WO2014116684A1 - Non-peptidic neuropeptide y receptor modulators - Google Patents

Non-peptidic neuropeptide y receptor modulators Download PDF

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WO2014116684A1
WO2014116684A1 PCT/US2014/012521 US2014012521W WO2014116684A1 WO 2014116684 A1 WO2014116684 A1 WO 2014116684A1 US 2014012521 W US2014012521 W US 2014012521W WO 2014116684 A1 WO2014116684 A1 WO 2014116684A1
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Edward Roberts
Gopi Kumar Mittapalli
Danielle VELLUCCI
Jun Yang
Miguel Guerrero
Mariangela URBANO
Hugh Rosen
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Edward Roberts
Gopi Kumar Mittapalli
Vellucci Danielle
Jun Yang
Miguel Guerrero
Urbano Mariangela
Hugh Rosen
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    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D487/04—Ortho-condensed systems

Definitions

  • Neuropeptide Y is a highly conserved 36-aminoacid peptide neurotransmitter, structurally and functionally related to the 36-amino acid pancreatic peptide (PYY) and pancreatic polypeptide (PP).
  • PYY 36-amino acid pancreatic peptide
  • PP pancreatic polypeptide
  • 5 Five different receptor subtypes [Yl, Y2, Y3, Y4 (PP), Y5] are abundantly expressed in both the central and peripheral nervous systems and have been identified as endogenous receptor proteins binding NPY, PYY and/or PP. All NPY receptor subtypes are G protein coupled receptors that typically couple to God signaling pathways.
  • the NPY-Y2 receptor (Y2R) has been of particular interest since it has been associated with various physiological and pathological processes such as affective disorders, infertility, bone mass formation, responses to ethanol and drugs of abuse, angiogenesis, and food intake. 3
  • NPY neuropeptide Y- Yl receptors
  • Blockade of Y2 receptors produces anti-stress effects indistinguishable from those produced by Yl agonism, presumably through potentiation of presynaptic release of endogenous NPY. Consequently, Y2R antagonists may prove useful in the treatment of depression, anxiety and stress-related disorders via the induced enhanced GABAergic and NPYergic effects.
  • NPY also plays a critical role in mediating endocrine functions such as the release of the luteinizing hormone (LH) involved in mammalian ovulation. 5 Particularly, suppression of LH secretion in human appears to be mediated by Y2Rs as demonstrated by the negative regulation of the reproductive axis in ovariectomized animals. 6 Therefore, Y2R antagonists could be useful for the treatment of infertility, particularly in women with luteal phase defects.
  • LH luteinizing hormone
  • NPY neuronal regulator of energy homeostasis
  • Yl and Y2 receptors have so far been implicated in the control of osteoblast activityand thus bone formation.
  • Analysis of brain specific NPY overexpressing and Y receptor knockout models has revealed a powerful anabolic pathway likely involving hypothalamic Y2 receptors and osteoblastic Yl receptors.
  • NPY has been demonstrated to have potent angiogenic effects and to play a significant role in ischemic revascularization, primarily via the activation of Y2Rs.
  • Y2R stimulation may afford a novel therapy for impaired vascularization in ischemia, wound healing, aging.
  • NPY is also involved in pathologic angiogenesis such as in tumors and retinopathy and, in these conditions, Y2R antagonists could be therapeutic.
  • 9 NPY has been strongly implicated in mediating pain and inflammation. Both the YIR and the Y2R are involved in mediating pain signaling in the brain. Injection of NPY elicits an analgesic response, which is thought to be a result of YIR or Y2Rmodulation.
  • NPY is considered to be the most powerful orexigenic peptide isolated.
  • 11 NPY receptor antagonists may be useful for the treatment of diabetes and eating disorders including obesity, anorexia and bulimia nervosa.
  • Y2R antagonism has been suggested to reduce body weight.
  • 11 ' 3 Y2R antagonists locally administered into the fat may be a novel way for reducing the fat and a therapy for obesity by their anti-angiogenic effects exerting an anti-adipogenic action mediated by an increased apoptosis of endothelial cells.
  • the invention is directed in various embodiments to compounds that at an effective concentration in vivo in a patient can modulate the action of a receptor of neuropeptide Y (NPY), to pharmaceutical formulations and combinations of the compounds, to use of the compounds for modulating NPY receptors, and to treatment of malconditions in patients wherein modulation of an NPY receptor is medically indicated.
  • NPY neuropeptide Y
  • the invention provides a compound of formula
  • ring A comprises 0-2 nitrogen atoms; or, ring B comprises 0-2 nitrogen atoms; or, both; and, each of ring A and ring B is independently substituted with n independently selected J groups;
  • ring A is absent and the two carbon atoms connecting X 1 and X 3 are mutually double bonded and each independently bears hydrogen or (C 1 -
  • ring B is absent and the two carbon atoms connecting X 1 and X 3 are mutually double bonded and each independently bears hydrogen or (C 1 -
  • X 1 is CR C or N, unless Cyc is bonded to X 1 , then X 1 is a carbon atom;
  • X 2 is CR C or N, unless Cyc is bonded to X 2 , then X 2 is a carbon atom;
  • W is CR C or N, each R cyc is independently selected halo, (Cl-C6)alkyl, or (C 1 -C6)alkoxyl; p is 0, 1, or 2; wherein wavy lines indicate points of bonding; or,
  • NRS(0) q wherein q is 0, 1, or 2;
  • HA is aryl or heteroaryl substituted with 0, 1 , or 2 substituents independently selected from the group consisting of halo, cyano, (Cl-C6)alkyl, (Cl-C6)alkoxyl, and C0 2 R', and further substituted with J HA ;
  • J HA is (CH 2 )o- 2 R J , (CH 2 )o- 2 OR J , (CH 2 ) 0 - 2 N(R J ) 2 , (CH 2 ) 0 - 2 SR J , (CH 2 )o- 2 SOR J , (CH 2 y 2 S0 2 R J , (CH 2 )o- 2 S0 2 N(R J ) 2 , (CH 2 ) 0 - 2 SO 3 R J , (CH 2 ) 0 - 2 C(O)R J , (CH 2 )o- 2 C(0)C(0)R J , (CH 2 )o- 2 C(0)CH 2 C(0)R J , (CH 2 ) 0 - 2 C(O)OR J , (CH 2 ) 0 - 2 OC(0)R J , (CH 2 y 2 OC(0)OR J , (CH 2 ) 0 - 2 C(O)N(R J ) 2 , (CH 2 ) 0
  • each independently selected R c is H, halo, (Cl-C6)alkyl, OH, or (Cl- C6)alkoxyl;
  • R is independently at each occurrence hydrogen or an alkyl, acyl, cycloalkyl, cycloalkylalkyl, aryl, aroyl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, wherein any alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl is substituted with 0-3 J; or wherein two R groups together with a nitrogen atom or with two adjacent nitrogen atoms to which they are bonded can together form a (C3-C8)heterocyclyl substituted with 0-3 J; optionally further comprising 1-3 additional heteroatoms selected from the group consisting of O, N, and S(0) q ; wherein any cycloalkyl, aryl, heterocyclyl, or heteroaryl can be fused, bridged,
  • J independently at each occurrence is selected from the group consisting of F, CI, Br, I, OR, CN, CF 3 , OCF 3 , O, S, C(O), S(O),
  • R J is independently at each occurrence selected from the group consisting of hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl, wherein any alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, is unsubstituted or is substituted with 1 , 2, or 3 substituents independently selected from the group consisting of (C 1 -C6)alkyl and (C6-C10)aryl; or wherein two R J groups together with a nitrogen atom or with two adjacent nitrogen atoms to which they are bonded can together form a (C3-C8)heterocyclyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of (Cl-C6)al
  • the invention can provide a compound of formula (III) as shown in Table 1.
  • the invention provides a compound of formula
  • Ar 1 , Ar 2 and Ar 3 each independently selected from the group consisting of cycloalkyl, aryl, heterocyclyl, and heteroaryl, provided that Ar 3 can also be hydrogen, wherein any cycloalkyl, aryl, heterocyclyl, or heteroaryl is mono- or independently multi-substituted with J, (Ci-C6)alkyl, (C 2 -Ce)alkenyl, (C 2 -C 6 )alkynyl, (Ci-C 6 )haloalkyl, (Ci-C 6 )alkoxy, (Ci-C 6 )haloalkoxy, cycloalkyl(Co-C6)alkyl, heterocyclyl(Co-Ce) alkyl, aryl(Co-Ce) alkyl, or heteroaryl(Co-Ce)alkyl; wherein any alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalky
  • R is independently at each occurrence selected from the group consisting of hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl, wherein any alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl is substituted with 0-3 J; or wherein two R groups together with a nitrogen atom or with two adjacent nitrogen atoms to which they are bonded can together form a (C 3 -C8)heterocyclyl substituted with 0-3 J; optionally further comprising 1 -3 additional heteroatoms selected from the group consisting of O, N, S, S(0) and S(0) 2 ;
  • any cycloalkyl, aryl, heterocyclyl, or heteroaryl can be fused, bridged, or in a spiro configuration with one or more additional optionally substituted cycloalkyl, aryl, heterocyclyl, and heteroaryl, monocyclic, bicyclic or polycyclic, saturated, partially unsaturated, or aromatic rings;
  • J independently at each occurrence is selected from the group consisting of F, CI, Br, I, OR, CN, CF 3 , OCF 3 , O, S, C(O), S(O),
  • R J is independently at each occurrence selected from the group consisting of hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl, or wherein two R J groups together with a nitrogen atom or with two adjacent nitrogen atoms to which they are bonded can together form a (C3-C8)heterocyclyl optionally further comprising 1 -3 additional heteroatoms selected from the group consisting of O, N, S, S(O) and S(0) 2 ;
  • the invention provides a compound of formula
  • each independently selected R is H, aryl, or heteroaryl
  • k 0, 1, or 2;
  • n 0, 1, 2, 3, or 4;
  • Cyc is or N, and wavy lines indicate points of bonding, or,
  • Cyc is N-o , and wavy lines indicate points of bonding, or,
  • Cyc is absent;
  • Q is S(0) q or NRS(0) q wherein q is 0, 1, or 2;
  • HA is aryl or heteroaryl, wherein any aryl or heteroaryl is substituted with 0, 1, 2, 3, or 4 J;
  • each independently selected R" is H, (C 1 -C6)alkyl, or (CH 2 ) m NR 2 wherein m is 1, 2, 3, or 4;
  • R is independently at each occurrence hydrogen or an alkyl, acyl, cycloalkyl, cycloalkylalkyl, aryl, aroyl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, wherein any alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl is substituted with 0-3 J; or wherein two R groups together with a nitrogen atom or with two adjacent nitrogen atoms to which they are bonded can together form a (C3-C8)heterocyclyl substituted with 0-3 J; optionally further comprising 1-3 additional heteroatoms selected from the group consisting of O, N, and S(0) q ; wherein any cycloalkyl, aryl, heterocyclyl, or heteroaryl can be fused, bridged,
  • J independently at each occurrence is selected from the group consisting of F, CI, Br, I, OR, CN, CF 3 , OCF 3 , O, S, C(O), S(O),
  • R J is independently at each occurrence selected from the group consisting of hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl, or wherein two R J groups together with a nitrogen atom or with two adjacent nitrogen atoms to which they are bonded can together form a (C3-C8)heterocyclyl optionally further comprising 1 -3 additional heteroatoms selected from the group consisting of O, N, S, S(O) and S(0) 2 ;
  • the invention provides pharmaceutical compositions and combinations comprising a compound of the invention, e.g., a compound of any one of formula (III), or of formula (I), or of formula (II).
  • the invention provides a method of modulating a Neuropeptide Y (NPY) receptor, comprising contacting the receptor and an effective amount or concentration of a compound of the invention, e.g., a compound of any one of formula (III), or of formula (I), or of formula (II).
  • a compound of the invention e.g., a compound of any one of formula (III), or of formula (I), or of formula (II).
  • the invention provides a method of treating a malcondition in a patient wherein modulation of an NPY receptor is medically indicated, comprising administering to the patient a compound of the invention, e.g., a compound of any one of formula (III), or of formula (I), or of formula (II), in a dose, at a frequency of administration, and for a duration of time sufficient to provide a beneficial effect to the patient.
  • a compound of the invention e.g., a compound of any one of formula (III), or of formula (I), or of formula (II)
  • the malcondition can include, but is not limited to, drug or alcohol abuse, anxiety disorders, depression, stress-related disorders, neurological disorders, nerve degeneration, osteoporosis or bone loss, sleep/wake disorders, cardiovascular diseases, obesity, anorexia, inovulation, fertility disorders, angiogenesis, cell proliferation, learning and memory disorders, migraine and pain.
  • the invention provides a dosage form comprising a compound, composition, or combination of the invention for administration to a patient when medically indicated.
  • Figure 1 shows dose-response curves for (A) compound 3 and (B) compound 4,shown in Table l,with respect to the Y2R and YIR neuropeptide Y receptor subclasses.
  • Figure 2 shows the effect of NPY Y2 antagonist compound 518 (see Table 1) on alcohol intake behaviors in rats.
  • Figure 3 shows data supporting that NPY Y2 antagonist compound 518 (i.c.v.) blocks tumor-induced bone loss and tactile hypersensitivity.
  • mammals include, for example, humans; non-human primates, e.g. apes and monkeys; and non-primates, e.g. dogs, cats, cattle, horses, sheep, and goats.
  • Non-mammals include, for example, fish and birds.
  • NPY plays a role in the biochemical mechanisms involved in the disease or malcondition such that a therapeutically beneficial effect can be achieved by acting on anNPY receptor.
  • Acting on an NPY receptor can include binding to an NPY receptor and/or inhibiting the bioactivity of an NPY receptor.
  • NPY refers to Neuropeptide Y, a peptidyl neurotransmitter discussed above.
  • An "NPY receptor” is a molecular entity found in living organisms such as human beings that interacts specifically with NPY and transduces the interaction of NPY into altered cellular function or behavior in the living organism.
  • Five different subtypes of endogenous binding receptor proteins have been identified, as discussed above, which are termed herein Y1R, Y2R, Y3R, Y4R,and Y5R.
  • an effective amount when used to describe therapy to an individual suffering from a disorder, refers to the amount of a compound of the invention that is effective to inhibit or otherwise act on an NPY receptor in the individual's tissues wherein such inhibition or other action occurs to an extent sufficient to produce a beneficial therapeutic effect.
  • a receptor is "modulated" by a compound when the compound is either an agonist or activator, or an antagonist, inhibitor or inverse agonist, of the receptor.
  • a compound is an agonist or activator when it acts on the receptor to stimulate the function of the receptor, such as is done by an endogenous agonist ligand.
  • a compound is an antagonist, inhibitor, or inverse agonist when the compound blocks the effect of an endogenous receptor ligand, preventing functioning of the receptor.
  • a compound is a "selective modulator" when it modulates one class or subclass of receptor, for example Y2R, at a concentration or in an amount that is not effective to modulate a different class or subclass of receptor, for example Y1R.
  • a compound of the invention is a selective modulator of Y2R when it has an effect on Y2R at a concentration or in an amount that does not modulate YIR, or does not modulate any other receptor in a patient to any significant extent, or both.
  • substantially as the term is used herein means completely or almost completely; for example, a composition that is "substantially free” of a component either has none of the component or contains such a trace amount that any relevant functional property of the composition is unaffected by the presence of the trace amount, or a compound is "substantially pure” is there are only negligible traces of impurities present.
  • Treating refers to an alleviation of symptoms associated with a disorder or disease, or inhibition of further progression or worsening of those symptoms, or prevention or prophylaxis of the disease or disorder, or curing the disease or disorder.
  • an "effective amount” or a “therapeutically effective amount” of a compound of the invention refers to an amount of the compound that alleviates, in whole or in part, symptoms associated with the disorder or condition, or halts or slows further progression or worsening of those symptoms, or prevents or provides prophylaxis for the disorder or condition.
  • a “therapeutically effective amount” refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic result.
  • a therapeutically effective amount is also one in which any toxic or detrimental effects of compounds of the invention are outweighed by the therapeutically beneficial effects.
  • chemically feasible is meant a bonding arrangement or a compound where the generally understood rules of organic structure are not violated; for example a structure within a definition of a claim that would contain in certain situations a pentavalent carbon atom that would not exist in nature would be understood to not be within the claim.
  • the structures disclosed herein, in all of their embodiments are intended to include only “chemically feasible” structures, and any recited structures that are not chemically feasible, for example in a structure shown with variable atoms or groups, are not intended to be disclosed or claimed herein.
