methoxy-N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1 -phenylbutan-2- yl)pyrimidine-2-carboxamide;
4,6-dimethoxy-N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1 -phenylbutan-2- yl)picolinamide;
6-methoxy-N,4-dimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2- yl)picolinamide; N,2,6-trimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2- yl)isonicotinamide;
N,2,5-trimethyl-N-(4-(1-methyl-1H-pyrrole-2-carboxamido)-1-phenylbutan-2- yl)isonicotinamide;
2-methoxy-N,5-dimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2- yl)isonicotinamide;
N-(3-(2-methoxy-N,6-dimethylisonicotinamido)-4-phenylbutyl)-1-methyl-1H- benzo[d]imidazole-2-carboxamide;
2-isopropyl-N,6-dimethyl-N-(4-(1-methyl-1H-pyrrole-2-carboxamido)-1-phenylbutan-2- yl)isonicotinamide;
N,2,5-trimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)nicotinamide;
5- chloro-2-methoxy-N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2- yl)nicotinamide;
2-ethyl-N-(4-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1-phenylbutan-2-yl)-N,6- dimethylisonicotinamide;
N-(4-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1-phenylbutan-2-yl)-2-methoxy-N,6- dimethylisonicotinamide;
2-ethoxy-N-(4-(1-ethyl-3-methyl-1 H-pyrazole-5-carboxamido)-1-phenylbutan-2-yl)-N,6- dimethylisonicotinamide;
N-(4-(1 -ethyl-3-methyl-1 H-pyrazole-5-carboxamido)-1 -phenylbutan-2-yl)-2,6-dimethoxy-N- methylisonicotinamide;
N-(4-(1 -ethyl-3-methyl-1 H-pyrazole-5-carboxamido)-1 -phenylbutan-2-yl)-4,6-dimethoxy-N- methylpyrimidine-2-carboxamide;
6- methoxy-N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1 -phenylbutan-2-yl)pyrazine- 2-carboxamide;
5-methoxy-N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2- yl)nicotinamide;
2-ethoxy-N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1 -phenylbutan-2-yl)pyrimidine- 4-carboxamide;
2-isopropoxy-N-methyi-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2- yl)pyrimidine-4-carboxamide;
2-methoxy-N,6-dimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1 -phenylbutan-2- yl)isonicotinamide; 2,6-dimethoxy-N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1 -phenylbutan-2- yl)pyrimidine-4-carboxamide;
N,2-dimethyl-N-(4-(1-methyl-1H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)-6-(pyrrolidin-1- yl)isonicotinamide;
N-(3-(2-methoxy-N,6-dimethylisonicotinamido)-4-phenylbutyl)-6-methylpicolinam
N-(3-(2,6-dimethoxy-N-methylisonicotinamido)-4-phenylbutyl)-6-methylpicolina
2-methoxy-N-methyl-N-(4-(6-methylpicolinamido)-1-phenylbu^
carboxamide;
2-methoxy-N-(4-(6-methoxypicolinamido)-1-phenylbutan-2-yl)-N-methylpyrimidine
carboxamide;
N-(3-(2-methoxy-N-methylpyrimidine-4-carboxamido)-4-phenylbutyl)-1-methyl-1 H- benzo[d]imidazole-2-carboxamide;
N,2-dimethyl-N-(4-(6-methylpicolinamido)-1-phenylbutan-2-yl)pyrimidine-4-carboxamide; N-(4-(6-methoxypicolinamido)-1-phenylbutan-2-yl)-N,2-dimethylpyrimidine-4-carboxamide; N-(3-(N,2-dimethylpyrimidine-4-carboxamido)-4-phenylbutyl)-1 -methyl-1 H-benzo[d]imidazole- 2-carboxamide;
6-methoxy-N-(3-(2-methoxy-N,6-dimethylisonicotinamido)-4-phenylbutyl)picolinamide;
N-(3-(2,6-dimethoxy-N-methylisonicotinamido)-4-phenylbutyl)-6-methoxypicolinamide;
1-ethyl-N,3-dimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)-1 H- pyrazole-5-carboxamide; and
N, 1 ,3,5-tetramethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1 -phenylbutan-2-yl)-1 H- pyrazole-4-carboxamide.
Embodiment 9: A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of embodiments 1 to 8 in free form or in salt form and one or more pharmaceutically acceptable carriers.
Embodiment 10: A combination comprising a therapeutically effective amount of the compound according to any one of embodiments 1 to 8 in free form or in salt form and one or more therapeutically active agents.
Embodiment 11 : A method of treating a disorder or a disease in a subject mediated by orexin receptors, wherein the method comprises administering to the subject a therapeutically effective amount of the compound according to any one of embodiments 1 to 8 in free form or in salt form.
Embodiment 12: A method according to embodiment 11 , wherein the disorder or disease is selected from sleep disorders, eating disorders, substance-related disorders or Alzheimers disease.
Embodiment 13: A compound according to any one of embodiments 1 to 8 in free form or in salt form, for use as a medicament.
Embodiment 14: A compound according to any one of claims 1 to 8 in free form or in salt form, for use in the treatment of a disorder or disease in a subject mediated by orexin receptors.
Embodiment 15: A compound according to embodiment 14 in free form or in salt form, wherein the disorder or disease mediated by orexin receptors sleep disorders, eating disorders, substance-related disorders or Alzheimers disease.
Embodiment 16: A compound of formula XIII
Figure imgf000199_0001
wherein R2, R3, R4, R5, Re, A and B are as defined according to embodiment 1 in free form or in salt form.

Claims

Claims:
1. A compound of the formula I
Figure imgf000200_0001
(I)
wherein
Ri is C -6alkyl, Ci-6halogenalkyl, C3-7cycloalkyl or C3.7cycloalkyl(Ci.4alkyl);
R2, R3- R5 and R6 are each independently selected from hydrogen, halogen, hydroxyl, d.
