WO2007115798A1 - Substituted phenylpiperidine derivatives as melanocortin-4 receptor modulators - Google Patents

Substituted phenylpiperidine derivatives as melanocortin-4 receptor modulators Download PDF

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WO2007115798A1
WO2007115798A1 PCT/EP2007/003115 EP2007003115W WO2007115798A1 WO 2007115798 A1 WO2007115798 A1 WO 2007115798A1 EP 2007003115 W EP2007003115 W EP 2007003115W WO 2007115798 A1 WO2007115798 A1 WO 2007115798A1
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alkyl
vacuo
added
room temperature
reaction mixture
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PCT/EP2007/003115
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Michael Soeberdt
Holger Deppe
Philipp Weyermann
Stephan Bulat
Andreas Von Sprecher
Achim Feurer
Cyrille Lescop
Marco Henneböhle
Sonja Nordhoff
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Santhera Pharmaceuticals (Schweiz) Ag
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Priority to US12/293,905 priority Critical patent/US20110086836A1/en
Priority to CA002648335A priority patent/CA2648335A1/en
Priority to DE602007010914T priority patent/DE602007010914D1/en
Priority to EP07724056A priority patent/EP2004604B1/en
Priority to AT07724056T priority patent/ATE490239T1/en
Priority to JP2009503494A priority patent/JP2009532405A/en
Publication of WO2007115798A1 publication Critical patent/WO2007115798A1/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
    • C07D401/10—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 carbon chain containing aromatic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A61P21/02—Muscle relaxants, e.g. for tetanus or cramps
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A61P21/06—Anabolic agents
    • 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
    • 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
    • A61P25/22—Anxiolytics
    • 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
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
    • C07D211/22—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/26—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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

Definitions

  • the present invention relates to substituted phenylpiperidine derivatives as melanocortin-4 receptor modulators.
  • the compounds of the invention are either selective agonists or selective antagonists of the human melanocortin-4 receptor (MC-4R).
  • the agonists can be used for the treatment of disorders and diseases such as obesity, diabetes and sexual dysfunction, whereas the antagonists are useful for the treatment of disorders and diseases such as cancer cachexia, muscle wasting, anorexia, anxiety and depression.
  • MC-4R human melanocortin-4 receptor
  • MCs Melanocortins stem from proopiomelanocortin (POMC) via proteolytic cleavage. These peptides, adrenocorticotropic hormone (ACTH), ⁇ -melanocyte-stimulating hormone ( ⁇ -MSH), ⁇ -MSH and ⁇ -MSH, range in size from 12 to 39 amino acids. The most important endogenous agonist for central MC-4R activation appears to be the tridecapeptide ⁇ - MSH. Among MCs, it was reported that ⁇ -MSH acts as a neurotransmitter or neuromodulator in the brain. MC peptides, particularly ⁇ -MSH, have a wide range of effects on biological functions including feeding behavior, pigmentation and exocrine function.
  • MC-Rs melanocortin receptors
  • MC-1 R was first found in melanocytes.
  • Naturally occurring inactive variants of MC-1 R in animals were shown to lead to alterations in pigmentation and a subsequent lighter coat color by controlling the conversion of phaeomelanin to eumelanin through the control of tyrosinase. From these and other studies, it is evident that MC-1 R is an important regulator of melanin production and coat color in animals and skin color in humans.
  • the MC-2R is expressed in the adrenal gland representing the ACTH receptor.
  • the MC- 2R is not a receptor for ⁇ -MSH but is the receptor for the adrenocorticotropic hormone I (ACTH I).
  • the MC-3R is expressed in the brain (predominately located in the hypothalamus) and peripheral tissues like gut and placenta, and knock-out studies have revealed that the MC-3R may be responsible for alterations in feeding behavior, body weight and thermogenesis.
  • the MC-4R is primarily expressed in the brain. Overwhelming data support the role of MC-4R in energy homeostasis. Genetic knock-outs and pharmacologic manipulation of MC-4R in animals have shown that agonizing the MC-4R causes weight loss and antagonizing the MC-4R produces weight gain (A. Kask et al., "Selective antagonist for the melanocortin-4 receptor (HS014) increases food intake in free-feeding rats," Biochem. Biophys. Res. Commun., 245: 90-93 (1998)).
  • MC-5R is ubiquitously expressed in many peripheral tissues including white fat, placenta and a low level of expression is also observed in the brain. However its expression is greatest in exocrine glands. Genetic knock-out of this receptor in mice results in altered regulation of exocrine gland function, leading to changes in water repulsion and thermoregulation. MC-5R knockout mice also reveal reduced sebaceous gland lipid production (Chen et al., Ce//, 91 : 789-798 (1997)).
  • MC-3R and MC-4R modulators have potent physiological effects besides their role in regulating pigmentation, feeding behavior and exocrine function.
  • ⁇ -MSH recently has been shown to induce a potent anti-inflammatory effect in both acute and chronic models of inflammation including inflammatory bowel-disease, renal ischemia/reperfusion injury and endotoxin-induced hepatitis.
  • Administration of ⁇ -MSH in these models results in substantial reduction of inflammation-mediated tissue damage, a significant decrease in leukocyte infiltration and a dramatic reduction in elevated levels of cytokines and other mediators to near baseline levels.
  • ⁇ -MSH anti-inflammatory actions of ⁇ -MSH are mediated by MC-1 R.
  • the mechanism by which agonism of MC-1 R results in an anti-inflammatory response is likely through inhibition of the pro-inflammatory transcription activator, NF- ⁇ B.
  • NF- ⁇ B is a pivotal component of the pro-inflammatory cascade, and its activation is a central event in initiating many inflammatory diseases.
  • anti-inflammatory actions of ⁇ -MSH may be, in part, mediated by agonism of MC-3R and/or MC-5R.
  • MC-4R signaling is important in mediating feeding behavior (S. Q. Giraudo et al., "Feeding effects of hypothalamic injection of melanocortin-4 receptor ligands," Brain Research, 80: 302-306 (1998)).
  • Further evidence for the involvement of MC-Rs in obesity includes: 1) the agouti (A ⁇ ) mouse which ectopically expresses an antagonist of the MC-1 R, MC-3R and MC-4R is obese, indicating that blocking the action of these three MC-R's can lead to hyperphagia and metabolic disorders; 2) MC-4R knockout mice (D.
  • MC-4R appears to play a role in other physiological functions as well, namely controlling grooming behavior, erection and blood pressure.
  • Erectile dysfunction denotes the medical condition of inability to achieve penile erection sufficient for successful intercourse.
  • the term "impotence" is often employed to describe this prevalent condition.
  • Synthetic melanocortin receptor agonists have been found to initiate erections in men with psychogenic erectile dysfunction (H. Wessells et al., "Synthetic Melanotropic Peptide Initiates Erections in Men With Psychogenic Erectile Dysfunction: Double-Blind, Placebo Controlled Crossover Study", J. Urol., 160: 389-393, (1998)).
  • Activation of melanocortin receptors of the brain appears to cause normal stimulation of sexual arousal.
  • Evidence for the involvement of MC-R in male and/or female sexual dysfunction is detailed in WO 00/74679.
  • Diabetes is a disease in which a mammal's ability to regulate glucose levels in the blood is impaired because the mammal has a reduced ability to convert glucose to glycogen for storage in muscle and liver cells. In Type I diabetes, this reduced ability to store glucose is caused by reduced insulin production.
  • Type Il diabetes or “Non-Insulin Dependent Diabetes Mellitus” (NIDDM) is the form of diabetes which is due to a profound resistance to insulin stimulating or regulatory effect on glucose and lipid metabolism in the main insulin-sensitive tissues, muscle, liver and adipose tissue. This resistance to insulin responsiveness results in insufficient insulin activation of glucose uptake, oxidation and storage in muscle, and inadequate insulin repression of lipolysis in adipose tissue and of glucose production and secretion in liver.
  • NIDDM Non-Insulin Dependent Diabetes Mellitus
  • Hyperinsulemia is associated with hypertension and elevated body weight. Since insulin is involved in promoting the cellular uptake of glucose, amino acids and triglycerides from the blood by insulin sensitive cells, insulin insensitivity can result in elevated levels of triglycerides and LDL which are risk factors in cardiovascular diseases.
  • MC-4R agonists might be useful in the treatment of NIDDM and Syndrome X.
  • the MC4 receptor is also of interest in terms of the relationship to stress and the regulation of emotional behavior, as based on the following findings. Stress initiates a complex cascade of responses that include endocrine, biochemical and behavioral events. Many of these responses are initiated by release of corticotropin-releasing factor (CRF) (MJ. Owen and CB. Nemeroff, "Physiology and pharmacology of corticotrophin releasing factor.” Pharmacol. Rev. 43: 425-473 (1991)).
  • CCF corticotropin-releasing factor
  • MCL0129 (1-[(S)-2-(4-Fluorophenyl)-2-(4- isopropylpiperadin-1-yl)ethyl]-4- [4-(2-methoxynaphthalen-1-yl)butyl]piperazine), a Novel and Potent Nonpeptide Antagonist of the Melanocortin-4 Receptor", J. Pharm. Exp. Ther. 304(2), 818-826 (2003)).
  • the increased body weight in the treated mice is attributable to a larger amount of lean body mass, which mainly consists of skeletal muscle (D. L. Marks et al. "Role of the central melanocortin system in cachexia.” Cancer Res. 61 : 1432-1438 (2001)).
  • WO 2004/024720 A1 describes piperazine urea derivatives which are selective agonists of the human melanocortin-4 receptor and as such they are claimed to be useful in the treatment of prevention of obesity-related disorders.
  • WO 2005/047253 A1 describes 4,4-disubstituted piperidine derivatives which are postulated to function as melanocortin receptor agonists.
  • Substituted piperidine derivatives are also described in DE 103 00973 which relates to carboxylic acids and esters having a piperidine ring or a piperazine ring as the central core of the molecule and wherein the core is further substituted in the para-position by a 5-7- membered heterocycle, a phenyl ring, a pyridine ring or a thiazole ring. Said rings are optionally substituted by an ester group.
  • the compounds are used in the preparation of a medicament for the treatment of headaches, non-insulin dependent diabetes mellitus (NIDDM), cardiovascularic diseases, morphintolerance, diseases of the skin, inflammations, allergic rhinitis, asthma, diseases with vascular dilatation and, consequently, with reduced blood circulation in tissues, acute or preemptive treatment of menopausal hot flashes of women with an estrogen deficiency or for the treatment of pain.
  • NIDDM non-insulin dependent diabetes mellitus
  • novel substituted phenylpiperidine derivatives with improved ability to cross the blood brain barrier, which are useful as melanocortin-4 receptor modulators to treat cancer cachexia, muscle wasting, anorexia, anxiety, depression, obesity, diabetes, sexual dysfunction and other diseases with MC-4R involvement.
  • the present invention relates to substituted phenylpiperidine derivatives of structural formula (I)
  • the phenylpiperidine derivatives of structural formula (I) are effective as melanocortin receptor modulators and are particularly effective as selective melanocortin-4 receptor (MC-4R) modulators. They are therefore useful for the treatment of disorders where the activation or inactivation of the MC-4R are involved.
  • Agonists can be used for the treatment of disorders and diseases such as obesity, diabetes and sexual dysfunction, whereas the antagonists are useful for the treatment of disorders and diseases such as cancer cachexia, muscle wasting, anorexia, anxiety and depression.
  • the present invention also relates to pharmaceutical compositions comprising the compounds of the present invention and a pharmaceutically acceptable carrier.
  • the present invention relates to substituted phenylpiperidine derivatives useful as melanocortin receptor modulators, in particular, selective MC-4R agonists and MC-4R antagonists.
  • R 1 is -(C(R 6 ) 2 ),-T, or
  • R 6 is independently selected from
  • Cs- 6 -cycloalkyl optionally substituted with 1 to 3 substituents selected from halogen, CN, OH and OCH 3 ;
  • T is NR 7 R 8 , morpholine,
  • R 7 and R 8 are independently from each other selected from
  • each alkyl, alkenyl and alkinyl is optionally substituted by one or more halogen atoms, CN or OH;
  • R 9 is independently selected from halogen, CN,
  • Ci- 6 -alkyl optionally substituted with 1 to 3 substituents selected from halogen, CN and OH, and
  • O-Ci-e-alkyl optionally substituted with 1 to 3 substituents selected from halogen, CN and OH 1 d-e-alkylene-O-d- ⁇ -alkyl optionally substituted with 1 to 3 substituents selected from halogen, CN and OH;
  • R 10 is H, or d-Ce-alkyl;
  • R 11 is independently selected from halogen
  • Ci- 6 -alkyl optionally substituted with 1 to 3 substituents selected from halogen, CN and OH 1 O-d-e-alkyl optionally substituted with 1 to 3 substituents selected from halogen,
  • Ci- ⁇ -alkylene-O-Ci- ⁇ -alkyl optionally substituted with 1 to 3 substituents selected from halogen, CN and OH, -NH 2 , -NH(d- 6 -alkyl), and
  • X is CH or N
  • Y is CH or N
  • Z is CH or N
  • A is a 3-7-membered saturated, unsaturated or aromatic ring containing 0-2 nitrogen atoms
  • R 2 is independently selected from F, Cl, CH 3 , and
  • R 3 is H, Cl 1 F, or CH 3 ;
  • R 4 is Cl or F;
  • morpholine optionally substituted by 1 to 3, same or different substituents R 14 , or
  • R 12 and R 13 are independently from each other selected from Ci- 6 -alkyl
  • R 14 is Ci- 6 -alkyl, d-e-alkylene-O-Ci- ⁇ -alkyl, d- 6 -alkylene-OH, or
  • Ci-6-alkylene-NH 2 Ci-6-alkylene-NH 2
  • Ci-e-alkylene-NHCd-e-alkyO ⁇ Ci-e-alkylene-N(Ci -6 -alkyl)2;
  • the compounds according to formula (I) adopt the structural conformation of the following stereoisomer formula (I 1 ):
  • R 2 represents Cl or F.
  • the phenyl ring directly connected with the piperidine ring is monosubstituted by a chlorine or fluorine atom in the meta or para-position.
  • R 3 represents H, Cl, or CH 3 , more preferably Cl. In an alternative embodiment, R 3 preferably represents F.
  • R 4 represents Cl
  • the variant R 1 represents -(CH 2 ) ⁇ -T or -O-(CH 2 ) m -T.
  • At least one of R 7 and R 8 is selected from Ci. 6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkinyl and C ⁇ -e-alkylene-O-Ci-e-alkyl, more preferably from C 2-6 -alkenyl, C 2- 6-alkinyl and C ⁇ - ⁇ -alkylene-O-d- ⁇ -alkyl.
  • R 9 is independently selected from halogen, CN, OH, Ci -6 -alkyl optionally substituted with 1 to 3 substituents selected from halogen, CN and OH, and O-Ci -6 -alkyl optionally substituted with 1 to 3 substituents selected from halogen, CN and OH.
  • the variant I is preferably selected from 2 or 3.
  • T is preferably selected from the group consisting of the following radicals:
  • R 5 is preferably selected from the group consisting of
  • Alkyl is a straight chain or branched alkyl having 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, or hexyl.
  • Alkenyl is a straight chain or branched alkyl having 2 to 6 carbon atoms and which contains at least one carbon-carbon double bond, such as vinyl, allyl, 1-propenyl, 2-butenyl, 2-methyl-2-butenyl, isopropenyl, pentenyl, or hexenyl.
  • Alkinyl is a straight chain or branched alkyl having 2 to 6 carbon atoms and which contains at least one carbon-carbon triple bond, such as ethinyl, 1-propinyl, 1-butinyl, 2-butinyl, pentinyl or hexinyl.
  • a 3-7-membered, saturated, unsaturated or aromatic ring containing 0-2 nitrogen atoms encompasses a 3-7-membered saturated carbocycle such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl. Said term further encompasses 3-7-membered unsaturated carbocycles such as cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclohexa-1 ,4-diene or cycloheptadienes, or aromatic rings such as benzene.
  • Nitrogen- containing, 3-7-membered, saturated, unsaturated or aromatic heterocycles are further encompassed by the above term. Examples thereof include azetidine, pyrrolidine, piperidine, azepane, piperazine, pyridine, pyrimidine, pyrazine, pyrrole, imidazole, and pyrazole.
  • the compounds of structural formula (I) are effective as melanocortin receptor modulators and are particularly effective as selective modulators of MC-4R. They are therefore useful for the treatment and/or prevention of disorders responsive to the activation and inactivation of MC-4R, such as cancer cachexia, muscle wasting, anorexia, anxiety, depression, obesity, diabetes, sexual dysfunction and other diseases with MC-4R involvement.
  • the compounds of structural formula (I) are particularly useful as antagonists of MC-4R. Thus, they are preferably used for the preparation of a medicament for the treatment and/or prevention of cancer cachexia, muscle wasting, anorexia, anxiety and depression.
  • Compounds of structural formula (I) contain one or more asymmetric centers and can occur as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. The present invention is meant to comprehend all such isomeric forms of the compounds of structural formula (I).
  • Compounds of structural formula (I) may be separated into their individual diastereoisomers by, for example, fractional crystallization from a suitable solvent, for example methanol or ethyl acetate or a mixture thereof, or via chiral chromatography using an optically active stationary phase.
  • Absolute stereochemistry may be determined by X-ray crystallography of crystalline products or crystalline intermediates which are derivatized, if necessary, with a reagent containing an asymmetric center of known absolute configuration.
  • any stereoisomer of a compound of the general formula (I) may be obtained by stereospecific synthesis using optically pure starting materials or reagents of known absolute configuration.
  • salts refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids including inorganic or organic bases and inorganic or organic acids.
  • Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc and the like. Particularly preferred are the ammonium, calcium, lithium, magnesium, potassium and sodium salts.
  • Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N.N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylamino- ethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like.
  • basic ion exchange resins such as arg
  • salts may be prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids.
  • acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, formic, furnaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, malonic, mucic, nitric, parnoic, pantothenic, phosphoric, propionic, succinic, sulfuric, tartaric, p-toluenesulfonic, trifluoroacetic acid and the like.
  • Particularly preferred are citric, fumaric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric and tartaric acids.
  • the compounds of formula (I) are melanocortin receptor modulators and as such are useful in the treatment, control or prevention of diseases, disorders or conditions responsive to the inactivation of one or more of the melanocortin receptors including, but not limited to, MC-1 R, MC-2R, MC-3R, MC-4R or MC-5R.
  • diseases, disorders or conditions include, but are not limited to, cancer cachexia, muscle wasting, anorexia, anxiety, depression, obesity (by reducing appetite, increasing metabolic rate, reducing fat intake or reducing carbohydrate craving), diabetes mellitus (by enhancing glucose tolerance, decreasing insulin resistance) and male and female sexual dysfunction
  • the compounds of formulas (I) can be further used in the treatment, control or prevention of hypertension, hyperlipidemia, osteoarthritis, cancer, gall bladder disease, sleep apnea, compulsion, neuroses, insomnia/sleep disorder, substance abuse, pain, fever, inflammation, immune-modulation, rheumatoid arthritis, skin tanning, acne and other skin disorders, neuroprotective and cognitive and memory enhancement including the treatment of Alzheimer's disease.
  • Any suitable route of administration may be employed for providing a mammal, especially a human with an effective dosage of a compound of the present invention.
  • oral, rectal, topical, parenteral, ocular, pulmonary, nasal and the like may be employed.
  • Dosage forms include tablets, troches, dispersions, suspensions, solutions, capsules, creams, ointments, aerosols and the like.
  • compounds of formula (I) are administered orally or topically.
  • the effective dosage of active ingredient employed may vary depending on the particular compound employed, the mode of administration, the condition being treated and the severity of the condition being treated. Such dosage may be ascertained readily by a person skilled in the art.
  • the compounds of the present invention are administered at a daily dosage of from about 0.001 milligram to about 100 milligrams per kilogram of body weight, preferably given in a single dose or in divided doses two to six times a day, or in sustained release form.
  • the total daily dose will generally be from about 0.07 milligrams to about 3500 milligrams. This dosage regimen may be adjusted to provide the optimal therapeutic response.
  • the compounds of the present invention are administered at a daily dosage of from about 0.001 milligram to about 100 milligrams per kilogram of body weight, preferably given in a single dose or in divided doses two to six times a day, or in sustained release form.
  • the total daily dose will generally be from about 0.07 milligrams to about 3500 milligrams. This dosage regimen may be adjusted to provide the optimal therapeutic response.
  • the compounds of the present invention are administered at a daily dosage of from about 0.001 milligram to about 100 milligram per kilogram of animal body weight, preferably given in a single dose or in divided doses two to six times a day, or in sustained release form.
  • the total daily dose will generally be from about 0.07 milligrams to about 3500 milligrams. This dosage regimen may be adjusted to provide the optimal therapeutic response.
  • compounds of the present invention are given in a dose range of 0.001 milligram to about 100 milligram per kilogram of body weight, preferably as a single dose orally or as a nasal spray.
  • the compounds of formula (I) are preferably formulated into a dosage form prior to administration. Accordingly the present invention also includes a pharmaceutical composition comprising a compound of formula (I) and a suitable pharmaceutical carrier.
  • the active ingredient (a compound of formula (I)) is usually mixed with a carrier, or diluted by a carrier, or enclosed within a carrier, which may be in the form of a capsule, sachet, paper or other container.
  • a carrier which may be in the form of a capsule, sachet, paper or other container.
  • the carrier serves as a diluent, it may be a solid, semisolid or liquid material which acts as a vehicle, excipient or medium for the active ingredient.
  • compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosol (as a solid or in a liquid medium), soft and hard gelatin capsules, suppositories, sterile injectable solutions and sterile packaged powders.
  • Suitable carriers, excipients and diluents include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water syrup, methyl cellulose, methyl and propylhydroxybenzoates, talc, magnesium stearate and mineral oil.
  • the formulations can additionally include lubricating agents, wetting agents, emulsifying and suspending agents, preserving agents, sweetening agents or flavoring agents.
  • the compositions of the invention may be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient.
  • the preparation of the compounds of the present invention may be carried out via sequential or convergent synthetic routes.
  • the skilled artisan will recognize that, in general, the A and B moieties of a compound of formula (I) are connected via amide bonds. The skilled artist can, therefore, readily envision numerous routes and methods of connecting the two moieties via standard peptide coupling reaction conditions.
  • standard peptide coupling reaction conditions means coupling a carboxylic acid with an amine using an acid activating agent such as EDCI, dicyclohexylcarbodiimide and benzotriazol-1-yloxytris(dimethylamino)-phosphonium hexafluorophosphate, in a inert solvent such as DCM, in the presence of a catalyst such as HOBt.
  • an acid activating agent such as EDCI, dicyclohexylcarbodiimide and benzotriazol-1-yloxytris(dimethylamino)-phosphonium hexafluorophosphate
  • a catalyst such as HOBt
  • Protecting groups like Z, Boc and Fmoc are used extensively in the synthesis, and their removal conditions are well known to those skilled in the art.
  • removal of Z groups can he achieved by catalytic hydrogenation with hydrogen in the presence of a noble metal or its oxide, such as palladium on activated carbon in a protic solvent, such as ethanol.
  • a protic solvent such as ethanol.
  • removal of Z can also be achieved by treatment with a solution of hydrogen bromide in acetic acid, or by treatment with a mixture of TFA and dimethylsulfide.
  • Removal of Boc protecting groups is carried out in a solvent such as methylene chloride, methanol or ethyl acetate with a strong acid, such as TFA or HCI or hydrogen chloride gas.
  • the B and C moieties of a compound of formula (I) are linked together via a urea function.
  • the skilled artist can, therefore, readily envision numerous routes and methods of connecting the two moieties using different well known methods.
  • the compounds of formula (I), when existing as a diastereomeric mixture, may be separated into diastereomeric pairs of enantiomers by fractional crystallization from a suitable solvent such as methanol, ethyl acetate or a mixture thereof.
  • a suitable solvent such as methanol, ethyl acetate or a mixture thereof.
  • the pair of enantiomers thus obtained may be separated into individual stereoisomers by conventional means by using an optically active acid as a resolving agent.
  • any enantiomer of a compound of the formula (I) may be obtained by stereospecific synthesis using optically pure starting materials or reagents of known configuration.
  • the compounds of formula (I) of the present invention can be prepared according to the procedures of the following schemes and examples, using appropriate materials and are further exemplified by the following specific examples. Moreover, by utilizing the procedures described herein, in conjunction with ordinary skills in the art, additional compounds of the present invention claimed herein can be readily prepared.
  • the compounds illustrated in the examples are not, however, to be construed as forming the only genus that is considered as the invention.
  • the examples further illustrate details for the preparation of the compounds of the present invention. Those skilled in the art will readily understand that known variations of the conditions and processes of the following preparative procedures can be used to prepare these compounds.
  • the instant compounds are generally isolated in the form of their pharmaceutically acceptable salts, such as those described previously.
  • the free amine bases corresponding to the isolated salts can be generated by neutralization with a suitable base, such as aqueous sodium hydrogencarbonate, sodium carbonate, sodium hydroxide and potassium hydroxide, and extraction of the liberated amine free base into an organic solvent followed by evaporation.
  • a suitable base such as aqueous sodium hydrogencarbonate, sodium carbonate, sodium hydroxide and potassium hydroxide
  • the amine free base isolated in this manner can be further converted into another pharmaceutically acceptable salt by dissolution in an organic solvent followed by addition of the appropriate acid and subsequent evaporation, precipitation or crystallization. All temperatures are degrees Celsius.
  • Cis-3-aza-bicyclo[3.1.0]hexane hydrochloride was prepared as described in US4, 183,857. Reaction scheme 1:
  • the resulting tetrahydropyridine can be hydrogenated in the presence of a catalyst, such as PtO 2 or Pd/C, to yield the protected piperidine.
  • a catalyst such as PtO 2 or Pd/C
  • the piperidine is further reacted with an alkylchloride or alkylbromide bearing the capping group T in the presence of a base such as Cs 2 CO 3 or NaH in an appropriate solvent such as DMF to give the Boc-protected A moiety.
  • the resulting tetrahydropyridine can be hydrogenated in the presence of a catalyst, such as PtO 2 or Pd/C, to yield the protected piperidine.
  • a catalyst such as PtO 2 or Pd/C
  • the methylether can be cleaved with a reagent such as aqueous hydroiodic acid in acetic acid or trimethylsilyl iodide in chloroform, at a suitable temperature to get access to the corresponding phenol as hydroiodide.
  • the Boc- protecting group which is lost during this process, can subsequently be reintroduced by using a reagent such as BoC 2 O in the presence of a base such as DIEA in an appropriate solvent such as DCM or DMF.
  • the Boc-protected piperidine is further reacted with an alkylchloride or alkylbromide bearing the capping group T in the presence of a base such as Cs 2 CO 3 or NaH in an appropriate solvent such as DMF to give the Boc-protected A moiety.
  • the intermediate product from Reaction schemes 1 and 2, optionally substituted 1-Boc-4-(2-hydroxy-phenyl)-piperidine can also be alkylated with an ⁇ -T-capped alkylalcohol in the presence of a reagent such as DEAD or DIAD and a phosphine such as PPh 3 in a suitable solvent such as THF to give the Boc-protected A moieties.
  • a reagent such as DEAD or DIAD and a phosphine such as PPh 3
  • a suitable solvent such as THF
  • the same intermediate can be reacted with an ⁇ -bromo alkylalcohol, using the reaction conditions described above, to give access to the corresponding phenolether which subsequently can be used to alkylate the capping group T in the presence of a suitable base such as K 2 CO 3 or NaH, in an appropriate solvent such as MeCN 1 THF 1 or DMF 1 at a suitable temperature, to yield the Boc-protected A moieties.
  • a suitable base such as K 2 CO 3 or NaH
  • MeCN 1 THF 1 or DMF 1 at a suitable temperature
  • Optionally substituted 2-bromotoluene is brominated with NBS in the presence of a radical starter such as Bz 2 O 2 in an appropriate solvent such as CCI 4 at a suitable temperature to yield the corresponding benzylbromide.
  • the benzylbromide is reacted with optionally substituted diethyl malonate in the presence of a base such as sodium ethoxide in a suitable solvent such as ethanol.
  • Optionally substituted 3-(2-bromophenyl)propionic acid amide can be reacted with 4-(4, 4,5,5- tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester in the presence of a base such as K 2 CO 3 and a catalyst such as dichloro(1 ,1'- bis(diphenylphosphino)-ferrocene)palladium(ll) DCM adduct, in an organic solvent such as DMF or toluene, at a suitable temperature to lead to the corresponding tetrahydropyridine.
  • a base such as K 2 CO 3
  • a catalyst such as dichloro(1 ,1'- bis(diphenylphosphino)-ferrocene)palladium(ll) DCM adduct
  • the resulting tetrahydropyridine can be hydrogenated in the presence of a catalyst, such as PtO 2 or Pd/C, to yield the protected piperidine.
  • a catalyst such as PtO 2 or Pd/C
  • the side chain amide function can be reduced using a reagent such as LiAIH 4 or borane-THF complex in an appropriate inert solvent such as diethyl ether or THF at a suitable temperature to yield the Boc-protected A moiety.