  • an isotopic form of one or more atoms in a molecule that is different from the naturally occurring isotopic distribution of the atom in nature is referred to as an "isotopically labeled form" of the molecule.
  • All isotopic forms of atoms are included as options in the composition of any molecule, unless a specific isotopic form of an atom is indicated.
  • any hydrogen atom or set thereof in a molecule can be any of the isotopic forms of hydrogen, i.e., protium (' ⁇ ), deuterium ( 2 H), or tritium ( 3 H) in any combination.
  • any carbon atom or set thereof in a molecule can be any of the isotopic form of carbons, such as 11 C, 12 C, 13 C, or 14 C, or any nitrogen atom or set thereof in a molecule can be any of the isotopic forms of nitrogen, such as 13 N, 14 N, or 15 N.
  • a molecule can include any combination of isotopic forms in the component atoms making up the molecule, the isotopic form of every atom forming the molecule being independently selected. In a multi- molecular sample of a compound, not every individual molecule necessarily has the same isotopic composition.
  • a sample of a compound can include molecules containing various different isotopic compositions, such as in a tritium or 14 C radiolabeled sample where only some fraction of the set of molecules making up the macroscopic sample contains a radioactive atom. It is also understood that many elements that are not artificially isotopically enriched themselves are mixtures of naturally occurring isotopic forms, such as 14 N and 15 N, 32 S and 34 S, and so forth. A molecule as recited herein is defined as including isotopic forms of all its constituent elements at each position in the molecule. As is well known in the art, isotopically labeled compounds can be prepared by the usual methods of chemical synthesis, except substituting an isotopically labeled precursor molecule.
  • the isotopes can be obtained by any method known in the art, such as generation by neutron absorption of a precursor nuclide in a nuclear reactor, by cyclotron reactions, or by isotopic separation such as by mass spectrometry.
  • the isotopic forms are incorporated into precursors as required for use in any particular synthetic route.
  • 14 C and 3 H can be prepared using neutrons generated in a nuclear reactor. Following nuclear transformation, 14 C and 3 H are incorporated into precursor molecules, followed by further elaboration as needed.
  • amino protecting group or "N-protected” as used herein refers to those groups intended to protect an amino group against undesirable reactions during synthetic procedures and which can later be removed to reveal the amine. Commonly used amino protecting groups are disclosed in Protective Groups in Organic Synthesis, Greene, T.W.; Wuts, P. G. M., John Wiley & Sons, New York, NY, (3rd Edition, 1999).
  • Amino protecting groups include acyl groups such as formyl, acetyl, propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl, 2- bromoacetyl, trifluoroacetyl, trichloroacetyl, o-nitrophenoxyacetyl, a- chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, 4-nitrobenzoyl, and the like; sulfonyl groups such as benzenesulfonyl, p-toluenesulfonyl and the like; alkoxy- or aryloxy-carbonyl groups (which form urethanes with the protected amine) such as benzyloxycarbonyl (Cbz), p-chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbony
  • Amine protecting groups also include cyclic amino protecting groups such as phthaloyl and dithiosuccinimidyl, which incorporate the amino nitrogen into a heterocycle.
  • amino protecting groups include formyl, acetyl, benzoyl, pivaloyl, ?-butylacetyl, phenylsulfonyl, Alloc, Teoc, benzyl, Fmoc, Boc and Cbz. It is well within the skill of the ordinary artisan to select and use the appropriate amino protecting group for the synthetic task at hand.
  • hydroxyl protecting group or "O-protected” as used herein refers to those groups intended to protect an OH group against undesirable reactions during synthetic procedures and which can later be removed to reveal the hydroxyl group. Commonly used hydroxyl protecting groups are disclosed in Protective Groups in Organic Synthesis, Greene, T.W.; Wuts, P. G. M., John Wiley & Sons, New York, NY, (3rd Edition, 1999). Hydroxyl protecting groups include acyl groups such as formyl, acetyl, propionyl, pivaloyl, t-butylacetyl, 2- chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl,
  • benzenesulfonyl p-toluenesulfonyl and the like; acyloxy groups (which form urethanes with the protected amine) such as benzyloxycarbonyl (Cbz), p- chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p- nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 3,5-dimethoxybenzyloxycarbonyl, 2,4- dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2-nitro-4,5- dimethoxybenzyloxycarbonyl, 3,4,5-trimethoxybenzyloxycarbonyl, 1 -(p- biphenylyl)- 1-methylethoxycarbonyl, a,a-dimethyl-3,5- dimethoxybenzy
  • cyclopentyloxycarbonyl adamantyloxycarbonyl, cyclohexyloxycarbonyl, phenylthiocarbonyl and the like; aralkyl groups such as benzyl, triphenylmethyl, benzyloxymethyl and the like; and silyl groups such as trimethylsilyl and the like. It is well within the skill of the ordinary artisan to select and use the appropriate hydroxyl protecting group for the synthetic task at hand.
  • substituted refers to an organic group as defined herein in which one or more bonds to a hydrogen atom contained therein are replaced by one or more bonds to a non-hydrogen atom such as, but not limited to, a halogen (i.e., F, CI, Br, and I); an oxygen atom in groups such as hydroxyl groups, alkoxy groups, aryloxy groups, aralkyloxy groups, oxo(carbonyl) groups, carboxyl groups including carboxylic acids, carboxylates, and carboxylate esters; a sulfur atom in groups such as thiol groups, alkyl and aryl sulfide groups, sulfoxide groups, sulfone groups, sulfonyl groups, and sulfonamide groups; a nitrogen atom in groups such as amines, hydroxylamines, nitriles, nitro groups, N-oxides, hydrazides, azides, and enamines
  • Non-limiting examples of substituents that can be bonded to a substituted carbon (or other) atom include F, CI, Br, I, OR, OC(0)N(R) 2 , CN, NO, N0 2 , ON0 2 , azido, CF 3 , OCF 3 , R, O (oxo), S (thiono), C(O), S(O), methylenedioxy, ethylenedioxy, N(R) 2 , SR, SOR, S0 2 R, S0 2 N(R) 2 , S0 3 R, C(0)R, C(0)C(0)R, C(0)CH 2 C(0)R, C(S)R, C(0)OR, OC(0)R, C(0)N(R) 2 , OC(0)N(R) 2 , C(S)N(R) 2 , (CH 2 )o- 2 N(R)C(0)R, (CH 2 ) 0 - 2 N(R)N(R) 2 ,
  • N(R)S0 2 N(R) 2 , N(R)C(0)OR, N(R)C(0)R, N(R)C(S)R, N(R)C(0)N(R) 2 , N(R)C(S)N(R) 2 , N(COR)COR, N(OR)R, C( NH)N(R) 2 , C(0)N(OR)R, or
  • R can be hydrogen or a carbon-based moiety, and wherein the carbon-based moiety can itself be further substituted.
  • each individual group designated by a variable is independent of any other similarly designated groups in the structure and need not be the same as another such group selected from a list of options recited.
  • a variable e.g., an "R” group or a "J” group
  • the two R groups on the carbon atom need not be the same group.
  • each J can be the same or different from other J groups within the overall list of optional groups at that position.
  • a substituent When a substituent is monovalent, such as, for example, F or CI, it is bonded to the atom it is substituting by a single bond.
  • a divalent substituent such as O, S, C(O), S(O), or
  • S(0)2 can be connected by two single bonds to two different carbon atoms.
  • O a divalent substituent
  • the O can be bonded to each of two adjacent carbon atoms to provide an epoxide group, or the O can form a bridging ether group, termed an "oxy" group, between adjacent or non-adjacent carbon atoms, for example bridging the 1,4-carbons of a cyclohexyl group to form a [2.2.1]- oxabicyclo system.
  • any substituent can be bonded to a carbon or other atom by a linker, such as (03 ⁇ 4) ⁇ or (CR2) n wherein n is 1, 2, 3, or more, and each R is independently selected.
  • C(O) and S(0)2groups can be bound to one or two heteroatoms, such as nitrogen, rather than to a carbon atom.
  • a C(O) group is bound to one carbon and one nitrogen atom
  • the resulting group is called an "amide” or “carboxamide.”
  • the functional group is termed a "urea”.
  • a S(0)2 group is bound to one carbon and one nitrogen atom
  • the resulting unit is termed a "sulfonamide.”
  • a S(0)2 group is bound to two nitrogen atoms, the resulting unit is termed a "sulfamide.”
  • Substituted alkyl, alkenyl, alkynyl, cycloalkyl, and cycloalkenyl groups as well as other substituted groups also include groups in which one or more bonds to a hydrogen atom are replaced by one or more bonds, including double or triple bonds, to a carbon atom, or to a heteroatom such as, but not limited to, oxygen in carbonyl (oxo), carboxyl, ester, amide, imide, urethane, and urea groups; and nitrogen in imines, hydroxyimines, oximes, hydrazones, amidines, guanidines, and nitriles.
  • Substituted ring groups such as substituted cycloalkyl, aryl, heterocyclyl and heteroaryl groups also include rings and fused ring systems in which a bond to a hydrogen atom is replaced with a bond to a carbon atom. Therefore, substituted cycloalkyl, aryl, heterocyclyl and heteroaryl groups can also be substituted with alkyl, alkenyl, and alkynyl groups as defined herein.
  • ring system as the term is used herein is meant a moiety comprising one, two, three or more rings, which can be substituted with non-ring groups or with other ring systems, or both, which can be fully saturated, partially unsaturated, fully unsaturated, or aromatic, and when the ring system includes more than a single ring, the rings can be fused, bridging, or spirocyclic.
  • spirocyclic is meant the class of structures wherein two rings are fused at a single tetrahedral carbon atom, as is well known in the art.
  • any of the groups described herein, which contain one or more substituents it is understood, of course, that such groups do not contain any substitution or substitution patterns which are sterically impractical and/or synthetically non-feasible.
  • the compounds of this disclosed subject matter include all stereochemical isomers arising from the substitution of these compounds.
  • Alkyl groups include straight chain and branched alkyl groups and cycloalkyl groups having from 1 to about 20 carbon atoms, and typically from 1 to 12 carbons or, in some embodiments, from 1 to 8 carbon atoms.
  • straight chain alkyl groups include those with from 1 to 8 carbon atoms such as methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, and n-octyl groups.
  • branched alkyl groups include, but are not limited to, isopropyl, iso-butyl, sec-butyl, t-butyl, neopentyl, isopentyl, and 2,2-dimethylpropyl groups.
  • Representative substituted alkyl groups can be substituted one or more times with any of the groups listed above, for example, amino, hydroxy, cyano, carboxy, nitro, thio, alkoxy, and halogen groups.
  • Cycloalkyl groups are cyclic alkyl groups such as, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups.
  • the cycloalkyl group can have 3 to about 8-12 ring members, whereas in other embodiments the number of ring carbon atoms range from 3 to 4, 5, 6, or 7.
  • Cycloalkyl groups further include polycyclic cycloalkyl groups such as, but not limited to, norbornyl, adamantyl, bornyl, camphenyl, isocamphenyl, and carenyl groups, and fused rings such as, but not limited to, decalinyl, and the like. Cycloalkyl groups also include rings that are substituted with straight or branched chain alkyl groups as defined above.
  • Representative substituted cycloalkyl groups can be mono-substituted or substituted more than once, such as, but not limited to, 2,2-, 2,3-, 2,4- 2,5- or 2,6-disubstituted cyclohexyl groups or mono-, di- or tri-substituted norbornyl or cycloheptyl groups, which can be substituted with, for example, amino, hydroxy, cyano, carboxy, nitro, thio, alkoxy, and halogen groups.
  • cycloalkyl as used herein can refer to a cycloalkenyl group comprising one or more double bond in the ring(s) thereof.
  • cycloalkenyl alone or in combination denotes a cyclic alkenyl group.
  • carbocyclic denotes a ring structure wherein the atoms of the ring are carbon, such as a cycloalkyl group or an aryl group.
  • the carbocycle has 3 to 8 ring members, whereas in other embodiments the number of ring carbon atoms is 4, 5, 6, or 7.
  • the carbocyclic ring can be substituted with as many as N- 1 substituents wherein N is the size of the carbocyclic ring with, for example, alkyl, alkenyl, alkynyl, amino, aryl, hydroxy, cyano, carboxy, heteroaryl, heterocyclyl, nitro, thio, alkoxy, and halogen groups, or other groups as are listed above.
  • a carbocyclyl ring can be a cycloalkyl ring, a cycloalkenyl ring, or an aryl ring.
  • a carbocyclyl can be monocyclic or polycyclic, and if polycyclic each ring can be independently be a cycloalkyl ring, a cycloalkenyl ring, or an aryl ring.
  • (Cycloalkyl)alkyl groups are alkyl groups as defined above in which a hydrogen or carbon bond of the alkyl group is replaced with a bond to a cycloalkyl group as defined above.
  • Alkenyl groups include straight and branched chain and cyclic alkyl groups as defined above, except that at least one double bond exists between two carbon atoms.
  • -CH C(CH 3 ) 2
  • -C(CH 3 ) CH 2
  • -C(CH 3 ) CH(CH 3 )
  • -C(CH 2 CH 3 ) CH 2
  • Cycloalkenyl groups include cycloalkyl groups having at least one double bond between 2 carbons.
  • cycloalkenyl groups include but are not limited to cyclohexenyl, cyclopentenyl, and cyclohexadienyl groups.
  • Cycloalkenyl groups can have from 3 to about 8-12 ring members, whereas in other embodiments the number of ring carbon atoms range from 3 to 5, 6, or 7.
  • Cycloalkyl groups further include polycyclic cycloalkyl groups such as, but not limited to, norbornyl, adamantyl, bornyl, camphenyl, isocamphenyl, and carenyl groups, and fused rings such as, but not limited to, decalinyl, and the like, provided they include at least one double bond within a ring. Cycloalkenyl groups also include rings that are substituted with straight or branched chain alkyl groups as defined above. (Cycloalkenyl)alkyl groups are alkyl groups as defined above in which a hydrogen or carbon bond of the alkyl group is replaced with a bond to a cycloalkenyl group as defined above.
  • Alkynyl groups include straight and branched chain alkyl groups, except that at least one triple bond exists between two carbon atoms.
  • alkynyl groups have from 2 to about 20 carbon atoms, and typically from 2 to 12 carbons or, in some embodiments, from 2 to 8 carbon atoms. Examples include, but are not limited to -C ⁇ CH, -C ⁇ C(CH 3 ), -C ⁇ C(CH 2 CH 3 ), -CH 2 C ⁇ CH,
  • heteroalkyl by itself or in combination with another term means, unless otherwise stated, a stable straight or branched chain alkyl group consisting of the stated number of carbon atoms and one or two heteroatoms selected from the group consisting of O, N, and S, and wherein the nitrogen and sulfur atoms may be optionally oxidized and the nitrogen heteroatom may be optionally quaternized.
  • the heteroatom(s) may be placed at any position of the heteroalkyl group, including between the rest of the heteroalkyl group and the fragment to which it is attached, as well as attached to the most distal carbon atom in the heteroalkyl group. Examples include: -0-CH 2 -CH 2 -CH 3 ,
  • Up to two heteroatoms may be consecutive, such as, for example, -CH 2 -NH-OCH 3 , or - CH 2 -CH 2 -S-S-CH 3 .
  • a “cycloheteroalkyl” ring is a cycloalkyl ring containing at least one heteroatom.
  • a cycloheteroalkyl ring can also be termed a “heterocyclyl,” described below.
  • heteroalkenyl by itself or in combination with another term means, unless otherwise stated, a stable straight or branched chain
  • Aryl groups are cyclic aromatic hydrocarbons that do not contain heteroatoms in the ring.
  • aryl groups include, but are not limited to, phenyl, azulenyl, heptalenyl, biphenyl, indacenyl, fluorenyl, phenanthrenyl, triphenylenyl, pyrenyl, naphthacenyl, chrysenyl, biphenylenyl, anthracenyl, and naphthyl groups.
  • aryl groups contain about 6 to about 14 carbons in the ring portions of the groups.
  • Aryl groups can be unsubstituted or substituted, as defined above.
  • Representative substituted aryl groups can be mono-substituted or substituted more than once, such as, but not limited to, 2-, 3-, 4-, 5-, or 6-substituted phenyl or 2-8 substituted naphthyl groups, which can be substituted with carbon or non-carbon groups such as those listed above.
  • Aralkyl groups are alkyl groups as defined above in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to an aryl group as defined above.
  • Representative aralkyl groups include benzyl and phenylethyl groups and fused (cycloalkylaryl)alkyl groups such as 4-ethyl-indanyl.