6alkyl, C -6halogenalkyl, C3-7cycloalkyl,
Figure imgf000200_0002
Ci-6alkoxy, or Ci.
ehalogenalkoxy;
or R2 and R3 together are oxo;
or R2 and R3 together with the carbon atom to which they are bound form a C3-7cycloalkyl; or R5 and R6 together are oxo;
or R5 and R6 together with the carbon atom to which they are bound form a C3-7cycloalkyl; R is hydrogen or Chalky!;
A is a group A1 , A2, A3 or A4
Figure imgf000200_0003
A1 A2 A3 M wherein
A1a is a five- to six-membered monocyclic aromatic ring system which contains from 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur, wherein the ring system may contain not more than 2 oxygen atoms and not more than 2 sulfur atoms, and wherein the ring system may be substituted once or more than once by R7, and wherein a substituent on a nitrogen in a heterocyclic ring system may not be halogen;
A1 b is a five- to six-membered monocyclic aromatic ring system which may contain from 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur, wherein the ring system may contain not more than 2 oxygen atoms and not more than 2 sulfur atoms, and wherein the ring system is fused to ring system A1 a via carbon and/or nitrogen atoms, and wherein the ring system may be substituted once or more than once by R8, and wherein a substituent on a nitrogen in a heterocyclic ring system may not be halogen;
each R7 or R8 independently is halogen, C1-6alkyl, C1-6halogenalkyl, C3-7cycloalkyl, C3- 7cycloalkyl(C1-4alkyl), C1-6alkoxy, or C1-6halogenalkoxy;
A2a is a five- to six-membered monocyclic aromatic ring system which contains from 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur, wherein the ring system may contain not more than 2 oxygen atoms and not more than 2 sulfur atoms, and wherein the ring system is fused to the phenyl ring via two carbon atoms, and wherein the ring system may be substituted once or more than once by R 0, and wherein a substituent on a nitrogen in a heterocyclic ring system may not be halogen;
n is 0, 1 , 2 or 3;
each R9 or R10 independently is halogen, C1-6alkyl, C1-6halogenalkyl, C3-7cycloalkyl, C3- 7cycloalkyl(C1-4alkyl), C1-6alkoxy, or C1-6halogenalkoxy;
each of A3a or A3b is independently a five- to six-membered monocyclic aromatic ring system which may contain from 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur, wherein the ring system may contain not more than 2 oxygen atoms and not more than 2 sulfur atoms, and wherein the ring system may be substituted once or more than once by Rn, and wherein a substituent on a nitrogen in a heterocyclic ring system may not be halogen;
each Rn independently is halogen, C1-6alkyl, C1-6halogenalkyl, C3-7cycloalkyl, C3.
7cycloalkyl(C1-4alkyl), C1-6alkoxy, or C1-6halogenalkoxy;
A4a is a five- to six-membered monocyclic aromatic ring system which contains from 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur, wherein the ring system may contain not more than 2 oxygen atoms and not more than 2 sulfur atoms, and wherein the ring system is substituted once or more than once by R12, and wherein a substituent on a nitrogen in a heterocyclic ring system may not be halogen;
each R12 independently is halogen; C1-6alkyl; C1-6halogenalkyl; C1-6alkoxy; or C^.
6halogenalkoxy; or a three- to eight-membered monocyclic or bicyclic saturated or unsaturated non-aromatic ring system which may contain from 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur, wherein the saturated or unsaturated non-aromatic ring system may contain not more than 2 oxygen atoms and not more than 2 sulfur atoms, wherein the saturated or unsaturated non-aromatic ring system may be attached directly to the ring system A4a or via a C1-4alkylene group, and wherein the saturated or unsaturated non-aromatic ring system may be substituted once or more than once by R 3, and wherein a substituent on a nitrogen in a heterocyclic saturated or unsaturated non-aromatic ring system may not be halogen; or two R12 at adjacent ring atoms of the ring system A4a form together with said ring atoms a fused five- to seven-membered unsaturated non-aromatic ring system which may contain from 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur, wherein the fused unsaturated non-aromatic ring system may contain not more than 2 oxygen atoms and not more than 2 sulfur atoms, and wherein the fused unsaturated non- aromatic ring system may in turn be substituted once or more than once by R14, and wherein a substituent on a nitrogen in a heterocyclic fused unsaturated non-aromatic ring system may not be halogen;
each R13 independently is halogen, C1-6alkyl, C1-6halogenalkyl, C3-7cycloalkyl, C3- 7cycloalkyl(C1-4alkyl), C1-6alkoxy, or C1-6halogenalkoxy; or two R13 at the same ring atom of the saturated or unsaturated non-aromatic ring system together are oxo;
each Ri4 independently is halogen or C1-6alkyl, or two R14 at the same ring atom of the fused unsaturated non-aromatic ring system together are oxo;
B is
Figure imgf000202_0001
p is 0 or 1 ;
R15 is halogen, Ci-6alkyl, C1-6halogenalkyl, C3-7cycloalkyl, C1-6alkoxy, or Ci-6halogenalkoxy; and
C is a five- to ten-membered monocyclic or fused polycyclic aromatic ring system which may contain from 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur, wherein the ring system may contain not more than 2 oxygen atoms and not more than 2 sulfur atoms, and wherein the ring system may be substituted once or more than once by R16, and wherein a substituent on a nitrogen in a heterocyclic ring system may not be halogen;
each R16 independently is C1-6alkyl; C1-6halogenalkyl; C1-6alkoxy; C1-6halogenalkoxy; halogen; cyano; or two Ri6 at adjacent ring atoms of the ring system C form together with said ring atoms a fused five- to seven-membered unsaturated non-aromatic ring system which may contain from 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur, wherein the fused unsaturated non-aromatic ring system may contain not more than 2 oxygen atoms and not more than 2 sulfur atoms, and wherein the fused unsaturated non-aromatic ring system may in turn be substituted once or more than once by R17, and wherein a substituent on a nitrogen in a heterocyclic fused unsaturated non-aromatic ring system may not be halogen; each R17 independently is halogen or C1-6alkyl, or two R17 at the same ring atom of the fused unsaturated non-aromatic ring system together are oxo;
and provided that the compounds
1 -methyl-1 H-benzoimidazole-2-carboxylic acid {(S)-3-[(1 H-indole-4-carbonyl)-methyl-amino]- 4-phenyl-butyl}-amide;
1 H-indole-5-carboxylic acid {(S)-1-benzyl-3-[(pyridine-2-carbonyl)-amino]-propyl}-methyl- amide;
1 H-indole-4-carboxylic acid {(S)-1 -benzyl-3-[(pyridine-2-carbonyl)-amino]-propyl}-methyl- amide;
pyridine-2-carboxylic acid {(S)-3-[(benzofuran-5-carbonyl)-methyl-amino]-4-phenyl-butyl}- amide;
1 -methyl-1 H-indole-7-carboxylic acid {(S)-1-benzyl-3-[(pyridine-2-carbonyl)-amino]-propyl}- methyl-amide;
1 H-indole-7-carboxylic acid {(S)-1-benzyl-3-[(pyridine-2-carbonyl)-amino]-propyl}-methyl- amide;
1 -methyl-1 H-indole-4-carboxylic acid {(S)-1-benzyl-3-[(pyridine-2-carbonyl)-amino]-propyl}- methyl-amide;
1 H-indole-6-carboxylic acid {(S)-1-benzyl-3-[(pyridine-2-carbonyl)-amino]-propyl}-methyl- amide;
1 -methyl-1 H-benzoimidazole-2-carboxylic acid {(S)-3-[(1 H-indole-5-carbonyl)-methyl-amino]- 4-phenyl-butyl}-amide;
1 -methyl-1 H-indole-5-carboxylic acid {(S)-1 -benzyl-3-[(pyridine-2-carbonyl)-amino]-propyl}- methyl-amide and
1 -methyl-1 H-indole-6-carboxylic acid {(S)-1-benzyl-3-[(pyridine-2-carbonyl)-amino]-propyl}- methyl-amide are excluded;
in free form or in salt form.