  • Optionally substituted 2'-bromo-cinnamic acid amide can be reacted with 4-(4 ,4,5,5-tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H- pyridine-1 -carboxylic acid tert-butyl ester in the presence of a base such as K 2 CO 3 and a catalyst such as dichloro(1 ,1'-bis(diphenylphosphino)-ferrocene)palladium(ll) DCM adduct, in an organic solvent such as DMF or toluene, at a suitable temperature to lead to the corresponding tetrahydropyridine.
  • a base such as K 2 CO 3
  • a catalyst such as dichloro(1 ,1'-bis(diphenylphosphino)-ferrocene)palladium(ll) DCM adduct
  • the resulting tetrahydropyridine and the cinnamic acid amide double bond can be hydrogenated in the presence of a catalyst, such as PtO 2 or Pd/C, to yield the protected piperidine.
  • a catalyst such as PtO 2 or Pd/C
  • the side chain amide function can be reduced using a reagent such as LiAIH 4 or borane-THF complex in an appropriate inert solvent such as diethyl ether or THF at a suitable temperature to yield the Boc-protected A moiety.
  • optionally substituted 3-(2-bromophenyl)propionic acid is reacted with methanol in the presence of a catalyst such as sulfuric acid to form the corresponding methyl ester.
  • a catalyst such as sulfuric acid
  • 3-(2-bromophenyl)propionic acid ester can be reacted with 4-(4,4,5,5-tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H- pyridine-1-carboxylic acid tert-butyl ester in the presence of a base such as K 2 CO 3 and a catalyst such as dichloro(1 ,1'-bis(diphenylphosphino)-ferrocene)palladium(ll) DCM adduct, in an organic solvent such as DMF or toluene, at a suitable temperature to lead to the corresponding tetrahydropyridine.
  • the resulting tetrahydropyridine can be hydrogenated in the presence of a catalyst, such as PtO 2 or Pd/C, to yield the protected piperidine.
  • a catalyst such as PtO 2 or Pd/C
  • the side chain ester function can be reduced using a reagent such as LiAIH 4 or borane-THF complex in an appropriate inert solvent such as diethyl ether or THF at a suitable temperature to yield the corresponding alcohol which can subsequently be oxidized using a reagent such as Dess-Martin periodinane in an appropriate solvent such as DCM or using sulfurtrioxide-pyridine complex with a base such as triethylamine in a suitable solvent such as DCM.
  • Optionally substituted 3-(2-bromophenyl)propionyl aldehyde is reacted with the capping group T in the presence of a reducing agent such as sodium triacetoxyborohydride in an appropriate solvent such as 1 ,2-dichloroethane to form the corresponding Boc-protected A moiety.
  • a reducing agent such as sodium triacetoxyborohydride
  • an appropriate solvent such as 1 ,2-dichloroethane
  • the resulting tetrahydropyridine can be hydrogenated in the presence of a catalyst, such as PtO 2 or Pd/C, to yield the protected piperidine.
  • a catalyst such as PtO 2 or Pd/C
  • the ester function can then be reduced to the corresponding aldehyde with DIBAL-H in an appropriate solvent such as Et 2 O or THF at a suitable temperature.
  • Reductive amination of the aldehyde with an amine T-H in the presence of a reducing agent such as sodium triacetoxyborohydride in an appropriate solvent such as 1 ,2-dichloroethane leads to the Boc-protected A moiety.
  • Optionally substituted 2'-bromo-phenylacetic amide can be reacted with 4-(4,4,5,5-tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H- pyridine-1 -carboxylic acid tert-butyl ester in the presence of a base such as K 2 CO 3 and a catalyst such as dichloro(1 ,1'-bis(diphenylphosphino)-ferrocene)palladium(ll) DCM adduct, in an organic solvent such as DMF or toluene, at a suitable temperature to lead to the corresponding tetrahydropyridine.
  • a base such as K 2 CO 3
  • a catalyst such as dichloro(1 ,1'-bis(diphenylphosphino)-ferrocene)palladium(ll) DCM adduct
  • the resulting tetrahydropyridine can be hydrogenated in the presence of a catalyst, such as PtO 2 or Pd/C, to yield the protected piperidine.
  • a catalyst such as PtO 2 or Pd/C
  • the side chain amide function can be reduced using a reagent such as LiAIH 4 or borane-THF complex in an appropriate inert solvent such as diethyl ether or THF at a suitable temperature to yield the Boc-protected A moiety.
  • Optionally substituted 2-bromophenylacetic acid is reduced with sodium borohydride in the presence of a reagent such like boron trifluoride diethyl etherate in an appropriate solvent such as THF at a suitable temperature to yield the corresponding phenylethylalcohol.
  • Reaction of the alcohol with a bromination reagent such as phosphorous tribromide in the presence of a base such as pyridine in an appropriate solvent like toluene at a suitable temperature leads to the phenylethylbromide.
  • the phenethylbromide is reacted with optionally substituted diethyl malonate in the presence of a base such as sodium hydride in a suitable solvent such as THF.
  • Subsequent saponification with a base such as KOH in an appropriate solvent such as water-ethanol mixture followed by a second saponification step with a suitable base such as KOH in a solvent such as water leads to the alkylated malonic acid which is decarboxylated at an appropriate temperature.
  • the product of this reaction is converted to the acid chloride using a reagent such as oxalyl chloride or thionyl chloride in an inert solvent such as DCM with a catalytic amount of DMF 1 and reacted with the capping group T to form the corresponding amide.
  • a reagent such as oxalyl chloride or thionyl chloride in an inert solvent such as DCM with a catalytic amount of DMF 1 and reacted with the capping group T to form the corresponding amide.
  • Optionally substituted 3-(2-bromophenyl)butanoic acid amide can be reacted with 4-(4 ,4,5,5-tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1 -carboxylic acid tert-butyl ester in the presence of a base such as K 2 CO 3 and a catalyst such as dichloro(1 ,1'-bis(diphenylphosphino)-ferrocene)palladium(ll) DCM adduct, in an organic solvent such as DMF or toluene, at a suitable temperature to lead to the corresponding tetrahydropyridine.
  • a base such as K 2 CO 3
  • a catalyst such as dichloro(1 ,1'-bis(diphenylphosphino)-ferrocene)palladium(ll) DCM adduct
  • the resulting tetrahydropyridine can be hydrogenated in the presence of a catalyst, such as PtO 2 or Pd/C, to yield the protected piperidine.
  • a catalyst such as PtO 2 or Pd/C
  • the side chain amide function can be reduced using a reagent such as LiAIH 4 or borane-THF complex in an appropriate inert solvent such as diethyl ether or THF at a suitable temperature to yield the Boc-protected A moiety.
  • the intermediate product from Reaction schemes 1 and 2 can also be alkylated with an alcohol which contains a cyclic tertiary amine moiety in the presence of a reagent such as DEAD or DIAD and a phosphine such as PPh 3 in a suitable solvent such as THF to give the Boc-protected A moieties.
  • a reagent such as DEAD or DIAD
  • a phosphine such as PPh 3
  • THF suitable solvent
  • an alcohol containing a protected cyclic secondary amine moiety can be introduced as building block using the conditions described above.
  • the protecting group has to be orthogonal to the Boc-protecting group used for protection of the piperidine. After coupling of the A moiety with the B-C moiety this protecting group can be removed using standard methods.
  • the starting material of Boc-protected phenylpiperidine (A moiety) can be deprotected in the presence of TFA/CH 2 CI 2 , HCI/EtOAc, HCI/dioxane or HCI in MeOH/dioxane with or without a cation scavenger, such as dimethyl sulfide (DMS) before being subjected to the coupling procedure. It can be converted to the free base before being subjected to the coupling procedure or in some cases used as the salt.
  • a cation scavenger such as dimethyl sulfide (DMS)
  • the B-C moieties can be synthesized as shown in Reaction scheme 13.
  • Optionally substituted phenylalanine can be converted to the corresponding methyl ester hydrochloride using an activating reagent such as thionyl chloride or oxalyl chloride in methanol.
  • Amino acid methyl ester hydrochloride can be reacted with a reagent such as triphosgene in the presence of a base such as NaHCO 3 (aq.) in a suitable solvent such as DCM to yield the isocyanate which can subsequently be reacted with an amine R 5 -H in a suitable solvent such as DCM.
  • the ester function can be hydrolyzed with a base such as LiOH in a suitable solvent or solvent mixture such as water/THF/methanol to give access to the B-C-moiety.
  • a moieties can be coupled with B-C moieties in the presence of EDCI/HOBt, a base such as N-methylmorpholine (NMM) and a solvent such as dichloromethane (DCM).
  • a suitable solvent such as DCM, DMF, THF or a mixture of the above solvents, can be used for the coupling procedure.
  • Suitable base include triethylamine (TEA), diisopropylethylamine (DIEA), N-methylmorpholine (NMM), collidine or 2,6-lutidine.
  • TAA triethylamine
  • DIEA diisopropylethylamine
  • NMM N-methylmorpholine
  • collidine or 2,6-lutidine.
  • a base may not be needed when EDCI/HOBt is used.
  • the reaction mixture can be diluted with an appropriate organic solvent, such as EtOAc, DCM or Et 2 O, which is then washed with aqueous solutions, such as water, HCI, NaHSO 4 , bicarbonate, NaH 2 PO 4 , phosphate buffer (pH 7), brine or any combination thereof.
  • aqueous solutions such as water, HCI, NaHSO 4 , bicarbonate, NaH 2 PO 4 , phosphate buffer (pH 7), brine or any combination thereof.
  • the reaction mixture can be concentrated and then be partitioned between an appropriate organic solvent and an aqueous solution.
  • the reaction mixture can be concentrated and subjected to chromatography without aqueous workup.
  • the product can be transferred to a pharmaceutically acceptable salt such as a hydrochloride, using HCI in a solvent or solvent mixture such as diethyl ether/acetone.
  • a pharmaceutically acceptable salt such as a hydrochloride
  • the three moieties can also be combined stepwise, as shown in Reaction scheme 15.
  • An appropriate A moiety is coupled to a Boc-protected B moiety in the presence of EDCI/HOBt, a base such as N-methylmorpholine (NMM) and a solvent such as dichloromethane (DCM) followed by Boc deprotection with the aid of hydrogen chloride in a mixture of dioxane and methanol.
  • NMM N-methylmorpholine
  • DCM dichloromethane
  • the product can be reacted with 4-nitrophenyl chloroformate in the presence of a base such as NMM in an appropriate solvent such as DCM to yield the 4-nitrophenyl carbamate which subsequently can be treated with an amine H-R 5 in the presence of a base such as DIEA in an appropriate solvent such as THF to give access to the target compound.
  • a base such as NMM
  • DIEA an appropriate solvent
  • THF an appropriate solvent
  • the final product can be converted to a pharmaceutically acceptable salt as described above.
  • the purified product was dissolved in EtOAc (3.00 ml), treated with 1 M HCI in Et 2 O (633 ⁇ l), and the resulting suspension was diluted with hexane (20 ml). The precipitate was filtered off, washed with hexane (5 ml), and dried in vacuo at room temperature over P 2 O 5 overnight. The product was obtained as a white solid.
  • the purified product was dissolved in ethyl acetate (300 ⁇ l), and treated with 1 M HCI in Et 2 O (26 ⁇ l) followed by hexane (3 ml). The precipitated salt was filtered off, washed with hexane (1 ml), and finally dried in vacuo at room temperature over P 2 O 5 overnight.
  • the purified product was dissolved in DCM and treated with 1 M HCI in Et 2 O (1.27 ml) and evaporated in vacuo. The residue was dissolved in DCM and treated with diethyl ether and hexane. The precipitated salt was filtered off, washed with hexane and diethyl ether, and finally dried in vacuo at 40 0 C for 2 h.
  • the purified product was dissolved in ethyl acetate (200 ⁇ l), cooled to 0 0 C and treated with 1 M HCI in Et 2 O (70 ⁇ l) and treated with diethyl ether (1 ml). The precipitate was filtered off and dried under vacuum over Sicapent. The product was obtained as an off-white solid.
  • the crude product was purified by vacuum distillation employing a 5 cm Vigreux column at a pressure of ca. 15 mbar (with an oil-bath temperature of ca. 120 0 C). The fraction distilling off at 89-90 0 C was collected. The product was obtained as a colorless oil.
  • the purified product was dissolved in DCM and treated with 1 M HCI in Et 2 O (73 ⁇ l) and evaporated in vacuo. The residue was dissolved in DCM and the salt was precipitated by addition of Et 2 O and hexane. The precipitate was filtered off, washed with hexane and Et 2 O and dried in vacuo at 40 0 C for 2 hours. The product was obtained as a white solid.
  • the purified product was dissolved in ethyl acetate (2 ml), treated with 1 M HCI in Et 2 O (200 ⁇ l), and the resulting suspension was diluted with hexane (20 ml). The precipitate was filtered off, washed with hexane and diethyl ether, and dried in vacuo at room temperature over P 2 O 5 overnight. The product was obtained as white solid.
  • the purified product was dissolved in DCM, treated with 1 M HCI in Et 2 O (66 ⁇ l), and the resulting suspension was diluted with diethyl ether and hexane. The precipitate was filtered off, washed with hexane and diethyl ether, and dried in vacuo at room temperature over P 2 Os overnight. The product was obtained as a white solid.
  • the purified product was dissolved in ethyl acetate and treated with 1 M HCI in Et 2 O (100 ⁇ l). The product was precipitated by addition of hexane (20 ml). The precipitate was filtered off and dried in vacuo over P 2 O 5 . The product was obtained as white solid.
  • the purified product was dissolved in ethyl acetate and treated with 1 M HCI in Et 2 O (100 ⁇ l). The product was precipitated by addition of hexane (20 ml). The precipitate was filtered off and dried in vacuo over P 2 O 5 . The product was obtained as a white solid.
  • Phosphorous tribromide (3.71 ml) was dissolved in toluene (30 ml) and cooled to 0 0 C. Then pyridine (1.68 ml) was added. To the suspension thus obtained, a solution of intermediate 44a) (18.6 g) and pyridine (0.56 ml) in toluene (30 ml) was added over 15 min. The cooling bath was removed and stirring was continued at room temperature for 1 h. Then the reaction mixture was heated to 100 0 C for another hour. The reaction mixture was cooled to ambient temperature, diluted with EtOAc (300 ml) and washed with water (2 x 100 ml).
  • the filtrate was extracted with EtOAc (2 x 100 ml) and the combined organic layer re- extracted with water and brine (100 ml each), dried (Na 2 SO 4 ) and concentrated in vacuo.
  • the crude product was purified by column chromatography to furnish the desired compound as a brownish resin.
  • the crude product was purified with flash chromatography.
  • the free base was dissolved in ethyl acetate (2 ml) and 1 M HCI in diethyl ether (200 ⁇ l) was added.
  • the product was precipitated by addition of hexane (20 ml). The precipitate was filtered off and dried in vacuo over P 2 O 5 .
  • reaction mixture was evaporated in vacuo at 40 0 C and the colorless oily residue was poured into ice-water (100 ml). The resulting white emulsion was extracted with Et 2 O
  • the crude product was purified with flash chromatography.
  • the free base was dissolved in ethyl acetate (2 ml) and 1 M HCI in diethyl ether (200 ⁇ l) was added.
  • the product was precipitated by addition of hexane (20 ml). The precipitate was filtered off and dried in vacuo over P 2 O 5 .
  • the combined aqueous layer was cooled in ice/H 2 O and acidified with 50% H 2 SO 4 to pH 1.
  • the purified product was dissolved in DCM, treated with 1 M HCI in Et 2 O (108 ⁇ l), and the resulting suspension was diluted with diethyl ether and hexane. The precipitate was filtered off, washed with hexane and diethyl ether, and dried in vacuo at 40 0 C for 2 h. The product was obtained as an off-white solid.
  • the purified product was dissolved in DCM, treated with 1 M HCI in Et 2 O (60 ⁇ l), and the resulting suspension was diluted with diethyl ether and hexane. The precipitate was filtered off, washed with hexane and diethyl ether, and dried in vacuo at 40 0 C for 2 h. The product was obtained as a white solid.
  • the suspension was put in the fridge overnight, filtered and the product, a white solid, was rinsed with water and diethyl ether. The filtrate was evaporated again to dryness and water (10 ml) was added. The suspension was put in the fridge overnight, filtered and the second batch of product was rinsed with water and diethyl ether. The solids from the two batches were combined and dried in vacuo.
  • Racemic intermediate 80c (313 mg) was dissolved in Tris-maleate buffer (26 ml, pH 7.8) containing 0.1 M KCI. To this solution was added L-amino acid oxidase (Sigma Type 1 , activity 0.33 units/mg; 10 mg) and catalase (1 mg). After 84 h, the reaction mixture was brought to pH 7 with 0.5 N HCI and purified by ion-exchange chromatography over Dowex 50, eluting the amino acid with 1 N ammonia. The solvent was removed under reduced pressure and the product was dried in vacuo at room temperature over P 2 O 5 overnight.
  • Phosphorous tribromide (735 ⁇ l) was added to a stirred solution of 4-chloro-2- methylbenzyl alcohol (3.5 g) in toluene (30 ml) at 40 0 C. The solution was heated to 100 0 C for 30 min, and the reaction was cooled to ambient temperature. The liquid was decanted and washed with water (2 x 50 ml) and brine (50 ml). The combined aqueous layer was extracted with diethyl ether (70 ml) and the combined organic layer was evaporated to yield a semisolid residue. The residue was dissolved in diethyl ether (350 ml) and washed with water (2 x 100 ml) and brine (100 ml). The organic phase was dried over Na 2 SO 4 , filtered and evaporated to yield a light yellow oil.
  • the combined organic layer was dried over Na 2 SO 4 , filtered and the solvent was removed under reduced pressure to give a yellow oil.
  • the crude product was dissolved in THF (20 ml) and 1 N aqueous sodium hydroxide (12.1 ml) was added portionwise at 0 0 C. The reaction mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure and water (50 ml) was added to the residue. The aqueous phase was washed with diethyl ether (2 x 100 ml) and DCM (2 x 100 ml) and then neutralized to pH 7 with 5N aqueous HCI (2 ml). The aqueous phase was evaporated under reduced pressure to yield the product as a white solid.
  • reaction mixture was acidified to pH 2 using 1N aqueous hydrochloric acid (1.3 ml) and extracted with DCM (3 x 20 ml). The combined organic layer was dried over Na 2 SO 4 , filtered and concentrated in vacuo to give a colorless wax.
  • the crude product was purified by column chromatography.
  • the purified product was dissolved in EtOAc (400 ⁇ l), treated with 0.1 M citric acid in EtOH (721 ⁇ l), and hexane (8.0 ml). The precipitate was filtered off, washed with hexane (1.0 ml) and dried in vacuo over P 2 O 5 at room temperature overnight.
  • a membrane binding assay is used to identify competitive inhibitors of fluorescence labeled NDP-alpha-MSH binding to HEK293 cell membrane preparations expressing human melanocortin receptors.
  • test compound or unlabeled NDP-alpha-MSH is dispensed at varying concentrations to a 384 well microtiter plate. Fluorescence labeled NDP-alpha-MSH is dispensed at a single concentration, followed by addition of membrane preparations. The plate is incubated for 5 h at room temperature.
  • the degree of fluorescence polarization is determined with a fluorescence polarization microplate reader.
  • Agonistic activity of human melanocortin receptors is determined in a homogeneous membrane based assay. Competition between unlabeled cAMP and a fixed quantity of fluorescence labeled cAMP for a limited number of binding sites on a cAMP specific antibody is revealed by fluorescence polarization.
  • test compound or unlabeled NDP-alpha-MSH is dispensed at varying concentrations to a 384 well microtiter plate.
  • Membrane preparations from HEK293 cells expressing the human melanocortin receptors are added.
  • an appropriate amount of ATP, GTP and the cAMP antibody is added and the plate is further incubated before the fluorescence labeled cAMP conjugate is dispensed.
  • the plate is incubated for 2 h at 4°C before it is read on a fluorescence polarization microplate reader.
  • the amount of cAMP produced as a response to a test compound is compared to the production of cAMP resulting from stimulation with NDP-alpha-MSH.
  • Representative compounds of the present invention were tested and found to bind to the melanocortin-4 receptor. These compounds were generally found to have IC50 values less than 2 ⁇ M.
  • Food intake in rats is measured after i.p. or p.o. administration of the test compound (see e.g. A.S. Chen et al. Transgenic Res 2000 Apr ;9(2): 145-154).
  • LPS lipopolysaccharide
  • This conditioning takes about 4 days.
  • Day 1 the animals are placed in a darkened restrainer and left for 15 - 30 minutes.
  • Day 2 the animals are restrained in a supine position in the restrainer for 15 - 30 minutes.
  • Day 3 the animals are restrained in the supine position with the penile sheath retracted for 15 - 30 minutes.
  • Day 4 the animals are restrained in the supine position with the penile sheath retracted until penile responses are observed.
  • Some animals require additional days of conditioning before they are completely acclimated to the procedures; non-responders are removed from further evaluation. After any handling or evaluation, animals are given a treat to ensure positive reinforcement.
  • Rats are gently restrained in a supine position with their anterior torso placed inside a cylinder of adequate size to allow for normal head and paw grooming.
  • the diameter of the cylinder is approximately 8 cm.
  • the lower torso and hind limbs are restrained with a nonadhesive material (vetrap).
  • An additional piece of vetrap with a hole in it, through which the glans penis will be passed, is fastened over the animal to maintain the preputial sheath in a retracted position.
  • Penile responses will be observed, typically termed ex copula genital reflex tests. Typically, a series of penile erections will occur spontaneously within a few minutes after sheath retraction.
  • the types of normal reflexogenic erectile responses include elongation, engorgement, cup and flip.
  • An elongation is classified as an extension of the penile body.
  • Engorgement is a dilation of the glans penis.
  • a cup is defined as an intense erection where the distal margin of the glans penis momentarily flares open to form a cup.
  • a flip is a dorsiflexion of the penile body.
  • Baseline and or vehicle evaluations are conducted to determine how, and if, an animal will respond. Some animals have a long duration until the first response while others are non-responders altogether. During this baseline evaluation latency to first response, number and type of responses are recorded. The testing time frame is 15 minutes after the first response.
  • test compound After a minimum of 1 day between evaluations, these same animals are administered the test compound at 20 mg/kg and evaluated for penile reflexes. All evaluations are videotaped and scored later. Data are collected and analyzed using paired 2 tailed t-tests to compared baseline and/or vehicle evaluations to drug treated evaluations for individual animals. Groups of a minimum of 4 animals are utilized to reduce variability.
  • mice can be dosed by a number of routes of administration depending on the nature of the study to be performed.
  • the routes of administration includes intravenous (IV), intraperitoneal (IP), subcutaneous (SC) and intracerebral ventricular (ICV).
  • Rodent assays relevant to female sexual receptivity include the behavioral model of lordosis and direct observations of copulatory activity. There is also a urethrogenital reflex model in anesthetized spinally transected rats for measuring orgasm in both male and female rats. These and other established animal models of female sexual dysfunction are described in K. E. McKenna et al, A Model For The Study of Sexual Function In Anesthetized Male And Female Rats, Am. J. Physiol. (Regulatory Integrative Comp. Physiol 30): R1276-R1285, 1991 ; K.E. McKenna et al, Modulation By Peripheral Serotonin of The Threshold For sexual Reflexes In Female Rats, Pharm. Bioch.
  • Example 2 As a specific embodiment of an oral composition of a compound of the present invention, 30 mg of Example 2 is formulated with sufficient finely divided lactose to provide a total amount of 580 to 590 mg to fill a size 0 hard gelatin capsule.
  • Example 20 As another specific embodiment of an oral composition of a compound of the present invention, 25 mg of Example 20 is formulated with sufficient finely divided lactose to provide a total amount of 580 to 590 mg to fill a size 0 hard gelatin capsule.

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Abstract

The present invention relates to substituted phenylpiperidine derivatives as melanocortin-4 receptor modulators. Depending on the structure and the stereochemistry the compounds of the invention are either selective agonists or selective antagonists of the human melanocortin-4 receptor (MC-4R). The agonists can be used for the treatment of disorders and diseases such as obesity, diabetes and sexual dysfunction, whereas the antagonists are useful for the treatment of disorders and diseases such as cancer cachexia, muscle wasting, anorexia, anxiety and depression. Generally all diseases and disorders where the regulation of the MC-4R is involved can be treated with the compounds of the invention.

Description

SUBSTITUTED PHENYLPIPERIDINE DERIVATIVES AS MELANOCORTIN-4 RECEPTOR MODULATORS
Field of the Invention
The present invention relates to substituted phenylpiperidine derivatives as melanocortin-4 receptor modulators. Depending on the structure and the stereochemistry the compounds of the invention are either selective agonists or selective antagonists of the human melanocortin-4 receptor (MC-4R). The agonists can be used for the treatment of disorders and diseases such as obesity, diabetes and sexual dysfunction, whereas the antagonists are useful for the treatment of disorders and diseases such as cancer cachexia, muscle wasting, anorexia, anxiety and depression. Generally all diseases and disorders where the regulation of the MC-4R is involved can be treated with the compounds of the invention.
Background of the Invention
Melanocortins (MCs) stem from proopiomelanocortin (POMC) via proteolytic cleavage. These peptides, adrenocorticotropic hormone (ACTH), α-melanocyte-stimulating hormone (α-MSH), β-MSH and γ-MSH, range in size from 12 to 39 amino acids. The most important endogenous agonist for central MC-4R activation appears to be the tridecapeptide α- MSH. Among MCs, it was reported that α-MSH acts as a neurotransmitter or neuromodulator in the brain. MC peptides, particularly α-MSH, have a wide range of effects on biological functions including feeding behavior, pigmentation and exocrine function. The biological effects of α-MSH are mediated by a sub-family of 7- transmembrane G-protein-coupled receptors, termed melanocortin receptors (MC-Rs). Activation of any of these MC-Rs results in stimulation of cAMP formation.
To date, five distinct types of receptor subtype for MC (MC-1 R to MC-5R) have been identified and these are expressed in different tissues. MC-1 R was first found in melanocytes. Naturally occurring inactive variants of MC-1 R in animals were shown to lead to alterations in pigmentation and a subsequent lighter coat color by controlling the conversion of phaeomelanin to eumelanin through the control of tyrosinase. From these and other studies, it is evident that MC-1 R is an important regulator of melanin production and coat color in animals and skin color in humans.
The MC-2R is expressed in the adrenal gland representing the ACTH receptor. The MC- 2R is not a receptor for α -MSH but is the receptor for the adrenocorticotropic hormone I (ACTH I).
The MC-3R is expressed in the brain (predominately located in the hypothalamus) and peripheral tissues like gut and placenta, and knock-out studies have revealed that the MC-3R may be responsible for alterations in feeding behavior, body weight and thermogenesis.
The MC-4R is primarily expressed in the brain. Overwhelming data support the role of MC-4R in energy homeostasis. Genetic knock-outs and pharmacologic manipulation of MC-4R in animals have shown that agonizing the MC-4R causes weight loss and antagonizing the MC-4R produces weight gain (A. Kask et al., "Selective antagonist for the melanocortin-4 receptor (HS014) increases food intake in free-feeding rats," Biochem. Biophys. Res. Commun., 245: 90-93 (1998)).
MC-5R is ubiquitously expressed in many peripheral tissues including white fat, placenta and a low level of expression is also observed in the brain. However its expression is greatest in exocrine glands. Genetic knock-out of this receptor in mice results in altered regulation of exocrine gland function, leading to changes in water repulsion and thermoregulation. MC-5R knockout mice also reveal reduced sebaceous gland lipid production (Chen et al., Ce//, 91 : 789-798 (1997)).
Attention has been focused on the study of MC-3R and MC-4R modulators and their use in treating body weight disorders, such as obesity and anorexia. However, evidence has shown that the MC peptides have potent physiological effects besides their role in regulating pigmentation, feeding behavior and exocrine function. In particular, α-MSH recently has been shown to induce a potent anti-inflammatory effect in both acute and chronic models of inflammation including inflammatory bowel-disease, renal ischemia/reperfusion injury and endotoxin-induced hepatitis. Administration of α-MSH in these models results in substantial reduction of inflammation-mediated tissue damage, a significant decrease in leukocyte infiltration and a dramatic reduction in elevated levels of cytokines and other mediators to near baseline levels. Recent studies have demonstrated that the anti-inflammatory actions of α-MSH are mediated by MC-1 R. The mechanism by which agonism of MC-1 R results in an anti-inflammatory response is likely through inhibition of the pro-inflammatory transcription activator, NF-κB. NF-κB is a pivotal component of the pro-inflammatory cascade, and its activation is a central event in initiating many inflammatory diseases. Additionally, anti-inflammatory actions of α-MSH may be, in part, mediated by agonism of MC-3R and/or MC-5R.