  • Aralkenyl group are alkenyl groups as defined above in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to an aryl group as defined above.
  • Heterocyclyl groups or the term "heterocyclyl” includes aromatic and non-aromatic ring compounds containing 3 or more ring members, of which, one or more is a heteroatom such as, but not limited to, N, O, and S.
  • a heterocyclyl can be a cycloheteroalkyl, or a heteroaryl, or if polycyclic, any combination thereof.
  • heterocyclyl groups include 3 to about 20 ring members, whereas other such groups have 3 to about 15 ring members.
  • a heterocyclyl group designated as a C 2 -heterocyclyl can be a 5-ring with two carbon atoms and three heteroatoms, a 6-ring with two carbon atoms and four heteroatoms and so forth.
  • a C4-heterocyclyl can be a 5-ring with one heteroatom, a 6-ring with two heteroatoms, and so forth.
  • the number of carbon atoms plus the number of heteroatoms sums up to equal the total number of ring atoms.
  • a heterocyclyl ring can also include one or more double bonds.
  • a heteroaryl ring is an embodiment of a heterocyclyl group.
  • the phrase "heterocyclyl group" includes fused ring species including those comprising fused aromatic and non-aromatic groups.
  • a dioxolanyl ring and a benzdioxolanyl ring system are both heterocyclyl groups within the meaning herein.
  • the phrase also includes polycyclic ring systems containing a heteroatom such as, but not limited to, quinuclidyl.
  • Heterocyclyl groups can be unsubstituted, or can be substituted as discussed above.
  • Heterocyclyl groups include, but are not limited to, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, thiophenyl,
  • benzothiophenyl benzofuranyl, dihydrobenzofuranyl, indolyl, dihydroindolyl, azaindolyl, indazolyl, benzimidazolyl, azabenzimidazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, imidazopyridinyl, isoxazolopyridinyl, thianaphthalenyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl,
  • substituted heterocyclyl groups can be mono-substituted or substituted more than once, such as, but not limited to, piperidinyl or quinolinyl groups, which are 2-, 3-, 4-, 5-, or 6-substituted, or disubstituted with groups such as those listed above.
  • Heteroaryl groups are aromatic ring compounds containing 5 or more ring members, of which, one or more is a heteroatom such as, but not limited to, N, O, and S; for instance, heteroaryl rings can have 5 to about 8-12 ring members.
  • a heteroaryl group is a variety of a heterocyclyl group that possesses an aromatic electronic structure.
  • a heteroaryl group designated as a C 2 - heteroaryl can be a 5-ring with two carbon atoms and three heteroatoms, a 6-ring with two carbon atoms and four heteroatoms and so forth.
  • a C 4 - heteroaryl can be a 5-ring with one heteroatom, a 6-ring with two heteroatoms, and so forth.
  • Heteroaryl groups include, but are not limited to, groups such as pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, thiophenyl, benzothiophenyl, benzofuranyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, azabenzimidazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, imidazopyridinyl, isoxazolopyridinyl, thianaphthalenyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl,
  • heteroaryl groups can be unsubstituted, or can be substituted with groups as is discussed above.
  • Representative substituted heteroaryl groups can be substituted one or more times with groups such as those listed above.
  • aryl and heteroaryl groups include but are not limited to phenyl, biphenyl, indenyl, naphthyl (1-naphthyl, 2-naphthyl), N- hydroxytetrazolyl, N-hydroxytriazolyl, N-hydroxyimidazolyl, anthracenyl (1- anthracenyl, 2- anthracenyl, 3-anthracenyl), thiophenyl (2-thienyl, 3-thienyl), furyl (2-furyl, 3-furyl), indolyl, oxadiazolyl, isoxazolyl, quinazolinyl, fluorenyl, xanthenyl, isoindanyl, benzhydryl, acridinyl, thiazolyl, pyrrolyl (2-pyrrolyl), pyrazolyl (3-pyrazolyl), imidazolyl (1-imidazolyl, 2-imid
  • 2,3-dihydro-benzo[b]thiophenyl (2-(2,3-dihydro-benzo[b]thiophenyl), 3-(2,3- dihydro-benzo[b]thiophenyl), 4-(2,3-dihydro-benzo[b]thiophenyl), 5-(2,3- dihydro-benzo[b]thiophenyl), 6-(2,3-dihydro-benzo[b]thiophenyl), 7-(2,3- dihydro-benzo[b]thiophenyl), indolyl (1 -indolyl, 2-indolyl, 3-indolyl, 4-indolyl, 5-indolyl, 6-indolyl, 7-indolyl), indazole (1-indazolyl, 3-indazolyl, 4-indazolyl, 5-indazolyl, 6-indazolyl, 7-indazolyl), benzimidazoly
  • Heterocyclylalkyl groups are alkyl groups as defined above in which a hydrogen or carbon bond of an alkyl group as defined above is replaced with a bond to a heterocyclyl group as defined above.
  • Representative heterocyclyl alkyl groups include, but are not limited to, furan-2-yl methyl, furan-3-yl methyl, pyridine-3-yl methyl, tetrahydrofuran-2-yl ethyl, and indol-2-yl propyl.
  • Heteroarylalkyl groups are alkyl groups as defined above in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to a heteroaryl group as defined above.
  • alkoxy refers to an oxygen atom connected to an alkyl group, including a cycloalkyl group, as are defined above.
  • linear alkoxy groups include but are not limited to methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, and the like.
  • branched alkoxy include but are not limited to isopropoxy, sec-butoxy, tert-butoxy, isopentyloxy, isohexyloxy, and the like.
  • cyclic alkoxy include but are not limited to cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like.
  • An alkoxy group can include one to about 12-20 carbon atoms bonded to the oxygen atom, and can further include double or triple bonds, and can also include heteroatoms.
  • an allyloxy group is an alkoxy group within the meaning herein.
  • a methoxyethoxy group is also an alkoxy group within the meaning herein, as is a methylenedioxy group in a context where two adjacent atoms of a structures are substituted therewith.
  • halo or “halogen” or “halide” by themselves or as part of another substituent mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom, preferably, fluorine, chlorine, or bromine.
  • a "haloalkyl” group includes mono-halo alkyl groups, poly-halo alkyl groups wherein all halo atoms can be the same or different, and per-halo alkyl groups, wherein all hydrogen atoms are replaced by halogen atoms, such as fluoro.
  • haloalkyl examples include trifluoromethyl, 1, 1-dichloroethyl, 1,2- dichloroethyl, l,3-dibromo-3,3-difluoropropyl, perfluorobutyl, and the like.
  • haloalkoxy includes mono-halo alkoxy groups, poly-halo alkoxy groups wherein all halo atoms can be the same or different, and per-halo alkoxy groups, wherein all hydrogen atoms are replaced by halogen atoms, such as fluoro.
  • haloalkoxy include trifluoromethoxy, 1,1 - dichloroethoxy, 1 ,2-dichloroethoxy, l,3-dibromo-3,3-difluoropropoxy, perfluorobutoxy, and the like.
  • (C x -C y )perfluoroalkyl wherein x ⁇ y, means an alkyl group with a minimum of x carbon atoms and a maximum of y carbon atoms, wherein all hydrogen atoms are replaced by fluorine atoms. Preferred is
  • (C x -C y )perfluoroalkylene wherein x ⁇ y, means an alkyl group with a minimum of x carbon atoms and a maximum of y carbon atoms, wherein all hydrogen atoms are replaced by fluorine atoms.
  • x ⁇ y means an alkyl group with a minimum of x carbon atoms and a maximum of y carbon atoms, wherein all hydrogen atoms are replaced by fluorine atoms.
  • Preferred is -(Ci-C6)perfluoroalkylene, more preferred is -(Ci-C3)perfluoroalkylene, most preferred is -CF 2 -
  • aryloxy and arylalkoxy refer to, respectively, an aryl group bonded to an oxygen atom and an aralkyl group bonded to the oxygen atom at the alkyl moiety. Examples include but are not limited to phenoxy, naphthyloxy, and benzyloxy.
  • acyl group refers to a group containing a carbonyl moiety wherein the group is bonded via the carbonyl carbon atom.
  • the carbonyl carbon atom is also bonded to another carbon atom, which can be part of an alkyl, aryl, aralkyl cycloalkyl, cycloalkylalkyl, heterocyclyl,
  • heterocyclylalkyl, heteroaryl, heteroarylalkyl group or the like In the special case wherein the carbonyl carbon atom is bonded to a hydrogen, the group is a "formyl" group, an acyl group as the term is defined herein.
  • An acyl group can include 0 to about 12-20 additional carbon atoms bonded to the carbonyl group.
  • An acyl group can include double or triple bonds within the meaning herein.
  • An acryloyl group is an example of an acyl group.
  • An acyl group can also include heteroatoms within the meaning here.
  • a nicotinoyl group (pyridyl-3-carbonyl) group is an example of an acyl group within the meaning herein.
  • haloacyl an example is a trifluoroacetyl group.
  • amine includes primary, secondary, and tertiary amines having, e.g., the formula N(group)3 wherein each group can independently be H or non-H, such as alkyl, aryl, and the like.
  • Amines include but are not limited to R-NH 2 , for example, alkylamines, arylamines, alkylarylamines; R 2 NH wherein each R is independently selected, such as dialkylamines, diarylamines, aralkylamines, heterocyclylamines and the like; and R 3 N wherein each R is independently selected, such as trialkylamines, dialkylarylamines,
  • alkyldiarylamines triarylamines, and the like.
  • amine also includes ammonium ions as used herein.
  • amino group is a substituent of the form -N3 ⁇ 4, -NHR, -NR 2 , -NR 3 , wherein each R is independently selected, and protonated forms of each, except for -NR 3 + , which cannot be protonated. Accordingly, any compound substituted with an amino group can be viewed as an amine.
  • An “amino group” within the meaning herein can be a primary, secondary, tertiary or quaternary amino group.
  • alkylamino includes a monoalkylamino, dialkylamino, and trialkylamino group.
  • ammonium ion includes the unsubstituted ammonium ion NH 4 + , but unless otherwise specified, it also includes any protonated or quaternarized forms of amines. Thus, trimethylammonium hydrochloride and
  • tetramethylammonium chloride are both ammonium ions, and amines, within the meaning herein.
  • amide includes C- and N-amide groups, i.e., -C(0)NR2, and -NRC(0)R groups, respectively.
  • Amide groups therefore include but are not limited to primary carboxamide groups (-C(0)NH2) and formamide groups (-NHC(O)H).
  • a "carboxamido” group is a group of the formula ( ⁇ (0) ⁇ 3 ⁇ 4, wherein R can be H, alkyl, aryl, etc.
  • azido refers to an N 3 group.
  • An “azide” can be an organic azide or can be a salt of the azide (N 3 ⁇ ) anion.
  • nitro refers to an NO2 group bonded to an organic moiety.
  • nitroso refers to an NO group bonded to an organic moiety.
  • nitrate refers to an ONO2 group bonded to an organic moiety or to a salt of the nitrate (NO3 ) anion.
  • urethane (“carbamoyl” or “carbamyl”) includes N- and O- urethane groups, i.e., -NRC(0)OR and -OC(0)NR 2 groups, respectively.
  • sulfonamide (or “sulfonamido”) includes S- and N- sulfonamide groups, i.e., -SO2NR2 and -NRSO2R groups, respectively.
  • Sulfonamide groups therefore include but are not limited to sulfamoyl groups (- SO2NH2).
  • An organosulfur structure represented by the formula -S(0)(NR)- is understood to refer to a sulfoximine, wherein both the oxygen and the nitrogen atoms are bonded to the sulfur atom, which is also bonded to two carbon atoms.
  • amidine or “amidino” includes groups of the formula -C(NR)NR 2 .
  • an amidino group is -C(NH)NH 2 .
  • guanidine or "guanidino” includes groups of the formula -NRC(NR)NR 2 .
  • a guanidino group is -NHC(NH)NH 2 .
  • a “salt” as is well known in the art includes an organic compound such as a carboxylic acid, a sulfonic acid, or an amine, in ionic form, in combination with a counterion.
  • acids in their anionic form can form salts with cations such as metal cations, for example sodium, potassium, and the like; with ammonium salts such as NH 4 + or the cations of various amines, including tetraalkyl ammonium salts such as tetramethylammonium, or other cations such as trimethylsulfonium, and the like.
  • a “pharmaceutically acceptable” or “pharmacologically acceptable” salt is a salt formed from an ion that has been approved for human consumption and is generally non-toxic, such as a chloride salt or a sodium salt.
  • a “zwitterion” is an internal salt such as can be formed in a molecule that has at least two ionizable groups, one forming an anion and the other a cation, which serve to balance each other. For example, amino acids such as glycine can exist in a zwitterionic form.
  • a “zwitterion” is a salt within the meaning herein.
  • the compounds of the present invention may take the form of salts.
  • the term “salts" embraces addition salts of free acids or free bases which are compounds of the invention. Salts can be “pharmaceutically- acceptable salts.”
  • the term “pharmaceutically-acceptable salt” refers to salts which possess toxicity profiles within a range that affords utility in
  • compositions of the invention may nonetheless possess properties such as high crystallinity, which have utility in the practice of the present invention, such as for example utility in process of synthesis, purification or formulation of compounds of the invention.
  • Suitable pharmaceutically-acceptable acid addition salts may be prepared from an inorganic acid or from an organic acid.
  • inorganic acids include hydrochloric, hydrobromic, hydriodic, nitric, carbonic, sulfuric, and phosphoric acids.
  • Appropriate organic acids may be selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic and sulfonic classes of organic acids, examples of which include formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic,
  • cyclohexylaminosulfonic stearic, alginic, ⁇ -hydroxybutyric, salicylic, galactaric and galacturonic acid.
  • pharmaceutically unacceptable acid addition salts include, for example, perchlorates and tetrafluoroborates.
  • Suitable pharmaceutically acceptable base addition salts of compounds of the invention include, for example, metallic salts including alkali metal, alkaline earth metal and transition metal salts such as, for example, calcium, magnesium, potassium, sodium and zinc salts.
  • Pharmaceutically acceptable base addition salts also include organic salts made from basic amines such as, for example, N,N-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine.
  • Examples of pharmaceutically unacceptable base addition salts include lithium salts and cyanate salts.
  • salts may be useful, for example as intermediates in the synthesis of Formula (I) compounds, for example in their purification by recrystallization. All of these salts may be prepared by conventional means from the corresponding compound according to Formula (I) by reacting, for example, the appropriate acid or base with the compound according to Formula (I).
  • pharmaceutically acceptable salts refers to nontoxic inorganic or organic acid and/or base addition salts, see, for example, Lit et al., Salt Selection for Basic Drugs (1986), Int J. Pharm., 33, 201 -217, incorporated by reference herein.
  • a “hydrate” is a compound that exists in a composition with water molecules.
  • the composition can include water in stoichiometric quantities, such as a monohydrate or a dihydrate, or can include water in random amounts.
  • a "hydrate” refers to a solid form, i.e., a compound in water solution, while it may be hydrated, is not a hydrate as the term is used herein.
  • a “solvate” is a similar composition except that a solvent other that water replaces the water.
  • a solvent other that water replaces the water.
  • methanol or ethanol can form an "alcoholate", which can again be stoichiometic or non-stoichiometric.
  • a “solvate” refers to a solid form, i.e., a compound in solution in a solvent, while it may be solvated, is not a solvate as the term is used herein.
  • prodrug as is well known in the art is a substance that can be administered to a patient where the substance is converted in vivo by the action of biochemicals within the patients body, such as enzymes, to the active pharmaceutical ingredient.
  • examples of prodrugs include esters of carboxylic acid groups, which can be hydrolyzed by endogenous esterases as are found in the bloodstream of humans and other mammals. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs", ed. H. Bundgaard, Elsevier, 1985.
  • the compound or set of compounds, such as are used in the inventive methods can be any one of any of the combinations and/or sub-combinations of the above-listed embodiments.
  • a compound of the formula (I) or a salt thereof may exhibit the phenomenon of tautomerism whereby two chemical compounds that are capable of facile interconversion by exchanging a hydrogen atom between two atoms, to either of which it forms a covalent bond. Since the tautomeric compounds exist in mobile equilibrium with each other they may be regarded as different isomeric forms of the same compound. It is to be understood that the formulae drawings within this specification can represent only one of the possible tautomeric forms. However, it is also to be understood that the invention encompasses any tautomeric form, and is not to be limited merely to any one tautomeric form utilized within the formulae drawings.