2. A compound of formula I according to claim 1 in free form or in salt form, wherein said compound is a compound of formula IA
(IA)
Figure imgf000203_0001
wherein R2, R3, R4, R5, R6, A, B and C are as defined according to claim 1.
3. A compound of formula I in free form or in salt form, wherein said compound is a compound of formula IB
Figure imgf000204_0001
wherein R2, R3, R4, R5, Re, A, B and C are as defined according to claim 1.
4. A compound of formula I according to claim 1 in free form or in salt form, wherein is d. 4alkyl and R2, R3, R4, R5 and R6 are each hydrogen.
5. A compound of formula I according to claim 1 in free form or in salt form, wherein A is a ring system selected from A1 , A2, A3 or A4
Figure imgf000204_0002
A1 A2 A3 A4 wherein
A1a is a five- to six-membered monocyclic aromatic ring system which contains from 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur, wherein the ring system may contain not more than 2 oxygen atoms and not more than 2 sulfur atoms, and wherein the ring system may be substituted once or more than once by R7, and wherein a substituent on a nitrogen in a heterocyclic ring system may not be halogen;
A1 b is a five- to six-membered monocyclic aromatic ring system which may contain from 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur, wherein the ring system may contain not more than 2 oxygen atoms and not more than 2 sulfur atoms, and wherein the ring system is fused to ring system A1a via carbon and/or nitrogen atoms, and wherein the ring system may be substituted once or more than once by R8, and wherein a substituent on a nitrogen in a heterocyclic ring system may not be halogen;
each R7 or R8 independently is halogen, Ci-ealkyl, C1-6halogenalkyl, C3-7cycloalkyl, C3.
7cycloalkyl(Ci.4alkyl), C1-6alkoxy, or C1-6halogenalkoxy; A2a is a six-membered monocyclic aromatic ring system which contains from 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur, wherein the ring system may contain not more than 2 oxygen atoms and not more than 2 sulfur atoms, and wherein the ring system is fused to the phenyl ring via two carbon atoms, and wherein the ring system may be substituted once or more than once by R10, and wherein a substituent on a nitrogen in a heterocyclic ring system may not be halogen;
n is 0, 1 , 2 or 3;
each R9 or R10 independently is halogen, C1-6alkyl, C1-6halogenalkyl, C3-7cycloalkyl, C3.
7cycloalkyl(C1-4alkyl), C1-6alkoxy, or C1-6halogenalkoxy;
each of A3a or A3b is independently a five- to six-membered monocyclic aromatic ring system which may contain from 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur, wherein the ring system may contain not more than 2 oxygen atoms and not more than 2 sulfur atoms, and wherein the ring system may be substituted once or more than once by Rn, and wherein a substituent on a nitrogen in a heterocyclic ring system may not be halogen;
each R independently is halogen, C1-6alkyl, C1-6halogenalkyl, C3-7cycloalkyl, C3- 7cycloalkyl(C1-4alkyl), C1-6alkoxy, or C1-6halogenalkoxy;
A4a is a five- to six-membered monocyclic aromatic ring system which contains from 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur, wherein the ring system may contain not more than 2 oxygen atoms and not more than 2 sulfur atoms, and wherein the ring system is substituted once or more than once by R12, and wherein a substituent on a nitrogen in a heterocyclic ring system may not be halogen;
each R12 independently is halogen; C1-6alkyl; C1-6halogenalkyl; C1-6alkoxy; or
6halogenalkoxy; or a three- to eight-membered monocyclic or bicyclic saturated or unsaturated non-aromatic ring system which may contain from 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur, wherein the saturated or unsaturated non-aromatic ring system may contain not more than 2 oxygen atoms and not more than 2 sulfur atoms, wherein the saturated or unsaturated non-aromatic ring system may be attached directly to the ring system A4a or via a C1-4alkylene group, and wherein the saturated or unsaturated non-aromatic ring system may be substituted once or more than once by R13, and wherein a substituent on a nitrogen in a heterocyclic saturated or unsaturated non-aromatic ring system may not be halogen; or two R12 at adjacent ring atoms of the ring system A4a form together with said ring atoms a fused five- to seven-membered unsaturated non-aromatic ring system which may contain from 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur, wherein the fused unsaturated non-aromatic ring system may contain not more than 2 oxygen atoms and not more than 2 sulfur atoms, and wherein the fused unsaturated non- aromatic ring system may in turn be substituted once or more than once by R14, and wherein a substituent on a nitrogen in a heterocyclic fused unsaturated non-aromatic ring system may not be halogen;
each R13 independently is halogen, C1-6alkyl, C1-6halogenalkyl, C3-7cycloalkyl, C3- 7cycloalkyl(C1-4alkyl), C1-6alkoxy, or C1-6halogenalkoxy; or two R13 at the same ring atom of the saturated or unsaturated non-aromatic ring system together are oxo;
each R14 independently is halogen or C1-6alkyl, or two R14 at the same ring atom of the fused unsaturated non-aromatic ring system together are oxo.
6. A compound of formula I according to claim 1 in free form or in salt form, wherein p is 0.
7. A compound of formula I according to claim 1 in free form or in salt form, wherein C is a five- to six-membered monocyclic aromatic ring system which may contain from 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur, and wherein the ring system may be substituted once or more than once by R16; and each R16 independently is halogen, C1- alkyl, Ci-4halogenalkyl, or C^alkoxy.