A specific single MC-R that may be targeted for the control of obesity has not yet been identified, although evidence has been presented that MC-4R signaling is important in mediating feeding behavior (S. Q. Giraudo et al., "Feeding effects of hypothalamic injection of melanocortin-4 receptor ligands," Brain Research, 80: 302-306 (1998)). Further evidence for the involvement of MC-Rs in obesity includes: 1) the agouti (A^) mouse which ectopically expresses an antagonist of the MC-1 R, MC-3R and MC-4R is obese, indicating that blocking the action of these three MC-R's can lead to hyperphagia and metabolic disorders; 2) MC-4R knockout mice (D. Huszar et al., Cell, 88: 131-141 (1997)) recapitulate the phenotype of the agouti mouse and these mice are obese; 3) the cyclic heptapeptide melanotanin Il (MT-II) (a non-selective MC-1 R, -3R, -4R, and -5R agonist) injected intracerebroventricularly (ICV) in rodents, reduces food intake in several animal feeding models (NPY, ob/ob, agouti, fasted) while ICV injected SHU-9119 (MC-3R and 4R antagonist; MC-1 R and -5R agonist) reverses this effect and can induce hyperphagia; 4) chronic intraperitoneal treatment of Zucker fatty rats with an α-NDP-MSH derivative (HP-228) has been reported to activate MC-1 R, -3R, -4R, and -5R and to attenuate food intake and body weight gain over a 12 week period (I. Corcos et al., ΗP-228 is a potent agonist of melanocortin receptor-4 and significantly attenuates obesity and diabetes in Zucker fatty rats", Society for Neuroscience Abstracts, 23: 673 (1997)).
MC-4R appears to play a role in other physiological functions as well, namely controlling grooming behavior, erection and blood pressure. Erectile dysfunction denotes the medical condition of inability to achieve penile erection sufficient for successful intercourse. The term "impotence" is often employed to describe this prevalent condition. Synthetic melanocortin receptor agonists have been found to initiate erections in men with psychogenic erectile dysfunction (H. Wessells et al., "Synthetic Melanotropic Peptide Initiates Erections in Men With Psychogenic Erectile Dysfunction: Double-Blind, Placebo Controlled Crossover Study", J. Urol., 160: 389-393, (1998)). Activation of melanocortin receptors of the brain appears to cause normal stimulation of sexual arousal. Evidence for the involvement of MC-R in male and/or female sexual dysfunction is detailed in WO 00/74679.
Diabetes is a disease in which a mammal's ability to regulate glucose levels in the blood is impaired because the mammal has a reduced ability to convert glucose to glycogen for storage in muscle and liver cells. In Type I diabetes, this reduced ability to store glucose is caused by reduced insulin production. "Type Il diabetes" or "Non-Insulin Dependent Diabetes Mellitus" (NIDDM) is the form of diabetes which is due to a profound resistance to insulin stimulating or regulatory effect on glucose and lipid metabolism in the main insulin-sensitive tissues, muscle, liver and adipose tissue. This resistance to insulin responsiveness results in insufficient insulin activation of glucose uptake, oxidation and storage in muscle, and inadequate insulin repression of lipolysis in adipose tissue and of glucose production and secretion in liver. When these cells become desensitized to insulin, the body tries to compensate by producing abnormally high levels of insulin and hyperinsulemia results. Hyperinsulemia is associated with hypertension and elevated body weight. Since insulin is involved in promoting the cellular uptake of glucose, amino acids and triglycerides from the blood by insulin sensitive cells, insulin insensitivity can result in elevated levels of triglycerides and LDL which are risk factors in cardiovascular diseases. The constellation of symptoms which includes hyperinsulemia combined with hypertension, elevated body weight, elevated triglycerides and elevated LDL, is known as Syndrome X. MC-4R agonists might be useful in the treatment of NIDDM and Syndrome X.
Among MC receptor subtypes, the MC4 receptor is also of interest in terms of the relationship to stress and the regulation of emotional behavior, as based on the following findings. Stress initiates a complex cascade of responses that include endocrine, biochemical and behavioral events. Many of these responses are initiated by release of corticotropin-releasing factor (CRF) (MJ. Owen and CB. Nemeroff, "Physiology and pharmacology of corticotrophin releasing factor." Pharmacol. Rev. 43: 425-473 (1991)). In addition to activation of the brain CRF system, there are several lines of evidence that melanocortins (MCs), which stem from proopiomelanocortin by enzymatic processing, mediate important behavioral and biochemical responses to stress and, consequently, stress-induced disorders like anxiety and depression (Shigeyuki Chaki et al, "Anxiolytic- Like and Antidepressant-Like Activities of MCL0129 (1-[(S)-2-(4-Fluorophenyl)-2-(4- isopropylpiperadin-1-yl)ethyl]-4- [4-(2-methoxynaphthalen-1-yl)butyl]piperazine), a Novel and Potent Nonpeptide Antagonist of the Melanocortin-4 Receptor", J. Pharm. Exp. Ther. 304(2), 818-826 (2003)).
Chronic diseases, such as malignant tumors or infections, are frequently associated with cachexia resulting from a combination of a decrease in appetite and a loss of lean body mass. Extensive loss of lean body mass is often triggered by an inflammatory process and is usually associated with increased plasma levels of cytokines (e.g. TNF-α), which increase the production of α-MSH in the brain. Activation of MC4 receptors in the hypothalamus by α-MSH reduces appetite and increases energy expenditure. Experimental evidence in tumor bearing mice suggests that cachexia can be prevented or reversed by genetic MC4 receptor knockout or MC4 receptor blockade. The increased body weight in the treated mice is attributable to a larger amount of lean body mass, which mainly consists of skeletal muscle (D. L. Marks et al. "Role of the central melanocortin system in cachexia." Cancer Res. 61 : 1432-1438 (2001)).
Modulators of the melanocortin receptor are already known from the literature. WO 2004/024720 A1 describes piperazine urea derivatives which are selective agonists of the human melanocortin-4 receptor and as such they are claimed to be useful in the treatment of prevention of obesity-related disorders.
WO 2005/047253 A1 describes 4,4-disubstituted piperidine derivatives which are postulated to function as melanocortin receptor agonists. Substituted piperidine derivatives are also described in DE 103 00973 which relates to carboxylic acids and esters having a piperidine ring or a piperazine ring as the central core of the molecule and wherein the core is further substituted in the para-position by a 5-7- membered heterocycle, a phenyl ring, a pyridine ring or a thiazole ring. Said rings are optionally substituted by an ester group. The compounds are used in the preparation of a medicament for the treatment of headaches, non-insulin dependent diabetes mellitus (NIDDM), cardiovascularic diseases, morphintolerance, diseases of the skin, inflammations, allergic rhinitis, asthma, diseases with vascular dilatation and, consequently, with reduced blood circulation in tissues, acute or preemptive treatment of menopausal hot flashes of women with an estrogen deficiency or for the treatment of pain.
In view of the unresolved deficiencies in treatment of various diseases and disorders as discussed above, it is an object of the present invention to provide novel substituted phenylpiperidine derivatives with improved ability to cross the blood brain barrier, which are useful as melanocortin-4 receptor modulators to treat cancer cachexia, muscle wasting, anorexia, anxiety, depression, obesity, diabetes, sexual dysfunction and other diseases with MC-4R involvement.
Summary of the Invention
The present invention relates to substituted phenylpiperidine derivatives of structural formula (I)
Figure imgf000007_0001
wherein R1, R2, R3, R4, R5 and n are defined as described below. The phenylpiperidine derivatives of structural formula (I) are effective as melanocortin receptor modulators and are particularly effective as selective melanocortin-4 receptor (MC-4R) modulators. They are therefore useful for the treatment of disorders where the activation or inactivation of the MC-4R are involved. Agonists can be used for the treatment of disorders and diseases such as obesity, diabetes and sexual dysfunction, whereas the antagonists are useful for the treatment of disorders and diseases such as cancer cachexia, muscle wasting, anorexia, anxiety and depression.
The present invention also relates to pharmaceutical compositions comprising the compounds of the present invention and a pharmaceutically acceptable carrier.
Detailed Description of the Invention
The present invention relates to substituted phenylpiperidine derivatives useful as melanocortin receptor modulators, in particular, selective MC-4R agonists and MC-4R antagonists.
The compounds of the present invention are represented by structural formula (I)
Figure imgf000008_0001
and the enantiomers, diastereomers, tautomers, solvates and pharmaceutically acceptable salts thereof, wherein
R1 is -(C(R6)2),-T, or
-O-(C(R6)2)m-T; R6 is independently selected from
H, F,
OH, OCH3, d-6-alkyl, optionally substituted with 1 to 3 substituents selected from halogen, CN, OH and OCH3, and
Cs-6-cycloalkyl, optionally substituted with 1 to 3 substituents selected from halogen, CN, OH and OCH3; T is NR7R8, morpholine,
Figure imgf000009_0001
R7 and R8 are independently from each other selected from
H, d-e-alkyl,
C2-6-alkenyl
C2-6-alkinyl, and C2-6-alkylene-O-Ci-6-alkyl, wherein each alkyl, alkenyl and alkinyl is optionally substituted by one or more halogen atoms, CN or OH; R9 is independently selected from halogen, CN,
OH, Ci-6-alkyl optionally substituted with 1 to 3 substituents selected from halogen, CN and OH, and
O-Ci-e-alkyl optionally substituted with 1 to 3 substituents selected from halogen, CN and OH1 d-e-alkylene-O-d-β-alkyl optionally substituted with 1 to 3 substituents selected from halogen, CN and OH; R10 is H, or d-Ce-alkyl;
R11 is independently selected from halogen,
CN, OH,
Ci-6-alkyl optionally substituted with 1 to 3 substituents selected from halogen, CN and OH1 O-d-e-alkyl optionally substituted with 1 to 3 substituents selected from halogen,
CN and OH,
Ci-β-alkylene-O-Ci-β-alkyl optionally substituted with 1 to 3 substituents selected from halogen, CN and OH, -NH2, -NH(d-6-alkyl), and
-N(C1-6-alkyl)2; X is CH or N; Y is CH or N; Z is CH or N; A is a 3-7-membered saturated, unsaturated or aromatic ring containing 0-2 nitrogen atoms;
R2 is independently selected from F, Cl, CH3, and
CF3;
R3 is H, Cl1 F, or CH3; R4 is Cl or F;
R5 is
Figure imgf000011_0001
. morpholine, optionally substituted by 1 to 3, same or different substituents R14, or
NR12R13;
R12 and R13 are independently from each other selected from Ci-6-alkyl,
C2-6-alkenyl,
C2-6-alkinyl, and
C2-6-alkylene-O-Ci-6-alkyl, or
C2-6-alkylene-N(Ci-6-alkyl)2; R14 is Ci-6-alkyl, d-e-alkylene-O-Ci-β-alkyl, d-6-alkylene-OH, or
Ci-6-alkylene-NH2,
Ci-e-alkylene-NHCd-e-alkyO∑, or Ci.6-alkylene-N(Ci-6-alkyl)2;
I is 1,2, 3, or 4; m is 0, 1, 2, 3, or 4; n is 0, 1,2, 3, or 4; o is 0, 1, or 2; pis 0, 1,2,3, or 4; qis 0, 1,2, or 3; ris 0, 1, 2, 3, or 4 and sis 1,or2. Preferably, the compounds according to formula (I) adopt the structural conformation of the following stereoisomer formula (I1):
Figure imgf000012_0001
In a preferred embodiment, R2 represents Cl or F. Preferably, the phenyl ring directly connected with the piperidine ring is monosubstituted by a chlorine or fluorine atom in the meta or para-position.
It is further preferred that R3 represents H, Cl, or CH3, more preferably Cl. In an alternative embodiment, R3 preferably represents F.
Preferably, R4 represents Cl.
In a preferred embodiment, the variant R1 represents -(CH2)ι-T or -O-(CH2)m-T.
In a further preferred embodiment at least one of R7 and R8 is selected from Ci.6-alkyl, C2-6-alkenyl, C2-6-alkinyl and C^-e-alkylene-O-Ci-e-alkyl, more preferably from C2-6-alkenyl, C2-6-alkinyl and C^-β-alkylene-O-d-β-alkyl.
It is preferred that R9 is independently selected from halogen, CN, OH, Ci-6-alkyl optionally substituted with 1 to 3 substituents selected from halogen, CN and OH, and O-Ci-6-alkyl optionally substituted with 1 to 3 substituents selected from halogen, CN and OH.
The variant I is preferably selected from 2 or 3.
The variant m is preferably selected from 2, 3 or 4, more preferably from 2 or 3. As regards compounds of formula (I), T is preferably selected from the group consisting of the following radicals:
Figure imgf000013_0001
Figure imgf000013_0002
Figure imgf000013_0003
a further preferred embodiment, R5 is preferably selected from the group consisting of
Figure imgf000014_0001
Figure imgf000014_0002
Figure imgf000014_0003
Compounds of the formula (I) in which some or all of the above-mentioned groups have the preferred or more preferred meanings are also an object of the present invention.
In the above and the following, the employed terms have the meaning as described below:
Alkyl is a straight chain or branched alkyl having 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, or hexyl.
Alkenyl is a straight chain or branched alkyl having 2 to 6 carbon atoms and which contains at least one carbon-carbon double bond, such as vinyl, allyl, 1-propenyl, 2-butenyl, 2-methyl-2-butenyl, isopropenyl, pentenyl, or hexenyl.
Alkinyl is a straight chain or branched alkyl having 2 to 6 carbon atoms and which contains at least one carbon-carbon triple bond, such as ethinyl, 1-propinyl, 1-butinyl, 2-butinyl, pentinyl or hexinyl.
A 3-7-membered, saturated, unsaturated or aromatic ring containing 0-2 nitrogen atoms encompasses a 3-7-membered saturated carbocycle such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl. Said term further encompasses 3-7-membered unsaturated carbocycles such as cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclohexa-1 ,4-diene or cycloheptadienes, or aromatic rings such as benzene. Nitrogen- containing, 3-7-membered, saturated, unsaturated or aromatic heterocycles are further encompassed by the above term. Examples thereof include azetidine, pyrrolidine, piperidine, azepane, piperazine, pyridine, pyrimidine, pyrazine, pyrrole, imidazole, and pyrazole.
The compounds of structural formula (I) are effective as melanocortin receptor modulators and are particularly effective as selective modulators of MC-4R. They are therefore useful for the treatment and/or prevention of disorders responsive to the activation and inactivation of MC-4R, such as cancer cachexia, muscle wasting, anorexia, anxiety, depression, obesity, diabetes, sexual dysfunction and other diseases with MC-4R involvement. The compounds of structural formula (I) are particularly useful as antagonists of MC-4R. Thus, they are preferably used for the preparation of a medicament for the treatment and/or prevention of cancer cachexia, muscle wasting, anorexia, anxiety and depression.
Optical Isomers - Diastereomers - Geometric Isomers - Tautomers
Compounds of structural formula (I) contain one or more asymmetric centers and can occur as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. The present invention is meant to comprehend all such isomeric forms of the compounds of structural formula (I).
Compounds of structural formula (I) may be separated into their individual diastereoisomers by, for example, fractional crystallization from a suitable solvent, for example methanol or ethyl acetate or a mixture thereof, or via chiral chromatography using an optically active stationary phase. Absolute stereochemistry may be determined by X-ray crystallography of crystalline products or crystalline intermediates which are derivatized, if necessary, with a reagent containing an asymmetric center of known absolute configuration.
Alternatively, any stereoisomer of a compound of the general formula (I) may be obtained by stereospecific synthesis using optically pure starting materials or reagents of known absolute configuration.
Salts
The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids including inorganic or organic bases and inorganic or organic acids. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc and the like. Particularly preferred are the ammonium, calcium, lithium, magnesium, potassium and sodium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N.N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylamino- ethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like.
When the compound of the present invention is basic, salts may be prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Such acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, formic, furnaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, malonic, mucic, nitric, parnoic, pantothenic, phosphoric, propionic, succinic, sulfuric, tartaric, p-toluenesulfonic, trifluoroacetic acid and the like. Particularly preferred are citric, fumaric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric and tartaric acids.
It will be understood that, as used herein, references to the compounds of formula (I) are meant to also include the pharmaceutically acceptable salts.
Utility
The compounds of formula (I) are melanocortin receptor modulators and as such are useful in the treatment, control or prevention of diseases, disorders or conditions responsive to the inactivation of one or more of the melanocortin receptors including, but not limited to, MC-1 R, MC-2R, MC-3R, MC-4R or MC-5R. Such diseases, disorders or conditions include, but are not limited to, cancer cachexia, muscle wasting, anorexia, anxiety, depression, obesity (by reducing appetite, increasing metabolic rate, reducing fat intake or reducing carbohydrate craving), diabetes mellitus (by enhancing glucose tolerance, decreasing insulin resistance) and male and female sexual dysfunction
(including impotence, loss of libido and erectile dysfunction). The compounds of formulas (I) can be further used in the treatment, control or prevention of hypertension, hyperlipidemia, osteoarthritis, cancer, gall bladder disease, sleep apnea, compulsion, neuroses, insomnia/sleep disorder, substance abuse, pain, fever, inflammation, immune-modulation, rheumatoid arthritis, skin tanning, acne and other skin disorders, neuroprotective and cognitive and memory enhancement including the treatment of Alzheimer's disease.
Administration and Dose Ranges
Any suitable route of administration may be employed for providing a mammal, especially a human with an effective dosage of a compound of the present invention. For example, oral, rectal, topical, parenteral, ocular, pulmonary, nasal and the like may be employed. Dosage forms include tablets, troches, dispersions, suspensions, solutions, capsules, creams, ointments, aerosols and the like. Preferably compounds of formula (I) are administered orally or topically.
The effective dosage of active ingredient employed may vary depending on the particular compound employed, the mode of administration, the condition being treated and the severity of the condition being treated. Such dosage may be ascertained readily by a person skilled in the art.
When treating cancer cachexia, muscle wasting or anorexia generally satisfactory results are obtained when the compounds of the present invention are administered at a daily dosage of from about 0.001 milligram to about 100 milligrams per kilogram of body weight, preferably given in a single dose or in divided doses two to six times a day, or in sustained release form. In the case of a 70 kg adult human, the total daily dose will generally be from about 0.07 milligrams to about 3500 milligrams. This dosage regimen may be adjusted to provide the optimal therapeutic response.
When treating obesity, in conjunction with diabetes and/or hyperglycemia, or alone, generally satisfactory results are obtained when the compounds of the present invention are administered at a daily dosage of from about 0.001 milligram to about 100 milligrams per kilogram of body weight, preferably given in a single dose or in divided doses two to six times a day, or in sustained release form. In the case of a 70 kg adult human, the total daily dose will generally be from about 0.07 milligrams to about 3500 milligrams. This dosage regimen may be adjusted to provide the optimal therapeutic response.
When treating diabetes mellitus and/or hyperglycemia, as well as other diseases or disorders for which compounds of formula (I) are useful, generally satisfactory results are obtained when the compounds of the present invention are administered at a daily dosage of from about 0.001 milligram to about 100 milligram per kilogram of animal body weight, preferably given in a single dose or in divided doses two to six times a day, or in sustained release form. In the case of a 70 kg adult human, the total daily dose will generally be from about 0.07 milligrams to about 3500 milligrams. This dosage regimen may be adjusted to provide the optimal therapeutic response.
For the treatment of sexual dysfunction, compounds of the present invention are given in a dose range of 0.001 milligram to about 100 milligram per kilogram of body weight, preferably as a single dose orally or as a nasal spray.
Formulation
The compounds of formula (I) are preferably formulated into a dosage form prior to administration. Accordingly the present invention also includes a pharmaceutical composition comprising a compound of formula (I) and a suitable pharmaceutical carrier.
The present pharmaceutical compositions are prepared by known procedures using well- known and readily available ingredients. In making the formulations of the present invention, the active ingredient (a compound of formula (I)) is usually mixed with a carrier, or diluted by a carrier, or enclosed within a carrier, which may be in the form of a capsule, sachet, paper or other container. When the carrier serves as a diluent, it may be a solid, semisolid or liquid material which acts as a vehicle, excipient or medium for the active ingredient. Thus, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosol (as a solid or in a liquid medium), soft and hard gelatin capsules, suppositories, sterile injectable solutions and sterile packaged powders. Some examples of suitable carriers, excipients and diluents include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water syrup, methyl cellulose, methyl and propylhydroxybenzoates, talc, magnesium stearate and mineral oil. The formulations can additionally include lubricating agents, wetting agents, emulsifying and suspending agents, preserving agents, sweetening agents or flavoring agents. The compositions of the invention may be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient.
Preparation of Compounds of the Invention
When describing the preparation of the present compounds of formula (I), the terms "A moiety", "B moiety" and "C moiety" are used below. This moiety concept is illustrated below:
Figure imgf000020_0001
The preparation of the compounds of the present invention may be carried out via sequential or convergent synthetic routes. The skilled artisan will recognize that, in general, the A and B moieties of a compound of formula (I) are connected via amide bonds. The skilled artist can, therefore, readily envision numerous routes and methods of connecting the two moieties via standard peptide coupling reaction conditions.
The phrase "standard peptide coupling reaction conditions" means coupling a carboxylic acid with an amine using an acid activating agent such as EDCI, dicyclohexylcarbodiimide and benzotriazol-1-yloxytris(dimethylamino)-phosphonium hexafluorophosphate, in a inert solvent such as DCM, in the presence of a catalyst such as HOBt. The uses of protective groups for amine and carboxylic acids to facilitate the desired reaction and minimize undesired reactions are well documented. Conditions required to remove protecting groups which may be present can be found in Greene et al., Protective Groups in Organic Synthesis, John Wiley & Sons, Inc., New York, NY 1991.
Protecting groups like Z, Boc and Fmoc are used extensively in the synthesis, and their removal conditions are well known to those skilled in the art. For example, removal of Z groups can he achieved by catalytic hydrogenation with hydrogen in the presence of a noble metal or its oxide, such as palladium on activated carbon in a protic solvent, such as ethanol. In cases where catalytic hydrogenation is contraindicated by the presence of other potentially reactive functionality, removal of Z can also be achieved by treatment with a solution of hydrogen bromide in acetic acid, or by treatment with a mixture of TFA and dimethylsulfide. Removal of Boc protecting groups is carried out in a solvent such as methylene chloride, methanol or ethyl acetate with a strong acid, such as TFA or HCI or hydrogen chloride gas.
The B and C moieties of a compound of formula (I) are linked together via a urea function. The skilled artist can, therefore, readily envision numerous routes and methods of connecting the two moieties using different well known methods.
The compounds of formula (I), when existing as a diastereomeric mixture, may be separated into diastereomeric pairs of enantiomers by fractional crystallization from a suitable solvent such as methanol, ethyl acetate or a mixture thereof. The pair of enantiomers thus obtained may be separated into individual stereoisomers by conventional means by using an optically active acid as a resolving agent. Alternatively, any enantiomer of a compound of the formula (I) may be obtained by stereospecific synthesis using optically pure starting materials or reagents of known configuration.
The compounds of formula (I) of the present invention can be prepared according to the procedures of the following schemes and examples, using appropriate materials and are further exemplified by the following specific examples. Moreover, by utilizing the procedures described herein, in conjunction with ordinary skills in the art, additional compounds of the present invention claimed herein can be readily prepared. The compounds illustrated in the examples are not, however, to be construed as forming the only genus that is considered as the invention. The examples further illustrate details for the preparation of the compounds of the present invention. Those skilled in the art will readily understand that known variations of the conditions and processes of the following preparative procedures can be used to prepare these compounds. The instant compounds are generally isolated in the form of their pharmaceutically acceptable salts, such as those described previously. The free amine bases corresponding to the isolated salts can be generated by neutralization with a suitable base, such as aqueous sodium hydrogencarbonate, sodium carbonate, sodium hydroxide and potassium hydroxide, and extraction of the liberated amine free base into an organic solvent followed by evaporation. The amine free base isolated in this manner can be further converted into another pharmaceutically acceptable salt by dissolution in an organic solvent followed by addition of the appropriate acid and subsequent evaporation, precipitation or crystallization. All temperatures are degrees Celsius.
In the schemes, preparations and examples below, various reagent symbols and abbreviations have the following meanings:
AcOH acetic acid Boc tert-butoxycarbonyl
Boc2O di-tert-butyl dicarbonate
Bz2O2 dibenzoylperoxide
DAST (diethylamino)sulfur trifluoride
DCM dichloromethane DEAD diethyl azodicarboxylate
DIBAL-H diisobutylaluminumhydride
DIAD diisopropyl azodicarboxylate
DIEA ethyl-diisopropylamine
DMA N,N-dimethylacetamide DMAP 4-dimethylaminopyridine
DMF N,N-dimethylformamide
DMS dimethylsulfide
DMSO dimethylsulfoxide dppf 1 , 1 '-bis(diphenylphosphino)-ferrocen
EDCI 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
Et2O diethyl ether
EtOAc ethyl acetate EtOH ethanol
Fmoc 9-fluorenylmethyloxycarbonyl
Fmoc-OSu θ-fluorenylmethyloxycarbonyl-N-hydroxysuccinimide
HOAt 1-hydoxy-7-azabenzotriazole
HOBt 1 -hydroxybenzotriazole hydrate h hour(s)
MeCN acetonitrile
MeOH methanol
NBS N-bromosuccinimide
NMM N-methylmorpholine PG protecting group
PPh3 triphenylphosphine
TEBAC benzyltriethylammonium chloride
TFA trifluoroacetic acid
THF tetrahydrofurane TMSCI trimethylsilylchloride
The following amino acid derivatives were custom synthesized by PepTech Corporation, 20 Mall Road, Suite 460, Burlington, MA 01803 USA: D-2-chloro-4-fluorophenylalanine methyl ester hydrochloride, D-4-chloro-2-fluorophenylalanine methyl ester hydrochloride, and D-2,4-difluoro-phenylalanine methyl ester hydrochloride.
Cis-3-aza-bicyclo[3.1.0]hexane hydrochloride was prepared as described in US4, 183,857. Reaction scheme 1:
Synthesis of A Moieties with Alkylether Spacer (R1 = -O(C(R6)2)m-T)
Figure imgf000024_0001
As shown in Reaction Scheme 1 , optionally substituted 2-bromo-phenol and 4-(4,4,5,5- tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (Tetrahedron Lett. 2000, 41, 3705-3708) are reacted in a Suzuki coupling in the presence of a base such as K2CO3 and a catalyst such as dichloro(1,1'-bis(diphenyl- phosphino)-ferrocene)palladium(ll) DCM adduct, in an organic solvent such as DMF or toluene, at a suitable temperature. The resulting tetrahydropyridine can be hydrogenated in the presence of a catalyst, such as PtO2 or Pd/C, to yield the protected piperidine. The piperidine is further reacted with an alkylchloride or alkylbromide bearing the capping group T in the presence of a base such as Cs2CO3 or NaH in an appropriate solvent such as DMF to give the Boc-protected A moiety.
Reaction scheme 2:
Alternative Synthesis of A Moieties with Alkylether Spacer (R1 = -O(C(R6)2)m-T)
Figure imgf000025_0001
Figure imgf000025_0002
The synthesis of A Moieties bearing an alkylether spacer (R1 = -O(C(R6)2)m-T) can alternatively be performed starting from optionally substituted 2-bromoanisole (see Reaction scheme 2). A Suzuki coupling with 4-(4,4,5,5-tetramethyl-[1 ,3,2]dioxaborolan-2- yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester in the presence of a base such as K2CO3 and a catalyst such as dichloro(1 ,1'-bis(diphenylphosphino)- ferrocene)palladium(ll) DCM adduct, in an organic solvent such as DMF or toluene, at a suitable temperature leads to the corresponding tetrahydropyridine. The resulting tetrahydropyridine can be hydrogenated in the presence of a catalyst, such as PtO2 or Pd/C, to yield the protected piperidine. The methylether can be cleaved with a reagent such as aqueous hydroiodic acid in acetic acid or trimethylsilyl iodide in chloroform, at a suitable temperature to get access to the corresponding phenol as hydroiodide. The Boc- protecting group, which is lost during this process, can subsequently be reintroduced by using a reagent such as BoC2O in the presence of a base such as DIEA in an appropriate solvent such as DCM or DMF. The Boc-protected piperidine is further reacted with an alkylchloride or alkylbromide bearing the capping group T in the presence of a base such as Cs2CO3 or NaH in an appropriate solvent such as DMF to give the Boc-protected A moiety.
Reaction scheme 3:
Synthesis of A Moieties with Alkylether Spacer (R1 = -O(C(R6)2)m-T) Using Mitsunobu
Conditions
Figure imgf000026_0001
As shown in Reaction scheme 3, the intermediate product from Reaction schemes 1 and 2, optionally substituted 1-Boc-4-(2-hydroxy-phenyl)-piperidine, can also be alkylated with an ω-T-capped alkylalcohol in the presence of a reagent such as DEAD or DIAD and a phosphine such as PPh3 in a suitable solvent such as THF to give the Boc-protected A moieties.
Similarly, the same intermediate can be reacted with an ω-bromo alkylalcohol, using the reaction conditions described above, to give access to the corresponding phenolether which subsequently can be used to alkylate the capping group T in the presence of a suitable base such as K2CO3 or NaH, in an appropriate solvent such as MeCN1 THF1 or DMF1 at a suitable temperature, to yield the Boc-protected A moieties.