  • tautomerism is amido-imido (lactam-lactim when cyclic) tautomerism, such as is seen in heterocyclic compounds bearing a ring oxygen atom adjacent to a ring nitrogen atom.
  • the equilibrium is an example of tautomerism.
  • a structure depicted herein as one tautomer is intended to also include the other tautomer.
  • the isomers resulting from the presence of a chiral center comprise a pair of non-superimposable isomers that are called "enantiomers.”
  • Single enantiomers of a pure compound are optically active, i.e., they are capable of rotating the plane of plane polarized light.
  • Single enantiomers are designated according to the Cahn-Ingold-Prelog system.
  • the priority of substituents is ranked based on atomic weights, a higher atomic weight, as determined by the systematic procedure, having a higher priority ranking. Once the priority ranking of the four groups is determined, the molecule is oriented so that the lowest ranking group is pointed away from the viewer.
  • Cahn-Ingold-Prelog ranking is A > B > C > D.
  • the lowest ranking atom, D is oriented away from the viewer.
  • the solid wedge indicates that the atom bonded thereby projects toward the viewer out of the plane of the paper, and a dashed wedge indicates that the atom bonded thereby projects away from the viewer out of the plan of the paper, i.e., the plane "of the paper" being defined by atoms A, C, and the chiral carbon atom for the (R) configuration shown below.
  • a carbon atom bearing the A-D atoms as shown above is known as a "chiral" carbon atom, and the position of such a carbon atom in a molecule is termed a “chiral center.”
  • Compounds of the invention may contain more than one chiral center, and the configuration at each chiral center is described in the same fashion.
  • the present invention is meant to encompass diastereomers as well as their racemic and resolved, diastereomerically and enantiomerically pure forms and salts thereof.
  • Diastereomeric pairs may be resolved by known separation techniques including normal and reverse phase chromatography, and
  • Isolated optical isomer means a compound which has been
  • the isolated isomer is at least about 80%, more preferably at least 90% pure, even more preferably at least 98% pure, most preferably at least about 99% pure, by weight.
  • Isolated optical isomers may be purified from racemic mixtures by well-known chiral separation techniques. According to one such method, a racemic mixture of a compound of the invention, or a chiral intermediate thereof, is separated into 99% wt.% pure optical isomers by HPLC using a suitable chiral column, such as a member of the series of DAI CEL ® CHIRALPAK ® family of columns (Daicel Chemical Industries, Ltd., Tokyo, Japan). The column is operated according to the manufacturer instructions.
  • a suitable chiral column such as a member of the series of DAI CEL ® CHIRALPAK ® family of columns (Daicel Chemical Industries, Ltd., Tokyo, Japan). The column is operated according to the manufacturer instructions.
  • the preferred compounds of the present invention have a particular spatial arrangement of substituents on the aromatic rings, which is related to the structure activity relationship demonstrated by the compound class. Often such substitution arrangement is denoted by a numbering system; however, numbering systems are often not consistent between different ring systems. In six-membered aromatic systems, the spatial arrangements are specified by the common nomenclature "para” for 1,4-substitution, "meta” for 1,3 -substitution and "ortho" for 1 ,2-substitution as shown below.
  • the compound or set of compounds such as are among the inventive compounds or are used in the inventive methods, can be any one of any of the combinations and/or sub-combinations of the above-listed embodiments.
  • a compound as shown in any of the Examples, or among the exemplary compounds is provided. Provisos may apply to any of the disclosed categories or embodiments wherein any one or more of the other above disclosed embodiments or species may be excluded from such categories or embodiments.
  • the present invention further embraces isolated compounds according to any of formulas(I), (II), or (III).
  • isolated compound refers to a preparation of a compound of any of those formulas, or a mixture of compounds according to any of those formulas, wherein the isolated compound has been separated from the reagents used, and/or byproducts formed, in the synthesis of the compound or compounds. "Isolated” does not mean that the preparation is technically pure (homogeneous), but it is sufficiently pure to compound in a form in which it can be used therapeutically.
  • an "isolated compound” refers to a preparation of a compound of formula (I), (II), or (III) or a mixture of compounds according to any of those formulas, which contains the named compound or mixture of compounds according to the respective formula in an amount of at least 10 percent by weight of the total weight.
  • the preparation contains the named compound or mixture of compounds in an amount of at least 50 percent by weight of the total weight; more preferably at least 80 percent by weight of the total weight; and most preferably at least 90 percent, at least 95 percent or at least 98 percent by weight of the total weight of the preparation.
  • the compounds of the invention and intermediates may be isolated from their reaction mixtures and purified by standard techniques such as filtration, liquid-liquid extraction, solid phase extraction, distillation, recrystallization or chromatography, including flash column chromatography, or HPLC.
  • the invention is directed, in various embodiments, to a compound that is a modulator of a neuropeptide Y (NPY) receptor.
  • the NPY receptor can be Y2R or Y1R.
  • a compound of the invention is a selective modulator of Y2R.
  • the invention is directed to methods of making a compound of the invention.
  • the invention is directed to methods of using a compound of the invention, e.g., for therapeutic purposes for treatment of a medical condition.
  • the invention provides a compound of formula
  • ring A comprises 0-2 nitrogen atoms; or, ring B comprises 0-2 nitrogen atoms; or, both; and, each of ring A and ring B is independently substituted with n independently selected J groups;
  • ring A is absent and the two carbon atoms connecting X 1 and X 3 are mutually double bonded and each independently bears hydrogen or (C 1 -
  • ring B is absent and the two carbon atoms connecting X 1 and X 3 are mutually double bonded and each independently bears hydrogen or (C 1 -
  • X 1 is a carbon atom
  • X 1 is CR C or N, unless Cyc is bonded to X 1 , then X 1 is a carbon atom;
  • X 2 is CR C or N, unless Cyc is bonded to X 2 , then X 2 is a carbon atom;
  • W is CR or N, each R cyc is independently selected halo, (Cl-C6)alkyl, or (C 1 -C6)alkoxyl; p is 0, 1, or 2; wherein wavy lines indicate points of bonding; or, wavy lines indicate points of bonding; and,
  • HA is aryl or heteroaryl substituted with 0, 1 , or 2 substituents independently selected from the group consisting of halo, cyano, (Cl-C6)alkyl, (Cl-C6)alkoxyl, and C0 2 R', and further substituted with J HA ;
  • J HA is (CH 2 )o- 2 R J , (CH 2 )o- 2 OR J , (CH 2 ) 0 - 2 N(R J ) 2 , (CH 2 ) 0 - 2 SR J , (CH 2 ) 0- 2 SOR J , (CH 2 )o- 2 S0 2 R J , (CH 2 )o- 2 S0 2 N(R J ) 2 , (CH 2 ) 0 - 2 SO 3 R J , (CH 2 ) 0 - 2 C(O)R J , (CH 2 )o- 2 C(0)C(0)R J , (CH 2 )o- 2 C(0)CH 2 C(0)R J , (CH 2 ) 0 - 2 C(O)OR J , (CH 2 ) 0 - 2 OC(0)R J , (CH 2 )o- 2 OC(0)OR J , (CH 2 ) 0 - 2 C(O)N(R J ) 2 , (CH 2
  • each independently selected R c is H, halo, (Cl-C6)alkyl, OH, or (Cl- C6)alkoxyl;
  • R is independently at each occurrence hydrogen or an alkyl, acyl, cycloalkyl, cycloalkylalkyl, aryl, aroyl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, wherein any alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl is substituted with 0-3 J; or wherein two R groups together with a nitrogen atom or with two adjacent nitrogen atoms to which they are bonded can together form a (C3-C8)heterocyclyl substituted with 0-3 J; optionally further comprising 1-3 additional heteroatoms selected from the group consisting of O, N, and S(0) q ; wherein any cycloalkyl, aryl, heterocyclyl, or heteroaryl can be fused, bridged,
  • J independently at each occurrence is selected from the group consisting of F, CI, Br, I, OR, CN, CF 3 , OCF 3 , O, S, C(O), S(O),
  • C10)aryl and optionally further comprising 1-3 additional heteroatoms selected from the group consisting of O, N, S, S(O) and S(0)2;
  • a double bond is present between X 1 and X 2 , and X 3 is O.
  • X 1 and X 2 are both C3 ⁇ 4 and X 3 is CH, Cyc being bonded to X 3 .
  • X 2 is NH or N(CH 3 )
  • X 3 is CH, C-OH, or C-CH 3 , Cyc being bonded to X 3 .
  • Cyc is piperidinyl or piperazinyl. In other embodiments, Cyc is
  • the Cyc group can be present in either orientation with respect to Q and to X .
  • HA is phenyl.
  • an HA group can be substituted with cyano, fluoro, or methyl.
  • J HA is a heterocyclyl or heteroaryl that is directly bonded to ring system HA.
  • the heterocyclyl or heteroaryl of J HA is linked to HA via an amide, sulfonamide, or urea bond.
  • a heterocyclyl or heteroaryl of is substituted with alkyl, such as methyl.
  • the invention provides a compound of formula (III), wherein the compound is any of the compounds shown in Table 1 , below.
  • Table 1 Specific Compounds of Formula (III)
  • Ar 1 , Ar 2 and Ar 3 each independently selected from the group consisting of cycloalkyl, aryl, heterocyclyl, and heteroaryl, provided that Ar 3 can also be hydrogen, wherein any cycloalkyl, aryl, heterocyclyl, or heteroaryl is mono- or independently multi-substituted with J, (Ci-C6)alkyl, (C 2 -C6)alkenyl, (C 2 -C 6 )alkynyl, (Ci-C 6 )haloalkyl, (Ci-C 6 )alkoxy, (Ci-C 6 )haloalkoxy, cycloalkyl(Co-C6)alkyl, heterocyclyl(Co-Ce) alkyl, aryl(Co-C6)alkyl, or heteroaryl(Co-Ce)alkyl; wherein any alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkyl;
  • W and Y are each independently selected from the group consisting of a single bond, a double bond, ((CH 2 )o-2CR2(CH2)o- 2 , (CH 2 )o-20(CH 2 )o-2, (CH 2 ) 0 - 2 C(0)(CH 2 )o- 2 ,
  • R is independently at each occurrence selected from the group consisting of hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl, wherein any alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl is substituted with 0-3 J; or wherein two R groups together with a nitrogen atom or with two adjacent nitrogen atoms to which they are bonded can together form a (C3-C8)heterocyclyl substituted with 0-3 J; optionally further comprising 1 -3 additional heteroatoms selected from the group consisting of O, N, S, S(0) and S(0) 2 ;
  • any cycloalkyl, aryl, heterocyclyl, or heteroaryl can be fused, bridged, or in a spiro configuration with one or more additional optionally substituted cycloalkyl, aryl, heterocyclyl, and heteroaryl, monocyclic, bicyclic or polycyclic, saturated, partially unsaturated, or aromatic rings;
  • J independently at each occurrence is selected from the group consisting of F, CI, Br, I, OR, CN, CF 3 , OCF 3 , O, S, C(O), S(O),
  • R J is independently at each occurrence selected from the group consisting of hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl, or wherein two R J groups together with a nitrogen atom or with two adjacent nitrogen atoms to which they are bonded can together form a (C3-C8)heterocyclyl optionally further comprising 1 -3 additional heteroatoms selected from the group consisting of O, N, S, S(O) and S(0) 2 ;
  • Groups W and Y are atoms and groups that serve to bond together in defined spatial arrangements the three core cyclic groups Ar 1 , Ar 2 and Ar 3 , which are cyclic groups as are defined herein.
  • Ar 1 can be aryl or heteroaryl.
  • Ar 1 can be phenyl, pyrrolyl, thiazolyl, or thiophenyl.
  • Ar 1 can be cycloalkyl or heterocyclyl.
  • Ar 1 can be piperidinyl or piperazinyl.
  • Ar 2 , Ar 3 , or both can be aryl or heteroaryl.
  • Ar 2 , Ar 3 , or both can be phenyl, biphenyl, phenanthridinyl, pyrazolylphenyl, pyridylphenyl, or thiophenylphenyl.
  • Ar 2 , Ar 3 , or both can be cycloalkyl or heterocyclyl.
  • Ar 2 , Ar 3 , or both can be piperidinyl, or piperazinyl.
  • the linkers W, Y, or both can be a
  • W or Y bonded to Ar 1 can form a urea or a thiourea moiety, e.g., wherein one of the nitrogen atoms of the urea or thiourea moiety is a member of the Ar 1 ring.
  • all of Ar 1 , Ar 2 and Ar 3 are aryl or heteroaryl. In other embodiments, each of Ar 1 , Ar 2 and Ar 3 can independently be cycloalkyl or saturated heterocyclyl groups.
  • the invention comprises a compound of formula (IA)
  • nl is 0-3, Ar 2 , Ar 3 , each independently selected R, and each independently selected J, are as defined for formula (I).
  • the invention comprises a compound of formula (IB)
  • nl, n2, and n3 is each independently 0-3, and each independently selected J and each independently selected R is as defined for formula (I).
  • the invention comprises a compound of formula
  • a ring “het” is a heterocyclyl or heteroaryl wherein the carboxamido and sulfonamido groups can be disposed at any two positions thereupon, and wherein m is 0 or 1, and nl, n2, and n3 is each independently 0- 3, each independently selected R and each independently selected J is as defined in claim 1.
  • the invention comprises a compound of formula
  • the invention comprises a compound of formula (IE1)
  • the invention comprises a compound of
  • the invention comprises a compound of of formula (IH1) or of formula (IH2)
  • the invention comprises a compound of
  • the invention comprises a compound of formula (IK1 or IK2)
  • R, X, Ar 2 , and Ar 3 are as defined for formula (I).
  • the invention comprises a compound of formula
  • J is H or OH and Z is CH or N
  • Ar3 is as defined for formula (I).
  • the invention comprises a compound of formula (IM1 or IM2)
  • each independently selected R, each independently selected X, Ar 2 , and Ar 3 is as defined for formula (I).
  • the invention provides any of the compounds listed below in Table 2: Specific Compounds of Formula (I), all of which have been synthesized and characterized. Many of the compounds in Table 1 have been tested with respect to bioactivity as a modulator of an NPY receptor or as a selective modulator of Y2R, and many have been found to have bioactivity at concentrations which indicate potential of the compounds as therapeutic agents for treatment of malconditions in humans for which modulation of an NPY receptor is medically indicated.
  • the invention provides a compound of formula
  • each independently selected R 1 is H, aryl, or heteroaryl
  • k 0, 1, or 2;
  • n 0, 1, 2, 3, or 4;
  • Cyc is f wherein W is CH or N, and wavy lines indicate points of bonding, or,
  • Cyc is , and wavy lines indicate points of bonding, or,
  • Q is S(0) q or NRS(0) q wherein q is 0, 1, or 2;
  • HA is aryl or heteroaryl, wherein any aryl or heteroaryl is substituted with O, 1, 2, 3, or 4 J;
  • each independently selected R" is H, (C 1 -C6)alkyl, or (CH 2 ) m NR 2 wherein m is 1, 2, 3, or 4;
  • R is independently at each occurrence hydrogen or an alkyl, acyl, cycloalkyl, cycloalkylalkyl, aryl, aroyl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, wherein any alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl is substituted with 0-3 J; or wherein two R groups together with a nitrogen atom or with two adjacent nitrogen atoms to which they are bonded can together form a (C3-C8)heterocyclyl substituted with 0-3 J; optionally further comprising 1-3 additional heteroatoms selected from the group consisting of O, N, and S(0) q ; wherein any cycloalkyl, aryl, heterocyclyl, or heteroaryl can be fused, bridged,
  • J independently at each occurrence is selected from the group consisting of F, CI, Br, I, OR, CN, CF 3 , OCF 3 , O, S, C(O), S(O),
  • R J is independently at each occurrence selected from the group consisting of hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl, or wherein two R J groups together with a nitrogen atom or with two adjacent nitrogen atoms to which they are bonded can together form a (C3-C8)heterocyclyl optionally further comprising 1 -3 additional heteroatoms selected from the group consisting of O, N, S, S(0) and S(0) 2 ;
  • Cyc is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • W is CH.
  • W is N.
  • Cyc is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • Cyc is absent.
  • R 1 is optionally substituted phenyl.
  • R 2 is OH
  • the compound is any of those of Table 3, below.
  • a compound of the invention is a modulator of a neuropeptide Y (NPY) receptor.
  • the NPY receptor can be Y2R or Y1R.
  • a compound of the invention is a selective modulator of Y2R.
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the invention and a pharmaceutically acceptable excipient, as discussed below.