8. A compound of formula I according to claim 1 in free form or in salt form, wherein said compound is selected from the group consisting of
N, 1 -dimethyl-N-(1 -phenyl-4-(picolinamido)butan-2-yl)-1 H-benzo[d]imidazole-2-carboxamide; N-methyl-N-(4-(1-methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)imidazo[1 ,2- a] pyrid i ne-6-carboxam ide ;
6-methyl-N-(3-(N-methyl-1 H-indazole-3-carboxamido)-4-phenylbutyl)imidazo[2, 1 -b]thiazole- 5-carboxamide;
N-methyl-N-(4-(1-methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)isoquinoline-1- carboxamide;
N,1-dimethyl-N-(4-(1-methyl-1H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)-1H-pyrrolo[2,3- b] pyridine-3-carboxamide;
N,1-dimethyl-N-(4-(1-methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)-1H-indazole-3- carboxamide;
N,1 ,5-trimethyl-N-(4-(1-methyl-1H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)-1H-indazole- 3-carboxamide; 2-methoxy-N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1 -phenylbutan-2- yl)quinoline-4-carboxamide;
5- fluoro-N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1 -phenylbutan-2-yl)-1 H-indole- 2-carboxamide;
N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1 -phenylbutan-2-yl)quinazoline-4- carboxamide;
N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)imidazo[1 , 5- a] pyridine-6-carboxamide;
N-methyl-N-(4-( 1 -methyl- 1 H-pyrrole-2-carboxamido)- 1 -phenylbutan-2-yl)-1 H-pyrrolo[2 , 3- b] pyridine-3-carboxamide;
N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)-1 H-indazole-3- carboxamide;
6- methyl-N-(3-(N-methyl-1H-pyrrolo[2,3-b]pyridine-3-carboxamido)-4- phenylbutyl)imidazo[2,1-b]thiazole-5-carboxamide;
N,2-dimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)pyrazolo[1 , 5- a]pyridine-3-carboxamide;
N,4,7-trimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)pyrazolo[5,1- c] [1 ,2,4]triazine-3-carboxamide;
5-methoxy-N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1 -phenylbutan-2- yl)pyrazolo[1 ,5-a]pyridine-3-carboxamide;
N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1 -phenylbutan-2-yl)imidazo[1 ,2- a]pyridine-7-carboxamide;
N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)benzo[d]isoxazole-3- carboxamide;
N,1-dimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)-1H- pyrazolo[3,4-b]pyridine-3-carboxamide;
N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1 -phenylbutan-2-yl)furo[2,3-c]pyridine-5- carboxamide;
1-methyl-N-(3-(N-methylbenzofuran-3-carboxam'ido)-4-phenylbutyl)-1H-pyrrole-2- carboxamide;
N, 1 -dimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1 -phenylbutan-2-yl)-1 H-indole-2- carboxamide;
N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1 -phenylbutan-2-yl)-1 H- benzo[d]imidazole-2-carboxamide; 5-fluoro-N-methyl-N-(4-(1-methyl-1 H-pyrrole-2-carboxamido)-1 -phenylbutan-2-yl)-1 H- indazole-3-carboxamide;
5- methoxy-N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1 -phenylbutan-2-yl)-1 H- indazole-3-carboxamide;
6- fluoro-N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)-1 H- indazole-3-carboxamide;
N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)quinoline-2- carboxamide;
N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1 -phenylbutan-2-yl)cinnoline-4- carboxamide;
N , 2,7-trimethyl-N-(4-( 1 -methyl-1 H-pyrrole-2-carboxamido)- 1 -phenylbutan-2-yl)pyrazolo[ 1 , 5- a] py ri m idi ne-6-carboxa mide ;
N,2,7-trimethyl-N-(4-(1-methyl-1H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)imidazo[1 ,2- a]pyridine-3-carboxamide;
N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)-1 ,6-naphthyr'idine- 2-carboxamide;
N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1 -phenylbutan-2-yl)pyrazolo[1 ,5- a]pyridine-3-carboxamide;
N,1-dimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)-1 H-indole-3- carboxamide;
5,7-difluoro-N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)-1 H- indole-2-carboxamide;
N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)-1H-indole-3- carboxamide;
N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)quinoline-3- carboxamide;
N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1 -phenylbutan-2-yl)quinoline-4- carboxamide;
N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxam'ido)-1-phenylbutan-2-yl)quinoxaline-2- carboxamide;
N , 5-dimethyl-N-(4-( 1 -methyl- 1 H-pyrrole-2-carboxamido)- 1 -phenylbutan-2-yl)- 1 H-indole-2- carboxamide;
N-(3-(N,3-dimethylbenzofuran-2-carboxamido)-4-phenylbutyl)-1-methyl-1 H-pyrrole-2- carboxamide; N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)isoquinoline-3- carboxamide;
N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)-[1,2,4]triazolo[1 , 5- a]pyrimidine-2-carboxamide;
N,2,8-trimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)imidazo[1 ,2- a]pyridine-3-carboxamide;
N,5,7-trimethyl-N-(4-(1-methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)pyrazolo[1 ,5- a] pyrimidine-2-carboxamide;
N, 5-dimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)-1 H-indazole-3- carboxamide;
N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)-1H-pyrrolo[2,3- b] pyrid i ne-4-carboxam ide ;
5- methoxy-N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1 -phenylbutan-2-yl)-1 H- indole-2-carboxamide;
6- chloro-N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1 -phenylbutan-2- yl)imidazo[1 ,2-a]pyridine-2-carboxamide;
N,2-dimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)-1 ,6- naphthyridine-3-carboxamide;
N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)imidazo[1 , 2- a]pyridine-3-carboxamide;
N,7-dimethyl-N-(4-(1-methyl-1H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)imidazo[1 ,2- a]pyridine-6-carboxamide;
N,2-dimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)quinoline-4- carboxamide;