Reaction scheme 4:
Synthesis of A Moieties with Alkylene Spacer (R1 = -(C(R6)2),-T, I = 3)
Figure imgf000027_0001
The first route for the synthesis of A moieties bearing an alkylene spacer (R1 = -(C(R6)2)ι-T) is depicted in Reaction scheme 4. Optionally substituted 2-bromotoluene is brominated with NBS in the presence of a radical starter such as Bz2O2 in an appropriate solvent such as CCI4 at a suitable temperature to yield the corresponding benzylbromide. The benzylbromide is reacted with optionally substituted diethyl malonate in the presence of a base such as sodium ethoxide in a suitable solvent such as ethanol. Subsequent saponification with a base such as KOH in an appropriate solvent such as water-ethanol mixture followed by a second saponification step with a suitable base such as KOH in a solvent such as water leads to the alkylated malonic acid which is decarboxylated at an appropriate temperature. The product of this reaction, optionally substituted 3-(2- bromophenyl)propionic acid, is converted to the acid chloride using a reagent such as oxalyl chloride or thionyl chloride in an inert solvent such as DCM with a catalytic amount of DMF, and reacted with the capping group T to form the corresponding amide. Optionally substituted 3-(2-bromophenyl)propionic acid amide can be reacted with 4-(4, 4,5,5- tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester in the presence of a base such as K2CO3 and a catalyst such as dichloro(1 ,1'- bis(diphenylphosphino)-ferrocene)palladium(ll) DCM adduct, in an organic solvent such as DMF or toluene, at a suitable temperature to lead to the corresponding tetrahydropyridine. The resulting tetrahydropyridine can be hydrogenated in the presence of a catalyst, such as PtO2 or Pd/C, to yield the protected piperidine. The side chain amide function can be reduced using a reagent such as LiAIH4 or borane-THF complex in an appropriate inert solvent such as diethyl ether or THF at a suitable temperature to yield the Boc-protected A moiety.
Reaction scheme 5:
Alternative Route for the Synthesis of A Moieties with Alkylene Spacer (R1 = -(CH2)ι-
T, l = 3)
Figure imgf000029_0001
An alternative approach for the synthesis of of A moieties bearing an alkylene spacer (R1 = -(CH2)I-T) starts with optionally substituted 2-bromobenzaldehyde (see Reaction scheme 5). Reaction with malonic acid in an appropriate solvent such as ethanol, in the presence of a base such as pyridine, at a suitable temperature, leads to the corresponding 2'-bromo- cinnamic acid. Said acid is activated with a reagent such as EDCI in the presence of a catalyst such as DMAP and a base such as NMM in DCM, and reacted with the capping group T to form the corresponding amide. Optionally substituted 2'-bromo-cinnamic acid amide can be reacted with 4-(4 ,4,5,5-tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H- pyridine-1 -carboxylic acid tert-butyl ester in the presence of a base such as K2CO3 and a catalyst such as dichloro(1 ,1'-bis(diphenylphosphino)-ferrocene)palladium(ll) DCM adduct, in an organic solvent such as DMF or toluene, at a suitable temperature to lead to the corresponding tetrahydropyridine. The resulting tetrahydropyridine and the cinnamic acid amide double bond can be hydrogenated in the presence of a catalyst, such as PtO2 or Pd/C, to yield the protected piperidine. The side chain amide function can be reduced using a reagent such as LiAIH4 or borane-THF complex in an appropriate inert solvent such as diethyl ether or THF at a suitable temperature to yield the Boc-protected A moiety. Reaction scheme 6:
Alternative Route for the Synthesis of A Moieties with Alkylene Spacer (R1 =
-(C(R6)2)rT, I = 3)
Figure imgf000030_0001
As shown in Reaction scheme 6, optionally substituted 3-(2-bromophenyl)propionic acid, is reacted with methanol in the presence of a catalyst such as sulfuric acid to form the corresponding methyl ester. Optionally substituted 3-(2-bromophenyl)propionic acid ester can be reacted with 4-(4,4,5,5-tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H- pyridine-1-carboxylic acid tert-butyl ester in the presence of a base such as K2CO3 and a catalyst such as dichloro(1 ,1'-bis(diphenylphosphino)-ferrocene)palladium(ll) DCM adduct, in an organic solvent such as DMF or toluene, at a suitable temperature to lead to the corresponding tetrahydropyridine. The resulting tetrahydropyridine can be hydrogenated in the presence of a catalyst, such as PtO2 or Pd/C, to yield the protected piperidine. The side chain ester function can be reduced using a reagent such as LiAIH4 or borane-THF complex in an appropriate inert solvent such as diethyl ether or THF at a suitable temperature to yield the corresponding alcohol which can subsequently be oxidized using a reagent such as Dess-Martin periodinane in an appropriate solvent such as DCM or using sulfurtrioxide-pyridine complex with a base such as triethylamine in a suitable solvent such as DCM. Optionally substituted 3-(2-bromophenyl)propionyl aldehyde is reacted with the capping group T in the presence of a reducing agent such as sodium triacetoxyborohydride in an appropriate solvent such as 1 ,2-dichloroethane to form the corresponding Boc-protected A moiety.
Reaction scheme 7: Synthesis of A Moieties with Alkylene Spacer (R1 = -(C(R6)2)rT, I = 3) Using a Negishi Coupling Reaction
Figure imgf000031_0001
As shown in Reaction scheme 7, the intermediate product from Reaction scheme 6, optionally substituted 3-(2-bromophenyl)propionic acid ester can also be subjected to a
Negishi coupling with (1-tert-butoxycarbonylpiperidin-4-yl)(iodo)zinc (J. Org. Chem. 2004,
69, 5120-5123) in the presence of copper(l) iodide and dichloro(1 ,1'-bis(diphenyl- phosphino)-ferrocene)palladium(ll) DCM adduct in an inert solvent such as DMA to yield the resulting phenylpiperidine which can be further processed as shown in Reaction scheme 6.
Reaction scheme 8:
Alternative Route for the Synthesis of A Moieties with Alkylene Spacer (R1 = -
(C(R6M-T, I = 2, 3)
Figure imgf000032_0001
As shown in Reaction scheme 8 optionally substituted 3-(2-bromophenyl)propionic acid or 2-(2-bromophenyl)acetic acid is transformed to the corresponding methyl ester using a catalyst such as sulfuric acid. The ester can be reacted with 4-(4,4,5,5-tetramethyl- [I .S^ldioxaborolan^-yO-S.e-dihydro^H-pyridine-i-carboxylic acid tert-butyl ester in the presence of a base such as K2CO3 and a catalyst such as dichloro(1,1'- bis(diphenylphosphino)-ferrocene)palladium(ll) DCM adduct, in an organic solvent such as DMF or toluene, at a suitable temperature to lead to the corresponding tetrahydropyridine. The resulting tetrahydropyridine can be hydrogenated in the presence of a catalyst, such as PtO2 or Pd/C, to yield the protected piperidine. The ester function can then be reduced to the corresponding aldehyde with DIBAL-H in an appropriate solvent such as Et2O or THF at a suitable temperature. Reductive amination of the aldehyde with an amine T-H in the presence of a reducing agent such as sodium triacetoxyborohydride in an appropriate solvent such as 1 ,2-dichloroethane leads to the Boc-protected A moiety. Reaction scheme 9:
Synthesis of A Moieties with Alkylene Spacer (R1 = -(C(R6)2)rT, I = 2)
Figure imgf000033_0001
Figure imgf000033_0002
Synthesis of A Moieties with alkylene Spacer (R1 = -(C(R6)2)ι-T, I = 2) can also be performed as described in Reaction scheme 9. Optionally substituted 2'- bromophenylacetic acid is activated with a reagent such as EDCI in the presence of a catalyst such as DMAP and a base such as NMM in DCM, and reacted with the capping group T to form the corresponding amide. Optionally substituted 2'-bromo-phenylacetic amide can be reacted with 4-(4,4,5,5-tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H- pyridine-1 -carboxylic acid tert-butyl ester in the presence of a base such as K2CO3 and a catalyst such as dichloro(1 ,1'-bis(diphenylphosphino)-ferrocene)palladium(ll) DCM adduct, in an organic solvent such as DMF or toluene, at a suitable temperature to lead to the corresponding tetrahydropyridine. The resulting tetrahydropyridine can be hydrogenated in the presence of a catalyst, such as PtO2 or Pd/C, to yield the protected piperidine. The side chain amide function can be reduced using a reagent such as LiAIH4 or borane-THF complex in an appropriate inert solvent such as diethyl ether or THF at a suitable temperature to yield the Boc-protected A moiety. Reaction scheme 10:
Synthesis of A Moieties with Alkylene Spacer (R1 = -(C(R6)2),-T, I = 4)
Figure imgf000034_0001
A route for the synthesis of A moieties bearing an C4-alkylene spacer (R1 = -(C(R6)2)ι-T, I = 4) is depicted in Reaction scheme 10. Optionally substituted 2-bromophenylacetic acid is reduced with sodium borohydride in the presence of a reagent such like boron trifluoride diethyl etherate in an appropriate solvent such as THF at a suitable temperature to yield the corresponding phenylethylalcohol. Reaction of the alcohol with a bromination reagent such as phosphorous tribromide in the presence of a base such as pyridine in an appropriate solvent like toluene at a suitable temperature leads to the phenylethylbromide. The phenethylbromide is reacted with optionally substituted diethyl malonate in the presence of a base such as sodium hydride in a suitable solvent such as THF. Subsequent saponification with a base such as KOH in an appropriate solvent such as water-ethanol mixture followed by a second saponification step with a suitable base such as KOH in a solvent such as water leads to the alkylated malonic acid which is decarboxylated at an appropriate temperature. The product of this reaction, optionally substituted 3-(2-bromophenyl)butanoic acid, is converted to the acid chloride using a reagent such as oxalyl chloride or thionyl chloride in an inert solvent such as DCM with a catalytic amount of DMF1 and reacted with the capping group T to form the corresponding amide. Optionally substituted 3-(2-bromophenyl)butanoic acid amide can be reacted with 4-(4 ,4,5,5-tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1 -carboxylic acid tert-butyl ester in the presence of a base such as K2CO3 and a catalyst such as dichloro(1 ,1'-bis(diphenylphosphino)-ferrocene)palladium(ll) DCM adduct, in an organic solvent such as DMF or toluene, at a suitable temperature to lead to the corresponding tetrahydropyridine. The resulting tetrahydropyridine can be hydrogenated in the presence of a catalyst, such as PtO2 or Pd/C, to yield the protected piperidine. The side chain amide function can be reduced using a reagent such as LiAIH4 or borane-THF complex in an appropriate inert solvent such as diethyl ether or THF at a suitable temperature to yield the Boc-protected A moiety.
Reaction scheme 11
Synthesis of A Moiety Containing Cyclic Amines
Figure imgf000035_0001
Figure imgf000036_0001
As shown in Reaction scheme 11 , the intermediate product from Reaction schemes 1 and 2, optionally substituted 1-Boc-4-(2-hydroxy-phenyl)-piperidine, can also be alkylated with an alcohol which contains a cyclic tertiary amine moiety in the presence of a reagent such as DEAD or DIAD and a phosphine such as PPh3 in a suitable solvent such as THF to give the Boc-protected A moieties.
Similarly, an alcohol containing a protected cyclic secondary amine moiety can be introduced as building block using the conditions described above. The protecting group has to be orthogonal to the Boc-protecting group used for protection of the piperidine. After coupling of the A moiety with the B-C moiety this protecting group can be removed using standard methods.
Reaction scheme 12 A Moiety Deprotection
Figure imgf000036_0002
Generally, the starting material of Boc-protected phenylpiperidine (A moiety) can be deprotected in the presence of TFA/CH2CI2, HCI/EtOAc, HCI/dioxane or HCI in MeOH/dioxane with or without a cation scavenger, such as dimethyl sulfide (DMS) before being subjected to the coupling procedure. It can be converted to the free base before being subjected to the coupling procedure or in some cases used as the salt. Reaction scheme 13: B-C Moiety Formation
Figure imgf000037_0001
The B-C moieties can be synthesized as shown in Reaction scheme 13. Optionally substituted phenylalanine can be converted to the corresponding methyl ester hydrochloride using an activating reagent such as thionyl chloride or oxalyl chloride in methanol. Amino acid methyl ester hydrochloride can be reacted with a reagent such as triphosgene in the presence of a base such as NaHCO3 (aq.) in a suitable solvent such as DCM to yield the isocyanate which can subsequently be reacted with an amine R5-H in a suitable solvent such as DCM. The ester function can be hydrolyzed with a base such as LiOH in a suitable solvent or solvent mixture such as water/THF/methanol to give access to the B-C-moiety.
Reaction scheme 14:
Coupling of A Moiety with B-C Moiety and Salt Formation
Figure imgf000038_0001
As shown in Reaction scheme 14, A moieties can be coupled with B-C moieties in the presence of EDCI/HOBt, a base such as N-methylmorpholine (NMM) and a solvent such as dichloromethane (DCM). A suitable solvent, such as DCM, DMF, THF or a mixture of the above solvents, can be used for the coupling procedure. Suitable base include triethylamine (TEA), diisopropylethylamine (DIEA), N-methylmorpholine (NMM), collidine or 2,6-lutidine. A base may not be needed when EDCI/HOBt is used.
Generally after the reaction is completed, the reaction mixture can be diluted with an appropriate organic solvent, such as EtOAc, DCM or Et2O, which is then washed with aqueous solutions, such as water, HCI, NaHSO4, bicarbonate, NaH2PO4, phosphate buffer (pH 7), brine or any combination thereof. The reaction mixture can be concentrated and then be partitioned between an appropriate organic solvent and an aqueous solution. The reaction mixture can be concentrated and subjected to chromatography without aqueous workup.
The product can be transferred to a pharmaceutically acceptable salt such as a hydrochloride, using HCI in a solvent or solvent mixture such as diethyl ether/acetone. Reaction scheme 15:
Urea Formation via Nitrophenylformate Intermediate
Figure imgf000039_0001
The three moieties can also be combined stepwise, as shown in Reaction scheme 15. An appropriate A moiety is coupled to a Boc-protected B moiety in the presence of EDCI/HOBt, a base such as N-methylmorpholine (NMM) and a solvent such as dichloromethane (DCM) followed by Boc deprotection with the aid of hydrogen chloride in a mixture of dioxane and methanol. The product can be reacted with 4-nitrophenyl chloroformate in the presence of a base such as NMM in an appropriate solvent such as DCM to yield the 4-nitrophenyl carbamate which subsequently can be treated with an amine H-R5 in the presence of a base such as DIEA in an appropriate solvent such as THF to give access to the target compound. The final product can be converted to a pharmaceutically acceptable salt as described above.
Reaction scheme 16:
Urea Formation Using 1-Methyl-3-(amino-1-carbonyl)-3H-imidazol-1-ium iodide as Reagent
Figure imgf000040_0001
As shown in Reaction scheme 16 1 ,1'-carbonyldiimidazole can be reacted with an amine in an appropriate solvent such as THF at a suitable temperature. The product of this reaction is further reacted with methyl iodide in a suitable solvent such as acetonitrile to yield the 1 -methyl-3-(amino-1 -carbonyl)-3H-imidazol-1 -ium iodide. This activated species is reacted with a deprotected A-B moiety in the presence of a base such as triethylamine in a suitable solvent such as THF to yield the final product The final product can be converted to a pharmaceutically acceptable salt as described above. Analytical LC-MS
The compounds of the present invention according to formula (I) were analyzed via analytical LC-MS. The conditions used in the analysis are summarized below.
Analytical conditions summary:
LC10Advp-Pump (Shimadzu) with SPD-M10Avp UV/Vis diode array detector and QP2010
MS-detector in ESI+ modus with UV-detection at 214, 254 and 275 nm, Column: Waters XTerra MS C18, 3.5 μm, 2.1 * 100 mm, linear gradient with acetonitrile in water (0.1% HCOOH)
Flow rate of 0,4 ml/min;
Mobile Phase A: water (0.1 % HCOOH)
Mobile Phase B: acetonitrile (0.1 % HCOOH)
Gradient A: linear gradient from 1 % to 95% acetonitrile in water (0.1 % HCOOH)
0.00 min 1% B
10.00 min 95% B
10.10 min 99% B
11.40 min 99% B
11.50 min 1% B
13.00 min Pump STOP
Gradient B: linear gradient from 1% to 95% acetonitrile in water (0.1% HCOOH)
0. 00 min 1 % B
5. 00 min 95 % B
5. 10 min 99 % B
6. 40 min 99 % B
6. 50 min 1 % B
8. 00 min Pump STOP Gradient C: linear gradient from 5% to 95% acetonitrile in water (0.1% HCOOH)
0.00 min 5% B
10.00 min 95% B
10.10 min 99% B
11.40 min 99% B
11.50 min 1 % B
13.00 min Pump STOP
Gradient D: linear gradient from 5% to 95% acetonitrile in water (0.1% HCOOH)
0.00 min 5% B
5.00 min 95 % B
5.10 min 99 % B 6.40 min 99 % B
6.50 min 1 % B
8.00 min Pump STOP
Gradient E: linear gradient from 10% to 60% acetonitrile in water (0.1 % HCOOH)
0.00 min 10% B
10.00 min 60% B
10.10 min 99% B
11.40 min 99% B 11.50 min 1% B
13.00 min Pump STOP
Gradient F: linear gradient from 1% to 30% acetonitrile in water (0.1% HCOOH) 0.00 min 1 % B
10.00 min 30% B 10.10 min 99% B 11.40 min 99% B 11.50 min 1% B 13.00 min Pump STOP
Gradient G: linear gradient from 1% to 70% acetonitrile in water (0.1% HCOOH)
0.00 min 1% B
10 .00 min 70% B
10. .10 min 99% B
11. .40 min 99% B
11. .50 min 1% B
13. .00 min Pump STOP
Gradient H: linear gradient from 1% to 60% acetonitrile in water (0.1% HCOOH)
0.00 mm 1% B
10.00 min 60% B
10.10 min 99% B
11.40 min 99% B
11.50 min 1% B
13.00 min Pump STOP
The following tables describe detailed examples of the invention which can be prepared according to the Reaction schemes 1 to 16. These examples are, however, not construed to limit the scope of the invention in any manner.
Figure imgf000044_0001
Figure imgf000044_0002
Figure imgf000045_0001
Figure imgf000046_0001
Figure imgf000047_0001
Figure imgf000048_0001
Figure imgf000049_0001
Figure imgf000050_0001
Figure imgf000051_0001
Figure imgf000052_0001
Figure imgf000053_0001
Table 2:
Figure imgf000053_0002
Figure imgf000054_0001
Table 3:
Figure imgf000054_0003
Figure imgf000054_0002
Table 4:
Figure imgf000054_0004
Figure imgf000055_0002
Figure imgf000055_0001
Table 5:
Figure imgf000055_0003
Figure imgf000056_0001
Figure imgf000056_0002
Figure imgf000057_0001
Table 7:
Figure imgf000057_0002
Figure imgf000058_0001
Table 8:
Figure imgf000058_0002
Figure imgf000059_0002
Figure imgf000059_0001
Table 9:
Figure imgf000059_0003
Figure imgf000060_0001
Table 10:
Figure imgf000060_0003
Figure imgf000060_0002
Table 11:
Figure imgf000060_0004
Figure imgf000061_0001
Figure imgf000062_0001
Figure imgf000063_0001
Table 12:
Figure imgf000063_0003
Figure imgf000063_0002
Table 13:
Figure imgf000063_0004
Figure imgf000064_0002
Figure imgf000064_0001
Table 14:
Figure imgf000064_0003
Figure imgf000065_0003
Figure imgf000065_0001
Table 15:
Figure imgf000065_0002
The following examples are provided to illustrate the invention and are not limiting the scope of the invention in any manner. Synthesis of B-C Moieties: B-C Moiety 1: Intermediate A1):
Figure imgf000066_0001
To a suspension of D-2,4-dichlorophenylalanine (10.00 g) in methanol (100 ml) was added dropwise thionylchloride (9.39 ml). During the course of the addition a clear solution was formed and the reaction started to reflux. The reaction mixture was kept under reflux for 2 h. After cooling to room temperature the mixture was evaporated to dryness at 400C. The crude product was triturated in diethyl ether, and the insoluble compound was filtered off, washed with diethyl ether, and finally dried in vacuo at room temperature over P2O5 overnight. The product was obtained in form of colorless needles.
Intermediate B1):
Figure imgf000066_0002
A 350 ml three-necked, flat-bottomed flask was equipped with a mechanical stirrer and charged with DCM (80 ml), saturated aqueous sodium bicarbonate solution (80 ml), and intermediate A1) (5.69 g). The biphasic mixture was cooled in an ice bath and stirred mechanically while triphosgene (1.96 g) was added in a single portion. The reaction mixture was stirred in the ice bath for 45 min and then poured into a 250 ml separatory funnel. The organic layer was collected, and the aqueous layer was extracted with three 20 ml portions of DCM. The combined organic layer was washed with water, dried over Na2SO4, filtered, and evaporated in vacuo to dryness to yield the crude product as a semisolid. The residue was purified by Kugelrohr distillation (200-2400C, 0.04-0.08 mbar). The product was obtained as clear colorless oil. Intermediate Ci):
Figure imgf000067_0001
To an ice cooled solution of intermediate B1) (4.99 g) in DCM (50 ml) was added pyrrolidine (4.56 ml). After 10 minutes the ice bath was removed and stirring was continued for 4 h. The reaction mixture was evaporated in vacuo. The residue was redissolved in EtOAc and the organic layer was washed with 1 N HCI, water, sat. Na2CO3, water and brine. All the aqueous layers were extracted with EtOAc. The combined organic layer was dried over Na2SO4 and evaporated in vacuo to dryness.
B-C Moiety 1:
Figure imgf000067_0002
Intermediate C1) (6.28 g) was dissolved in MeOH (100 ml) and THF (30 ml) at 00C. A solution of lithium hydroxide monohydrate (1.53 g) in water (30 ml) was added dropwise over the course of 5 min. The mixture was stirred at 00C for 60 min and then acidified by adding 0.5 M HCI. The reaction mixture was extracted two times with EtOAc. The combined organic layer was washed two times with water and with brine, dried over
Na2SO4 and evaporated in vacuo. The solid residue was triturated in Et2O, then filtered off and washed with Et2O. The product was obtained as a white solid. B-C Moiety 2: Intermediate A2):
Figure imgf000068_0001
To an ice cooled solution of intermediate B1) (1.00 g) in DCM (10 ml) was added morpholine (954 μl). After 10 minutes the ice bath was removed and stirring was continued for 4 h. The reaction mixture was evaporated in vacuo. The residue was redissolved in EtOAc and the organic layer was washed with 1 N HCI, water, sat. Na2CO3, water and brine. All the aqueous layers were extracted with EtOAc. The combined organic layer was dried over Na2SO4 and evaporated in vacuo to dryness.
B-C Moiety 2:
Figure imgf000068_0002
Intermediate A2) (1.26 g) was dissolved in MeOH (20 ml) and THF (6 ml) at O0C. A solution of lithium hydroxide monohydrate (293 mg) in water (6 ml) was added dropwise over the course of 5 min. The mixture was stirred at O0C for 60 min and then acidified by adding 0.5 M HCI. The reaction mixture was extracted two times with EtOAc. The combined organic layer was washed two times with water and with brine, dried over Na2SO4 and evaporated in vacuo. The solid residue was triturated in Et2O, then filtered off and washed with Et2O. The product was obtained as a white solid. B-C Moiety 3: Intermediate A3):
Figure imgf000069_0001
To an ice cooled solution of intermediate B1) (1.37 g) in DCM (15 ml) was added DIEA (2.61 ml) followed by 3-hydroxyazetidine hydrochloride (1.64 g). After 30 minutes the ice bath was removed and stirring was continued for 6 h. The reaction mixture was evaporated in vacuo. The residue was redissolved in EtOAc and the organic layer was washed with 1 N HCI (3x40 ml), sat. Na2CO3 (3x25 ml), water (2x25 ml) and brine (30 ml). The combined organic layer was dried over MgSO4 and evaporated in vacuo to dryness. The product was purified by flash chromatography.
Intermediate B3):
Figure imgf000069_0002
To an ice/NaCI-cooled solution of DAST (390 μl) in CH2CI2 (3.0 ml) was added dropwise a solution of intermediate A3 in CH2CI2 (6.0 ml). After 60 minutes the ice/NaCI bath was removed and stirring continued at room temperature for 2 h. The reaction mixture was treated with MeOH (5 ml) and evaporated in vacuo. The residue was redissolved in EtOAc (50 ml) and the organic layer was washed with 1 M HCI (3x20 ml), sat. Na2CO3 (3x15 ml), water (2x15 ml) and brine (10 ml). The organic layer was dried over MgSO4 and evaporated in vacuo to dryness. The crude product was purified by flash chromatography. B-C Moiety 3:
Figure imgf000070_0001
Intermediate B3) (150 mg) was dissolved in MeOH (3.00 ml) and THF (1.00 ml) at 00C. A solution of lithium hydroxide monohydrate (35 mg) in water (1.25 ml) was added dropwise over the course of 5 min. The mixture was stirred at 00C for 2 h and then acidified by adding 0.5 M HCI. The reaction mixture was extracted two times with EtOAc. The combined organic layer was washed two times with water and with brine, dried over MgSO4 and evaporated in vacuo.
All B-C moieties used in this patent application can be prepared using this method starting from an appropriate Boc-protected amino acid and an appropriate amine. The introduction of basic C moieties was usually achieved using the 4- nitrophenylcarbamate pathway (Reaction scheme 15).
Synthesis of Example 2: Intermediate 2a):
Figure imgf000070_0002
To a solution of 1-Boc-4-(2-hydroxy-phenyl)-piperidine (789 mg) in DMF (15 ml) was added 1-(2-chloroethyl)pyrrolidine hydrochloride (605 mg) and Cs2CO3 (3243 mg). The reaction was stirred at room temperature for 18 h. An additional amount of 1-(2- chloroethyl)pyrrolidine hydrochloride (483 mg) and Cs2CO3 (926 mg) was added and stirring at room temperature was continued for another 6 h. The reaction mixture was evaporated at 500C in vacuo to dryness and the residue was partitioned between Et2O (75 ml) and water (25 ml). The aqueous layer was extracted with Et2O (25 ml). The combined organic layer was washed with water (10 ml) and brine (15 ml). The organic layer was dried over Na2SO4 and evaporated in vacuo to dryness. The residue was finally dried under high vacuum at room temperature overnight.
Intermediate 2b):
Figure imgf000071_0001
To Boc-protected intermediate 2a) (1002 mg) in methanol (5 ml) was added hydrogen chloride, 4.0 M sol. in 1 ,4-dioxane (25 ml) and the solution was stirred at room temperature for 2 h. The solvent was removed under reduced pressure. The residue was triturated in acetone (30 ml), filtered off, and washed with acetone (2 x 5 ml). Finally, it was dried in vacuo at room temperature over P2O5 overnight to yield a white solid.
Example 2:
Figure imgf000071_0002
Intermediate 2b) (260 mg), B-C Moiety 1 (310 mg), and HOBt (172 mg) were dissolved in DCM (10 ml). NMM (227 μl) was added and the mixture stirred at room temperature for 30 min. EDCI (252 mg) was added, and the reaction stirred at room temperature for another 60 min. An additional amount of NMM (62 μl) was added and stirring continued at room temperature overnight. The reaction mixture was diluted with EtOAc (100 ml) and washed with sat. Na2CO3 (3 x 30 ml), water (2 x 20 ml) and brine (25 ml). The organic layer was dried over Na2SO4 and evaporated in vacuo. The crude product was purified by flash chromatography. The purified product was dissolved in EtOAc (3.00 ml), treated with 1 M HCI in Et2O (633 μl), and the resulting suspension was diluted with hexane (20 ml). The precipitate was filtered off, washed with hexane (5 ml), and dried in vacuo at room temperature over P2O5 overnight. The product was obtained as a white solid.
Synthesis of Example 3: Intermediate 3a):
Figure imgf000072_0001
A solution of 1-Boc-4-(2-hydroxy-phenyl)-piperidine (1110 mg), 2-bromoethanol (565 μl), and triphenylphosphine (2100 mg) in THF (40 ml) under argon, was cooled in ice/H2O. DEAD (ca. 40% in toluene, 3666 μl) was added dropwise, at a rate to keep the temperature below 5°C (ca. 25 min). After stirring for another 15 min in ice/H2O, the cooling bath was removed and the mixture was stirred at room temperature overnight. Finally, the mixture was heated in an oil bath (45°C) for 4 h. The reaction mixture was cooled down to room temperature and then evaporated to dryness in vacuo at 400C. The crude product was purified by flash chromatography to yield a slightly yellowish clear oil.
Intermediate 3 b):
Figure imgf000072_0002
A suspension of intermediate 3a) (130 mg), (R)-2-fluoropyrrolidine hydrochloride (90 mg) and potassium carbonate (234 mg) in MeCN (5 ml) in a tightly capped flask was heated at 45°C in an oil-bath for 48 h. The reaction mixture was diluted with EtOAc (25 ml), filtered, and the filtrate was evaporated in vacuo. The product was purified by flash chromatography.
Intermediate 3c):
Figure imgf000073_0001
To Boc-protected intermediate 3b) (105 mg) in methanol (1 ml) was added hydrogen chloride, 4.0 M sol. in 1 ,4-dioxane (5 ml) and the solution was stirred at room temperature for 2 h. The solvent was removed under reduced pressure. The residue was triturated in acetone (6 ml), filtered off, and washed two times with acetone. Finally, it was dried in vacuo at room temperature over P2Os overnight to yield a white solid.
Example 3:
Figure imgf000073_0002
Intermediate 3c) (30 mg), B-C Moiety 1 (36 mg), and HOBt (19 mg) were dissolved in DCM (2.5 ml). NMM (26 μl) was added and the mixture stirred at room temperature for 30 min. EDCI (29 mg) was added, and the reaction stirred at room temperature for another 60 min. An additional amount of NMM (7 μl) was added and stirring continued at room temperature overnight. The reaction mixture was evaporated in vacuo, diluted with EtOAc, washed with sat. Na2CO3, water and brine. The aqueous layers were extracted with EtOAc. The combined organic layer was dried over Na2SO4, filtered and evaporated in vacuo to dryness. The residue was purified by flash chromatography. The purified product was dissolved in ethyl acetate (300 μl), and treated with 1 M HCI in Et2O (26 μl) followed by hexane (3 ml). The precipitated salt was filtered off, washed with hexane (1 ml), and finally dried in vacuo at room temperature over P2O5 overnight.