  • the invention provides a method of modulation a neuropeptide Y receptor comprising contacting the receptor with an effective amount or concentration of a compound of the invention.
  • a compound of the invention can be an agonist or activator when it acts on the receptor to stimulate the function of the receptor, such as is done by an endogenous agonist ligand.
  • a compound of the invention can be an antagonist or inhibitor when the compound blocks the effect of an endogenous receptor ligand, preventing functioning of the receptor.
  • a compound of the invention can be a "selective modulator" when it modulates one class or subclass of receptor, for example Y2R, at a concentration or in an amount that is not effective to modulate a different class or subclass of receptor, for example Y1R.
  • a compound of the invention can displace a known ligand bound to an NPY receptor.
  • the NPY receptor can be contacted by a compound of the inventions vivo in a human patient, at a concentration or in an amount that is effective to modulate the receptor. In various embodiments, the amount or concentration of the compound can be effective to selectively modulate the NPY receptor Y2R.
  • the invention provides a method of treatment of a malcondition in a patient for which modulation of a neuropeptide Y receptor is medically indicated, comprising administering to the patient a compound of the invention in a dose, at a frequency, and for a duration sufficient to provide a beneficial effect to the patient.
  • the malcondition can comprise drug or alcohol abuse, anxiety disorders, depression, stress-related disorders, neurological disorders, nerve degeneration, osteoporosis or bone loss, sleep/wake disorders, cardiovascular diseases, obesity, anorexia, inovulation, fertility disorders, angiogenesis, cell proliferation, learning and memory disorders, migraine and pain., or any disorder that involves activation or inhibition of the effect or function of an NPY receptor.
  • the invention provides a use of a compound of the invention in treatment of a malcondition in a human patient.
  • Modulation of one or more NPY receptors modulated by the inventive compound can be medically indicated for treatment of the malcondition.
  • the malcondition can comprise drug or alcohol abuse, anxiety disorders, depression, stress-related disorders, neurological disorders, nerve degernation, osteoporosis or bone loss, sleep/wake disorders, cardiovascular diseases, obesity, anorexia, inovulation, or fertility disorders, or any disorder that involves activation or inhibition of the effect or function of an NPY receptor.
  • Another aspect of an embodiment of the invention provides compositions of the compounds of the invention, alone or in combination with another neuropeptide Y receptor modulator or another type of therapeutic agent, or both.
  • compositions containing a compound of the invention can be prepared by conventional techniques, e.g. as described in Remington: The Science and Practice of Pharmacy, 19th Ed., 1995, incorporated by reference herein.
  • the compositions can appear in conventional forms, for example capsules, tablets, aerosols, solutions, suspensions or topical applications.
  • compositions include a compound of the invention and a pharmaceutically acceptable excipient which can be a carrier or a diluent.
  • the active compound will usually be mixed with a carrier, or diluted by a carrier, or enclosed within a carrier which can be in the form of an ampoule, capsule, sachet, paper, or other container.
  • the active compound when mixed with a carrier, or when the carrier serves as a diluent, it can be solid, semi-solid, or liquid material that acts as a vehicle, excipient, or medium for the active compound.
  • the active compound can be adsorbed on a granular solid carrier, for example contained in a sachet.
  • suitable carriers are water, salt solutions, alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil, peanut oil, olive oil, gelatin, lactose, terra alba, sucrose, dextrin, magnesium carbonate, sugar, cyclodextrin, amylose, magnesium stearate, talc, gelatin, agar, pectin, acacia, stearic acid or lower alkyl ethers of cellulose, silicic acid, fatty acids, fatty acid amines, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters, polyoxyethylene, hydroxymethylcellulose and polyvinylpyrrolidone.
  • the carrier or diluent can include any sustained release material known in the art, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax.
  • the formulations can be mixed with auxiliary agents which do not deleteriously react with the active compounds.
  • auxiliary agents which do not deleteriously react with the active compounds.
  • Such additives can include wetting agents, emulsifying and suspending agents, salt for influencing osmotic pressure, buffers and/or coloring substances preserving agents, sweetening agents or flavoring agents.
  • the compositions can also be sterilized if desired.
  • the route of administration can be any route which effectively transports the active compound of the invention to the appropriate or desired site of action, such as oral, nasal, pulmonary, buccal, subdermal, intradermal, transdermal or parenteral, e.g., rectal, depot, subcutaneous, intravenous, intraurethral, intramuscular, intranasal, ophthalmic solution or an ointment, the oral route being preferred.
  • the preparation can be tabletted, placed in a hard gelatin capsule in powder or pellet form or it can be in the form of a troche or lozenge. If a liquid carrier is used, the preparation can be in the form of a syrup, emulsion, soft gelatin capsule or sterile injectable liquid such as an aqueous or non-aqueous liquid suspension or solution.
  • Injectable dosage forms generally include aqueous suspensions or oil suspensions which can be prepared using a suitable dispersant or wetting agent and a suspending agent Injectable forms can be in solution phase or in the form of a suspension, which is prepared with a solvent or diluent.
  • Acceptable solvents or vehicles include sterilized water, Ringer's solution, or an isotonic aqueous saline solution.
  • sterile oils can be employed as solvents or suspending agents.
  • the oil or fatty acid is non-volatile, including natural or synthetic oils, fatty acids, mono-, di- or tri-glycerides.
  • the formulation can also be a powder suitable for reconstitution with an appropriate solution as described above. Examples of these include, but are not limited to, freeze dried, rotary dried or spray dried powders, amorphous powders, granules, precipitates, or particulates.
  • the formulations can optionally contain stabilizers, pH modifiers, surfactants, bioavailability modifiers and combinations of these.
  • the compounds can be formulated for parenteral administration by injection such as by bolus injection or continuous infusion.
  • a unit dosage form for injection can be in ampoules or in multi-dose containers.
  • compositions contemplated by the present invention can include, for example, micelles or liposomes, or some other encapsulated form, or can be administered in an extended release form to provide a prolonged storage and/or delivery effect. Therefore, the formulations can be compressed into pellets or cylinders and implanted intramuscularly or subcutaneously as depot injections. Such implants can employ known inert materials such as silicones and biodegradable polymers, e.g., polylactide-polyglycolide. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides).
  • the preparation can contain a compound of the invention, dissolved or suspended in a liquid carrier, preferably an aqueous carrier, for aerosol application.
  • a liquid carrier preferably an aqueous carrier
  • the carrier can contain additives such as solubilizing agents, e.g., propylene glycol, surfactants, absorption enhancers such as lecithin (phosphatidylcholine) or cyclodextrin, or preservatives such as parabens.
  • injectable solutions or suspensions preferably aqueous solutions with the active compound dissolved in polyhydroxylated castor oil.
  • Tablets, dragees, or capsules having talc and/or a carbohydrate carrier or binder or the like are particularly suitable for oral application.
  • Preferable carriers for tablets, dragees, or capsules include lactose, corn starch, and/or potato starch.
  • a syrup or elixir can be used in cases where a sweetened vehicle can be employed.
  • a typical tablet that can be prepared by conventional tabletting techniques can contain:
  • Active compound 250 mg
  • a typical capsule for oral administration contains compounds of the invention (250 mg), lactose (75 mg) and magnesium stearate (15 mg). The mixture is passed through a 60 mesh sieve and packed into a No. 1 gelatin capsule.
  • a typical injectable preparation is produced by aseptically placing 250 mg of compounds of the invention into a vial, aseptically freeze-drying and sealing. For use, the contents of the vial are mixed with 2 mL of sterile physiological saline, to produce an injectable preparation.
  • the compounds of the invention can be administered to a human in need of such treatment, prevention, elimination, alleviation or amelioration of a malcondition that is mediated through the action of a neuropeptide Y receptor such as Y1R or Y2R, for example, drug or alcohol abuse, anxiety disorders, depression, neurological disorders, nerve degeneration, osteoporosis or bone loss, sleep/wake disorders, cardiovascular diseases, obesity, anorexia, inovulation, or fertility disorders.
  • a neuropeptide Y receptor such as Y1R or Y2R
  • the compounds of the invention are effective over a wide dosage range.
  • dosages from about 0.05 to about 5000 mg, preferably from about 1 to about 2000 mg, and more preferably between about 2 and about 2000 mg per day can be used.
  • a typical dosage is about 10 mg to about 1000 mg per day.
  • the exact dosage will depend upon the activity of the compound, mode of administration, on the therapy desired, form in which administered, the subject to be treated and the body weight of the subject to be treated, and the preference and experience of the physician or veterinarian in charge.
  • NPY receptor modulation bioactivity of the compounds of the invention can be determined by use of an in vitro assay system which measures the displacement of a known ligand of NPY receptors, e.g., compound BIIE0246, which can be expressed as IC50 values, as are well known in the art inhibitors of the invention can be determined by the method described in the Examples.
  • the compounds of the invention are dispensed in unit dosage form including from about 0.05 mg to about 1000 mg of active ingredient together with a pharmaceutically acceptable carrier per unit dosage.
  • dosage forms suitable for oral, nasal, pulmonal or transdermal administration include from about 125 ⁇ g to about 1250 mg, preferably from about 250 ⁇ g to about 500 mg, and more preferably from about 2.5 mg to about 250 mg, of the compounds admixed with a pharmaceutically acceptable carrier or diluent.
  • Dosage forms can be administered daily, or more than once a day, such as twice or thrice daily. Alternatively dosage forms can be administered less frequently than daily, such as every other day, or weekly, if found to be advisable by a prescribing physician.
  • An embodiment of the invention also encompasses prodrugs of a compound of the invention which on administration undergo chemical conversion by metabolic or other physiological processes before becoming active pharmacological substances. Conversion by metabolic or other physiological processes includes without limitation enzymatic (e.g, specific enzymatically catalyzed) and non-enzymatic (e.g., general or specific acid or base induced) chemical transformation of the prodrug into the active pharmacological substance.
  • prodrugs will be functional derivatives of a compound of the invention which are readily convertible in vivo into a compound of the invention. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in Design of Prodrugs, ed. H. Bundgaard, Elsevier, 1985.
  • a composition of a compound described herein including formulating a compound of the invention with a pharmaceutically acceptable carrier or diluent.
  • the pharmaceutically acceptable carrier or diluent is suitable for oral administration.
  • the methods can further include the step of formulating the composition into a tablet or capsule.
  • the pharmaceutically acceptable carrier or diluent is suitable for parenteral administration.
  • the methods further include the step of lyophilizing the composition to form a lyophilized preparation.
  • the invention provides a method of synthesis of a compound of formula (I), contacting a compound of formula (IPA) wherein a ring labeled Ar 1 is as defined for Ar 1 herein,
  • the activity of compounds of the invention were evaluated in comparison to BIIE0246.
  • the compounds were initially tested at 10 ⁇ using a cAMP biosensor approach.
  • the cAMP biosensor assay cell lines containing either the Y2R or the Y1R were purchased from BD Biosciences (Rockville, MD) as HEK293 cells stably expressing a cyclic nucleotide-gated (CNG) channel and either Y2R (catalog # BD344870) or Y1R (catalog # BD344869).
  • CNG cyclic nucleotide-gated
  • Y2R catalog # BD344870
  • Y1R catalog # BD344869
  • Cells were cultured in T-175 cm 2 flasks at 37 C and 95% relative humidity.
  • Cells were plated and maintained in growth medium consisting of DMEM (Invitrogen catalog #11965) supplemented with 10% fetal bovine serum, 250 ⁇ g/m
  • HEK293-CNG cells were diluted in growth medium and dispensed into 384-well black- wall, clear-bottom, PDL-coated plates (final concentration: 14,000 cells/well in 20 ⁇ ) and allowed to incubate for 24 hours at 37 C. Next, 20 ⁇ ⁇ of 2.5x concentrated membrane potential dye, prepared according to manufacturer instructions, was dispensed into each well. After incubating for 3 hours at room temperature, an initial fluorescent measurement (TO) was performed (510-545 nm excitation and 565-625 nm emission) using a EnVision fluorescence plate reader (Perkin Elmer, Turku,
  • Test compounds (10 ⁇ final concentration), DMSO alone (2% final concentration), or BIIE0246 (10 ⁇ final concentration) was added to sample or appropriate control wells, respectively along with NPY (50 nM final concentration), NECA (400 tiM final concentration; an al adrenergic receptor agonist that is used in all experiments to initiate a cAMP response that can then be modulated by Y2R ligands) and the phosphodiesterase inhibitor Ro-20- 1724 (25 ⁇ final concentration).
  • the plates were incubated for 45 minutes (Y2R) or 30 minutes (Y1R) at room temperature before the final fluorescence measurement (T45 or T30) was taken.
  • T45 or T30 value was divided by the background (TO).
  • "% antagonist activity" scores were then calculated by averaging replicate wells, subtracting background fluorescence (obtained in 1 ⁇ NPY alone treated wells) and then dividing by BIIE0246 treatment values, also tested at 10 ⁇ and after subtracting background.
  • BIIE0246 has the followin formula:
  • the antagonist activity percentage scores were calculated by averaging replicate wells, subtracting background fluorescence and then dividing by BIIE0246 treatment values, also tested at 10 ⁇ and after subtracting background (Tables 4-12).
  • NA not active
  • nt not tested.
  • NA not active
  • nt not tested.
  • NA not active
  • nt not tested.
  • Ph phenyl
  • Me methyl
  • Ac acetyl
  • Figure 2 shows the effect of NPY Y2 antagonist compound 518 (see Table 1) on alcohol intake behaviors in rats.
  • Figure 3 shows data supporting that NPY Y2 antagonist compound 518 (i.c.v.) blocks tumor-induced bone loss and tactile hypersensitivity.
  • Reagents and conditions (i) HSO 3 CI, reflux, overnight (general yields 70-90%); (ii) Py, 2,5-dimethyl aniline, DCM, rt, overnight (general yields 22-93%); (iii) 2- aminobiphenyl, HOBt, EDC1, DMF, rt, overnight (general yields 20-72%). Pyridine was not used for the synthesis of intermediates of certain members of the series.
  • Reagents and conditions (i) CH 3 I, K2CO3, CH3CN, DMF, reflux, overnight (yield 42%); (ii) LiOH, MeOH, THF, H 2 0 (yield 95%); (iii) 2-aminobiphenyl, HOBt, EDCl, DMF, rt, overnight (yield 22%); (iv) CH 3 I, t-BuOK, 18-crown-6, THF, rt, overnight (yield 47%).
  • a,a-diphenyl-4-piperidinemethanol (azacyclonol) analogues (3a-j), as shown in Table 4, above, were synthesized following the protocol described in scheme 5. Piperidine and the appropriate isocyanate or isothiocyanate were stirred for two hours in toluene.
  • Piperazine compounds (5a-k) were prepared according to Scheme 7similarly to procedures described for 3a-j; an iso(thio)cyanate was reacted with 1-benzhydrylpiperazine in toluene to form the corresponding (thio)urea in two hours.
  • Reagents and conditions (a) NaBH(OAc) 3 , AcOH, aniline, DCE, overnight, rt, (yield 84%); (b) TFA, DCM, lh, rt, quant; (c) toluene, 2h, rt, (general yields 5- 23%).
  • Reagents and conditions (a) B0C2O, 1,4-dioxane, H2O, NaOH, overnight, rt, (yield 94%); (b) HOBt, EDCl, TEA,DMF, NHMeOMe-HCl, overnight, rt, (yield 42%); (c) BuLi, 2-bromobiphenyl, TMEDA, THF, 3h, -78°C, (yield 35%) ; (d) TFA, DCM , lh, rt, (yield quant); (e) toluene, 2h, (yield 24%), (f) NaBH 4 , THF, MeOH, overnight, rt, (yield 25%).
  • Reagents and conditions (a) HOBt, EDCl, DCM, overnight, rt, (yield 69%); (b) TFA, DCM, lh, rt, (yield quant); (c) isothiocyanate, toluene, 2h, (yield 10%).
  • Amidesll were synthesized from a coupling between diphenylacetic acid and 1 -boc-4-aminopiperidine in the presence of HOBt and EDCl. After a deprotection, the piperidine reacted on the iso(thio)cyanate to give the corresponding (thio)urea lla-llb.
  • Compound 19 was synthesized from a coupling between the deprotected piperidone derivative and cyclopentylethanol which was first mesylated by a treatment with methansulfonylchloride. Then, in a similar manner as compound 15, 16, 17, 18, reductive animation followed by acetylation produced expected compound 20.
  • W is a linker as defined above, and core cyclic groups Ar 2 and Ar 3 are as defined above, the indole or indoline corresponding to group Ar 1 .