2-chloro-N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1 -phenylbutan-2-yl)quinoline-4- carboxamide;
N,8-dimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)imidazo[1 , 2- a]pyridine-2-carboxamide;
N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)furo[3,2-b]pyridine- 5-carboxamide;
N,1 ,3-trimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)-1 H-thieno[2,3- c] pyrazole-5-carboxamide;
5-chloro-N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1 -phenylbutan-2- yl)imidazo[1 ,2-a]pyridine-2-carboxamide; N,6-dimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)furo[2,3- b]pyridine-5-carboxamide;
N,2-dimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)imidazo[1 , 2- a]pyridine-3-carboxamide;
N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)imidazo[1 ,2- a]pyridine-8-carboxamide;
N-methyl-N-(4-(1-methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)imidazo[1 ,2- a] pyridine-5-carboxamide;
N,6-dimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1 -phenylbutan-2-yl)imidazo[2, 1 - b] thiazole-5-carboxamide;
N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)imidazo[2,1- b]thiazole-6-carboxamide;
N,2,3-trimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)imidazo[2,1- b]thiazole-6-carboxamide;
N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)-1 ,8-naphthyridine-
4- carboxamide;
7-methoxy-N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2- yl)isoquinoline-4-carboxamide;
N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)furo[2,3-b]pyridine-
5- carboxamide;
N,6-dimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)furo[3,2- b] pyrid i ne-5-carboxam ide ;
6- bromo-N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1 -phenyl butan-2- yl)imidazo[1 ,2-a]pyridine-7-carboxamide;
N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)imidazo[2,1- b]thiazole-5-carboxamide;
N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1 -phenylbutan-2-yl)isoquinoline-4- carboxamide;
N, 2,6-trimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)imidazo[2,1- b][1,3,4]thiadiazole-5-carboxamide;
N,4-dimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)-4H-furo[3,2- b]pyrrole-5-carboxamide;
N,2-dimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)imidazo[2,1- b][1 ,3,4]thiadiazole-6-carboxamide; N-methyl-N-(4-(1-methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)imidazo[1 ,2- a] pyrimidine-2-carboxamide;
N,1 ,5-trimethyl-N-(4-(1-methyl-1 H-benzo[d]imidazole-2-carboxamido)-1-phenylbutan-2-yl)^ 1 H-indazole-3-carboxamide;
1-methyl-N-(3-(N-methylbenzofuran-3-carboxamido)-4-phenylbutyl)-1 H-benzo[d]imidazole-2- carboxamide;
N-(4-(1-ethyl-3-methyl-1 H-pyrazole-5-carboxamido)-1-phenylbutan-2-yl)-N-methylfuro[2,3- c]pyridine-5-carboxamide;
1-ethyl-3-methyl-N-(3-(N-methylbenzofuran-3-carboxamido)-4-phenylbutyl)-1 H-pyrazole-5- carboxamide;
N-(4-(1-ethyl-3-methyl-1 H-pyrazole-5-carboxamido)-1-phenylbutan-2-yl)-N,1 ,5-trimethyl-1 H- indazole-3-carboxamide;
N-(4-(1-ethyl-3-methyl-1 H-pyrazole-5-carb0xamido)-1-phenylbutan-2-yl)-N-methylfuro[2,3- b] py rid i ne-5-ca rboxam ide ;
N -dimethyl-N-(4-(1-methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)-1 H-pyrrolo[2^ b]pyridine-4-carboxamide;
N-(4-(1-ethyl-3-methyl-1 H-pyrazole-5-carboxamido)-1-phenylbutan-2-yl)-N- methylisoquinoline-1-carboxamide;
N-(4-(1-ethyl-3-methyl-1 H-pyrazole-5-carboxamido)-1-phenylbutan-2-yl)-N,1 ,3-trimethyl-1 H- thieno[2,3-c]pyrazole-5-carboxamide;
N-(4-(1-ethyl-3-methyl-1 H-pyrazole-5-carboxamido)-1-phenylbutan-2-yl)-N- methylisoquinoline-4-carboxamide;
N-(4-(1-ethyl-3-methyl-1 H-pyrazole-5-carboxamido)-1-phenylbutan-2-yl)-N,2- dimethylpyrazolo[1 ,5-a]pyridine-3-carboxamide;
N-(4-(1 -ethyl-3-methyl-1 H-pyrazole-5-carboxamido)-1 -phenylbutan-2-yl)-N- methylimidazo[1 ,2-a]pyridine-5-carboxamide;
6-methyl-N-(3-(N-methylbenzofuran-3-carboxamido)-4-phenylbutyl)picolinamide;
N ,5-trimethyl-N-(4-(6-methylpicolinamido)-1-phenylbutan-2-yl)-1 H-indazole-3-carboxamide N,2-dimethyl-N-(4-(6-methylpicolinamido)-1-phenylbutan-2-yl)pyrazolo[1 ,5-a]pyridine-3- carboxamide;
6-methoxy-N-(3-(N-methylbenzofuran-3-carboxamido)-4-phenylbutyl)picolinamide;
N-(4-(6-methoxypicolinamido)-1-phenylbutan-2-yl)-N ,5-trimethyl-1 H-indazole-^^ carboxamide; N-(4-(6-methoxypicolinamido)-1-phenylbutan-2-yl)-N,2-dimethylpyrazolo[1 ,5-a]pyridine-3- carboxamide;
5- (4-fluorophenyl)-N,2-dimethyl-N-(4-(1-methyl-1H-pyrrole-2-carboxamido)-1-phenylbutan-2- yl)thiazole-4-carboxamide;
N,5,7-trimethyl-N-(4-(1-methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)pyrazolo[1 ,5- a]pyrimidine-3-carboxamide;
N,3-dimethyl-N-(4-(1-methyl-1H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)-5- phenylisoxazole-4-carboxamide;
N-methyl-N-(4-(1-methyl-1H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)imidazo[1 ,2- a]pyridine-2-carboxamide;
N-methyl-N-(4-(1-methyl-1H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)pyrazolo[1 ,5- a]pyrimidine-3-carboxamide;
3-bromo-5-chloro-N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1 -phenylbutan-2- yl)imidazo[1 ,2-a]pyridine-2-carboxamide;
N-(4-(1 -ethyl-3-methyl-1 H-pyrazole-5-carboxamido)-1 -phenylbutan-2-yl)-N,6- dimethylfuro[2,3-b]pyridine-5-carboxamide;
1-methyl-N-(4-phenyl-3-(N,5,6-trimethylbenzofuran-3-carboxamido)butyl)-1H-pyrrole-2- carboxamide;
N-(4-phenyl-3-(N,2,3-trimethylbenzofuran-6-carboxamido)butyl)picolinamide;
1- methyl-N-(3-(N-methylbenzofuran-5-carboxamido)-4-phenylbutyl)-1 H-pyrrole-2- carboxamide;
6- methyl-N-(3-(N-methyl-1 H-indole-5-carboxamido)-4-phenylbutyl)imidazo[2,1-b]thiazole-5- carboxamide;
N-(3-(N,1-dimethyl-1H-indole-4-carboxamido)-4-phenylbutyl)-1 -methyl-1 H-benzo[d]imidazole-
2- carboxamide;
5-(4-fluorophenyl)-2-methyl-N-(3-(N-methylbenzofuran-4-carboxamido)-4- phenylbutyl)thiazole-4-carboxamide;