Synthesis of Example 13: Intermediate 13a):
Figure imgf000074_0001
To a solution of 1-Boc-4-(2-hydroxy-phenyl)-piperidine (500 mg) in DMF (7.5 ml) was added 1 -(2-chloroethyl) imidazole hydrochloride (680 mg) and Cs2CO3 (2060 mg). The reaction was stirred at room temperature for 18 h. An additional amount of 1-(2- chloroethyl) imidazole hydrochloride (300 mg) and Cs2CO3 (590 mg) were added and stirring at room temperature was continued for another 74 h. The reaction mixture was evaporated in vacuo to dryness and the residue was partitioned between Et2O (75 ml) and water (25 ml). The aqueous layer was extracted with Et2O (25 ml). The combined organic layer was washed with water (10 ml) and brine (15 ml). The organic layer was dried over Na2SO4 and evaporated in vacuo to dryness. The residue was finally dried under high vacuum at room temperature overnight and purified by flash chromatography.
Intermediate 13b):
Figure imgf000074_0002
To Boc-protected intermediate 13a) (680 mg) in methanol (5 ml) was added hydrogen chloride, 4.0 M sol. in 1 ,4-dioxane (10 ml) and the solution was stirred at room temperature for 2 h. The solvent was removed under reduced pressure. The residue was triturated in acetone (30 ml), filtered off, and washed with acetone and diethyl ether. Finally, it was dried in vacuo at room temperature over P2O5 overnight to yield a white solid.
Example 13:
Figure imgf000075_0001
Intermediate 13b) (30 mg), B-C Moiety 1 (26 mg), and HOBt (14 mg) were dissolved in DCM (2 ml). NMM (19 μl) was added and the mixture stirred at room temperature for 30 min. EDCI (21 mg) was added, and the reaction stirred at room temperature for another 60 min. An additional amount of NMM (5 μl) was added and stirring continued at room temperature overnight. The reaction mixture was evaporated in vacuo, diluted with EtOAc, washed with sat. Na2CO3, water and brine. The aqueous layers were extracted with EtOAc. The combined organic layer was dried over Na2SO4, filtered and evaporated in vacuo to dryness. The residue was purified by flash chromatography. The purified product was dissolved in DCM, and treated with 1 M HCI in Et2O (27 μl) and evaporated in vacuo to yield the hydrochloride as clear colorless oil.
Synthesis of Example 14: Intermediate 14a):
Figure imgf000075_0002
A solution of intermediate 276) (100 mg) and N-(Fmoc)-ethanolamine (182 mg), and triphenylphosphine (168 mg) in anhydrous THF (4 ml) under argon, was cooled in ice/H2O. Then DEAD (ca. 40% in toluene, 294 μl) was added dropwise, at a rate to keep the temperature below 5°C (ca. 15 min). After stirring for another 10 min in ice/H2O, the cooling bath was removed and the mixture was stirred at room temperature overnight. The reaction mixture was evaporated to dryness in vacuo at 400C. The product was purified by column chromatography.
Intermediate 14b):
Figure imgf000076_0001
To Boc-protected intermediate 14a) (156 mg) in dioxane (0.5 ml) was added hydrogen chloride, 4.0 M sol. in 1 ,4-dioxane (3.0 ml) and the solution was stirred at room temperature for 2 h. The solvent was removed under reduced pressure. The residue was triturated in acetone and Et2O1 filtered off, and washed with acetone/Et2O. Finally, it was dried in vacuo at room temperature over P2O5 overnight to yield a white solid.
Intermediate 14c):
Figure imgf000076_0002
Intermediate 14b) (50 mg), B-C Moiety 1 (40 mg), and HOBt (22 mg) were dissolved in DCM (2 ml). NMM (19 μl) was added and the mixture stirred at room temperature for 30 min. EDCI (33 mg) was added, and the reaction stirred at room temperature for another 60 min. An additional amount of NMM (8 μl) was added and stirring continued at room temperature overnight. The reaction mixture was evaporated in vacuo, diluted with EtOAc1 washed with sat. Na2CO3, water and brine. The aqueous layers were extracted with EtOAc. The combined organic layer was dried over Na2SO4, filtered and evaporated in vacuo to dryness. The residue was purified by flash chromatography.
Example 14:
Figure imgf000077_0001
To a solution of intermediate 14c) (86 mg) in CH2CI2 (2 ml) was added diethylamine (1 ml) and the reaction mixture was stirred at room temperature for 4 h. The reaction mixture was evaporated in vacuo and the residue was purified by flash chromatography. The purified product was dissolved in DCM and treated with 1 M HCI in Et2O (97 μl) and evaporated in vacuo. The residue was dissolved in DCM and treated with diethyl ether. The precipitated salt was filtered off, washed with diethyl ether, and finally dried in vacuo at 400C for 2 h.
Synthesis of Example 20: Intermediate 20a):
Figure imgf000077_0002
To a solution of intermediate 27d) (887 mg) in DMF (15 ml) was added 1-(3- chloroethyl)pyrrolidine hydrochloride (605 mg) and Cs2CO3 (3243 mg). The reaction was stirred at room temperature for 18 h. An additional amount of 1-(3-chloroethyl)pyrrolidine hydrochloride (483 mg) and Cs2CO3 (926 mg) were added and stirring at room temperature was continued for 6 h. The reaction mixture was evaporated at 400C in vacuo to dryness and the residue was partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc. The combined organic layer was washed with water and brine. The organic layer was dried over Na2SO4 and evaporated in vacuo to dryness. The crude product was purified using flash chromatography.
Intermediate 20b):
Figure imgf000078_0001
To Boc-protected intermediate 20a) (1170 mg) in dioxane (5 ml) was added hydrogen chloride, 4.0 M sol. in 1 ,4-dioxane (20 ml) and the solution was stirred at room temperature for 2 h. The solvent was removed under reduced pressure. The residue was triturated in acetone and Et2O, filtered off, and washed with Et2O. Finally, it was dried in vacuo at room temperature over P2O5 overnight to yield a white solid.
Example 20:
Figure imgf000078_0002
Intermediate 20b) (510 mg), B-C Moiety 1 (590 mg), and HOBt (308 mg) were dissolved in DCM (30 ml). NMM (417 μl) was added and the mixture stirred at room temperature for 30 min. EDCI (470 mg) was added, and the reaction stirred at room temperature for another 60 min. An additional amount of NMM (122 μl) was added and stirring continued at room temperature overnight. The reaction mixture was evaporated in vacuo, diluted with EtOAc, washed with sat. Na2CO3, water and brine. The aqueous layers were extracted with EtOAc. The combined organic layer was dried over Na2SO4, filtered and evaporated in vacuo to dryness. The residue was purified by flash chromatography. The purified product was dissolved in DCM and treated with 1 M HCI in Et2O (1.27 ml) and evaporated in vacuo. The residue was dissolved in DCM and treated with diethyl ether and hexane. The precipitated salt was filtered off, washed with hexane and diethyl ether, and finally dried in vacuo at 400C for 2 h.
Synthesis of Example 21: Intermediate 21a):
Figure imgf000079_0001
To a mixture of 48% aqueous HBr (89.5 ml) and water (90 ml) was added 6-amino-m- cresol (10.O g). The mixture was kept under reflux for 10 min and then stirred at room temperature for 2 h. The suspension was cooled down to -15°C (ice/NaCI) and NaNO2 (5.49 g) dissolved in water (90 ml) was added dropwise in a way to keep the temperature below -5°C. The mixture was stirred for 10 min and was added dropwise to an ice-cooled mixture of 48% aqueous HBr (53.7 ml), EtOAc (300 ml) and CuBr (22.8 g) during a period of 15 min. The resulting brown suspension was stirred at room temperature for 1 h and at 400C for 3 h. The reaction mixture was diluted with EtOAc (300 ml), the organic phase was removed and the aqueous phase was extracted with diethyl ether (3 x 200ml). The combined organic layer was washed with 48% aqueous HBr (2 x 50 ml) followed by water (5 x 100 ml) and brine (70 ml), dried over Na2SO4 and evaporated to give a brown oil. The crude product was purified by distillation. All fractions which distilled of at normal pressure up to 60°C were discarded. Vacuum was applied and the fraction distilling off at 45°C was collected. This fraction was further purified by column chromatography. Intermediate 21b):
Figure imgf000080_0001
Intermediate 21a) (2.07 g), /V-Boc-I ^.S.e-tetrahydropyridine^-boronic acid pinacol ester (3.42 g) and potassium carbonate (4.59 g) were dissolved in DMF (58 ml). The solution was degassed by bubbling with argon for 1 h. Then [Pd(dppf)CI2] (542 mg) was added. The brown suspension was then heated under argon in an oil bath at 85°C for 3 d. Another load of catalyst was added (220 mg) and the reaction mixture was stirred at 85°C for 7 h. The reaction mixture was filtered through Celite and rinsed with ethyl acetate. The combined filtrates were evaporated and the residue was partitioned between ethyl acetate (150 ml) and water (150 ml). The mixture was filtered through Celite again and rinsed with ethyl acetate. The phases were separated and the aqueous layer was extracted with ethyl acetate (2 x 60 ml). The combined organic layer was washed with water (60 ml) and brine (60 ml), dried over Na2SO4, filtered and evaporated in vacuo to dryness. The residue was purified by flash chromatography.
Intermediate 21c):
Figure imgf000080_0002
Intermediate 21b) (438 mg) was dissolved in dry ethanol (18 ml) and acetic acid (18 ml) and the solution was degassed by bubbling with argon. Platinum(IV) oxide (120 mg) was added and the reaction mixture was placed under a H2 atmosphere using a balloon. The reaction mixture was then stirred at room temperatur for 2 h. The reaction mixture was filtered through Celite, rinsed with EtOAc and evaporated to dryness in vacuo. The residue was coevaporated with toluene (3x 40 ml) and finally dried under high vacuum overnight to give a yellow oil that started to crystallize on standing.
Intermediate 21 d):
Figure imgf000081_0001
To a solution of intermediate 21c) (256 mg) in DMF (5.0 ml) was added 1 -(2-chloroethyl)- pyrrolidine hydrochloride (179 mg) and cesium carbonate (958 mg). The reaction mixture was stirred at room temperature for 36 h. The reaction mixture was evaporated and the residue was partitioned between ethyl acetate (50 ml) and water (40 ml). The organic layer was washed with water (20 ml) and brine (20 ml), dried over Na2SO4 and evaporated in vacuo to dryness. The crude product was purified by flash chromatography.
Intermediate 21 e):
Figure imgf000081_0002
Intermediate 21 d) (408 mg) was dissolved in dioxane (2.0 ml) and 4M HCI in dioxane (20 ml) was added at 00C. The reaction mixture was stirred at room temperature for 90 min. The reaction mixture was evaporated to dryness in vacuo and the residue triturated in acetone (1 ml), ethyl acetate (1 ml) and Et2O (1 ml). A beige sticky compound was obtained. A few drops of MeOH were added to get a beige powder that was filtered off, rinsed with Et2O and dried. Example 21:
Figure imgf000082_0001
Intermediate 21 e) (30 mg), B-C Moiety 1 (35 mg), and HOBt (19 mg) were dissolved in DCM (2.5 ml). NMM (27 μl) was added and the mixture stirred at room temperature for 30 min. EDCI (24 mg) was added, and the reaction stirred at room temperature for another 60 min. An additional amount of NMM (9 μl) was added and stirring continued at room temperature overnight. The reaction mixture was diluted with EtOAc, washed with water, sat. Na2CO3 and brine. The organic layer was dried over Na2SO4, filtered and evaporated in vacuo to dryness. The residue was purified by flash chromatography. The purified product was dissolved in ethyl acetate (200 μl), cooled to 00C and treated with 1 M HCI in Et2O (70 μl) and treated with diethyl ether (1 ml). The precipitate was filtered off and dried under vacuum over Sicapent. The product was obtained as an off-white solid.
Synthesis of Example 23: Intermediate 23a):
Figure imgf000082_0002
A suspension of pyrrolidine (8.35 ml), 3-bromo-1-propanol (8.67 ml), and potassium carbonate (17.28 g) in MeCN (100 ml) was heated under reflux overnight. The reaction mixture was filtered and evaporated in vacuo. The residue was partitioned between EtOAc (100 ml) and 1 M HCI (50 ml). The organic layer was separated and extracted with 1 M HCI (2 x 25 ml). The combined acidic extract was adjusted to pH 13 with solid KOH, while cooling in ice/H2O. The resulting clear, slightly yellowish solution was extracted with DCM (5 x 50 ml). The combined organic extract was dried over Na2SO4 and evaporated in vacuo. The crude product was purified by vacuum distillation employing a 5 cm Vigreux column at a pressure of ca. 15 mbar (with an oil-bath temperature of ca. 1200C). The fraction distilling off at 89-900C was collected. The product was obtained as a colorless oil.
Intermediate 23b):
Figure imgf000083_0001
A solution of intermediate 27d) (468 mg), intermediate 23a) (388 mg), and triphenylphosphine (787 mg) in THF (15 ml) under argon, was cooled in ice/H2O. DEAD (ca. 40% in toluene, 1375 μl) was added dropwise, at a rate to keep the temperature below 5°C (ca. 15 min). After stirring for another 10 min in ice/H2O, the cooling bath was removed and the mixture was stirred at room temperature overnight. The reaction mixture was evaporated to dryness in vacuo at 400C. The crude product was purified by flash chromatography to yield a clear yellowish oil.
Intermediate 23c):
To Boc-protected intermediate 23b) (635 mg) in methanol (3 ml) was added hydrogen chloride, 4.0 M sol. in 1 ,4-dioxane (11 ml) and the solution was stirred at room temperature for 2 h. The solvent was removed under reduced pressure. The residue was triturated in acetone and diethyl ether, filtered off, and washed with diethyl ether. Finally, it was dried in vacuo at room temperature over P2Os overnight to yield a beige solid. Example 23:
Figure imgf000084_0001
Intermediate 23c) (30 mg), B-C Moiety 1 (31 mg), and HOBt (17 mg) were dissolved in DCM (2.5 ml). NMM (23 μl) was added and the mixture stirred at room temperature for 30 min. EDCI (25 mg) was added, and the reaction stirred at room temperature for another 60 min. An additional amount of NMM (6 μl) was added and stirring continued at room temperature overnight. The reaction mixture was evaporated in vacuo, diluted with EtOAc, washed with sat. Na2CO3, water and brine. The aqueous layers were extracted with EtOAc. The combined organic layer was dried over Na2SO4, filtered and evaporated in vacuo to dryness. The residue was purified by flash chromatography. The purified product was dissolved in DCM and treated with 1 M HCI in Et2O (73 μl) and evaporated in vacuo. The residue was dissolved in DCM and the salt was precipitated by addition of Et2O and hexane. The precipitate was filtered off, washed with hexane and Et2O and dried in vacuo at 400C for 2 hours. The product was obtained as a white solid.
Synthesis of Example 26: Intermediate 26a):
Figure imgf000084_0002
2-Bromo-4,5-difluorophenol (2857 μl), N-Boc-I ^.S^-tetrahydropyridine^-boronic acid pinacol ester (7.73 g), potassium carbonate (10.36 g) and dichloro(1 ,1'-bis(diphenyl- phosphino)-ferrocene)palladium(ll) DCM adduct (1.22 g) were dissolved in DMF (150 ml) in a dry apparatus under argon and the mixture was degassed by bubbling with argon for 30 min. The orange suspension was then heated under argon in an oil bath at 85°C for 1 day to give a dark purple suspension. The reaction mixture was filtered through Celite and evaporated to dryness in vacuo. The crude product was purified by flash chromatography to yield pale green crystals.
Intermediate 26b):
Figure imgf000085_0001
Intermediate 26a) (1404 mg) was dissolved in EtOH (50 ml) and AcOH (50 ml) and platinum(IV) oxide (102 mg) was added. The reaction mixture was evacuated three times and purged with hydrogen. The reaction mixture was then stirred at room temperature for 2 h. The reaction mixture was filtered and evaporated to dryness in vacuo. The residue was coevaporated with toluene (3 x 75 ml) and was finally dried under high vacuum at room temperature overnight to yield a beige solid.
Intermediate 26c):
Figure imgf000085_0002
To a solution of intermediate 26b) (674 mg) in DMF (15 ml) was added 1-(2- chloroethyl)piperidine hydrochloride (605 mg) and Cs2CO3 (2453 mg). The reaction was stirred at room temperature for 2 days. An additional amount of 1 -(2-chloroethyl)piperidine hydrochloride (199 mg) and Cs2CO3 (352 mg) was added and stirring at room temperature was continued for another 3 d. The reaction mixture was evaporated at 500C in vacuo to dryness and the residue was partitioned between Et2O (75 ml) and water (25 ml). The aqueous layer was extracted with Et2O (25 ml). The combined organic layer was washed with water (10 ml) and brine (15 ml). The organic layer was dried over Na2SO4 and evaporated in vacuo to dryness. The residue was finally dried under high vacuum at room temperature overnight. The crude product was purified by flash chromatography.
Intermediate 26d):
Figure imgf000086_0001
To Boc-protected intermediate 26c) (490 mg) in methanol (2 ml) and dioxane (10 ml) was added hydrogen chloride, 4.0 M sol. in 1 ,4-dioxane (10 ml) and the solution was stirred at room temperature for 30 min. The solvent was removed under reduced pressure. The residue was triturated in acetone and Et2O, filtered off, and washed with Et2O. Finally it was dried in vacuo at room temperature over P2O5 overnight to yield an off-white solid.
Example 26:
Figure imgf000086_0002
Intermediate 26d) (64 mg), B-C-Moiety 1 (58 mg), and HOBt (27 mg) were dissolved in DCM (2 ml). NMM (26 μl) was added and the mixture stirred at room temperature for 20 min. EDCI (46 mg) was added, and the reaction stirred at room temperature for another 60 min. An additional amount of NMM (20 μl) was added and stirring continued at room temperature overnight. The reaction mixture was diluted with EtOAc (50 ml) and washed with sat. Na2CO3 (3 x 20 ml), water (2 x 10 ml) and brine (10 ml). The organic layer was dried over Na2SO4 and evaporated in vacuo. The crude product was purified by flash chromatography. The purified product was dissolved in ethyl acetate (2 ml), treated with 1 M HCI in Et2O (200 μl), and the resulting suspension was diluted with hexane (20 ml). The precipitate was filtered off, washed with hexane and diethyl ether, and dried in vacuo at room temperature over P2O5 overnight. The product was obtained as white solid.
Synthesis of Example 27: Intermediate 27a):
Figure imgf000087_0001
2-Bromo-5-chloroanisole (5.54 g), 1-(2(H)-pyridine-carboxylic acid-3,6-dihydro-4-(4,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)-tert. -butyl ester (7.73 g), dichloro(1 ,1'-bis(diphenyl- phosphino)-ferrocene)palladium(ll) DCM adduct (1.22 g) and K2CO3 (10.36 g) were dissolved in degassed DMF in a dry apparatus under argon and the mixture was degassed again by evacuation followed by refilling with argon. The resulting suspension was heated in an oil bath at 85°C overnight. The mixture was cooled, filtered through Celite and evaporated to dryness. The crude product was purified by flash chromatography to yield a clear yellowish oil. Intermediate 27b):
Figure imgf000088_0001
Intermediate 27a) (2.18 g) was dissolved in EtOH (80 ml) and AcOH (80 ml) under argon. Platinum(IV) oxide (0.23 g) was added and the reaction mixture was placed under an H2 atmosphere using a balloon. The reaction mixture was then stirred at room temperature for 120 min. The reaction mixture was filtered through Celite and evaporated to dryness in vacuo. The residue was coevaporated with toluene (3 x 40 ml). The crude product was purified by flash chromatography to yield a clear colorless oil.
Intermediate 27c):
Figure imgf000088_0002
To a solution of intermediate 27b) (1.56 g) in AcOH (6.5 ml) was added hydroiodic acid (5.2 ml of a 57 wt.% aq. solution) and the mixture was heated under reflux (oil bath at
1400C) in an argon atmosphere for 2 h. The reaction mixture was cooled to room temperature and then evaporated to dryness in vacuo. The residue was coevaporated with toluene (3 x 30 ml). The crude product was triturated in Et2O (40 ml), the insoluble compound was filtered off and washed with Et2O (10 ml). Finally, the product was dried in vacuo over P2O5 at room temperature overnight to yield a white solid. Intermediate 27d):
Figure imgf000089_0001
To a solution of intermediate 27c) (1.55 g) in DMF (10 ml) was added DIEA (0.88 ml) followed by di-tert.-butyl-dicarbonate (1.01 g). The reaction mixture was stirred at room temperature for 4 h. The mixture was evaporated in vacuo to dryness and partitioned between 0.5 M HCI (50 ml) and EtOAc (100 ml). The organic layer was washed with water (25 ml) and brine (30 ml). The organic layer was dried with MgSO4 and evaporated in vacuo to dryness to yield a yellowish solid. The solid residue was triturated in EtOAc (1 ml) and Et2O (10 ml), and left in the fridge overnight to complete crystallization of the product. The precipitate was then filtered off, washed with cold Et2O (1 ml), and finally dried in vacuo at room temperature over P2O5 overnight. The product was obtained in form of a white solid.
Intermediate 27e):
Figure imgf000089_0002
To a solution of intermediate 27d) (468 mg) in DMF (8 ml) was added 1-(3- chloropropyl)piperidine hydrochloride (373 mg) and Cs2CO3 (1710 mg). The reaction was stirred at room temperature for 18 h. An additional amount of 1-(3-chloropropyl)piperidine hydrochloride (297 mg) and Cs2CO3 (489 mg) were added and stirring at room temperature was continued for 3 d. The reaction mixture was evaporated at 400C in vacuo to dryness and the residue was partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc. The combined organic layer was washed with water and brine. The organic layer was dried over Na2SO4 and evaporated in vacuo to dryness. The crude product was purified using flash chromatography.
Intermediate 27 f):
Figure imgf000090_0001
To Boc-protected intermediate 27e) (651 mg) in methanol (3 ml) was added hydrogen chloride, 4.0 M sol. in 1 ,4-dioxane (11 ml) and the solution was stirred at room temperature for 90 min. The solvent was removed under reduced pressure. The residue was triturated in acetone and Et2O, filtered off, and washed with Et2O. Finally, it was dried in vacuo at room temperature over P2O5 overnight to yield a white solid.
Example 27:
Figure imgf000090_0002
Intermediate 27f) (30 mg), B-C Moiety 1 (30 mg), and HOBt (17 mg) were dissolved in DCM (2 ml). NMM (22 μl) was added and the mixture stirred at room temperature for 30 min. EDCI (25 mg) was added, and the reaction stirred at room temperature for another 60 min. An additional amount of NMM (6 μl) was added and stirring continued at room temperature overnight. The reaction mixture was diluted with EtOAc (50 ml) and washed with sat. Na2CO3 (3 x 20 ml), water (2 x 10 ml) and brine (10 ml). The organic layer was dried over Na2SO4 and evaporated in vacuo. The crude product was purified by flash chromatography. The purified product was dissolved in DCM, treated with 1 M HCI in Et2O (66 μl), and the resulting suspension was diluted with diethyl ether and hexane. The precipitate was filtered off, washed with hexane and diethyl ether, and dried in vacuo at room temperature over P2Os overnight. The product was obtained as a white solid.
Synthesis of Example 36: Intermediate 36a):
Figure imgf000091_0001
(2-Bromo-phenyl)-acetic acid (5.38 g) was dissolved in methanol (20.26 ml). Then concentrated sulfuric acid (0.27 ml) was added, and the reaction mixture was heated under reflux overnight (oil bath temperature 850C) with exclusion of humidity by means of a drying tube (blue silica gel). The reaction mixture was evaporated in vacuo at 400C and the colorless oily residue was poured into ice-water (50 ml). The resulting white emulsion was extracted with Et2O (75 ml), and the organic phase was washed with sat. Na2CO3 (3 x 20 ml), H2O (15 ml), and brine (15 ml). The organic phase was dried with MgSO4 and evaporated in vacuo to yield a colorless clear oil.
Intermediate 36b):
Figure imgf000091_0002
Intermediate 36a) (4.00 g), N-Boc-1 ,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester (5.40 g), potassium carbonate (7.24 g), and dichloro(1,1'-bis(diphenyl-phosphino)- ferrocene)palladium(ll) DCM adduct (860 mg) were dissolved in DMF (150 ml) in a dry apparatus under argon and the mixture was degassed by bubbling with argon for 30 min. The orange suspension was then heated under argon in an oil bath at 85°C overnight. The reaction mixture was filtered through Celite and evaporated to dryness in vacuo. The residue was triturated in DCM (50 ml) and the insoluble parts were filtered off. The filtrate was concentrated and subjected to flash chromatography. The product was obtained as clear yellow oil.
Intermediate 36c):
Figure imgf000092_0001
Intermediate 36b) (1.99 g) was dissolved in EtOH (30 ml) and AcOH (30 ml) and platinum(IV) oxide (400 mg) was added. The reaction mixture was evacuated three times and purged with hydrogen. The reaction mixture was then stirred at room temperature for 2 h. The reaction mixture was filtered and evaporated to dryness in vacuo. The residue was coevaporated with toluene (3 x 75 ml) and was finally dried under high vacuum at room temperature overnight.
Intermediate 36d):
Figure imgf000092_0002
Intermediate 36c) (2.85 g) was dissolved in dry diethyl ether (30 ml) under inert atmosphere and cooled to -72°C. At this temperature diisobutylaluminum hydride, 1.0 M in hexane (12.8 ml) was added dropwise in the course of 30 min. The reaction mixture was stirred at -72°C for 2 h. Methanol (173 μl) was added and the mixture was warmed up to 00C. Water (1.5 ml) was added and the mixture was filtered through a bed of sodium sulfate. After washing twice with diethyl ether (30 ml each) the combined organic filtrate was concentrated in vacuo. The crude product was purified by flash chromatography to yield a colorless oil.
Intermediate 36e):
Figure imgf000093_0001
To a solution of the intermediate 36d) (121 mg) and 4-fluoropiperidine hydrochloride (56 mg) in dichloroethane (5 ml), DIEA (139 μl) was added followed by sodium triacetoxyborohydride (119 mg). The reaction mixture was then stirred for 4 h at room temperature. The mixture was diluted with EtOAc (70 ml) and washed two times with sat. NaHCO3 (25 ml each), water and brine (25 ml each). The organic phase was dried over Na2SO4 and concentrated. The crude product was purified using flash chromatography.
Intermediate 361):
Figure imgf000093_0002
To intermediate 36e) (102 mg) in dioxane (5 ml) and methanol (1 ml) was added hydrogen chloride, 4.0 M sol. in 1 ,4-dioxane (5 ml) and the solution was stirred for 30 min at room temperature. The solvent was removed under reduced pressure, the residue was triturated with acetone (5 ml) and diethyl ether (25 ml) and the product was filtered off. Example 36:
Figure imgf000094_0001
Intermediate 36f) (29 mg), B-C Moiety 1 (28 mg), and HOBt (14 mg) were dissolved in DCM (1 ml). NMM (13 μl) was added and the mixture stirred at room temperature for 20 min. EDCI (23 mg) was added, and the reaction stirred at room temperature for another 60 min. An additional amount of NMM (10 μl) was added and stirring continued at room temperature overnight. The reaction mixture was poured into water (20 ml), diluted with ethyl acetate and the organic phase was separated. The aqueous phase was extracted two times with ethyl acetate. The combined organic phase was washed three times with saturated sodium bicarbonate solution, dried over Na2SO4 and concentrated. The residue was purified by flash chromatography. The purified product was dissolved in ethyl acetate and treated with 1 M HCI in Et2O (100 μl). The product was precipitated by addition of hexane (20 ml). The precipitate was filtered off and dried in vacuo over P2O5. The product was obtained as white solid.
Synthesis of Example 37: Intermediate 37a):
Figure imgf000094_0002
2-Bromo-4-fluorophenylacetic acid (2330 mg), EDCI (2109 mg) and DMAP (100 mg) were dissolved in DCM (100 ml). Pyrrolidine (918 μl) was added and the reaction mixture was stirred overnight. The reaction mixture was poured into water (100 ml) and the organic layer was separated. The aqueous layer was extracted twice with DCM. The combined organics were washed three times with 0.5 N HCI (30 ml each), three times with 1 M sodium hydroxide solution and brine, dried over Na2SO4 and the solvent was removed under reduced pressure. The crude product was purified by flash chromatography.
Intermediate 37b):
Figure imgf000095_0001
Intermediate 37a) (1692 mg), N-Boc-1 ,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester (1920 mg), potassium carbonate (2450 mg), and dichloro(1 ,1'-bis(diphenyl- phosphino)-ferrocene)palladium(ll) DCM adduct (286 mg) were dissolved in DMF (70 ml) in a dry apparatus under argon and the mixture was degassed by bubbling with argon for 30 min. The orange suspension was then heated under Argon in an oil bath at 85°C overnight. The reaction mixture was filtered through Celite and evaporated to dryness in vacuo. The residue was triturated in DCM (50 ml) and the insoluble parts were filtered off. The filtrate was concentrated and subjected to flash chromatography.