  • Reagents and conditions i) K 2 C0 3 , DMF, 80 °C, 5 h; (ii) TFA/CH 2 C1 2 , rt, 2 h; (iii) l l-chloro-5H-dibenzo[b,e]azepin-6(HH)-one (or) 1 l-chloro-5-methyl-5H- dibenzo[b,e]azepin-6(l lH)-one, DIEA, CH 3 CN, 1 10 °C, 1 h, microwave; (iv) SnCi 2 .2H 2 0, EtOH, 4 h; (V) RCOCl, Et 3 N, CH 2 C1 2 , 3 h (or) RNCO, CH 2 C1 2 , 3 h (or) RCOOH, EDCI, HOBt, CH 2 C1 2 , 18 h.
  • EtOH was heated to reflux for 4-6 h (monitored by LC-MS).
  • the solvents were removed in vacuo, the residue taken in 3 ⁇ 40, basified with IN aq.NaOH and CH 2 CI 2 was added.
  • the mixture was stirred for 2 h, transferred into a separating funnel; organic layer was separated, washed with 3 ⁇ 40 and sat.brine solution.
  • the organic layer was separated, dried over anhyd.Na 2 S0 4 , solvents removed in vacuo and the crude product was used for next step without purification.
  • Reagents and conditions i) K 2 C0 3 , DMF, 80 °C, 5 h; (ii) SnCl 2 .2H 2 0, EtOH, 4 h or 10%Pd-C, H 2 , MeOH, 4 h; (iii) RCOCl, Et 3 N, CH 2 C1 2 , 3 h (or) RCOOH, EDCI, HOBt, CH 2 C1 2 , 18 h; (iv) TFA/CH 2 C1 2 , rt, 2 h; (v) Ar 2 CHCl or
  • N-Boc deprotected intermediate 5 (1.1 equiv.), tricyclic or bicyclic chloride (1 equiv.) and DIEA (2 equiv.) in dry DMF or dry CH3CN was heated to 1 10 °C for 1 h under microwave irradiation.
  • the reaction mixture was diluted with ethyl acetate and washed with sat. NaHCC>3, H2O and sat. brine solution.
  • the organic layer was separated, dried over anhyd.Na2S0 4 , solvents removed in vacuo and the crude was purified by column chromatography.
  • Reagents and conditions i) DMSO, 80 °C, 5 h; (ii) DMF, 1 10 °C, 1 h, microwave; (iii) 2N aq.NaOH, MeOH, 50 °C, 4 h; (iv) RNH 2 , EDCI, HOBt, Et 3 N, DMF, 18 h.
  • Reagents and conditions i) dry THF, reflux, 2-4 h; (ii) CHCI 3 , H 2 S0 4 , reflux, 3 h; (iii) 10%Pd-C, H 2 , MeOH/CH 2 Cl 2 , overnight; (iv) K 2 C0 3 , DMF, 80 °C, overnight; (iv) 10%Pd-C, H 2 , MeOH, overnight; (v) RCOC1, Et 3 N, CH 2 C1 2 , 3 h (or) RNCO, CH 2 C1 2 , 3 h (or) RCOOH, EDCI, HOBt, CH 2 C1 2 , 18 h.
  • Reagents and conditions i) Pd(PPh 3 ) 4 , K2CO 3 , dioxane, 3 ⁇ 40, microwave, 150 °C, 1 h; (ii) 10%Pd-C, H 2 , MeOH, 2-5 h; (iii) RCOC1, Et 3 N, CH 2 C1 2 , 3 h (or) RCOOH, EDCI, HOBt, CH 2 C1 2 , 18 h; (iv) TFA/CH 2 C1 2 , rt, 3 h; (v) Ar-Cl, DIEA, DMF, 1 10 °C, 1 h, microwave.
  • N-Boc deprotected intermediate 17 (1.1 equiv.), tricyclic or bicyclic chloride (1 equiv.; prepared following the literature procedure) and DIEA (3 equiv.) in dry DMF or dry CH 3 CN was heated to 1 10 °C for 1 h under microwave irradiation.
  • the reaction mixture was diluted with ethyl acetate and washed with sat. NaHCC>3, 3 ⁇ 40 and sat. brine solution.
  • the organic layer was separated, dried over anhyd.Na2S0 4 , solvents removed in vacuo and the crude was purified by column chromatography.
  • Reagents and conditions i) K2CO 3 , DMF, 80 °C, overnight.
  • n erme a e Reagents and conditions i) K 2 C0 3 , DMF, 80 °C, overnight; (ii) 2N aq.NaOH, MeOH, 50 °C, 2 h; (iii) EDCI, HOBt, dry DMF, lh, then alkylamide oxime 4 h at r.t. and overnight at 50 °C; (iv) TFA/CH 2 C1 2 , rt, 2-3 h; (v) Ar 2 CH-Cl, DIEA, CH 3 CN, 1 10 °C, 1 h, microwave.

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Abstract

The invention provides compounds that are modulators of neuropeptide Y (NPY) receptors, which can be selective inhibitors of NPY receptor Y2R. NPY receptor modulatory compounds are of the general formula Ar2-Y-Ar1-W-Ar3, wherein the variables are as defined herein. Compounds of the invention can be used for treatment of malconditions in patients wherein modulation of an NPY receptor is medically indicated, for example including drug or alcohol abuse, anxiety disorders, depression, stress-related disorders, neurological disorders, nerve degeneration, osteoporosis or bone loss, sleep/wake disorders, cardiovascular diseases, obesity, anorexia, inovulation, fertility disorders, angiogenesis, cell proliferation, learning and memory disorders, migraine and pain.

Description

NON-PEPTIDIC NEUROPEPTIDE Y RECEPTOR MODULATORS
CROSS-REFERENCE TO RELATED APPLICATIONS
This application claims the priority of U.S. provisional application Serial No. 61/755,183, filed January 22, 2013, the disclosure of which is incorporated herein by reference in its entirety.
STATEMENT OF GOVERNMENT SUPPORT
This work was supported by MH084512 from the National Institutes of Health. The goverment has certain rights in this invention.
BACKGROUND
Neuropeptide Y (NPY) is a highly conserved 36-aminoacid peptide neurotransmitter, structurally and functionally related to the 36-amino acid pancreatic peptide (PYY) and pancreatic polypeptide (PP).1 2Five different receptor subtypes [Yl, Y2, Y3, Y4 (PP), Y5] are abundantly expressed in both the central and peripheral nervous systems and have been identified as endogenous receptor proteins binding NPY, PYY and/or PP. All NPY receptor subtypes are G protein coupled receptors that typically couple to God signaling pathways. The NPY-Y2 receptor (Y2R) has been of particular interest since it has been associated with various physiological and pathological processes such as affective disorders, infertility, bone mass formation, responses to ethanol and drugs of abuse, angiogenesis, and food intake.3
Animal and human studies have suggested that NPY might be directly implicated in the pathophysiology of affective disorders such as depression, anxiety, and stress-related disorders. Low levels of NPY have been found in cerebrospinal fluid and plasma of patients with major depression as well as in individuals predisposed to anxiety-related depression.2' 4 Therefore, compounds that mimic NPY may be useful for the treatment of anxiolytic disorders. The anxiolytic properties of NPY are mediated through postsynaptic neuropeptide Y- Yl receptors (YIRs), whereas presynaptic Y2Rs negatively control the release of NPY and other cotransmitters such as GAB A. Blockade of Y2 receptors produces anti-stress effects indistinguishable from those produced by Yl agonism, presumably through potentiation of presynaptic release of endogenous NPY. Consequently, Y2R antagonists may prove useful in the treatment of depression, anxiety and stress-related disorders via the induced enhanced GABAergic and NPYergic effects.3
NPY also plays a critical role in mediating endocrine functions such as the release of the luteinizing hormone (LH) involved in mammalian ovulation.5 Particularly, suppression of LH secretion in human appears to be mediated by Y2Rs as demonstrated by the negative regulation of the reproductive axis in ovariectomized animals.6 Therefore, Y2R antagonists could be useful for the treatment of infertility, particularly in women with luteal phase defects.
In addition, NPY, a classic neuronal regulator of energy homeostasis, is now also known to beinvolved in the control of bone homeostasis. Of the five known Y receptors through which the NPY familyof ligands signals, the Yl and Y2 receptors have so far been implicated in the control of osteoblast activityand thus bone formation. Analysis of brain specific NPY overexpressing and Y receptor knockout modelshas revealed a powerful anabolic pathway likely involving hypothalamic Y2 receptors and osteoblastic Yl receptors. Furthering our understanding of the mechanisms underlying the involvement of the NPY systemin the control of bone could lead to the development of therapies to improve bone mass in patientswith diseases such as osteoporosis e.g Post- menapausal osteoporosis and in bone cancer pain and bone loss (Herzog, 2009).
Recently, the involvement of presynaptic Y2Rs has been suggested in the central regulation of bone mass homeostasis and Y2R antagonist effect has been shown to result in an increased bone formation.7 Pharmacological studies have also demonstrated a decreased ethanol consumption in Y2R knockout mice, thus suggesting a possible therapeutic application of Y2R modulators in the alcohol and drug abuse.8
NPY has been demonstrated to have potent angiogenic effects and to play a significant role in ischemic revascularization, primarily via the activation of Y2Rs. Thus, Y2R stimulation may afford a novel therapy for impaired vascularization in ischemia, wound healing, aging. On the other hand, NPY is also involved in pathologic angiogenesis such as in tumors and retinopathy and, in these conditions, Y2R antagonists could be therapeutic.9 NPY has been strongly implicated in mediating pain and inflammation. Both the YIR and the Y2R are involved in mediating pain signaling in the brain. Injection of NPY elicits an analgesic response, which is thought to be a result of YIR or Y2Rmodulation. Experiments on rodents and monkeys have also shown that many of the small dorsal root ganglion, which relay sensory information from the periphery to the spine, express both Yl and Y2 receptors. The Y2 receptor may be of particular interest when considering peripheral-to -central pain sensory transmission, and it has been proposed that a peripherally active Y2R antagonist would be useful in reducing pain sensitivity.
To date, NPY is considered to be the most powerful orexigenic peptide isolated.11 NPY receptor antagonists may be useful for the treatment of diabetes and eating disorders including obesity, anorexia and bulimia nervosa. Despite an increase in the amount of food intake associated with the lack of feedback inhibition of the postprandially released PYY, Y2R antagonism has been suggested to reduce body weight.11 ' 3Y2R antagonists locally administered into the fat, may be a novel way for reducing the fat and a therapy for obesity by their anti-angiogenic effects exerting an anti-adipogenic action mediated by an increased apoptosis of endothelial cells.9
Grouzmann and coworkers described a peptide-based ligand T4-[NPY 33-36], which showed nanomolar antagonist activity at Y2Rs (IC50 = 67 nM). BIIE0246 was then demonstrated to elicit more potent antagonist activity at the Y2Rs (IC50 = 3.3 nM). However, the potential therapeutic application of these compounds is limited due to their peptide-like structure, high molecular weight,
12
poor brain penetration and selectivity issues. Several attempts have been made to create a selective Y2R antagonist, with relatively little success.
SUMMARY
The invention is directed in various embodiments to compounds that at an effective concentration in vivo in a patient can modulate the action of a receptor of neuropeptide Y (NPY), to pharmaceutical formulations and combinations of the compounds, to use of the compounds for modulating NPY receptors, and to treatment of malconditions in patients wherein modulation of an NPY receptor is medically indicated. In various embodiments, the invention provides a compound of formula
Figure imgf000006_0001
wherein
ring A comprises 0-2 nitrogen atoms; or, ring B comprises 0-2 nitrogen atoms; or, both; and, each of ring A and ring B is independently substituted with n independently selected J groups;
or, ring A is absent and the two carbon atoms connecting X1 and X3 are mutually double bonded and each independently bears hydrogen or (C 1 -
C6)alkyl, or the two carbon atoms are mutually single bonded and together with a methano bridge therebetween form a cyclopropyl, and ring B is substituted with n independently selected J groups;
or, ring B is absent and the two carbon atoms connecting X1 and X3 are mutually double bonded and each independently bears hydrogen or (C 1 -
C6)alkyl, or the two carbon atoms are mutually single bonded and together with a methano bridge therebetween form a cyclopropyl, and ring A is substituted with n independently selected J groups; and,
Cyc is single -bonded or double -bonded to any one of X1, X2, or X3, provided that when X3 is C=0 or O, Cyc is bonded to X1 or X2; and, a single bond or a double bond is present between X1 and X2; such that,
when a single bond is present between X1 and X2,
X1 is CHRC, C=0, or NR', unless Cyc is single-bonded to X1, then X1 is CRC or N, or unless Cyc is double-bonded to X1, then X1 is a carbon atom; X2 is CHRC, C=0, or NR', unless Cyc is single-bonded to X2, then X2 is CRC or N, or unless Cyc is double-bonded to X2, then X2 is a carbon atom;
X3 is CHRC, NR', C=0, or O; unless Cyc is single-bonded to X3, then X3 is CRC or N, or unless Cyc is double-bonded to X3, then X3 is a carbon atom; provided that when one of X and X is C=0 and the other of X and X is NR', tthheenn XX33 iiss CCRRCC oorr NN aanndd CCyycc iiss ssingle-bonded to X3; or X3 is a carbon atom and Cyc is double-bonded thereto,
or, when a double bond is present between X1 and X2,
X1 is CRC or N, unless Cyc is bonded to X1, then X1 is a carbon atom; X2 is CRC or N, unless Cyc is bonded to X2, then X2 is a carbon atom; X3 is CRC, NR', C=0, or O; unless Cyc is single-bonded to X3, then X3 or N, or unless Cyc is double-bonded to X3, then X3 is a carbon atom; each n is independently 0, 1, 2, 3, or 4;
Cyc is
Figure imgf000007_0001
Figure imgf000007_0002
Figure imgf000007_0003
wherein W is CRC or N, each Rcyc is independently selected halo, (Cl-C6)alkyl, or (C 1 -C6)alkoxyl; p is 0, 1, or 2; wherein wavy lines indicate points of bonding; or,
Cyc is
Figure imgf000008_0001
lines indicate points of bonding; and, Q is a bond, C(=NR)NR, C(=N-CN)NR, OC(=NR)NR, OC(=N-CN)NR, NRC(=NR)NR, NRC(=N-CN)NR, C(=0)NR, C(=0)0, OC(=0)0, OC(=0)NR, NRC(=0)NR, C(=S)NR, OC(=S)NR, NRC(=S)NR, C(=CR2)NR, OC(=CR2)NR, NRC(=CR2)NR, NR, C(=0)CHR"NRC(=0)OCH2,
C(=0)CHR"NRC(=0)NRCH2, C(=0)CHR"NRC(=S)NRCH2, C(=O)(CR2)0-3,
Figure imgf000008_0002
NRS(0)q wherein q is 0, 1, or 2;
HA is aryl or heteroaryl substituted with 0, 1 , or 2 substituents independently selected from the group consisting of halo, cyano, (Cl-C6)alkyl, (Cl-C6)alkoxyl, and C02R', and further substituted with JHA;
JHA is (CH2)o-2RJ, (CH2)o-2ORJ, (CH2)0-2N(RJ)2, (CH2)0-2SRJ, (CH2)o- 2SORJ, (CH2y2S02RJ, (CH2)o-2S02N(RJ)2, (CH2)0-2SO3RJ, (CH2)0-2C(O)RJ, (CH2)o-2C(0)C(0)RJ, (CH2)o-2C(0)CH2C(0)RJ, (CH2)0-2C(O)ORJ, (CH2)0- 2OC(0)RJ, (CH2y2OC(0)ORJ, (CH2)0-2C(O)N(RJ)2, (CH2)0-2OC(O)N(RJ)2, (CH2)o-2N(RJ)C(0)RJ, (CH2)o-2N(RJ)C(0)ORJ, (CH2)0-2N(RJ)C(O)N(RJ)2, (CH2)o-2N(RJ)N(RJ)C(0)RJ, (CH2)0-2N(RJ)N(RJ)C(O)ORJ, (CH2)0- 2N(RJ)N(RJ)CON(RJ)2, (CH2)0-2N(RJ)SO2RJ, (CH2)0-2N(RJ)SO2N(RJ)2, (CH2)0- 2C(S)RJ, (CH2)o-2OC(S)RJ, (CH2)0-2N(RJ)C(S)RJ, (CH2)0-2N(RJ)C(S)N(RJ)2, (CH2)o-2C(S)N(RJ)2, (CH2)o-2N(CORJ)CORJ, (CH2)0-2N(ORJ)RJ, (CH2)0- 2C(=NRJ)N(RJ)2, (CH2)o-2C(0)N(ORJ)RJ, and (CH2)0-2C(=NORJ)RJ,
each independently selected R' is H or (C 1 -C6)alkyl, and n' = 0, 1, or 2; each independently selected R" is H, (C 1 -C6)alkyl, or (CH2)mNR2 wherein m is 1, 2, 3, or 4;
each independently selected Rc is H, halo, (Cl-C6)alkyl, OH, or (Cl- C6)alkoxyl;
R is independently at each occurrence hydrogen or an alkyl, acyl, cycloalkyl, cycloalkylalkyl, aryl, aroyl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, wherein any alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl is substituted with 0-3 J; or wherein two R groups together with a nitrogen atom or with two adjacent nitrogen atoms to which they are bonded can together form a (C3-C8)heterocyclyl substituted with 0-3 J; optionally further comprising 1-3 additional heteroatoms selected from the group consisting of O, N, and S(0)q; wherein any cycloalkyl, aryl, heterocyclyl, or heteroaryl can be fused, bridged, or in a spiro configuration with one or more additional optionally substituted cycloalkyl, aryl, heterocyclyl, and heteroaryl, monocyclic, bicyclic or polycyclic, saturated, partially unsaturated, or aromatic rings;
wherein J independently at each occurrence is selected from the group consisting of F, CI, Br, I, OR, CN, CF3, OCF3, O, S, C(O), S(O),
methylenedioxy, ethylenedioxy, (CH2)o-2N(RJ)2, (CH2)0-2SRJ, (CH2)0-2SORJ, (CH2)o-2S02RJ, (CH2)o-2S02N(RJ)2, (CH2)0-2SO3RJ, (CH2)0-2C(O)RJ, (CH2)0- 2C(0)C(0)RJ, (CH2)o-2C(0)CH2C(0)RJ, (CH2)0-2C(S)RJ, (CH2)0-2C(O)ORJ, (CH2)o-2OC(0)RJ, (CH2)o-2OC(0)ORJ, (CH2)0-2C(O)N(RJ)2, (CH2)0- 2OC(0)N(RJ)2, (CH2)o-2C(S)N(RJ)2, (CH2)0-2N(RJ)C(O)RJ, (CH2)0- 2N(RJ)N(RJ)C(0)RJ, (CH2)o-2N(RJ)N(RJ)C(0)ORJ, (CH2)0- 2N(RJ)N(RJ)CON(RJ)2, (CH2)0-2N(RJ)SO2RJ, (CH2)0-2N(RJ)SO2N(RJ)2, (CH2)0- 2N(RJ)C(0)ORJ, (CH2)o-2N(RJ)C(0)RJ, (CH2)0-2N(RJ)C(S)RJ, (CH2)0-
2N(RJ)C(0)N(RJ)2, (CH2)o-2N(RJ)C(S)N(RJ)2, (CH2)0-2N(CORJ)CORJ, (CH2)0- 2N(ORJ)RJ, (CH2)o-2C(=NRJ)N(RJ)2, (CH2)0-2C(O)N(ORJ)RJ, and (CH2)0- 2C(=NORJ)RJ,
wherein RJ is independently at each occurrence selected from the group consisting of hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl, wherein any alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, is unsubstituted or is substituted with 1 , 2, or 3 substituents independently selected from the group consisting of (C 1 -C6)alkyl and (C6-C10)aryl; or wherein two RJ groups together with a nitrogen atom or with two adjacent nitrogen atoms to which they are bonded can together form a (C3-C8)heterocyclyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of (Cl-C6)alkyl and (C6- C10)aryl, and optionally further comprising 1-3 additional heteroatoms selected from the group consisting of O, N, S, S(O) and S(0)2;
or a pharmaceutically acceptable salt thereof.