N,2-dimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)-2H-indazole-4- carboxamide;
N,1-dimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1 -phenylbutan-2-yl)-1 H- benzo[d][1 ,2,3]triazole-7-carboxamide;
N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)benzo[d]oxazole-6- carboxamide; N,2-dimethyl-N-(4-(1 -methyl- 1 H-pyrrole-2-carboxamido)-1 -phenylbutan-2- yl)benzo[d]oxazole-6-carboxamide;
N,2-dimethyl-N-(4-(1-methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2- yl)benzo[d]oxazole-5-carboxamide;
N,3-dimethyl-N-(4-(1-methyl-1H-pyrrole-2-carboxam'ido)-1-phenylbutan-2- yl)benzo[d]isoxazole-6-carboxamide;
N,3-dimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1 -phenylbutan-2- yl)benzo[d]isoxazole-5-carboxamide;
N, 1 -dimethyl-N-(1 -phenyl-4-(picolinamido)butan-2-yl)-1 H-indole-7-carboxamide;
N-methyl-N-(1-phenyl-4-(picolinamido)butan-2-yl)-1 H-indole-7-carboxamide;
N,1-dimethyl-N-(1-phenyl-4-(picolinamido)butan-2-yl)-1 H-indole-4-carboxamide;
1-methyl-N-(3-(N-methyl-1 H-indole-4-carboxamido)-4-phenylbutyl)-1H-benzo[d]imidazole-2- carboxamide;
1 -methyl-N-(3-(N-methyl-1 H-indole-5-carboxamido)-4-phenylbutyl)-1 H-benzo[d]imidazole-2- carboxamide;
N-methyl-N-(1-phenyl-4-(picolinamido)butan-2-yl)quinoxaline-6-carboxamide;
N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)benzo[d]oxazole-5- carboxamide;
N-(3-(N,2-dimethylbenzofuran-5-carboxamido)-4-phenylbutyl)-1-methyl-1H-pyrrole-2- carboxamide;
N-methyl-N-(1-phenyl-4-(picolinamido)butan-2-yl)-1 H-indole-4-carboxamide;
N, 1 -dimethyl-N-(1 -phenyl-4-(picolinamido)butan-2-yl)-1 H-indole-5-carboxamide;
N, 1 -dimethyl-N-(1 -phenyl-4-(p'icolinamido)butan-2-yl)-1 H-indole-6-carboxamide;
N-(3-(N-methylbenzofuran-5-carboxamido)-4-phenylbutyl)picolinamide;
N-methyl-N-(1-phenyl-4-(picolinamido)butan-2-yl)-1H-indole-6-carboxamide;
N-methyl-N-(1-phenyl-4-(picolinamido)butan-2-yl)-1 H-indole-5-carboxamide;
N-(3-(N-methylbenzofuran-4-carboxamido)-4-phenylbutyl)picolinamide;
1-methyl-N-(3-(N-methylbenzofuran-4-carboxamido)-4-phenylbutyl)-1H-pyrrole-2- carboxamide;
1-methyl-N-(3-(N-methylbenzofuran-4-carboxamido)-4-phenylbutyl)-1 H-benzo[d]imidazole-2- carboxamide;
N, 1 -dimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1 -phenylbutan-2-yl)-1 H-indole-5- carboxamide; N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1 -phenylbutan-2-yl)-1 H-indole-5- carboxamide;
N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)quinoline-6- carboxamide;
N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)-1H-indole-4- carboxamide;
N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1 -phenylbutan-2-yl)quinoxaline-6- carboxamide;
6-methyl-N-(3-(N-methylquinoxaline-6-carboxamido)-4-phenylbutyl)imidazo[2,1-b]thiazole-5- carboxamide;
6-methyl-N-(3-(N-methyl-1H-indole-4-carboxamido)-4-phenylbutyl)imidazo[2,1-b]thiazole-5- carboxamide;
6-methyl-N-(3-(N-methylquinoline-6-carboxamido)-4-phenylbutyl)imidazo[2,1-b]thiazole-5- carboxamide;
N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1 -phenylbutan-2- yl)benzo[c][1 ,2,5]thiadiazole-5-carboxamide;
N-(3-(3-bromo-N-methylbenzofuran-5-carboxamido)-4-phenylbutyl)-1 -methyl-1 H-pyrrole-2- carboxamide;
N,2-dimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1 -phenylbutan-2- yl)benzo[d]thiazole-5-carboxamide;
N-(3-(N,3-dimethylbenzofuran-5-carboxamido)-4-phenylbutyl)-1-methyl-1H-pyrrole-2- carboxamide;
1-methyl-N-(3-(N-methylbenzofuran-6-carboxamido)-4-phenylbutyl)-1 H-pyrrole-2- carboxamide;
N,1-dimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)-1 H- benzo[d][1 ,2,3]triazole-5-carboxamide;
N, 1-dimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)-1 H-indazole-5- carboxamide;
N,2-dimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)-2H- benzo[d][1 ,2,3]triazole-4-carboxamide;
N, 1-dimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1 -phenylbutan-2-yl)-1 H- benzo[d][ 1 , 2, 3]triazole-4-carboxamide;
N, 1 -dimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1 -phenylbutan-2-yl)-1 H-indazole-4- carboxamide; N-methyl-N-(4-(1-methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)-1 H- benzo[d][1 ,2,3]triazole-5-carboxamide;
N,2-dimethyl-N-(4-(1-methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)-1 H- benzo[d]imidazole-5-carboxamide;
N-methyl-N-(4-(1-methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)-1 H-indazole-5- carboxamide;
N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1 -phenylbutan-2-yl)-1 H- benzo[d]imidazole-5-carboxamide;
N-methyl-N-(4-(1-methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)benzo[d]thiazole-6- carboxamide;
N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)quinoline-8- carboxamide;
N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)benzo[d]oxazole-4- carboxamide;
N,2-dimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1 -phenylbutan-2- yl)benzo[d]oxazole-4-carboxamide;
N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)benzo[d]thiazole-5- carboxamide;
N-methyl-N-(4-(1-methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2- yl)benzo[c][ 1 , 2 , 5]oxadiazole-5-carboxam ide;
N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)quinoline-5- carboxamide;
6-chloro-N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)quinoline-8- carboxamide;
N, 2,4-trimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)quinoline-8- carboxamide;
N,2,5-trimethyl-N-(4-(1-methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)quinoline-8- carboxamide;
5,6-dimethoxy-N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1 -phenylbutan-2- yl)quinoline-8-carboxamide;
6-bromo-N,2-dimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2- yl)quinoline-8-carboxamide;
6-methoxy-N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1 -phenylbutan-2- yl)quinoline-8-carboxamide; 6-methoxy- , 2-dimethyl-N-(4-( 1 -methyl- 1 H-pyrrole-2-carboxamido)- 1 -phenylbutan-2- yl)quinoline-8-carboxamide;