Intermediate 37c):
Figure imgf000095_0002
Intermediate 37b) (2266 mg) was dissolved in EtOH (50 ml) and AcOH (50 ml) and platinum(IV) oxide (132 mg) was added. The reaction mixture was evacuated three times and purged with hydrogen. The reaction mixture was then stirred at room temperature for
2 h. The reaction mixture was filtered and evaporated to dryness in vacuo. The residue was coevaporated with toluene (3 x 75 ml) and was finally dried under high vacuum at room temperature overnight. The crude product was purified by flash chromatography to yield a white solid. Intermediate 37d):
Figure imgf000096_0001
Intermediate 37c) (1392 mg) in diethyl ether (20 ml) was slowly added to a mixture of lithium aluminum hydride (203 mg) and diethyl ether (30 ml) at 00C. After addition the reaction mixture was stirred at 00C for 1 h. The reaction mixture was hydrolyzed with a minimum amount of water. The inorganic precipitate was filtered off and washed twice with diethyl ether. The combined filtrates were dried over sodium sulfate, filtered, and the solvent was removed under reduced pressure. The product was purified by flash chromatography.
Intermediate 37e):
Figure imgf000096_0002
To intermediate 37d) (373 mg) in dioxane (10 ml) and methanol (2 ml) was added hydrogen chloride, 4.0 M sol. in 1 ,4-dioxane (10 ml) and the solution was stirred for 30 min at room temperature. The solvent was removed under reduced pressure, the residue was triturated with acetone (10 ml) and diethyl ether (50 ml) and the product was filtered off. Example 37:
Figure imgf000097_0001
Intermediate 37e) (28 mg), B-C Moiety 1 (28 mg), and HOBt (14 mg) were dissolved in DCM (1 ml). NMM (13 μl) was added and the mixture stirred at room temperature for 20 min. EDCI (23 mg) was added, and the reaction stirred at room temperature for another 60 min. An additional amount of NMM (10 μl) was added and stirring continued at room temperature overnight. The reaction mixture was poured into water (20 ml), diluted with ethyl acetate and the organic phase was separated. The aqueous phase was extracted two times with ethyl acetate. The combined organic phase was washed three times with saturated sodium bicarbonate solution, dried over Na2SO4 and concentrated. The residue was purified by flash chromatography. The purified product was dissolved in ethyl acetate and treated with 1 M HCI in Et2O (100 μl). The product was precipitated by addition of hexane (20 ml). The precipitate was filtered off and dried in vacuo over P2O5. The product was obtained as a white solid.
Synthesis of Example 42: Intermediate 42a):
Figure imgf000097_0002
2-Bromo-5-chlorotoluene (8.26 ml) and N-bromosuccinimide (11.03 g) in carbon- tetrachloride (50 ml) were treated with a catalytic amount of benzoylperoxide (100 mg) and heated under reflux until the reaction had reached completion as monitored by TLC. The reaction mixture was then allowed to cool and filtered. The filtrate was washed twice with water and brine, dried over sodium sulfate and concentrated in vacuo. Intermediate 42b):
Figure imgf000098_0001
To a solution of sodium ethoxide (2.79 g) in ethanol (30 ml) was added diethyl malonate (6.54 ml) and the mixture was stirred for 1 h at room temperature. The mixture was cooled in an ice-bath and intermediate 42a) (11.67 g) was slowly added and the reaction mixture was kept under reflux overnight. The reaction mixture was evaporated in vacuo and the residue was partioned between diethyl ether and water and the aqueous layer extracted two times with diethyl ether. The combined organic layer was washed twice with water and brine. The combined organic layer was dried over Na2SO4 and evaporated in vacuo to dryness. The product was purified by Kugelrohr distillation. The fractions which distilled off between 160 and 2300C at 0.2-0.3 mbar were collected.
Intermediate 42c) :
Intermediate 42b) (8.98 g) was heated under reflux in 1.8 M KOH in H2O/EtOH (60 ml) for 5 h. After evaporation of the ethanol an additional amount of KOH (18 g) was added to the residue, and the reaction mixture was stirred for 2 h at 1000C. The reaction mixture was diluted with 100 ml of H2O, extracted with Et2O and the organic layer was washed with H2O. The combined aqueous layer was cooled with ice/H2O and acidified with 50 % H2SO4 to pH 1. The precipitate was extracted twice with Et2O (100 ml each) and the organic layers were washed with water and brine. The combined organic layers were dried over Na2SO4 and evaporated in vacuo to dryness. The residue was triturated in hexane and less Et2O1 then filtered and washed with hexane and less Et2O. The solid residue was decarboxylated by heating at 200°C. The development of CO2 ceased after 20 min and the melt was cooled to room temperature. The residue was crushed with a glass rod to get a homogeneous beige solid.
Intermediate 42d):
Figure imgf000099_0001
Intermediate 42c) (2320 mg), pyrrolidine (808 μl), EDCI (1856 mg) and DMAP (100 mg) were dissolved in DCM (100 ml) and stirred overnight. The reaction mixture was poured into water (100 ml) and the organic layer was separated. The aqueous layer was extracted twice with DCM. The combined organics were washed three times with with 0.5 N HCI (30 ml each), three times with 1 M sodium hydroxide solution and brine, dried over Na2SO4 and the solvent was removed under reduced pressure. The product was obtained as off- white solid after purification by flash chromatography.
Intermediate 42e):
Figure imgf000099_0002
Intermediate 42d) (1901 mg), N-Boc-1 ,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester (1948 mg), potassium carbonate (3317 mg) and dichloro(1 ,1'-bis(diphenyl- phosphino)-ferrocene)palladium(ll) DCM adduct (294 mg) were dissolved in DMF (70 ml) in a dry apparatus under argon and the mixture was degassed by bubbling with argon for 30 min. The orange suspension was then heated under argon in an oil bath at 85°C for 3 days to give a dark purple suspension. The reaction mixture was filtered through Celite and evaporated to dryness in vacuo. The crude product was purified by column chromatography. Intermediate 421):
Figure imgf000100_0001
Intermediate 42e) (2372 mg) was dissolved in EtOH (50 ml) and AcOH (50 ml) and platinum(IV) oxide (129 mg) was added. The reaction mixture was evacuated three times and purged with hydrogen. The reaction mixture was then stirred at room temperature for 2 h. The reaction mixture was filtered and evaporated to dryness in vacuo. The residue was coevaporated with toluene (3 x 75 ml) and was finally dried under high vacuum at room temperature overnight.
Intermediate 42g):
Figure imgf000100_0002
Intermediate 42f) (1687 mg) in diethyl ether (20 ml) was slowly added to a mixture of lithium aluminum hydride (228 mg) and diethyl ether (30 ml) at 00C. After addition, the reaction mixture was stirred at 00C for 1 h. The reaction mixture was hydrolyzed with a minimum amount of water. The inorganic precipitate was filtered off and washed twice with diethyl ether. The combined filtrates were dried over sodium sulfate, filtered, and the solvent was removed under reduced pressure. The crude product was purified by flash chromatography to yield a colorless oil. Intermediate 42h):
Figure imgf000101_0001
To intermediate 42g) (864 mg) in dioxane (10 ml) and methanol (2 ml) was added hydrogen chloride, 4.0 M sol. in 1 ,4-dioxane (10 ml) and the solution was stirred for 30 min at room temperature. The solvent was removed under reduced pressure, the residue was triturated with acetone (5 ml) and diethyl ether (50 ml) and the product was filtered off. The product was obtained as off-white solid.
Example 42:
Figure imgf000101_0002
Intermediate 42h) (61 mg), B-C Moiety 1 (58 mg), and HOBt (27 mg) were dissolved in DCM (2 ml). NMM (26 μl) was added and the mixture stirred at room temperature for 20 min. EDCI (46 mg) was added, and the reaction stirred at room temperature for another 60 min. An additional amount of NMM (20 μl) was added and stirring continued at room temperature overnight. The reaction mixture was diluted with EtOAc (50 ml) and washed with sat. Na2CO3 (3 x 20 ml), water (2 x 10 ml) and brine (10 ml). The organic layer was dried over Na2SO4 and evaporated in vacuo. The crude product was purified by flash chromatography. The purified product was dissolved in ethyl acetate (2 ml), treated with 1 M HCI in Et2O (200 μl), and the resulting suspension was diluted with hexane (20 ml). The precipitate was filtered off, washed with hexane and diethyl ether, and dried in vacuo at room temperature over P2O5 overnight. The product was obtained as a white solid. Synthesis of Example 44: Intermediate 44a):
Figure imgf000102_0001
A solution of 2-bromo-5-chlorophenylacetic acid (20.0 g) in THF (200 ml) was added to a suspension of sodium borohydride (3.18 g) in THF (50 ml) over 30 min at room temperature. After being stirred for 15 min, boron trifluoride diethyl etherate (13.2 ml) was added over 30 min while the temperature was maintained at 25-35°C. The resulting slurry was stirred for 1 h at room temperature, then cooled to O0C and carefully hydrolyzed by addition of sat. NH4CI (50 ml). The main part of the THF was removed in vacuo, the residue was diluted with sat. NH4CI and water (each with 50 ml), followed by extraction with diethyl ether (3 x 100 ml). The combined ether layer was washed with 1 M NaOH (2 x 100 ml) and water (100 ml). All aqueous phases were combined and extracted with diethyl ether (2 x 100 ml). All organic layers were combined, washed with brine (100 ml), and dried (Na2SO4). Evaporation of the solvent afforded the desired product as a yellowish oil.
Intermediate 44b):
Figure imgf000102_0002
Phosphorous tribromide (3.71 ml) was dissolved in toluene (30 ml) and cooled to 00C. Then pyridine (1.68 ml) was added. To the suspension thus obtained, a solution of intermediate 44a) (18.6 g) and pyridine (0.56 ml) in toluene (30 ml) was added over 15 min. The cooling bath was removed and stirring was continued at room temperature for 1 h. Then the reaction mixture was heated to 1000C for another hour. The reaction mixture was cooled to ambient temperature, diluted with EtOAc (300 ml) and washed with water (2 x 100 ml). The combined aqueous layer was extracted with EtOAc (100 ml), all organic extracts were merged and washed with brine (100 ml), dried (Na2SO4), and concentrated in vacuo. The crude product was purified by column chromatography to furnish the desired compound as a colorless oil.
Intermediate 44c):
Figure imgf000103_0001
Diethyl malonate (9.59 ml) was added dropwise to a suspension of sodium hydride, 60% dispersion in mineral oil (2.42 g) in THF (50 ml) at 00C. The cooling bath was removed and stirring was continued for 30 min at room temperature. Then a solution of intermediate 44b) (15.7 g) in THF (50 ml) was added and the reaction mixture was kept under reflux overnight. The suspension was concentrated in vacuo. The residue was diluted with water (300 ml) and extracted with diethyl ether (3 x 200 ml). The combined organic layer was washed with brine (200 ml), dried (Na2SO4), and concentrated in vacuo. The crude product was purified by column chromatography to furnish the desired compound as a colorless oil.
Intermediate 44d):
Figure imgf000103_0002
An emulsion of intermediate 44c) and potassium hydroxide (11.6 g) in a 1 :1 mixture of EtOH and water (100 ml) was heated under reflux for 5 h. The main part of EtOH was evaporated, more potassium hydroxide (19.3 g) was added and the reaction mixture was heated to 1000C for 45 min. After dilution with water (150 ml), the solution was extracted with diethyl ether (2 x 50 ml). The combined ether layer was re-extracted with water (50 ml). The two water layers were combined and acidified with 50% H2SO4 to pH 1 , extracted with diethyl ether (3 x 100 ml), re-extracted with water (100 ml). Following drying over Na2SO4 the solvent was evaporated to afford the corresponding malonic acid derivative in form of a white solid. Decarboxylation was achieved by heating the product at 2000C until evolution of carbon dioxide ceased to provide the desired compound as a slightly brownish solid.
Intermediate 44e):
Figure imgf000104_0001
A solution of intermediate 44d) (5.03 g) in DCM (130 ml) was cooled to 00C. To this solution a solution of oxalyl chloride (1.69 ml) in DCM (20 ml) was added dropwise. DMF (5 drops) was added and the reaction mixture was stirred at 00C for 1 h and then at room temperature until the gas formation ceased. Concentration in vacuo furnished the desired product in form of a yellowish oil.
Intermediate 441):
Figure imgf000104_0002
A solution of intermediate 44e) (5.31 g) in DCM (70 ml) was cooled to 00C. Pyrrolidine (4.49 ml) was added dropwise and stirring was continued at 00C for 45 min. The ice bath was removed and stirring was continued at room temperature. After being stirred for 2 h in total the reaction mixture was diluted with DCM (100 ml) and washed with 1 M HCI, 1 M NaOH (each with 3 x 50 ml), water and brine (each with 50 ml). The organic phase was dried (Na2SO4) and evaporated to afford the desired product as a yellow oil. Intermediate 44g):
Figure imgf000105_0001
A mixture of intermediate 44f) (5.50 g), /V-Boc-1 ,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester (5.40 g), potassium carbonate (6.90 g), and dichloro(1 ,1'-bis(diphenyl- phosphino)-ferrocene)palladium(ll) DCM adduct (0.82 g) in degassed DMF (100 ml) was heated under argon at 85°C overnight. The reaction mixture was evaporated. The residue was partitioned between EtOAc and water (each with 100 ml) and filtered through Celite. The filtrate was extracted with EtOAc (2 x 100 ml) and the combined organic layer re- extracted with water and brine (100 ml each), dried (Na2SO4) and concentrated in vacuo. The crude product was purified by column chromatography to furnish the desired compound as a brownish resin.
Intermediate 44h):
Figure imgf000105_0002
To a solution of intermediate 44g) (6.06 g) in EtOH and AcOH (100 ml each) platinum(IV) oxide (0.32 g) was added. The flask was purged with H2 at atmospheric pressure. The reaction mixture was then vigorously stirred for 3 h at room temperature. Filtration through Celite, evaporation of the solvent and purification of the residue by column chromatography afforded the desired product in form of a colorless oil. Intermediate AAi):
Figure imgf000106_0001
Under vigorous stirring a solution of intermediate 44h) (2.16 g) in diethyl ether (20 ml) was added to a suspension of lithium aluminum hydride (0.28 g) in diethyl ether (30 ml) at 00C under argon. The reaction mixture was stirred for 1 h at this temperature and was then hydrolyzed by addition of water (0.5 ml). The inorganic precipitate thus obtained was filtered off and washed with diethyl ether (3 x 40 ml). The filtrate was dried (Na2SO4) and concentrated in vacuo. Purification of the crude product by column chromatography furnished the desired compound as a colorless resin.
Intermediate 44)'):
Figure imgf000106_0002
To Boc-protected intermediate 44i) (670 mg) in MeOH (5 ml) was added hydrogen chloride, 4.0 M sol. in 1 ,4-dioxane (5 ml) and the solution was stirred at room temperature for 30 min. The solvent was completely removed in vacuo to afford the desired compound as a white solid. Example 44
Figure imgf000107_0001
Intermediate 44j) (65 mg) and B-C Moiety 1 (71 mg), 1 -hydroxy-benzotriazole hydrate (38 mg) and Λ/-methylmorpholine (51 μl) were dissolved in DMF (5 ml). After being stirred for 30 min at room temperature, Λ/-(3-dimethylaminopropyl)-Λ/'-ethylcarbodiimide hydochloride (57 mg) was added and stirring was continued for another hour. An additional amount of Λ/-methylmorpholine (14 μl) was added and stirring was continued overnight. The reaction mixture was diluted with EtOAc (70 ml), washed with sat. Na2CO3 (3 x 25 ml), H2O and brine (each with 25 ml). The organic layer was dried (Na2SO4) and the solvent removed in vacuo. Purification of the crude product by column chromatography furnished the corresponding amine in form of a yellowish oil. This was dissolved in EtOAc (1 ml) and treated with hydrogen chloride solution, 1.0 M in diethyl ether (235 μl). The resulting suspension was diluted with ether and hexane (3 ml each) in order to obtain a complete precipitation of the corresponding hydrochloride. The solid was filtered off, washed with hexane, and dried in vacuo over P2O5 overnight to provide the desired compound in form of an off-white solid.
Synthesis of Examples 49 and 50: Intermediate 49-5Oa):
Figure imgf000107_0002
To a solution of DL-2-amino-1-propanol (5.34 ml) and 1 ,4-dibromobutane (7.91 ml) in acetonitrile (67 ml) was added potassium carbonate (18.52 g) and the resulting solution was stirred at reflux temperature for 20 h. The reaction mixture was evaporated in vacuo and the residue was partioned between EtOAc and water. The organic layer was washed with water and brine. The aqueous layers were re-extracted with EtOAc. The combined organic layer was dried over Na2SO4 and evaporated in vacuo to dryness. The crude product was purified by Kugelrohr distillation (20 mbar, 103-1120C) to yield a clear colorless oil.
Intermediate 49-5Ob):
Figure imgf000108_0001
A solution of intermediate 27d) (1.21 g), intermediate 49-5Oa) (1.00 g), and triphenylphosphine (2.03 g) in THF (30 ml) under argon, was cooled in ice/H2O. DEAD (ca. 40% in toluene, 1.42 ml) was added dropwise, at a rate to keep the temperature below 5°C (ca. 15 min). After stirring for another 10 min in ice/H2O, the cooling bath was removed and the mixture was stirred at room temperature overnight. The reaction mixture was evaporated to dryness in vacuo at 400C. The crude product was purified by flash chromatography.
Intermediate 49-5Oc):
Figure imgf000108_0002
To Boc-protected intermediate 49-5Ob) (1.25 g) in dioxane (5 ml) was added hydrogen chloride, 4.0 M sol. in 1 ,4-dioxane (20 ml) and the solution was stirred at room temperature for 60 min. The solvent was removed under reduced pressure. The residue was triturated in acetone and Et2O1 filtered off, and washed with Et2O. Finally, it was dried in vacuo at room temperature over P2O5 overnight to yield a white solid.
Examples 49 and 50:
Figure imgf000109_0001
Intermediate 49-5Oc) (100 mg), B-C Moiety 1 (105 mg), and HOBt (58 mg) were dissolved in DCM (7 ml). NMM (77 μl) was added and the mixture stirred at room temperature for 30 min. EDCI (85 mg) was added, and the reaction stirred at room temperature for another 60 min. An additional amount of NMM (21 μl) was added and stirring continued at room temperature overnight. The reaction mixture was evaporated in vacuo, diluted with EtOAc and washed with sat. Na2CO3 water and brine. The organic layer was dried over Na2SO4 and evaporated in vacuo. The two products were separated by flash chromatography. The free base of example 49 was dissolved in DCM, treated with 1 M HCI in Et2O (172 μl), and evaporated in vacuo. The residue was dissolved in DCM and the salt precipitated by addition of diethyl ether and hexane. The precipitate was filtered off, washed with hexane and diethyl ether, and dried in vacuo at room temperature for 2 h. The product was obtained as a white solid. The free base of example 50 was dissolved in DCM, treated with 1 M HCI in Et2O (44 μl), and evaporated in vacuo. The residue was dissolved in DCM and the salt precipitated by addition of diethyl ether and hexane. The precipitate was filtered off, washed with hexane and diethyl ether, and dried in vacuo at room temperature for 2 h. The product was obtained as a white solid. Synthesis of Example 57: Intermediate 57a):
Figure imgf000110_0001
A mixture of (R)-(-)-2-amino-1-butanol (4.24 ml), formaldehyde solution (36.5% in H2O, 10.87 ml) and formic acid (6.79 ml) in water (34.06 ml) was heated under reflux for 24 h. The reaction mixture was concentrated in vacuo, the residue was diluted with water (80 ml) and made alkaline by addition of NaOH 1 N (pH 14). The aqueous solution was extracted with CH2CI2 (3 x 60 ml) and the organic layers were washed with water (25 ml) and brine (25 ml). The combined organic layer was dried over Na2SO4 and evaporated in vacuo at 400C. The crude product was purified by Kugelrohr distillation (atmospheric pressure / 155 - 250°C) to yield a clear colorless oil.
Intermediate 57b):
Figure imgf000110_0002
A solution of intermediate 27d) (1.00 g), intermediate 57a) (0.75 g), and triphenylphosphine (1.68 g) in THF (30 ml) under argon, was cooled in ice/H2O. DEAD (ca. 40% in toluene, 2.94 ml) was added dropwise, at a rate to keep the temperature below 5°C (ca. 15 min). After stirring for another 10 min in ice/H2O, the cooling bath was removed and the mixture was stirred at room temperature overnight. The reaction mixture was evaporated to dryness in vacuo at 4O0C. The two regioisomeric products A and B were separated by flash chromatography. Intermediate 57c):
Figure imgf000111_0001
To Boc-protected intermediate 57b) (product A) (825 mg) in dioxane (2.5 ml) was added hydrogen chloride, 4.0 M sol. in 1 ,4-dioxane (11 ml) and the solution was stirred at room temperature for 120 min. The solvent was removed under reduced pressure. The residue was triturated in a mixture of acetone, methanol and Et2O, filtered off, and washed with Et2O. Finally it was dried in vacuo at room temperature over P2Os overnight to yield a white solid.
Example 57:
Figure imgf000111_0002
Intermediate 57c) (40 mg), B-C Moiety 1 (43 mg), and HOBt (24 mg) were dissolved in DCM (3 ml). NMM (31 μl) was added and the mixture stirred at room temperature for 30 min. EDCI (55 mg) was added, and the reaction stirred at room temperature for another 60 min. An additional amount of NMM (9 μl) was added and stirring continued at room temperature overnight. The reaction mixture was evaporated in vacuo, diluted with EtOAc and washed with sat. Na2CO3, water and brine. The organic layer was dried over Na2SO4 and evaporated in vacuo. The crude product was purified by flash chromatography. The purified product was dissolved in DCM, treated with 1 M HCI in Et2O (106 μl), and the resulting suspension was diluted with diethyl ether and hexane. The precipitate was filtered off, washed with hexane and diethyl ether, and dried in vacuo at 400C for 2 h. The product was obtained as a white solid. Synthesis of Example 58: Intermediate 58a):
Figure imgf000112_0001
To Boc-protected intermediate 57b) (product B) (251 mg) in dioxane (0.75 ml) was added hydrogen chloride, 4.0 M sol. in 1,4-dioxane (3.5 ml) and the solution was stirred at room temperature for 120 min. The reaction mixture was diluted with Et2O, the precipitated salt was filtered off, and washed with Et2O. Finally it was dried in vacuo at room temperature over P2O5 overnight to yield a white solid.
Example 58:
Figure imgf000112_0002
Intermediate 58a) (40 mg), B-C Moiety 1 (43 mg), and HOBt (24 mg) were dissolved in DCM (3 ml). NMM (31 μl) was added and the mixture stirred at room temperature for 30 min. EDCI (55 mg) was added, and the reaction stirred at room temperature for another 60 min. An additional amount of NMM (9 μl) was added and stirring continued at room temperature overnight. The reaction mixture was evaporated in vacuo, diluted with EtOAc and washed with sat. Na2CO3, water and brine. The organic layer was dried over Na2SO4 and evaporated in vacuo. The crude product was purified by flash chromatography. The purified product was dissolved in DCM, treated with 1 M HCI in Et2O (96 μl), and the resulting suspension was diluted with diethyl ether and hexane. The precipitate was filtered off, washed with hexane and diethyl ether, and dried in vacuo at 400C for 2 h. The product was obtained as a white solid. Synthesis of Example 59: Intermediate 59a):
Figure imgf000113_0001
To a solution of sodium ethoxide (1.26 g) in ethanol (30 ml) was added diethyl methylmalonate (3.31 ml) followed by intermediate 42a) (5.26 g) and the reaction mixture was kept under reflux overnight. The reaction mixture was evaporated in vacuo and the residue was partitioned between diethyl ether and water. The aqueous layer was extracted two times with diethyl ether. The combined organic layer was washed twice with water and brine. The organic layer was dried over Na2SO4 and evaporated in vacuo to dryness. The product was purified by distillation. The fractions which distilled off between 140 and 2200C at 0.2 mbar were collected.
Intermediate 59b):
Figure imgf000113_0002
Intermediate 59a) (5.89 g) was heated under reflux in 1.8 M KOH in H2O/EtOH (60 ml) for 5 h. After evaporation of the ethanol, an additional amount of KOH (18 g) was added to the residue, and the reaction mixture was stirred at 1000C for 2 h. The reaction mixture was diluted with 100 ml of H2O1 extracted with Et2O, and the organic layer was washed with H2O. The combined aqueous layer was cooled in ice/H2O and acidified with 50% H2SO4 to pH 1. The resulting suspension was extracted twice with Et2O (100 ml each) and the organic layers were washed with water and brine. The combined organic layer was dried over Na2SO4 and evaporated in vacuo to dryness. The residue was triturated in hexane and less Et2O, then filtered and washed with hexane and less Et2O. The solid residue was decarboxylated by heating at 2000C. The evolution of CO2 ceased after 20 min and the product was left to cool to room temperature to yield a brown oil. Intermediate 59c):
Figure imgf000114_0001
Intermediate 59b) (3.08 g mmol) was dissolved in dry DCM (85 ml) and cooled to 00C in an ice-water bath. Oxalyl chloride (1.03 ml) in DCM (15 ml) was added dropwise followed by the addition of 1-2 drops of DMF. This mixture was stirred at 00C for 1.5 h and at room temperature for 2 h (no more gas evolution, clear solution obtained) and then concentrated. The product was dried under reduced pressure.
Intermediate 59d):
Figure imgf000114_0002
To a solution of intermediate 59c) (3.24 g) in DCM (70 ml) at 00C was added pyrrolidine (2.73 ml) dropwise and the reaction mixture was stirred at 00C for 2 h. The reaction mixture was diluted with DCM (100 ml) and washed twice each with 1 M HCI, 1 M NaOH and once with brine. The organic phase was dried over sodium sulfate and the solvent was distilled off.
Intermediate 59e):
Figure imgf000114_0003
Intermediate 59d) (3226 mg), N-Boc-1 ,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester (3170 mg), potassium carbonate (4047 mg) and dichloro(1,1'-bis(diphenyl- phosphino)-ferrocene)palladium(ll) DCM adduct (482 mg) were dissolved in DMF (100 ml) in a dry apparatus under argon and the mixture was degassed by bubbling with argon for 30 min. The orange suspension was then heated under argon in an oil bath at 85°C overnight to give a dark purple suspension. The reaction mixture was filtered through Celite and evaporated to dryness in vacuo. The crude product was purified by column chromatography.
Intermediate 59Q:
Figure imgf000115_0001
Intermediate 59e) (2793 mg) was dissolved in EtOH (50 ml) and AcOH (50 ml) and platinum(IV) oxide (148 mg) was added. The reaction mixture was evacuated three times and purged with hydrogen. The reaction mixture was then stirred at room temperature under hydrogen for 2 h. The reaction mixture was filtered and evaporated to dryness in vacuo. The residue was coevaporated with toluene (3 x 75 ml) and was finally dried under high vacuum at room temperature overnight. The crude product was purified by column chromatography.
Intermediate 59g):
Figure imgf000115_0002
Intermediate 59f) (2092 mg) in diethyl ether (20 ml) was slowly added to a mixture of lithium aluminum hydride (274 mg) and diethyl ether (30 ml) at O0C. After addition, the reaction mixture was stirred at 00C for 2 h. The reaction mixture was hydrolyzed with a minimum amount of water. The inorganic precipitate was filtered off and washed twice with diethyl ether. The combined filtrate was dried over sodium sulfate, filtered again, and the solvent was removed under reduced pressure. The crude product was purified by flash chromatography to yield a colorless oil.
Intermediate 59h):
Figure imgf000116_0001
To intermediate 59g) (901 mg) in dioxane (10 ml) and methanol (2 ml) was added hydrogen chloride, 4.0 M sol. in 1 ,4-dioxane (10 ml) and the solution was stirred for 30 min at room temperature. The solvent was removed under reduced pressure, the residue was triturated with acetone (5 ml) and diethyl ether (50 ml), and the product was filtered off. The product was obtained as a white solid.
Example 59:
Figure imgf000116_0002
Intermediate 59h) (63 mg), B-C Moiety 1 (58 mg), and HOBt (27 mg) were dissolved in DMF (2 ml). NMM (26 μl) was added and the mixture stirred at room temperature for 20 min. EDCI (34 mg) was added, and the reaction stirred at room temperature for another 60 min. An additional amount of NMM (20 μl) was added and stirring continued at room temperature overnight. The reaction mixture was poured into brine and extracted with EtOAc and the phases were separated. The aqueous phase was extracted twice with ethyl acteate. The combined organic layer was washed twice with sat. Na2CO3, twice with water and brine. The organic layer was dried over Na2SO4 and evaporated in vacuo. The crude product was purified with flash chromatography. The free base was dissolved in ethyl acetate (2 ml) and 1 M HCI in diethyl ether (200 μl) was added. The product was precipitated by addition of hexane (20 ml). The precipitate was filtered off and dried in vacuo over P2O5.