For example, the invention can provide a compound of formula (III) as shown in Table 1.
In various embodiments, the invention provides a compound of formula
(I):
Ar2^ ^ Ar\ ^ Ar3
Y W
(I)
wherein Ar1, Ar2 and Ar3 each independently selected from the group consisting of cycloalkyl, aryl, heterocyclyl, and heteroaryl, provided that Ar3 can also be hydrogen, wherein any cycloalkyl, aryl, heterocyclyl, or heteroaryl is mono- or independently multi-substituted with J, (Ci-C6)alkyl, (C2-Ce)alkenyl, (C2-C6)alkynyl, (Ci-C6)haloalkyl, (Ci-C6)alkoxy, (Ci-C6)haloalkoxy, cycloalkyl(Co-C6)alkyl, heterocyclyl(Co-Ce) alkyl, aryl(Co-Ce) alkyl, or heteroaryl(Co-Ce)alkyl; wherein any alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, aryl, heterocyclyl, or heteroaryl can be further substituted with J;
W and Y are each independently selected from the group consisting of a single bond, a double bond, ((CH2)o-2CR2(CH2)o-2, (CH2)o-20(CH2)0-2, (CH2)0- 2C(0)(CH2)o-2, (CH2)o-2C(OR)(R)(CH2)o-2, (CH2)o-2N(R)C(0)(CH2)0-2, (CH2)0- 2N(R)C(S)(CH2)o-2R, 0(CR2)nO wherein n is 1 to 4, (CH2)o-2N(R)(CH2)0-2, (CH2)o-2S(0)q(CH2)o-2 wherein q = 0, 1, or 2, (CH2)o-2S02N(R)(CH2)o-2, (CH2)0- 2S03(CH2)o-2, (CH2)o-2C(0)C(0)(CH2)o-2, (CH2)o-2C(0)CH2C(0)(CH2)o-2, (CH2)o-2C(S)(CH2)o-2, (CH2)o-2C(0)0(CH2)o-2, (CH2)o-2C(0)C(R)2(CH2)o-2, (CH2)o-20C(0)0(CH2)o-2, (CH2)o-20C(0)N(R)(CH2)o-2, (CH2)o- 2N(R)C(0)N(R)(CH2)o-2, (CH2)o-2N(R)C(S)N(R)(CH2)o-2, (CH2)o- 2C(S)N(R)(CH2)o-2, (CH2)o-2N(R)N(R)C(0)(CH2)o-2, (CH2)o- 2N(R)N(R)C(0)0(CH2)o-2, (CH2)o-2N(R)N(R)CON(R)(CH2)0-2, (CH2)0- 2N(R)S02(CH2)o-2, (CH2)o-2N(R)S02N(R)(CH2)o-2, (CH2)o-2N(COR)CO(CH2)o-2, (CH2)o-2N(OR)(CH2)o-2, (CH2)0- 2C(=NR)N(R)(CH2)o-2, (CH2)o-2C(=CR2)N(R)(CH2)o-2, (CH2)0- 2C(0)N(OR)(CH2)o-2, (CH2)o-2C(=NOR)(CH2)o-2 and thiazolyl;
or wherein an R group of Y together with Ar2 and the atom to which it is bonded together form a heterocyclyl or cycloalkyl ring; or wherein an R group of W together with Ar3 and the atom to which it is bonded together form a heterocyclyl or cycloalkyl ring; or both;
wherein R is independently at each occurrence selected from the group consisting of hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl, wherein any alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl is substituted with 0-3 J; or wherein two R groups together with a nitrogen atom or with two adjacent nitrogen atoms to which they are bonded can together form a (C3-C8)heterocyclyl substituted with 0-3 J; optionally further comprising 1 -3 additional heteroatoms selected from the group consisting of O, N, S, S(0) and S(0)2;
wherein any cycloalkyl, aryl, heterocyclyl, or heteroaryl can be fused, bridged, or in a spiro configuration with one or more additional optionally substituted cycloalkyl, aryl, heterocyclyl, and heteroaryl, monocyclic, bicyclic or polycyclic, saturated, partially unsaturated, or aromatic rings;
wherein J independently at each occurrence is selected from the group consisting of F, CI, Br, I, OR, CN, CF3, OCF3, O, S, C(O), S(O),
methylenedioxy, ethylenedioxy, N(RJ)2, SRJ, SORJ, S02RJ, S02N(RJ)2, S03RJ, C(0)RJ, C(0)C(0)RJ, C(0)CH2C(0)RJ, C(S)RJ, C(0)ORJ, OC(0)RJ,
OC(0)ORJ, C(0)N(RJ)2, OC(0)N(RJ)2, C(S)N(RJ)2, (CH2)0-2NHC(O)RJ,
N(RJ)N(RJ)C(0)RJ, N(RJ)N(RJ)C(0)ORJ, N(RJ)N(RJ)CON(RJ)2, N(RJ)S02RJ, N(RJ)S02N(RJ)2, N(RJ)C(0)ORJ, N(RJ)C(0)RJ, N(RJ)C(S)RJ, N(RJ)C(0)N(RJ)2, N(RJ)C(S)N(RJ)2, N(CORJ)CORJ, N(ORJ)RJ, C(=NRJ)N(RJ)2, C(0)N(ORJ)RJ, and C(=NORJ)RJ,
wherein RJ is independently at each occurrence selected from the group consisting of hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl, or wherein two RJ groups together with a nitrogen atom or with two adjacent nitrogen atoms to which they are bonded can together form a (C3-C8)heterocyclyl optionally further comprising 1 -3 additional heteroatoms selected from the group consisting of O, N, S, S(O) and S(0)2;
or a salt or hydrate thereof;
following:
Figure imgf000012_0001
Figure imgf000013_0001
Figure imgf000014_0001
In various embodiments, the invention provides a compound of formula
(Π)
Figure imgf000014_0002
wherein
each independently selected R is H, aryl, or heteroaryl;
each independently selected R2 is H, OH, (Cl-C6)alkoxy, NR2, (Cl- C6)alkoxycarbonyl, -N(R)C(=0)(Cl-C6)alkyl,or -C(=0)NR2;
k is 0, 1, or 2;
n is 0, 1, 2, 3, or 4;
Cyc is
Figure imgf000014_0003
or N, and wavy lines indicate points of bonding, or,
Cyc is N-o , and wavy lines indicate points of bonding, or,
Cyc is absent; Q is a bond, C(=NR)NR, OC(=NR)NR, NRC(=NR)NR, C(=0)NR, C(=0)0, OC(=0)0, OC(=0)NR, NRC(=0)NR, C(=S)NR, OC(=S)NR, NRC(=S)NR, C(=CR2)NR, OC(=CR2)NR, NRC(=CR2)NR, NR,
C(=0)CHR"NRC(=0)OCH2, C(=0)CHR"NRC(=0)NRCH2,
C(=0)CHR"NRC(=S)NRCH2, C(=O)(CHR)0-3,C(=C(CN)(CO2CH3))NH, or Q is
Figure imgf000015_0001
wherein a wavy line indicated a point of attachment, or, Q is S(0)q or NRS(0)q wherein q is 0, 1, or 2;
HA is aryl or heteroaryl, wherein any aryl or heteroaryl is substituted with 0, 1, 2, 3, or 4 J;
each independently selected R" is H, (C 1 -C6)alkyl, or (CH2)mNR2 wherein m is 1, 2, 3, or 4;
R is independently at each occurrence hydrogen or an alkyl, acyl, cycloalkyl, cycloalkylalkyl, aryl, aroyl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, wherein any alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl is substituted with 0-3 J; or wherein two R groups together with a nitrogen atom or with two adjacent nitrogen atoms to which they are bonded can together form a (C3-C8)heterocyclyl substituted with 0-3 J; optionally further comprising 1-3 additional heteroatoms selected from the group consisting of O, N, and S(0)q; wherein any cycloalkyl, aryl, heterocyclyl, or heteroaryl can be fused, bridged, or in a spiro configuration with one or more additional optionally substituted cycloalkyl, aryl, heterocyclyl, and heteroaryl, monocyclic, bicyclic or polycyclic, saturated, partially unsaturated, or aromatic rings;
wherein J independently at each occurrence is selected from the group consisting of F, CI, Br, I, OR, CN, CF3, OCF3, O, S, C(O), S(O),
methylenedioxy, ethylenedioxy, N(RJ)2, SRJ, SORJ, S02RJ, S02N(RJ)2, S03RJ, C(0)RJ, C(0)C(0)RJ, C(0)CH2C(0)RJ, C(S)RJ, C(0)ORJ, OC(0)RJ,
OC(0)ORJ, C(0)N(RJ)2, OC(0)N(RJ)2, C(S)N(RJ)2, (CH2)0-2NHC(O)RJ, N(RJ)N(RJ)C(0)RJ, N(RJ)N(RJ)C(0)ORJ, N(RJ)N(RJ)CON(RJ)2, N(RJ)S02RJ, N(RJ)S02N(RJ)2, N(RJ)C(0)ORJ, N(RJ)C(0)RJ, N(RJ)C(S)RJ, N(RJ)C(0)N(RJ)2, N(RJ)C(S)N(RJ)2, N(CORJ)CORJ, N(ORJ)RJ, C(=NRJ)N(RJ)2, C(0)N(ORJ)RJ, and C(=NORJ)RJ,
wherein RJ is independently at each occurrence selected from the group consisting of hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl, or wherein two RJ groups together with a nitrogen atom or with two adjacent nitrogen atoms to which they are bonded can together form a (C3-C8)heterocyclyl optionally further comprising 1 -3 additional heteroatoms selected from the group consisting of O, N, S, S(O) and S(0)2;
or a salt or hydrate thereof,
following:
Figure imgf000016_0001
Figure imgf000017_0001
Figure imgf000018_0001
In various embodiments, the invention provides pharmaceutical compositions and combinations comprising a compound of the invention, e.g., a compound of any one of formula (III), or of formula (I), or of formula (II).
In various embodiments, the invention provides a method of modulating a Neuropeptide Y (NPY) receptor, comprising contacting the receptor and an effective amount or concentration of a compound of the invention, e.g., a compound of any one of formula (III), or of formula (I), or of formula (II).
In various embodiments, the invention provides a method of treating a malcondition in a patient wherein modulation of an NPY receptor is medically indicated, comprising administering to the patient a compound of the invention, e.g., a compound of any one of formula (III), or of formula (I), or of formula (II), in a dose, at a frequency of administration, and for a duration of time sufficient to provide a beneficial effect to the patient. The malcondition can include, but is not limited to, drug or alcohol abuse, anxiety disorders, depression, stress-related disorders, neurological disorders, nerve degeneration, osteoporosis or bone loss, sleep/wake disorders, cardiovascular diseases, obesity, anorexia, inovulation, fertility disorders, angiogenesis, cell proliferation, learning and memory disorders, migraine and pain. In various embodiments, the invention provides a dosage form comprising a compound, composition, or combination of the invention for administration to a patient when medically indicated. BRIEF DESCRIPTION OF THE FIGURES
Figure 1 shows dose-response curves for (A) compound 3 and (B) compound 4,shown in Table l,with respect to the Y2R and YIR neuropeptide Y receptor subclasses.
Figure 2 shows the effect of NPY Y2 antagonist compound 518 (see Table 1) on alcohol intake behaviors in rats. A) Drinking In the Dark: Limited access for four hours per day. Ethanol-concentration increases over training time with the final concentration being 10%. B) Operant self-administration at FR-1, 10% ethanol-solution.
Figure 3 shows data supporting that NPY Y2 antagonist compound 518 (i.c.v.) blocks tumor-induced bone loss and tactile hypersensitivity. A.
Representative images of contralateral (control) and ipsilateral (tumor) bones 15 days following implantation of cancer cells. Tumor growth produced bone loss in the proximal end of the tumor bearing bone in the vehicle treated rats (arrow), compound 518 administration (i.c.v.) blocked the tumor induced bone loss. B. Injection of tumor into the bone produced tactile hypersensitivity within 15 days in the vehicle treated rats. This was blocked in the compound 518 treated rats. Graphs mean ± SEM, n=4-6.
DETAILED DESCRIPTION
Definitions
As used in the specification and the appended claims, the singular forms "a," "an" and "the" include plural referents unless the context clearly dictates otherwise.
The term "about" as used herein, when referring to a numerical value or range, allows for a degree of variability in the value or range, for example, within 10%, or within 5% of a stated value or of a stated limit of a range. As used herein, "individual" (as in the subject of the treatment) means both mammals and non-mammals. Mammals include, for example, humans; non-human primates, e.g. apes and monkeys; and non-primates, e.g. dogs, cats, cattle, horses, sheep, and goats. Non-mammals include, for example, fish and birds.