N,6-dimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)quinoline-8- carboxamide;
N-(3-(5-fluoro-N-methylbenzofuran-6-carboxamido)-4-phenylbutyl)-1-methyl-1 H-pyrrole-2- carboxamide;
N-(3-(N,5-dimethylbenzofuran-6-carboxamido)-4-phenylbutyl)-1 -methyl-1 H-pyrrole-2- carboxamide;
N, 1-dimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)-1 H-indole-4- carboxamide;
N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)benzo[d]oxazole-7- carboxamide;
N,2-dimethyl-N-(4-(1-methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2- yl)benzo[d]oxazole-7-carboxamide;
N,2-dimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1 -phenylbutan-2-yl)quinoline-8- carboxamide;
N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)quinoxaline-5- carboxamide;
N, 1 ,2-trimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1 -phenylbutan-2-yl)-1 H-indole-4- carboxamide;
N,1 ,3-trimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)-1 H-indole-4- carboxamide;
,5-trimethyl-N-(4-(1-methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)-1 H-indole-4- carboxamide;
N,1 ,7-trimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)-1 H-indole-4- carboxamide;
N-(4-(1-ethyl-3-methyl-1 H-pyrazole-5-carboxamido)-1-phenylbutan-2-yl)-N- methylbenzo[d]oxazole-5-carboxamide;
4-chloro-N,1-dimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1 -phenylbutan-2-yl)-1 H- indole-5-carboxamide;
6-chloro-N, 1 -dimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1 -phenylbutan-2-yl)-1 H- indole-5-carboxamide;
N,1 ,6-trimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)-1 H-indole-4- carboxamide; 1-methyl-N-(3-(N-methyl-3-(5-methyloxazol-2-yl)benzamido)-4-phenylbutyl)-1 H-pyrrole-2- carboxamide;
1 -methyl-N-(3-(N-methyl-3-(1 H-pyrrol-1 -yl)benzamido)-4-phenylbutyl)-1 H-pyrrole-2- carboxamide;
N-(3-(N-methylbiphenyl-2-ylcarboxamido)-4-phenylbutyl)picolinamide;
5-(2-fluorophenyl)-N,2-dimethyl-N-(4-(1 -methyl-1 H-benzo[d]imidazole-2-carboxamido)-1- phenylbutan-2-yl)thiazole-4-carboxamide;
N-(3-(3-(3,5-dimethyl-1 H-pyrazol-1 -yl)-N-methylbenzamido)-4-phenylbutyl)-1 -methyl-1 H- pyrrole-2-carboxamide;
1 -methyl-N-(3-(N-methyl-3-(5-methyl-1 ,2,4-oxadiazol-3-yl)benzamido)-4-phenylbutyl)-1 H- pyrrole-2-carboxamide;
1 -methyl-N-(3-(N-methyl-3-(1 H-tetrazol-1 -yl)benzamido)-4-phenylbutyl)-1 H-pyrrole-2- carboxamide;
1 -methyl-N-(3-(N-methyl-3-(5-methyl-1 ,3,4-oxadiazol-2-yl)benzamido)-4-phenylbutyl)-1 H- pyrrole-2-carboxamide;
1 - methyl-N-(3-(N-methyl-3-(1 -methyl-1 H-pyrazol-5-yl)benzamido)-4-phenylbutyl)-1 H-pyrrole-
2- carboxamide;
1- methyl-N-(3-(N-methyl-3-(oxazol-5-yl)benzamido)-4-phenylbutyl)-1 H-pyrrole-2- carboxamide;
1 -methyl-N-(3-(N-methyl-3-(1 -methyl-1 H-pyrazol-3-yl)benzamido)-4-phenylbutyl)-1 H-pyrrole-
2- carboxamide;
1 -methyl-N-(3-(N-methyl-3-(1 H-pyrazol-3-yl)benzamido)-4-phenylbutyl)-1 H-pyrrole-2- carboxamide;
1 -methyl-N-(3-(N-methyl-3-(1 H-tetrazol-5-yl)benzamido)-4-phenylbutyl)-1 H-pyrrole-2- carboxamide;
1- methyl-N-(3-(N-methyl-3-(5-methyl-1 H-pyrazol-1 -yl)benzamido)-4-phenylbutyl)-1H-pyrrole-
2- carboxamide;
1 -methyl-N-(3-(N-methyl-3-(3-methyl-1 H-pyrazol-1 -yl)benzamido)-4-phenylbutyl)-1 H-pyrrole- 2-carboxamide;
1-methyl-N-(3-(N-methyl-3-(pyridin-2-yl)benzamido)-4-phenylbutyl)-1 H-pyrrole-2- carboxamide;
1-methyl-N-(3-(N-methyl-3-(pyrimidin-2-yl)benzamido)-4-phenylbutyl)-1H-pyrrole-2- carboxamide; N,5-dimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1 -phenylbutan-2-yl)-3- phenylisoxazole-4-carboxamide;
1 -methyl-N-(3-(N-methyl-3-(1 H-pyrazol-1 -yl)benzamido)-4-phenylbutyl)-1 H-pyrrole-2- carboxamide;
N-(3-(N,5-dimethyl-2-(2H-1 ,2,3-tr'iazol-2-yl)benzamido)-4-phenylbutyl)-1-methyl-1 H-pyrrole-2- carboxamide;
N-(3-(N,5-dimethyl-2-(pyrimidin-2-yl)benzamido)-4-phenylbutyl)-1-methyl-1 H-pyrrole-2- carboxamide;
5- (2-fluorophenyl)-N,2-dimethyl-N-(1-phenyl-4-(picolinamido)butan-2-yl)thiazole-4- carboxamide;
N-(3-(N,5-dimethyl-2-(2H-1 ,2,3-triazol-2-yl)benzamido)-4-phenylbutyl)-1-ethyl-3-methyl-1 H- pyrazo le-5-ca rboxam ide ;
N-(3-(3-(1 H-im'idazol-1 -yl)-N-methylbenzam'ido)-4-phenylbutyl)-1 -methyl-1 H-pyrrole-2- carboxamide;
2-methoxy-N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1 -phenylbutan-2- yl)isonicotinamide;
2-chloro-6-methoxy-N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1 -phenylbutan-2- yl)isonicotinamide;
2-chloro-N,6-dimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2- yl)isonicotinamide;
6- methoxy-N-methyl-N-(1-phenyl-4-(picolinamido)butan-2-yl)picolinamide;
6-methoxy-N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1 -phenylbutan-2- yl)nicotinamide;
3.5- difluoro-N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxam'ido)-1-phenylbutan-2- yl)picol'inamide;
2.6- dichloro-N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2- yl)isonicotinamide;
N,2-dimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1 -phenylbutan-2-yl)isonicotinamide; 2,6-difluoro-N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1 -phenylbutan-2- yl)isonicotinamide;
6-methoxy-N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1 -phenylbutan-2- yl)picol'inamide;
4,6-dimethoxy-N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2- yl)pyrimidine-2-carboxamide; 4-methoxy-N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2- yl)picolinamide;
N,6-dimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)picolinamide; N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)-1 ,4,5,6- tetrahydrocyclopenta[c]pyrazole-3-carboxamide;
N,2-dimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)-4,5,6,7- tetrahydro-2H-indazole-3-carboxamide;
N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)-4,5,6,7-tetrahydro- 2H-indazole-3-carboxamide;