Synthesis of Example 63: Intermediate 63a):
Figure imgf000117_0001
To a solution of sodium ethoxide (2.72 g) in ethanol (60 ml) was added diethyl methylmalonate (7.87 ml) followed by intermediate 42a) (11.38 g) and the reaction mixture was kept under reflux overnight. The reaction mixture was evaporated in vacuo and the residue was partitioned between diethyl ether and water. The aqueous layer was extracted two times with diethyl ether. The combined organic layer was washed twice with water and brine. The organic layer was dried over Na2SO4 and evaporated in vacuo to dryness. The product was purified by distillation. The fractions which distilled off between 140 and 2200C at 0.2 mbar were collected.
Intermediate 63b):
Figure imgf000117_0002
Intermediate 63a) (12.11 g) was heated under reflux in 1.8 M KOH in H2O/EtOH (150 ml) for 5 h. After evaporation of the ethanol, an additional amount of KOH (54 g) was added to the residue, and the reaction mixture was stirred at 1000C for 2 h. The reaction mixture was diluted with H2O (200 ml), extracted with Et2O, and the organic layer was washed with H2O. The combined aqueous layer was cooled in ice/H2O and acidified with 50% H2SO4 to pH 1. The resulting suspension was extracted twice with Et2O (200 ml each) and the organic layers were washed with water and brine. The combined organic layer was dried over Na2SO4 and evaporated in vacuo to dryness. The residue was triturated in hexane and less Et2O, then filtered and washed with hexane and less Et2O. The solid residue was decarboxylated by heating at 2000C. The evolution of CO2 ceased after 20 min and the product was left to cool to room temperature to yield a brown oil.
Intermediate 63c):
Figure imgf000118_0001
Intermediate 63b) (5.43 g) was dissolved in methanol (11.93 ml). Then sulfuric acid (365 μl) was added, and the reaction mixture was heated under reflux overnight (oil bath temperature 85°C) with exclusion of humidity by means of a drying tube (blue silica gel).
The reaction mixture was evaporated in vacuo at 400C and the colorless oily residue was poured into ice-water (100 ml). The resulting white emulsion was extracted with Et2O
(100 ml), and the organic phase was washed with sat. Na2CO3 (3 x 30 ml), H2O (20 ml), and brine (20 ml). The organic phase was then dried over MgSO4 and evaporated in vacuo.
Intermediate 63d):
Figure imgf000118_0002
Zinc activation. Celite (174 mg) was added into a flame dried 50 ml Schlenk flask and dried by heating in vacuo. Then zinc dust (883 mg) and dry DMA (1.5 ml) were added under argon. The mixture was stirred at room temperature while a 7:5 v/v mixture of TMSCI/1 ,2-dibromoethane (153 μl TMSCI, 109 μl 1 ,2-dibromoethane, solution in 0.7 ml of DMA) was added at a rate to maintain the temperature below 65°C. The resulting slurry was aged for 15 min.
Zink insertion. A solution of Boc-4-iodopiperidine (3364 mg) in dry DMA (6.8 ml) was slowly added under argon atmosphere to the mixture described above at a rate to maintain the temperature below 65°C. The reaction mixture was then aged for 30 min at room temperature.
Coupling. A 50 ml three-necked flask was charged with dichloro-1,1'- bis(diphenylphosphino)-ferrocene-palladium(ll) DCM adduct (188 mg), copper iodide (88 mg) and intermediate 63c) (2.36 g) in DMA (11 ml) The resulting mixture was degassed three times and the filtrate of the zinc insertion reaction was then added. The reaction mixture was degassed two times, then heated to 800C and stirred overnight. The reaction mixture was concentrated under high vacuum at 600C and the remainig black oil was taken up in a mixture of ethyl acetate and water. The mixture was filtered through Celite and the phases were separated. The aqueous phase was extracted twice with ethyl acetate. The combined organic layer was washed with water and brine, dried over sodium sulfate and the solvent was removed under reduced pressure. The product was purified using flash chromatography.
Intermediate 63e):
Figure imgf000119_0001
Intermediate 63d) (571 mg) in diethyl ether (20 ml) was slowly added to a mixture of lithium aluminum hydride (79 mg) and diethyl ether (30 ml) at 00C. After addition the reaction mixture was stirred at 00C for 2 h. The reaction mixture was hydrolyzed with a minimum amount of water. The inorganic precipitate was filtered off and washed twice with diethyl ether. The combined filtrate was dried over sodium sulfate, filtered, and the solvent was removed under reduced pressure.
Intermediate 630;
Figure imgf000120_0001
lntermediate 63e) (450 mg) was dissolved in dry DMSO (6 ml) and triethylamine (1151 μl). A solution of sulfurtrioxide-pyridine complex (563 mg) in dry DMSO (6 ml) was slowly added while the reaction mixture was maintained at 25°C. The reaction mixture was stirred for 4 h. After acidification of the reaction mixture to pH 4.5-5 with 1 N HCI, it was poured into water. The resulting emulsion was extracted three times with diethyl ether. The combined organic layer was washed with water and brine, dried over sodium sulfate, and the solvent was removed under reduced pressure. The crude product was purified by flash chromatography.
Intermediate 63g):
Figure imgf000120_0002
To a solution of intermediate 63f) (97 mg) and (R)-3-fluoropyrrolidine hydrochloride (33 mg) in 1 ,2-dichloroethane (3 ml), DIEA (67 μl) was added followed by sodium triacetoxyborohydride (74 mg). The reaction mixture was then stirred at room temperature overnight. The mixture was diluted with EtOAc (70 ml) and washed two times with sat. NaHCO3 (25 ml), water and brine (25 ml each). The organic phase was dried over Na2SO4 and concentrated. The product was purified with flash chromatography.
Intermediate 63h):
Figure imgf000121_0001
To intermediate 63g) (101 mg) in dioxane (5 ml) and methanol (1 ml) was added hydrogen chloride, 4.0 M sol. in 1 ,4-dioxane (5 ml) and the solution was stirred for 60 min at room temperature. Then the solvent was removed under reduced pressure to yield the product as a colorless glassy solid.
Example 63:
Figure imgf000121_0002
Intermediate 63h) (47 mg), B-C Moiety 1 (39 mg), and HOBt (27 mg) were dissolved in DMF (1 ml). NMM (18 μl) was added and the mixture stirred at room temperature for 20 min. EDCI (23 mg) was added, and the reaction stirred at room temperature for another 60 min. An additional amount of NMM (10 μl) was added and stirring continued at room temperature overnight. The reaction mixture was poured into brine and extracted with EtOAc and the phases were separated. The aqueous phase was extracted twice with ethyl acteate. The combined organic layer was washed twice with sat. Na2CO3, twice with water and brine. The organic layer was dried over Na2SO4 and evaporated in vacuo. The crude product was purified with flash chromatography. The free base was dissolved in ethyl acetate (2 ml) and 1 M HCI in diethyl ether (200 μl) was added. The product was precipitated by addition of hexane (20 ml). The precipitate was filtered off and dried in vacuo over P2O5.
Synthesis of Example 65: Intermediate 65a):
Figure imgf000122_0001
To a solution of sodium ethoxide (1.26 g) in ethanol (30 ml) was added diethyl ethylmalonate (3.64 ml) followed by 2-bromo-5-fluorobenzylbromide (4.96 g) and the reaction mixture was kept under reflux overnight. The reaction mixture was evaporated in vacuo and the residue was partitioned between diethyl ether and water and the aqueous layer was extracted two times with diethyl ether. The combined organic layer was washed twice with water and brine. The organic layer was dried over Na2SO4 and evaporated in vacuo to dryness. The product was purified using flash chromatography.
Intermediate 65b):
Figure imgf000122_0002
Intermediate 65a) (5.27 g) was heated under reflux in 1.8 M KOH in H2O/EtOH (60 ml) for 5 h. After evaporation of the ethanol an additional amount of KOH (18 g) was added to the residue, and the reaction mixture was stirred at 1000C for 2 h. The reaction mixture was diluted with H2O (100 ml), extracted with Et2O and the organic layer was washed with H2O.
The combined aqueous layer was cooled in ice/H2O and acidified with 50% H2SO4 to pH 1.
The resulting suspension was extracted twice with Et2O (100 ml each) and the organic layers were washed with water and brine. The combined organic layer was dried over
Na2SO4 and evaporated in vacuo to dryness. The residue was triturated in hexane and less Et2O, then filtered and washed with hexane and less Et2O. The solid residue was decarboxylated by heating at 2000C. The evolution of CO2 ceased after 20 min and the melt was left to cool to room temperature to yield beige needles.
Intermediate 65c):
Figure imgf000123_0001
Intermediate 65b) (2.71 g) was dissolved in methanol (7.53 ml). Then sulfuric acid (100 μl) was added, and the reaction mixture was heated under reflux overnight (oil bath temperature 85°C) with exclusion of humidity by means of a drying tube (blue silica gel). The reaction mixture was evaporated in vacuo at 400C and the colorless oily residue was poured into ice-water (50 ml). The resulting white emulsion was extracted with Et2O (75 ml), and the organic phase was washed with sat. Na2CO3 (3 x 20 ml), H2O (15 ml), and brine (15 ml). The organic phase was then dried over MgSO4 and evaporated in vacuo.
Intermediate 65d):
Figure imgf000123_0002
Intermediate 65c) (2520 mg), N-Boc-1 ,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester (2829 mg), potassium carbonate (3611 mg) and dichloro(1 ,1'-bis(diphenyl- phosphino)-ferrocene)palladium(ll) DCM adduct (425 mg) were dissolved in DMF (100 ml) in a dry apparatus under argon and the mixture was degassed by bubbling with argon for 30 min. The orange suspension was then heated under argon in an oil bath at 85°C overnight to give a dark purple suspension. The reaction mixture was filtered through Celite and evaporated to dryness in vacuo. The crude product was purified by column chromatography. Intermediate 65e):
Figure imgf000124_0001
Intermediate 65d) (1453 mg) was dissolved in ethanol (50 ml) and 10% palladium on activated carbon (150 mg) was added. The reaction mixture was purged three times with hydrogen (5 bar) and stirred under a hydrogen atmosphere (25 bar) overnight. The crude mixture was filtered through Celite and the solvent was removed under reduced pressure to yield a beige oil.
Intermediate 651):
Figure imgf000124_0002
Intermediate 65e) (1288 mg) in diethyl ether (20 ml) was slowly added to a mixture of lithium aluminum hydride (186 mg) and diethyl ether (30 ml) at 0cC. After addition, the reaction mixture was stirred at 00C for 2 h. The reaction mixture was hydrolyzed with a minimum amount of water. The inorganic precipitate was filtered off and washed twice with diethyl ether. The combined filtrate was dried over sodium sulfate, filtered again, and the solvent was removed under reduced pressure. Intermediate 65g):
Figure imgf000125_0001
To a solution of intermediate 65f) (1001 mg) in DCM (20 ml) was slowly added Dess- Martin periodinane (1510 mg). After addition, the reaction mixture was stirred at room temperature for 3 h. TLC indicated that the reaction was not complete. A second batch of
Dess-Martin periodinane (755 mg) was added and the reaction was stirred overnight. The reaction mixture was diluted with DCM and washed three times with saturated sodium bicarbonate solution and brine. The organic phase was dried over sodium sulfate, filtered, and the solvent was removed under reduced pressure. The product was purified by flash chromatography.
Intermediate 65h):
Figure imgf000125_0002
To a solution of intermediate 65g) (91 mg) and dimethylamine, 2.0 M solution in THF (250 μl) in 1 ,2-dichloroethane (3 ml), sodium triacetoxyborohydride (74 mg) was added. The reaction mixture was then stirred at room temperature overnight. The mixture was diluted with EtOAc (70 ml) and washed two times with sat. NaHCO3 (25 ml), water and brine (25 ml each). The organic phase was dried over Na2SO4 and concentrated. The product was purified by flash chromatography. Intermediate 65i):
Figure imgf000126_0001
To intermediate 65h) (74 mg) in dioxane (5 ml) and methanol (1 ml) was added hydrogen chloride, 4.0 M sol. in 1 ,4-dioxane (5 ml) and the solution was stirred for 60 min at room temperature. The solvent was removed under reduced pressure to yield the product as a colorless glassy solid.
Example 65:
Figure imgf000126_0002
Intermediate 65i) (35 mg), B-C Moiety 1 (34 mg), and HOBt (16 mg) were dissolved in DMF (1 ml). NMM (26 μl) was added and the mixture stirred at room temperature for 20 min. EDCI (20 mg) was added, and the reaction stirred at room temperature for another 60 min. An additional amount of NMM (10 μl) was added and stirring continued at room temperature overnight. The reaction mixture was poured into brine and extracted with EtOAc and the phases were separated. The aqueous phase was extracted twice with ethyl acteate. The combined organic layer was washed twice with sat. Na2CO3, twice with water and brine. The organic layer was dried over Na2SO4 and evaporated in vacuo. The crude product was purified with preparative HPLC-MS. Synthesis of Example 69: Intermediate 69a):
Figure imgf000127_0001
A mixture of D-prolinol (2.50 ml), formaldehyde solution (3.23 ml, 36.5% in H2O) and formic acid (1.93 ml) in water (17 ml) was kept under reflux for 24 h. The reaction mixture was concentrated in vacuo, the residue was diluted with water and made alkaline by addition of 1 N NaOH (pH 10-11). The aqueous solution was extracted twice with Et2O and the organic layers were washed with water and brine. The combined organic layer was dried over Na2SO4 and evaporated in vacuo to dryness. The combined aqueous layer was saturated with NaCI and the pH was adjusted to 14 by adding 1 N NaOH. The aqueous solution was extracted twice with CH2CI2. The combined organic layer was dried over Na2SO4 and evaporated in vacuo to dryness. Extract 1 and extract 2 were combined and purified by Kugelrohr-distillation (20 mbar/ 90-1100C).
Intermediate 69b):
Figure imgf000127_0002
A solution of intermediate 27d) (0.50 g), intermediate 69a) (0.37 g), and triphenylphosphine (0.84 g) in THF (15 ml) under argon, was cooled in ice/H2O. DEAD (ca.
40% in toluene, 1.47 ml) was added dropwise, at a rate to keep the temperature below 5°C
(ca. 15 min). After stirring for another 10 min in ice/H2O, the cooling bath was removed and the mixture was stirred at room temperature overnight. The reaction mixture was evaporated to dryness in vacuo at 400C. The two regioisomeric products were separated by flash chromatography. Intermediate 69c):
Figure imgf000128_0001
To Boc-protected intermediate 69b) (product A) (358 mg) in dioxane (2 ml) was added hydrogen chloride, 4.0 M sol. in 1 ,4-dioxane (5 ml) and the solution was stirred at room temperature for 1 h. The solvent was removed under reduced pressure. The residue was dissolved in iso-propanol and the salt precipitated after 5 min. The suspension was diluted with acetone and Et2O, the solid was filtered off, washed with acetone and Et2O and finally dried in vacuo over Sicapent overnight.
Example 69:
Figure imgf000128_0002
Intermediate 69c) (50 mg), B-C Moiety 1 (40 mg), and HOBt (30 mg) were dissolved in DCM (3 ml). NMM (40 μl) was added and the mixture stirred at room temperature for 30 min. EDCI (44 mg) was added, and the reaction stirred at room temperature for another 60 min. An additional amount of NMM (11 μl) was added and stirring continued at room temperature overnight. The reaction mixture was evaporated in vacuo, diluted with EtOAc and washed with sat. Na2CO3, water and brine. The organic layer was dried over Na2SO4 and evaporated in vacuo. The crude product was purified by flash chromatography. The purified product was dissolved in DCM, treated with 1 M HCI in Et2O (108 μl), and the resulting suspension was diluted with diethyl ether and hexane. The precipitate was filtered off, washed with hexane and diethyl ether, and dried in vacuo at 400C for 2 h. The product was obtained as an off-white solid.
Synthesis of Example 70: Intermediate 70a):
Figure imgf000129_0001
To Boc-protected intermediate 69b) (product B) (84 mg) in dioxane (0.5 ml) was added hydrogen chloride, 4.0 M sol. in 1 ,4-dioxane (1.5 ml) and the solution was stirred at room temperature for 1 h. The solvent was removed under reduced pressure. The residue was dissolved in iso-propanol and the salt precipitated after 5 min. The suspension was diluted with acetone and Et2O, the solid was filtered off, washed with acetone and Et2O and finally dried in vacuo over Sicapent overnight.
Example 70:
Figure imgf000129_0002
Intermediate 70a) (24 mg), B-C Moiety 1 (26 mg), and HOBt (15 mg) were dissolved in DCM (2 ml). NMM (19 μl) was added and the mixture stirred at room temperature for 30 min. EDCI (21 mg) was added, and the reaction stirred at room temperature for another 60 min. An additional amount of NMM (5 μl) was added and stirring continued at room temperature overnight. The reaction mixture was evaporated in vacuo, diluted with EtOAc and washed with sat. Na2CO3, water and brine. The organic layer was dried over Na2SO4 and evaporated in vacuo. The crude product was purified by flash chromatography. The purified product was dissolved in DCM, treated with 1 M HCI in Et2O (60 μl), and the resulting suspension was diluted with diethyl ether and hexane. The precipitate was filtered off, washed with hexane and diethyl ether, and dried in vacuo at 400C for 2 h. The product was obtained as a white solid.
Synthesis of Example 71: Intermediate 71a):
Figure imgf000130_0001
A solution of intermediate 27d) (250 mg) and N-(Fmoc)-4-piperidinol (519 mg), and triphenylphosphine (521 mg) in anhydrous THF (8 ml) under argon, was cooled in ice/H2O. Then DEAD (ca. 40% in toluene, 735 μl) was added dropwise, at a rate to keep the temperature below 5°C (ca. 15 min). After stirring for another 10 min in ice/H2O, the cooling bath was removed and the mixture was stirred at room temperature overnight and at 45°C for 3 h. The reaction mixture was evaporated to dryness in vacuo, diluted with EtOAc, washed with 0.5 N HCI, sat. Na2CO3, H2O and brine. The aqueous layers were extracted with EtOAc. The combined organic layer was dried over Na2SO4, filtered and evaporated in vacuo to dryness. The residue was triturated in CH2CI2 and EtOAc, the insoluble solid was filtered off and washed CH2CI2 and EtOAc. The filtrate was evaporated in vacuo to dryness and the residue was purified by flash column chromatography. Intermediate 71b):
Figure imgf000131_0001
To Boc-protected intermediate 71a) (40 mg) in dioxane (0.5 ml) was added hydrogen chloride, 4.0 M solution in 1 ,4-dioxane (2.0 ml) and the solution was stirred at room temperature for 1.5 h. The solvent was removed under reduced pressure. The residue was dissolved in acetone and the product was precipitated by addition Et2O and hexane. The product was filtered off, and washed with hexane and Et2O.
Intermediate 71 c) :
Figure imgf000131_0002
B-C Moiety 1 (14 mg) and HOAt (6 mg) were dissolved in CH2CI2 (2 ml), then EDCI (11 mg) was added and the reaction mixture was stirred at room temperature for 30 min. Then intermediate 71b) (21 mg) was added, followed by NMM (10 μl), and the reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with EtOAc, washed with HCI 0.5 N, sat. Na2CO3, H2O and brine. The aqueous layers were extracted with EtOAc. The combined organic layer was dried over Na2SO4, filtered and evaporated in vacuo to dryness. Example 71:
Figure imgf000132_0001
Diethylamine (0.5 ml) was added to a solution of intermediate 71c) (31 mg) in CH2CI2 (1 ml) and the reaction mixture was stirred at room temperature overnight. The reaction mixture was evaporated in vacuo and the residue purified by flash chromatography. The free base was dissolved in CH2CI2, acidified with HCI in Et2O 1 M (25 μl) and evaporated in vacuo. The residue was dissolved in CH2CI2 and the salt was precipitated by addition of Et2O and hexane. The precipitate was filtered off, washed with hexane and Et2O and dried in vacuo at 400C for 2 hours. The product was obtained as a white solid
Synthesis of Example 80: Intermediate 80a):
Figure imgf000132_0002
N-(Diphenylmethylene) glycine ethyl ester (9.29 g), 1 -(bromomethyl)-4-chloro-2- fluorobenzene (8.63 g) and benzyltriethylammonium chloride (TEBAC) (7.91 g) were dissolved in DCM (100 ml) and 10% aqueous KOH (91 ml) was added. The resulting two- phase mixture was stirred at room temperature for 24 hours. Then the organic layer was separated and concentrated. The residue was taken up in diethyl ether (200 ml) and washed with water (150 ml) followed by brine (100 ml) and the organic layer was dried over Na2SO4. The solvent was removed under reduced pressure. The product was purified by flash chromatography. Intermediate BOb):
Figure imgf000133_0001
5% aq. HCI in H2O (9 ml) was added portionwise to a solution of intermediate 80a) (1 g) in THF (3.4 ml) at 00C. A precipitate appeared after the addition. The mixture was stirred at room temperature for 1 h. THF was evaporated under reduced pressure. Water (50 ml) was added to the residue. The aqueous solution was washed with diethyl ether (3 x 75 ml) and with DCM (75 ml). The aqueous layer was then basified with 5 N aqueous NaOH (2 ml) and 1 N aqueous NaOH (12 ml) to get pH7/8. The compound was extracted with DCM (5 x 100 ml). The combined organic layer was dried over Na2SO4, filtered and evaporated under reduced pressure. The crude compound was purified by column chromatography.
Intermediate 80c):
Figure imgf000133_0002
1 N Aqueous sodium hydroxide (5.5 ml) was added portionwise to a solution of intermediate 80b) (446 mg) in THF (5 ml) at 00C. The reaction mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure and water (60 ml) was added to the residue. The aqueous phase was washed with diethyl ether (2 x 90 ml; 3 x 30 ml) and DCM (2 x 100 ml). The aqueous phase was neutralized with 5 N aqueous HCI (1 ml). The impurities were extracted with diethyl ether (2 x 100 ml). The aqueous phase was evaporated to dryness and water (40 ml) was added. The suspension was put in the fridge overnight, filtered and the product, a white solid, was rinsed with water and diethyl ether. The filtrate was evaporated again to dryness and water (10 ml) was added. The suspension was put in the fridge overnight, filtered and the second batch of product was rinsed with water and diethyl ether. The solids from the two batches were combined and dried in vacuo.
Intermediate 8Od):
Figure imgf000134_0001
Racemic intermediate 80c) (313 mg) was dissolved in Tris-maleate buffer (26 ml, pH 7.8) containing 0.1 M KCI. To this solution was added L-amino acid oxidase (Sigma Type 1 , activity 0.33 units/mg; 10 mg) and catalase (1 mg). After 84 h, the reaction mixture was brought to pH 7 with 0.5 N HCI and purified by ion-exchange chromatography over Dowex 50, eluting the amino acid with 1 N ammonia. The solvent was removed under reduced pressure and the product was dried in vacuo at room temperature over P2O5 overnight.
Intermediate 8Oe):
Figure imgf000134_0002
Intermediate 8Od) (360 mg) was dissolved in 2 M sodium hydroxide (0.7 ml) and cooled to 00C. Di-tert-butyl dicarbonate (188 mg) in dioxane (1 ml) was slowly added. After half an hour, the reaction mixture was warmed to room temperature and allowed to stir overnight. A second batch of di-tert-butyl-dicarbonate (79 mg) was added and stirring was continued for another 4 h. The reaction mixture was evaporated to dryness and water (20 ml) was added. The aqueous phase was washed with diethyl ether (5 x 40 ml) and DCM (3 x 30 ml). The aqueous phase was acidified to pH 2 using 1 N aqueous hydrochloric acid and extracted with ethyl acetate (3 x 40 ml). The combined organic layer was then dried over Na2SO4, filtered and concentrated in vacuo. Intermediate 8Of):
Figure imgf000135_0001
To a solution of intermediate 8Oe) (60 mg) in dry DMF (3.6 ml) was added HOBt (32 mg), EDCI (40 mg) and NMM (83 μl). The reaction mixture was stirred for 5 min and then intermediate 20b) (79 mg) was added as a solid at 00C. The reaction stirred at room temperature overnight. The solvent was evaporated and the residue was diluted with ethyl acetate (35 ml) and successively washed with water (20 ml), followed by saturated NaHCO3 (20 ml) and brine (35 ml). The aqueous phases were extracted again with ethyl acetate (20 ml). The combined organic layer was dried over Na2SO4, filtered and evaporated. The crude compound was purified by column chromatography.
intermediate 8Og)
Figure imgf000135_0002
Intermediate 8Of) (95 mg) was dissolved in dioxane (1.6 ml) and 4M HCI in dioxane (1.13 ml) was added at 00C. The reaction mixture was stirred at room temperature for 90 min. The reaction mixture was evaporated to dryness in vacuo. The residue was dissolved in MeOH and triturated with Et2O. A beige solid compound was obtained. It was filtered off, rinsed with Et2O and dried under high vacuum. Example 80:
Figure imgf000136_0001
Intermediate 8Og) (58 mg) was dissolved in 1 ,2-dichloroethane (3 ml) and triethylamine (45 μl) was added followed by intermediate 104i) (37 mg) and the reaction mixture was stirred in an oil bath at 600C overnight. The reaction mixture was diluted with ethyl acetate (25 ml) and washed with sat. NaHCO3 (2 x 10 ml), water (2 x 10 ml) and brine (10 ml). The organic layer was dried over Na2SO4, filtered and evaporated in vacuo to give a yellow oil. The crude product was purified by flash chromatography.
The free base was dissolved in ethyl acetate (100 μl), treated with 1N HCI in Et2O (53 μl), and the resulting suspension was diluted with diethyl ether (0.5 ml). The precipitate was filtered off, washed with diethyl ether, and dried in vacuo over Sicapent.
Synthesis of Example 96: Intermediate 96a):
Figure imgf000136_0002
A mixture of 2-bromo-5-fluorobenzaldehyde (10.15 g), malonic acid (5.72 g) and pyridine (1.5 ml) in ethanol (25 ml) was kept under reflux for 7.5 h. After cooling in an ice bath the crystal mass was filtered off. The crystals were washed with cold ethanol (10 ml) and then washed twice with diethyl ether (10 ml each). The residue was suspended in ethanol (60 ml) and kept under reflux for 2-3 h. The mixture was cooled and filtered and the solid was dried under reduced pressure. The product was obtained in form of colorless needles. Intermediate 96b):
Figure imgf000137_0001
Intermediate 96a) (2451 mg), pyrrolidine (918 μl), EDCI (2109 mg) and DMAP (100 mg) were dissolved in DCM (100 ml) and stirred overnight. The reaction mixture was poured into water (100 ml) and the organic layer was separated. The aqueous layer was extracted twice with DCM. The combined organics were washed three times with with 0.5 N HCI (30 ml each), three times with 1 M sodium hydroxide solution and brine, dried over Na2SO4 and the solvent was removed under reduced pressure. The crude product was purified by flash chromatography to yield a white solid.
Intermediate 96c):
Figure imgf000137_0002
Intermediate 96b) (1130 mg), N-Boc-1,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester (1231 mg), potassium carbonate (1571 mg) and dichloro(1 ,1'-bis(diphenyl- phosphino)-ferrocene)palladium(ll) DCM adduct (188 mg) were dissolved in DMF (50 ml) in a dry apparatus under argon and the mixture was degassed by bubbling with argon for 30 min. The orange suspension was then heated under argon in an oil bath at 85°C for 1 day. The reaction mixture was filtered through Celite and evaporated to dryness in vacuo. The crude product was purified by flash chromatography to yield a beige solid. Intermediate 96d):
Figure imgf000138_0001
Intermediate 96c) (1459 mg) was dissolved in ethanol (50 ml) and 10% palladium on activated carbon (150 mg) was added. The reaction mixture was purged three times with hydrogen (5 bar) and stirred under hydrogen atmosphere (10 bar) for 3 days. The crude mixture was filtered through Celite and the solvent was removed under reduced pressure to yield a yellow-grey oil.
Intermediate 9Se):
Figure imgf000138_0002
Intermediate 96d) (1472 mg) in diethyl ether (20 ml) was slowly added to a mixture of lithium aluminum hydride (207 mg) and diethyl ether (30 ml) at 00C. After addition the reaction mixture was stirred at 00C for 1 h. The reaction mixture was hydrolyzed with a minimum amount of water. The inorganic precipitate was filtered off and washed twice with diethyl ether. The combined filtrates were dried over sodium sulfate, filtered, and the solvent was removed under reduced pressure. The crude product was purified by flash chromatography to yield a pale yellow oil. Intermediate 961):
Figure imgf000139_0001
To intermediate 96e) (654 mg) in dioxane (10 ml) and methanol (2 ml) was added hydrogen chloride, 4.0 M sol. in 1 ,4-dioxane (10 ml) and the solution was stirred for 30 min at room temperature. The solvent was removed under reduced pressure, the residue was triturated with acetone (5 ml) and diethyl ether (50 ml) and the product was filtered off to yield an off-white solid.