N,3,5-trimethyl-N-(4-(1-methyl-1H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)isoxazole-4- carboxamide;
2-ethoxy-N,6-dimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2- yl)isonicotinamide;
2-methoxy-N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1 -phenylbutan-2- yl)nicotinamide;
2, 6-dimethoxy-N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1 -phenylbutan-2- yl)isonicotinamide;
2-methoxy-N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2- yl)pyrimidine-4-carboxamide;
N,2-dimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)nicotinamide; 4-methoxy-N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2- yl)nicotinamide;
2-ethyl-N,6-dimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2- yl)isonicotinamide;
4,6-dichloro-N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2- yl)picolinamide;
4-methoxy-N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1 -phenylbutan-2- yl)pyrimidine-2-carboxamide;
4,6-dimethoxy-N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2- yl)picolinamide;
6-methoxy-N,4-dimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2- yl)picolinamide;
N,2,6-trimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2- yl)isonicotinamide; , 2, 5-trimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2- yl)isonicotinamide;
2-methoxy-N,5-dimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2- yl)isonicotinamide;
N-(3-(2-methoxy-N,6-dimethylisonicotinamido)-4-phenylbutyl)-1 -methyl-1 H- benzo[d]imidazole-2-carboxamide;
2-isopropyl-N,6-dimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2- yl)isonicotinamide;
N,2,5-trimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)nicotinamide;
5- chloro-2-methoxy-N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1 -phenylbutan-2- yl)nicotinamide;
2-ethyl-N-(4-(1 -ethyl-3-methyl-1 H-pyrazole-5-carboxamido)-1 -phenylbutan-2-yl)-N,6- dimethylisonicotinamide;
N-(4-(1 -ethyl-3-methyl-1 H-pyrazole-5-carboxamido)-1 -phenylbutan-2-yl)-2-methoxy-N,6- dimethylisonicotinamide;
2-ethoxy-N-(4-(1 -ethyl-3-methyl-1 H-pyrazole-5-carboxamido)-1 -phenylbutan-2-yl)-N,6- dimethylisonicotinamide;
N-(4-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1-phenylbutan-2-yl)-2,6-dimethoxy-N- methylisonicotinamide;
N-(4-(1 -ethyl-3-methyl-1 H-pyrazole-5-carboxamido)-1 -phenylbutan-2-yl)-4,6-dimethoxy-N- methylpyrimidine-2-carboxamide;
6- methoxy-N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1 -phenylbutan-2-yl)pyrazine- 2-carboxamide;
5-methoxy-N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2- yl)nicotinamide;
2-ethoxy-N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1 -phenylbutan-2-yl)pyrimidine- 4-carboxamide;
2-isopropoxy-N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1 -phenylbutan-2- yl)pyrimidine-4-carboxamide;
2-methoxy-N,6-dimethyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2- yl)isonicotinamide;
2, 6-dimethoxy-N-methyl-N-(4-(1 -methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2- yl)pyrimidine-4-carboxamide; N,2-dimethyl-N-(4-(1-methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)-6-(pyrrolidi yl)isonicotinamide;
N-(3-(2-methoxy-N,6-dimethylisonicotinamido)-4-phenylbutyl)-6-methylpicolinami
N-(3-(2,6-dimethoxy-N-methylisonicotinamido)-4-phenylbutyl)-6-methylpicolinami
2-methoxy-N-methyl-N-(4-(6-methylpicolinamido)-1-phenylbutan-2-yl)pyrimidine-4- carboxamide;
2-methoxy-N-(4-(6-methoxypicolinamido)-1-phenylbutan-2-yl)-N-methylpyrimidine-4- carboxamide;
N-(3-(2-methoxy-N-methylpyrimidine-4-carboxamido)-4-phenylbutyl)-1-methyl-1 H- benzo[d]imidazole-2-carboxamide;
N,2-dimethyl-N-(4-(6-methylpicolinamido)-1-phenylbutan-2-yl)pyrimidine-4-carboxam N-(4-(6-methoxypicolinamido)-1-phenylbutan-2-yl)-N,2-dimethylpyrimidine-4-carboxam N-(3-(N,2-dimethylpyrimidine-4-carboxamido)-4-phenylbutyl)-1-methyl-1H-benzo[d]imi 2-carboxamide;
6-methoxy-N-(3-(2-methoxy-N,6-dimethylisonicotinamido)-4-phenylbutyl)picolinam
N-(3-(2,6-dimethoxy-N-methylisonicotinamido)-4-phenylbutyl)-6-methoxypicolinam
1-ethyl-N,3-dimethyl-N-(4-(1-methyl-1H-pyrrole-2-carboxamido)-1-phenylbutan-2-y^ pyrazole-5-carboxamide; and
N,1 ,3,5-tetramethyl-N-(4-(1-methyl-1 H-pyrrole-2-carboxamido)-1-phenylbutan-2-yl)-1 H- pyrazole-4-carboxamide.
9. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 8 in free form or in salt form and one or more pharmaceutically acceptable carriers.
10. A combination comprising a therapeutically effective amount of the compound according to any one of claims 1 to 8 in free form or in salt form and one or more therapeutically active agents.
11. A method of treating a disorder or a disease in a subject mediated by orexin receptors, wherein the method comprises administering to the subject a therapeutically effective amount of the compound according to any one of claims 1 to 8 in free form or in salt form.
12. A method according to claim 11 , wherein the disorder or disease is selected from sleep disorders, eating disorders, substance-related disorders or Alzheimers disease.
13. A compound according to any one of claims 1 to 8 in free form or in salt form, for use as a medicament.
14. A compound according to any one of claims 1 to 8 in free form or in salt form, for use in the treatment of a disorder or disease in a subject mediated by orexin receptors.
15. A compound according to claim 14 in free form or in salt form, wherein the disorder or disease mediated by orexin receptors sleep disorders, eating disorders, substance-related disorders or Alzheimers disease.
16. A compound of formula XIII
Figure imgf000222_0001
wherein R2, R3, R4, R5, R6, A and B are as defined according to claim 1 in free form or in salt form.
PCT/EP2010/069889 2009-12-18 2010-12-16 4-aryl-butane-1,3-diamides WO2011073316A1 (en)

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