Example 96:
Figure imgf000139_0002
Intermediate 96f) (58 mg), B-C Moiety 2 (61 mg), and HOBt (27 mg) were dissolved in DCM (2 ml). NMM (26 μl) was added and the mixture stirred at room temperature for 20 min. EDCI (46 mg) was added, and the reaction stirred at room temperature for another 60 min. An additional amount of NMM (20 μl) was added and stirring continued at room temperature overnight. The reaction mixture was diluted with EtOAc (50 ml) and washed with sat. Na2CO3 (3 x 20 ml), water (2 x 10 ml) and brine (10 ml). The organic layer was dried over Na2SO4 and evaporated in vacuo. The crude product was purified with flash chromatography. The purified product was dissolved in ethyl acetate (2 ml), treated with 1 M HCI in Et2O (200 μl), and the resulting suspension was diluted with hexane (20 ml). The precipitate was filtered off, washed with hexane and diethyl ether, and dried in vacuo at room temperature over P2O5 overnight. The product was obtained as a white solid. Synthesis of Example 104: Intermediate 104a):
Figure imgf000140_0001
Phosphorous tribromide (735 μl) was added to a stirred solution of 4-chloro-2- methylbenzyl alcohol (3.5 g) in toluene (30 ml) at 400C. The solution was heated to 1000C for 30 min, and the reaction was cooled to ambient temperature. The liquid was decanted and washed with water (2 x 50 ml) and brine (50 ml). The combined aqueous layer was extracted with diethyl ether (70 ml) and the combined organic layer was evaporated to yield a semisolid residue. The residue was dissolved in diethyl ether (350 ml) and washed with water (2 x 100 ml) and brine (100 ml). The organic phase was dried over Na2SO4, filtered and evaporated to yield a light yellow oil.
Intermediate 104b):
Figure imgf000140_0002
N-(Diphenylmethylene) glycine ethyl ester (5.27 g), intermediate 104a) (4.81 g) and benzyltriethylammonium chloride (TEBAC) (4.49 g) were dissolved in DCM (52 ml) and 10% aqueous KOH (52 ml) was added. The resulting two-phase mixture was stirred at room temperature for 24 h. The organic layer was separated and concentrated. The residue was taken up with diethyl ether (125 ml) and washed with water (100 ml) followed by brine (100 ml) and dried over Na2SO4. The solvent was removed to give the crude product as a yellow oil. The crude product was purified by flash column chromatography. Intermediate 104c):
Figure imgf000141_0001
5% Aqueous HCI (50 ml) was added portionwise to a solution of intermediate 104b) (5.6 g) in THF (20 ml) at 00C. The mixture was then stirred at room temperature for 2 h. The solvent was evaporated under reduced pressure and water (200 ml) was added to the residue. The aqueous phase was washed with diethyl ether (3 x 250 ml) and DCM (250 ml). The aqueous phase was then basified with 5N aqueous NaOH (11 ml) to get pH 7/8 and extracted with DCM (8 x 400 ml). The aqueous phase was concentrated to a volume of 150 ml and extracted with DCM (11 x 150 ml). The combined organic layer was dried over Na2SO4, filtered and the solvent was removed under reduced pressure to give a yellow oil. The crude product was dissolved in THF (20 ml) and 1 N aqueous sodium hydroxide (12.1 ml) was added portionwise at 00C. The reaction mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure and water (50 ml) was added to the residue. The aqueous phase was washed with diethyl ether (2 x 100 ml) and DCM (2 x 100 ml) and then neutralized to pH 7 with 5N aqueous HCI (2 ml). The aqueous phase was evaporated under reduced pressure to yield the product as a white solid.
Intermediate 104d):
Figure imgf000141_0002
Intermediate 104c) (2.96 g) was dissolved in Tris-maleate buffer (125 ml_) containing 0.1 M KCI. To the turbid solution was added L-amino acid oxidase (sigma Type I, 85 mg) and catalase (8.5 mg). After 84 h of vigorous stirring at 35°C, the reaction was brought to pH 7 with 0.5N HCI (4.5 ml). The aqueous solution was reduced to a volume of 10 ml and then purified by ion exchange using Dowex 50 (60 ml). The product was eluted with water (500 ml), then 1 N ammonia (800 ml). The combined eluants were evaporated under reduced pressure to yield the title compound.
Intermediate 104e):
Figure imgf000142_0001
Intermediate 104d) (88 mg) was dissolved in 2N aqueous sodium hydroxide (0.58 ml) and cooled to 00C. Di-tert-butyl dicarbonate (101 mg) was slowly added followed by dioxane (0.5 ml). After half an hour, the reaction mixture was warmed to room temperature and allowed to stir for 12 h. Di-tert-butyl-dicarbonate (101 mg) and 1N aqueous NaOH (0.29 ml) were added. The reaction was stirred at room temperature for another 20 h. The reaction mixture was evaporated to dryness and water (2 ml) was added. The reaction mixture was acidified to pH 2 using 1N aqueous hydrochloric acid (1.3 ml) and extracted with DCM (3 x 20 ml). The combined organic layer was dried over Na2SO4, filtered and concentrated in vacuo to give a colorless wax. The crude product was purified by column chromatography.
Intermediate 1041):
Figure imgf000142_0002
To a solution of intermediate 104e) (35 mg) in dry DMF (2 ml) was added HOBt (19 mg), EDCI (23 mg) and NMM (49 μl). The reaction mixture was stirred for 5 min and then intermediate 20b) (47 mg) was added as a solid at 00C. The reaction was stirred at room temperature overnight. The solvent was evaporated and the residue was diluted with ethyl acetate (25 ml) and successively washed with water (15 ml), followed by saturated NaHCO3 (15 ml) and brine (25 ml). The aqueous phases were extracted again with ethyl acetate (15 ml). The combined organic layer was dried over Na2SO4, filtered and evaporated. The crude compound was purified by column chromatography.
Intermediate 104g)
Figure imgf000143_0001
Intermediate 104f) (23 mg) was dissolved in dioxane (0.4 ml) and 4M HCI in dioxane (0.28 ml) was added at O0C. The reaction mixture was stirred at room temperature for 90 min. The reaction mixture was evaporated to dryness in vacuo. The residue was dissolved in MeOH (0.1 ml) and triturated with Et2O. A beige solid compound was obtained. It was filtered off, rinsed with Et2O and dried under high vacuum.
Intermediate 104h)
Figure imgf000143_0002
Pyrrolidine (2295 μl) and 1 ,1'-carbonyldiimidazole (4865 mg), were dissolved in dry THF (10 ml) and the reaction mixture was heated under reflux overnight. The reaction mixture was evaporated in vacuo to dryness. The residue was dissolved in CH2Cb (100 ml), and washed with H2O (2x100 ml). The organic phase was dried with MgSO4 and evaporated in vacuo. The product was obtained as a colorless crystalline solid.
Intermediate 104i)
Figure imgf000143_0003
Intermediate 104h) (3725 mg) was dissolved in dry MeCN (35 ml). Methyl iodide (9200 μl) was added and the reaction mixture was stirred at room temperature under exclusion of light for 24 h. The reaction mixture was evaporated in vacuo to dryness. The residue was dried under high vacuum for 4 h at room temperature. The crude product was triturated in hot acetone (25 ml), left to cool down to room temperature, and was then stirred vigorously overnight. The insoluble crystalline compound was filtered off, washed with acetone (3x6 ml), and finally dried in vacuo over P2O5 overnight to yield a colorless crystalline solid.
Example 104:
Figure imgf000144_0001
Intermediate 104g) (17 mg) was dissolved in 1 ,2-dichloroethane (2 ml) and triethylamine (14 μl) was added followed by intermediate 104i) (11 mg) and the reaction mixture was stirred in an oil bath at 600C overnight. The reaction mixture was diluted with ethyl acetate (20 ml) and washed with sat. NaHCO3 (2 x 10 ml), water (2 x 10 ml) and brine (10 ml). The organic layer was dried over Na2SO4, filtered and evaporated in vacuo to give a yellow oil. The crude product was purified by flash chromatography.
The free base was dissolved in ethyl acetate (25 μl), treated with 1 N HCI in Et2O (20 μl), and the resulting suspension was diluted with diethyl ether (0.5 ml). The precipitate was filtered off, washed with diethyl ether, and dried in vacuo over Sicapent.
Synthesis of Example 113: Intermediate 113a):
Figure imgf000145_0001
To Boc-D-2,4-dichlorophenylalanine (685 mg) in DCM (20 ml) was added the amine hydrochloride from 2b) (347 mg), N-methylmorpholine (311 μl), HOBt (230 mg) and the mixture was stirred for 30 min. EDCI (351 mg) was added and stirring was continued for 1 h. An additional amount of N-methylmorpholine (91 μl) was added and stirred overnight. The reaction mixture was evaporated in vacuo, diluted with EtOAc1 washed with sat. Na2CO3, water and brine. The aqueous layers were extracted with EtOAc. The combined organic layer was dried over Na2SO4, filtered and evaporated in vacuo to dryness. Purification by flash chromatography yielded the title compound as a white foam.
Intermediate 113b):
Figure imgf000145_0002
To Boc-protected intermediate 113a) (560 mg) in methanol (5 ml) was added hydrogen chloride, 4.0 M sol. in 1 ,4-dioxane (9 ml) and the solution was stirred at room temperature for 90 min. The reaction mixture was evaporated in vacuo to dryness. The residue was triturated in Et2O, filtered off and washed with Et2O to yield a beige solid. Intermediate 113c):
Figure imgf000146_0001
Intermediate 113b) was suspended in DCM (15 ml) and NMM (171 μl) was added. The mixture was cooled in an ice bath with stirring. Then 4-nitrophenyl chloroformate (134 mg) was added, and the reaction mixture was stirred at 00C for 60 min. The ice bath was then removed and stirring was continued at room temperature overnight. The reaction mixture was diluted with EtOAc and washed with sat. Na2CO3, water, and brine. The aqueous layers were extracted with EtOAc. The combined organic layer was dried over Na2SO4 and evaporated in vacuo. The residue was purified by flash chromatography to yield a yellow oil.
Example 113:
Figure imgf000146_0002
To a solution of intermediate 113c) (25 mg) in THF (1 ml) was added (3S)-3- dimethylaminopyrrolidine (22 mg) and the reaction mixture was stirred at room temperature overnight. The reaction mixture was evaporated in vacuo. The residue was redissolved in EtOAc and the organic layer was washed with sat. Na2CO3, water and brine. The aqueous layers were extracted with EtOAc. The combined organic layer was dried over Na2SO4 and evaporated in vacuo to dryness. The crude product was purified by flash chromatography. The purified product was dissolved in DCM, treated with 1 M HCI in Et2O (296 μl), and evaporated in vacuo. The residue was dissolved in DCM and the salt was precipitated by addition of hexane and diethyl ether. The precipitate was filtered off, washed with hexane and dried in vacuo. The product was obtained as a white solid.
Synthesis of Example 119: Example 119:
Figure imgf000147_0001
Intermediate 20b) (31 mg), B-C Moiety 3 (37 mg), and HOBt (19 mg) were dissolved in DCM (2.5 ml). NMM (26 μl) was added and the mixture stirred at room temperature for 30 min. EDCI (29 mg) was added, and the reaction stirred at room temperature for another 60 min. An additional amount of NMM (7 μl) was added and stirring continued at room temperature overnight. The reaction mixture was evaporated in vacuo, diluted with EtOAc, washed with sat. Na2CO3, water and brine. The aqueous layers were extracted with EtOAc. The combined organic layer was dried over Na2SO4, filtered and evaporated in vacuo to dryness. The residue was purified by flash chromatography. The purified product was dissolved in EtOAc (400 μl), treated with 0.1 M citric acid in EtOH (721 μl), and hexane (8.0 ml). The precipitate was filtered off, washed with hexane (1.0 ml) and dried in vacuo over P2O5 at room temperature overnight.
Synthesis of Example 121: Intermediate 121a):
Figure imgf000147_0002
3-Amino-1 N-Boc-azetidine (500 mg) and formaldehyde solution (> 36.5% in H2O, 876 μl) were dissolved in of 1 ,2-dichloroethane (1 ml) and sodium triacetoxyborohydride (5.46 g) was added at room temperature in one portion and the reaction mixture was cooled down to room temperature with a ice/water bath. The mixture was stirred at room temperature for 90 min. Then the reaction mixture was quenched by adding aqueous sat. NaHCO3 and the product was extracted with EtOAc. The organic layer was washed with H2O and brine. The aqueous layers were extracted with EtOAc. The combined organic layer was dried over Na2SO4 and evaporated in vacuo to dryness.
The crude product was dissolved in CH2CI2 (7 ml), Fmoc-OSu (911 mg) was added and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated in vacuo, redissolved in EtOAc and washed with HCI 0.1 N, water and brine. The combined aqueous layers were basified with sat. Na2CO3 and extracted twice with EtOAc. The organic layers were washed with water and brine, then combined and evaporated in vacuo to dryness. The residue was purified by flash chromatography.
Intermediate 121b):
UNH
Intermediate 121a) (280 mg) was dissolved in CH2CI2 (5 ml), and TFA (1.3 ml) was added at room temperature. The reaction mixture was stirred at O0C for 2 h. The reaction mixture was basified by adding aqueous sat. Na2CO3 and the mixture was extracted with three times with CH2CI2. The aqueous layer was saturated with NaCI and extracted twice with THF. The combined THF-layer was dried over Na2SO4 and concentrated in vacuo. The product was obtained as solution in water and THF (~2 ml).
Intermediate 121c):
Figure imgf000148_0001
To Boc-D-2,4-dichlorophenylalanine (1336 mg) in DCM (20 ml) was added the amine hydrochloride from 20b) (1145 mg), N-methylmorpholine (935 μl), HOBt (689 mg) and the mixture was stirred for 30 min. EDCI (1052 mg) was added and stirring was continued for 1 h. An additional amount of N-methylmorpholine (275 μl) was added and stirred overnight. The reaction mixture was diluted with EtOAc (180 ml), washed with sat. Na2CO3 (3x30 ml), water (2x30 ml) and brine (25 ml). The organic layer was dried over Na2SO4, filtered and evaporated in vacuo to dryness. Purification by flash chromatography yielded the title compound as a white foam.
Intermediate 121 d):
Figure imgf000149_0001
To Boc-protected intermediate 121c) (1756 mg) in dioxane (5 ml) was added hydrogen chloride, 4.0 M sol. in 1 ,4-dioxane (30 ml) and the solution was stirred at room temperature for 2 h. The reaction mixture was evaporated in vacuo to dryness. The residue was triturated in acetone (30 ml), filtered off and washed with acetone (3 ml) and Et2O (2x5 ml) to yield a white solid which was dried in vacuo over P2O5 at room temperature overnight.
Intermediate 121e):
Figure imgf000149_0002
Intermediate 121d) (149 mg) was suspended in DCM (7.5 ml) and NMM (96 μl) was added. The mixture was cooled in an ice bath with stirring. Then 4-nitrophenyl chloroformate (76 mg) was added, and the reaction mixture was stirred at 00C for 60 min. The ice bath was then removed and stirring was continued at room temperature overnight. The reaction mixture was diluted with EtOAc and washed with sat. Na2CO3 (3x25 ml), water (20 ml), and brine (15 ml). The organic layer was dried over Na2SO4 and evaporated in vacuo.
Example 121:
Figure imgf000150_0001
To a solution of intermediate 121e) (50 mg) in THF (4 ml) was added intermediate 121b) (-104 mg in 2 ml water/THF) and the reaction mixture was stirred at room temperature overnight. The reaction mixture was evaporated in vacuo. The residue was redissolved in
EtOAc and the organic layer was washed with sat. Na2CO3, water and brine. The aqueous layers were extracted with EtOAc. The combined organic layer was dried over Na2SO4 and evaporated in vacuo to dryness. The crude product was purified by flash chromatography following purification with preparative HPLC MS.
Further examples are exemplified below.
Figure imgf000151_0001
Figure imgf000152_0001
Biological Assays
A. Binding Assay
A membrane binding assay is used to identify competitive inhibitors of fluorescence labeled NDP-alpha-MSH binding to HEK293 cell membrane preparations expressing human melanocortin receptors.
The test compound or unlabeled NDP-alpha-MSH is dispensed at varying concentrations to a 384 well microtiter plate. Fluorescence labeled NDP-alpha-MSH is dispensed at a single concentration, followed by addition of membrane preparations. The plate is incubated for 5 h at room temperature.
The degree of fluorescence polarization is determined with a fluorescence polarization microplate reader.
B. Functional Assay
Agonistic activity of human melanocortin receptors is determined in a homogeneous membrane based assay. Competition between unlabeled cAMP and a fixed quantity of fluorescence labeled cAMP for a limited number of binding sites on a cAMP specific antibody is revealed by fluorescence polarization.
The test compound or unlabeled NDP-alpha-MSH is dispensed at varying concentrations to a 384 well microtiter plate. Membrane preparations from HEK293 cells expressing the human melanocortin receptors are added. After a short preincubation period, an appropriate amount of ATP, GTP and the cAMP antibody is added and the plate is further incubated before the fluorescence labeled cAMP conjugate is dispensed. The plate is incubated for 2 h at 4°C before it is read on a fluorescence polarization microplate reader. The amount of cAMP produced as a response to a test compound is compared to the production of cAMP resulting from stimulation with NDP-alpha-MSH. Representative compounds of the present invention were tested and found to bind to the melanocortin-4 receptor. These compounds were generally found to have IC50 values less than 2 μM.
Table 16: Biological data for selected examples of the invention
Figure imgf000154_0001
C. In Vivo Food Intake Models
1. Spontaneous Feeding Paradigm
Food intake in rats is measured after i.p. or p.o. administration of the test compound (see e.g. A.S. Chen et al. Transgenic Res 2000 Apr ;9(2): 145-154).
2. Model of LPS-lnduced Anorexia and Tumor-Induced Cachexia
Prevention or amelioration of anorexia induced by either lipopolysaccharide (LPS) administration or cachexia induced by tumor growth is determined upon i.p. or p.o. administration of test compounds to rats (see e.g. D.L. Marks, N. Ling, and R. D. Cone, Cancer Res 2001 Feb 15;61 (4): 1432-1438). D. Rat Ex Copula Assay
Sexually mature male Caesarian Derived Sprague Dawley (CD) rats (over 60 days old) are used with the suspensory ligament surgically removed to prevent retraction of the penis back into the penile sheath during the ex copula evaluations. Animals receive food and water ad lib and are kept on a normal light/dark cycle. Studies are conducted during the light cycle.
1. Conditioning to Supine Restraint for Ex Copula Reflex Tests
This conditioning takes about 4 days. Day 1 , the animals are placed in a darkened restrainer and left for 15 - 30 minutes. Day 2, the animals are restrained in a supine position in the restrainer for 15 - 30 minutes. Day 3, the animals are restrained in the supine position with the penile sheath retracted for 15 - 30 minutes. Day 4, the animals are restrained in the supine position with the penile sheath retracted until penile responses are observed. Some animals require additional days of conditioning before they are completely acclimated to the procedures; non-responders are removed from further evaluation. After any handling or evaluation, animals are given a treat to ensure positive reinforcement.
2. Ex Copula Reflex Tests
Rats are gently restrained in a supine position with their anterior torso placed inside a cylinder of adequate size to allow for normal head and paw grooming. For a 400 - 500 gram rat, the diameter of the cylinder is approximately 8 cm. The lower torso and hind limbs are restrained with a nonadhesive material (vetrap). An additional piece of vetrap with a hole in it, through which the glans penis will be passed, is fastened over the animal to maintain the preputial sheath in a retracted position. Penile responses will be observed, typically termed ex copula genital reflex tests. Typically, a series of penile erections will occur spontaneously within a few minutes after sheath retraction. The types of normal reflexogenic erectile responses include elongation, engorgement, cup and flip. An elongation is classified as an extension of the penile body. Engorgement is a dilation of the glans penis. A cup is defined as an intense erection where the distal margin of the glans penis momentarily flares open to form a cup. A flip is a dorsiflexion of the penile body. Baseline and or vehicle evaluations are conducted to determine how, and if, an animal will respond. Some animals have a long duration until the first response while others are non-responders altogether. During this baseline evaluation latency to first response, number and type of responses are recorded. The testing time frame is 15 minutes after the first response.
After a minimum of 1 day between evaluations, these same animals are administered the test compound at 20 mg/kg and evaluated for penile reflexes. All evaluations are videotaped and scored later. Data are collected and analyzed using paired 2 tailed t-tests to compared baseline and/or vehicle evaluations to drug treated evaluations for individual animals. Groups of a minimum of 4 animals are utilized to reduce variability.
Positive reference controls are included in each study to assure the validity of the study. Animals can be dosed by a number of routes of administration depending on the nature of the study to be performed. The routes of administration includes intravenous (IV), intraperitoneal (IP), subcutaneous (SC) and intracerebral ventricular (ICV).
E. Models of Female Sexual Dysfunction
Rodent assays relevant to female sexual receptivity include the behavioral model of lordosis and direct observations of copulatory activity. There is also a urethrogenital reflex model in anesthetized spinally transected rats for measuring orgasm in both male and female rats. These and other established animal models of female sexual dysfunction are described in K. E. McKenna et al, A Model For The Study of Sexual Function In Anesthetized Male And Female Rats, Am. J. Physiol. (Regulatory Integrative Comp. Physiol 30): R1276-R1285, 1991 ; K.E. McKenna et al, Modulation By Peripheral Serotonin of The Threshold For Sexual Reflexes In Female Rats, Pharm. Bioch. Behav., 40:151-156, 1991 ; and L.K. Takahashi et al, Dual Estradiol Action In The Diencephalon And The Regulation of Sociosexual Behavior In Female Golden Hamsters, Brain Res., 359: 194- 207, 1985. Examples of a Pharmaceutical Composition
As a specific embodiment of an oral composition of a compound of the present invention, 30 mg of Example 2 is formulated with sufficient finely divided lactose to provide a total amount of 580 to 590 mg to fill a size 0 hard gelatin capsule.
As another specific embodiment of an oral composition of a compound of the present invention, 25 mg of Example 20 is formulated with sufficient finely divided lactose to provide a total amount of 580 to 590 mg to fill a size 0 hard gelatin capsule.
While the invention has been described and illustrated in reference to certain preferred embodiments thereof, those skilled in the art will appreciate that various changes, modifications and substitutions can be made therein without departing from the spirit and scope of the invention. For example, effective dosages, other than the preferred doses as set forth above, may be applicable as a consequence of the specific pharmacological responses observed and may vary depending upon the particular active compound selected, as well as from the type of formulation and mode of administration employed, and such expected variations or differences in the results are contemplated in accordance with the objects and practices of the present invention. It is intended, therefore, that the invention be limited only by the scope of the claims which follow and that such claims be interpreted as broadly as is reasonable.

Claims

Claims:
1. A compound according to formula (I)
Figure imgf000158_0001
and the enantiomers, diastereomers, tautomers, solvates and pharmaceutically acceptable salts thereof, wherein
R1 is -(C(R6)2),-T, or -O-(C(R6)2)m-T;
R6 is independently selected from H1 F,
OH, OCH3, d-β-alkyl, optionally substituted with 1 to 3 substituents selected from halogen, CN, OH and OCH3, and
C^-cycloalkyl, optionally substituted with 1 to 3 substituents selected from halogen, CN, OH and OCH3;
T is NR7R8, morpholine,
Figure imgf000158_0002
Figure imgf000159_0001
R7 and R8 are independently from each other selected from H, d-6-alkyl, C2-6-alkenyl
C2-6-alkinyl, and
C2-6-alkylene-O-Ci-6-alkyl, wherein each alkyl, alkenyl and alkinyl is optionally substituted by one or more halogen atoms, CN or OH; R9 is independently selected from halogen,
CN,
OH, d-e-alkyl optionally substituted with 1 to 3 substituents selected from halogen, CN and OH, and
O-d-6-alkyl optionally substituted with 1 to 3 substituents selected from halogen, CN and OH,
Ci-6-alkylene-O-Ci-6-alkyl optionally substituted with 1 to 3 substituents selected from halogen, CN and OH; R10 is H, or
Ci-Ce-alkyl;
R11 is independently selected from halogen, CN, OH,
Ci-6-alkyl optionally substituted with 1 to 3 substituents selected from halogen, CN and OH, O-Ci-6-alkyl optionally substituted with 1 to 3 substituents selected from halogen, CN and OH, d-e-alkylene-O-d-e-alkyl optionally substituted with 1 to 3 substituents selected from halogen, CN and OH, -NH2,
-NH(Ci-6-alkyl), and -N(Ci-β-alkyl)2;
X is CH or N;
Y is CH or N; Z is CH or N;
A is a 3-7-membered saturated, unsaturated or aromatic ring containing 0-2 nitrogen atoms;
R2 is independently selected from
F, Cl,
CH3, and
CF3;
R3 is H1 Cl, F, or
CH3;
R4 is Cl or F; R5 is
Figure imgf000160_0001
morpholine, optionally substituted by 1 to 3, same or different substituents R14, or
NR12R13;
R12 and R13 are independently from each other selected from d-e-alkyl,
C2-6-alkenyl, C2-6-alkinyl,
C2-6-alkylene-O-Ci-6-alkyl, and C2-6-alkylene-N-(Ci.6-alkyl)2; R14is Ci-6-alkyl, d-s-alkylene-O-Ci-e-alkyl,
Ci-6-alkylene-OH,
Ci-6-alkylene-NH2,
Ci-e-alkylene-NH-Ci-e-alkyl, or Ci-6-alkylene-N(Ci-6-alkyl)2;
Ms 1,2,3, or 4; mis 0, 1,2, 3, or 4; n is O11, 2, 3, or 4; ois 0,1, or 2; pis 0, 1,2,3, or 4; qis 0, 1,2, or3;
Ms O11,
2, 3, or 4 and sis 1,or2.
The compound of claim 1 according to formula (I')
Figure imgf000161_0001
wherein R1, R2, R3, R4, R5 and n are as defined in claim 1.
3. The compound of claim 1 or 2, wherein R1 is -(CH2)I-T,
-O-(CH2)m-T;
T is NR7R8, morpholine,
Figure imgf000162_0001
R7 and R8 are independently from each other selected from
Ci-6-alkyl, C2-6-alkenyl C2-6-alkinyl, and C2-6-alkylene-O-Ci-6-alkyl; R9 is independently selected from halogen,
CN,
OH,
Ci-6-alkyl optionally substituted with 1 to 3 substituents selected from halogen, CN and OH1 and
O-Ci-6-alkyl optionally substituted with 1 to 3 substituents selected from halogen, CN and OH;
X is CH or N;
Y is CH or N; Z is CH or N;
R2 is independently selected from F,
Cl,
CH3, and
CF3;
R3 is H,
Cl, or
CH3;
R4 is Cl;
R5 is
Figure imgf000163_0001
morpholine, optionally substituted by 1 to 3, same or different substituents R14 or
NR12R13;
R11 is independently selected from halogen,
CN,
OH, d-e-alkyl optionally substituted with 1 to 3 substituents selected from halogen,
CN and OH, O-Ci-6-alkyl optionally substituted with 1 to 3 substituents selected from halogen, CN and OH, d-e-alkylene-O-Ci-β-alkyl optionally substituted with 1 to 3 substituents selected from halogen, CN and OH,
-NH2, -NH(Ci.6-alkyl), and
-N(Ci.6-alkyl)2; R12 and R13 are independently from each other selected from Ci-6-alkyl, C2-6-alkenyl, C2-6-alkinyl, C2-6-alkylene-O-Ci-6-alkyl;
R14is Ci-6-alkyl, d-β-alkylene-O-Ci-β-alkyl, d-6-alkylene-OH, d-6-alkylene-NH2, d-β-alkylene-NH-Ci-β-alkyl, or d-6-alkylene-N(d-6-alkyl)2;
A is a 3-7-membered saturated, unsaturated or aromatic ring containing 0-2 nitrogen atoms;
I is 1,2, 3, or 4; mis 2, 3, or 4, nis 0,1,2, 3, or 4; ois 0,1, or 2; pis 0,1,2, 3, or 4; qis 0, 1,2, or 3; ris O11, 2, 3, or 4; and sis 1,or2.
4. The compound of any of claims 1 to 3, wherein at least one of R7 and R8 is selected from C2-6-alkenyl,
C2-6-alkinyl, and C^β-alkylene-O-d-β-alkyl.
5. The compound of any of claims 1 to 4, wherein R2is F or Cl, and R3 is Cl.
6. The compound of any of claims 1 to 5 wherein I is 2 or 3, and m is 2 or 3.
7. The compound of any of claims 1 to 6 as medicament.
8. Use of the compound of any of claims 1 to 6 for the preparation of a medicament for the treatment or prophylaxis of disorders, diseases or conditions responsive to the inactivation or activation of the melanocortin-4 receptor in a mammal.
9. Use according to claim 8 for the preparation of a medicament for the treatment or prophylaxis of cancer cachexia.
10. Use according to claim 8 for the preparation of a medicament for the treatment or prophylaxis of muscle wasting.
11. Use according to claim 8 for the preparation of a medicament for the treatment or prophylaxis of anorexia.
12. Use according to claim 8 for the preparation of a medicament for the treatment or prophylaxis of anxiety and/or depression.
13. Use according to claim 8 for the preparation of a medicament for the treatment or prophylaxis of obesity.
14. Use according to claim 8 for the preparation of a medicament for the treatment or prophylaxis of diabetes mellitus.
15. Use according to claim 8 for the preparation of a medicament for the treatment or prophylaxis of male or female sexual dysfunction.
16. Use according to claim 8 for the preparation of a medicament for the treatment or prophylaxis of erectile dysfunction.
17. A pharmaceutical composition comprising a compound of any of claims 1 to 6 and a pharmaceutically acceptable carrier.
PCT/EP2007/003115 2006-04-07 2007-04-05 Substituted phenylpiperidine derivatives as melanocortin-4 receptor modulators WO2007115798A1 (en)

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