The term "disease" or "disorder" or "malcondition" are used
interchangeably, and are used to refer to diseases or conditions wherein NPY plays a role in the biochemical mechanisms involved in the disease or malcondition such that a therapeutically beneficial effect can be achieved by acting on anNPY receptor. "Acting on" an NPY receptor can include binding to an NPY receptor and/or inhibiting the bioactivity of an NPY receptor.
"NPY" refers to Neuropeptide Y, a peptidyl neurotransmitter discussed above. An "NPY receptor" is a molecular entity found in living organisms such as human beings that interacts specifically with NPY and transduces the interaction of NPY into altered cellular function or behavior in the living organism. Five different subtypes of endogenous binding receptor proteins have been identified, as discussed above, which are termed herein Y1R, Y2R, Y3R, Y4R,and Y5R.
The expression "effective amount", when used to describe therapy to an individual suffering from a disorder, refers to the amount of a compound of the invention that is effective to inhibit or otherwise act on an NPY receptor in the individual's tissues wherein such inhibition or other action occurs to an extent sufficient to produce a beneficial therapeutic effect.
A receptor is "modulated" by a compound when the compound is either an agonist or activator, or an antagonist, inhibitor or inverse agonist, of the receptor. A compound is an agonist or activator when it acts on the receptor to stimulate the function of the receptor, such as is done by an endogenous agonist ligand. A compound is an antagonist, inhibitor, or inverse agonist when the compound blocks the effect of an endogenous receptor ligand, preventing functioning of the receptor. A compound is a "selective modulator" when it modulates one class or subclass of receptor, for example Y2R, at a concentration or in an amount that is not effective to modulate a different class or subclass of receptor, for example Y1R. As the term is used herein, a compound of the invention is a selective modulator of Y2R when it has an effect on Y2R at a concentration or in an amount that does not modulate YIR, or does not modulate any other receptor in a patient to any significant extent, or both.
"Substantially" as the term is used herein means completely or almost completely; for example, a composition that is "substantially free" of a component either has none of the component or contains such a trace amount that any relevant functional property of the composition is unaffected by the presence of the trace amount, or a compound is "substantially pure" is there are only negligible traces of impurities present.
"Treating" or "treatment" within the meaning herein refers to an alleviation of symptoms associated with a disorder or disease, or inhibition of further progression or worsening of those symptoms, or prevention or prophylaxis of the disease or disorder, or curing the disease or disorder.
Similarly, as used herein, an "effective amount" or a "therapeutically effective amount" of a compound of the invention refers to an amount of the compound that alleviates, in whole or in part, symptoms associated with the disorder or condition, or halts or slows further progression or worsening of those symptoms, or prevents or provides prophylaxis for the disorder or condition. In particular, a "therapeutically effective amount" refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic result. A therapeutically effective amount is also one in which any toxic or detrimental effects of compounds of the invention are outweighed by the therapeutically beneficial effects.
By "chemically feasible" is meant a bonding arrangement or a compound where the generally understood rules of organic structure are not violated; for example a structure within a definition of a claim that would contain in certain situations a pentavalent carbon atom that would not exist in nature would be understood to not be within the claim. The structures disclosed herein, in all of their embodiments are intended to include only "chemically feasible" structures, and any recited structures that are not chemically feasible, for example in a structure shown with variable atoms or groups, are not intended to be disclosed or claimed herein. When a substituent is specified to be an atom or atoms of specified identity, "or a bond", a configuration is referred to when the substituent is "a bond" that the groups that are immediately adjacent to the specified substituent are directly connected to each other in a chemically feasible bonding configuration.
All chiral, diastereomeric, racemic forms of a structure are intended, unless a particular stereochemistry or isomeric form is specifically indicated. Compounds used in the present invention can include enriched or resolved optical isomers at any or all asymmetric atoms as are apparent from the depictions, at any degree of enrichment. Both racemic and diastereomeric mixtures, as well as the individual optical isomers can be isolated or synthesized so as to be substantially free of their enantiomeric or diastereomeric partners, and these are all within the scope of the invention.
The inclusion of an isotopic form of one or more atoms in a moleculethat is different from the naturally occurring isotopic distribution of the atom in nature is referred to as an "isotopically labeled form" of the molecule. All isotopic forms of atoms are included as options in the composition of any molecule, unless a specific isotopic form of an atom is indicated. For example, any hydrogen atom or set thereof in a molecule can be any of the isotopic forms of hydrogen, i.e., protium ('Η), deuterium (2H), or tritium (3H) in any combination. Similarly, any carbon atom or set thereof in a molecule can be any of the isotopic form of carbons, such as 11 C, 12C, 13C, or 14C, or any nitrogen atom or set thereof in a molecule can be any of the isotopic forms of nitrogen, such as 13N, 14N, or 15N. A molecule can include any combination of isotopic forms in the component atoms making up the molecule, the isotopic form of every atom forming the molecule being independently selected. In a multi- molecular sample of a compound, not every individual molecule necessarily has the same isotopic composition. For example, a sample of a compound can include molecules containing various different isotopic compositions, such as in a tritium or 14C radiolabeled sample where only some fraction of the set of molecules making up the macroscopic sample contains a radioactive atom. It is also understood that many elements that are not artificially isotopically enriched themselves are mixtures of naturally occurring isotopic forms, such as 14N and 15N, 32S and 34S, and so forth. A molecule as recited herein is defined as including isotopic forms of all its constituent elements at each position in the molecule. As is well known in the art, isotopically labeled compounds can be prepared by the usual methods of chemical synthesis, except substituting an isotopically labeled precursor molecule. The isotopes, radiolabeled or stable, can be obtained by any method known in the art, such as generation by neutron absorption of a precursor nuclide in a nuclear reactor, by cyclotron reactions, or by isotopic separation such as by mass spectrometry. The isotopic forms are incorporated into precursors as required for use in any particular synthetic route. For example, 14C and 3H can be prepared using neutrons generated in a nuclear reactor. Following nuclear transformation, 14C and 3H are incorporated into precursor molecules, followed by further elaboration as needed.
The term "amino protecting group" or "N-protected" as used herein refers to those groups intended to protect an amino group against undesirable reactions during synthetic procedures and which can later be removed to reveal the amine. Commonly used amino protecting groups are disclosed in Protective Groups in Organic Synthesis, Greene, T.W.; Wuts, P. G. M., John Wiley & Sons, New York, NY, (3rd Edition, 1999). Amino protecting groups include acyl groups such as formyl, acetyl, propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl, 2- bromoacetyl, trifluoroacetyl, trichloroacetyl, o-nitrophenoxyacetyl, a- chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, 4-nitrobenzoyl, and the like; sulfonyl groups such as benzenesulfonyl, p-toluenesulfonyl and the like; alkoxy- or aryloxy-carbonyl groups (which form urethanes with the protected amine) such as benzyloxycarbonyl (Cbz), p-chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2- nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, 3,4- dimethoxybenzyloxycarbonyl, 3,5-dimethoxybenzyloxycarbonyl, 2,4- dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2-nitro-4,5- dimethoxybenzyloxycarbonyl, 3,4,5-trimethoxybenzyloxycarbonyl, 1 -(p- biphenylyl)- l-methylethoxycarbonyl, a,a-dimethyl-3,5- dimethoxybenzyloxycarbonyl, benzhydryloxycarbonyl, t-butyloxycarbonyl (Boc), diisopropylmethoxycarbonyl, isopropyloxycarbonyl, ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl (Alloc), 2,2,2-trichloroethoxycarbonyl, 2- trimethylsilylethyloxycarbonyl (Teoc), phenoxycarbonyl, 4- nitrophenoxycarbonyl, fluorenyl-9-methoxycarbonyl (Fmoc),
cyclopentyloxycarbonyl, adamantyloxycarbonyl, cyclohexyloxycarbonyl, phenylthiocarbonyl and the like; aralkyl groups such as benzyl, triphenylmethyl, benzyloxymethyl and the like; and silyl groups such as trimethylsilyl and the like. Amine protecting groups also include cyclic amino protecting groups such as phthaloyl and dithiosuccinimidyl, which incorporate the amino nitrogen into a heterocycle. Typically, amino protecting groups include formyl, acetyl, benzoyl, pivaloyl, ?-butylacetyl, phenylsulfonyl, Alloc, Teoc, benzyl, Fmoc, Boc and Cbz. It is well within the skill of the ordinary artisan to select and use the appropriate amino protecting group for the synthetic task at hand.
The term "hydroxyl protecting group" or "O-protected" as used herein refers to those groups intended to protect an OH group against undesirable reactions during synthetic procedures and which can later be removed to reveal the hydroxyl group. Commonly used hydroxyl protecting groups are disclosed in Protective Groups in Organic Synthesis, Greene, T.W.; Wuts, P. G. M., John Wiley & Sons, New York, NY, (3rd Edition, 1999). Hydroxyl protecting groups include acyl groups such as formyl, acetyl, propionyl, pivaloyl, t-butylacetyl, 2- chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl,
o-nitrophenoxyacetyl, a-chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4- bromobenzoyl, 4-nitrobenzoyl, and the like; sulfonyl groups such as
benzenesulfonyl, p-toluenesulfonyl and the like; acyloxy groups (which form urethanes with the protected amine) such as benzyloxycarbonyl (Cbz), p- chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p- nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 3,5-dimethoxybenzyloxycarbonyl, 2,4- dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2-nitro-4,5- dimethoxybenzyloxycarbonyl, 3,4,5-trimethoxybenzyloxycarbonyl, 1 -(p- biphenylyl)- 1-methylethoxycarbonyl, a,a-dimethyl-3,5- dimethoxybenzyloxycarbonyl, benzhydryloxycarbonyl, t-butyloxycarbonyl (Boc), diisopropylmethoxycarbonyl, isopropyloxycarbonyl, ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl (Alloc), 2,2,2-trichloroethoxycarbonyl, 2- trimethylsilylethyloxycarbonyl (Teoc), phenoxycarbonyl, 4- nitrophenoxycarbonyl, fluorenyl-9-methoxycarbonyl (Fmoc),
cyclopentyloxycarbonyl, adamantyloxycarbonyl, cyclohexyloxycarbonyl, phenylthiocarbonyl and the like; aralkyl groups such as benzyl, triphenylmethyl, benzyloxymethyl and the like; and silyl groups such as trimethylsilyl and the like. It is well within the skill of the ordinary artisan to select and use the appropriate hydroxyl protecting group for the synthetic task at hand.
In general, "substituted" refers to an organic group as defined herein in which one or more bonds to a hydrogen atom contained therein are replaced by one or more bonds to a non-hydrogen atom such as, but not limited to, a halogen (i.e., F, CI, Br, and I); an oxygen atom in groups such as hydroxyl groups, alkoxy groups, aryloxy groups, aralkyloxy groups, oxo(carbonyl) groups, carboxyl groups including carboxylic acids, carboxylates, and carboxylate esters; a sulfur atom in groups such as thiol groups, alkyl and aryl sulfide groups, sulfoxide groups, sulfone groups, sulfonyl groups, and sulfonamide groups; a nitrogen atom in groups such as amines, hydroxylamines, nitriles, nitro groups, N-oxides, hydrazides, azides, and enamines; and other heteroatoms in various other groups. Non-limiting examples of substituents that can be bonded to a substituted carbon (or other) atom include F, CI, Br, I, OR, OC(0)N(R)2, CN, NO, N02, ON02, azido, CF3, OCF3, R, O (oxo), S (thiono), C(O), S(O), methylenedioxy, ethylenedioxy, N(R)2, SR, SOR, S02R, S02N(R)2, S03R, C(0)R, C(0)C(0)R, C(0)CH2C(0)R, C(S)R, C(0)OR, OC(0)R, C(0)N(R)2, OC(0)N(R)2, C(S)N(R)2, (CH2)o-2N(R)C(0)R, (CH2)0-2N(R)N(R)2,
N(R)N(R)C(0)R, N(R)N(R)C(0)OR, N(R)N(R)CON(R)2, N(R)S02R,
N(R)S02N(R)2, N(R)C(0)OR, N(R)C(0)R, N(R)C(S)R, N(R)C(0)N(R)2, N(R)C(S)N(R)2, N(COR)COR, N(OR)R, C(=NH)N(R)2, C(0)N(OR)R, or
C(=NOR)R wherein R can be hydrogen or a carbon-based moiety, and wherein the carbon-based moiety can itself be further substituted.
When a group is said to be "each independently" chosen or selected "independently at each occurrence," each individual group designated by a variable (e.g., an "R" group or a "J" group) is independent of any other similarly designated groups in the structure and need not be the same as another such group selected from a list of options recited. For example, in a group such as - CR2-, when each R is "independently" selected, the two R groups on the carbon atom need not be the same group. Similarly, if a ring, for example, is substituted with n number of J substituent groups, each J can be the same or different from other J groups within the overall list of optional groups at that position.
When a substituent is monovalent, such as, for example, F or CI, it is bonded to the atom it is substituting by a single bond. When a substituent is more than monovalent, such as O, which is divalent, it can be bonded to the atom it is substituting by more than one bond, i.e., a divalent substituent is bonded by a double bond; for example, a C substituted with O forms a carbonyl group, C=0, which can also be written as "CO", "C(O)", or "C(=0)", wherein the C and the O are double bonded. When a carbon atom is substituted with a double-bonded oxygen (=0) group, the oxygen substituent is termed an "oxo" group. When a divalent substituent such as NR is double-bonded to a carbon atom, the resulting C(=NR) group is termed an "imino" group.When a divalent substituent such as S is double -bonded to a carbon atom, the results C(=S) group is termed a "thiocarbonyl" group.
Another divalent substituent is an alkylidene carbon, represented as C= and signifying that the carbon atom so indicated, which also bears two additional groups, is double bonded to a third group. For example, (CH3)2C= indicates an isopropylidene group bonded to another carbon or nitrogen atom.
Alternatively, a divalent substituent such as O, S, C(O), S(O), or
S(0)2 can be connected by two single bonds to two different carbon atoms. For example, O, a divalent substituent, can be bonded to each of two adjacent carbon atoms to provide an epoxide group, or the O can form a bridging ether group, termed an "oxy" group, between adjacent or non-adjacent carbon atoms, for example bridging the 1,4-carbons of a cyclohexyl group to form a [2.2.1]- oxabicyclo system. Further, any substituent can be bonded to a carbon or other atom by a linker, such as (0¾)η or (CR2)n wherein n is 1, 2, 3, or more, and each R is independently selected.
C(O) and S(0)2groups can be bound to one or two heteroatoms, such as nitrogen, rather than to a carbon atom. For example, when a C(O) group is bound to one carbon and one nitrogen atom, the resulting group is called an "amide" or "carboxamide." When a C(O) group is bound to two nitrogen atoms, the functional group is termed a "urea". When a S(0)2 group is bound to one carbon and one nitrogen atom, the resulting unit is termed a "sulfonamide." When a S(0)2 group is bound to two nitrogen atoms, the resulting unit is termed a "sulfamide."
Substituted alkyl, alkenyl, alkynyl, cycloalkyl, and cycloalkenyl groups as well as other substituted groups also include groups in which one or more bonds to a hydrogen atom are replaced by one or more bonds, including double or triple bonds, to a carbon atom, or to a heteroatom such as, but not limited to, oxygen in carbonyl (oxo), carboxyl, ester, amide, imide, urethane, and urea groups; and nitrogen in imines, hydroxyimines, oximes, hydrazones, amidines, guanidines, and nitriles.
Substituted ring groups such as substituted cycloalkyl, aryl, heterocyclyl and heteroaryl groups also include rings and fused ring systems in which a bond to a hydrogen atom is replaced with a bond to a carbon atom. Therefore, substituted cycloalkyl, aryl, heterocyclyl and heteroaryl groups can also be substituted with alkyl, alkenyl, and alkynyl groups as defined herein.
By a "ring system" as the term is used herein is meant a moiety comprising one, two, three or more rings, which can be substituted with non-ring groups or with other ring systems, or both, which can be fully saturated, partially unsaturated, fully unsaturated, or aromatic, and when the ring system includes more than a single ring, the rings can be fused, bridging, or spirocyclic. By "spirocyclic" is meant the class of structures wherein two rings are fused at a single tetrahedral carbon atom, as is well known in the art.
As to any of the groups described herein, which contain one or more substituents, it is understood, of course, that such groups do not contain any substitution or substitution patterns which are sterically impractical and/or synthetically non-feasible. In addition, the compounds of this disclosed subject matter include all stereochemical isomers arising from the substitution of these compounds.
When a group is recited, wherein the group can be present in more than a single orientation within a structure resulting in more than single molecular structure, e.g., a carboxamide group C(=0)NR, it is understood that the group can be present in any possible orientation, e.g., X-C(=0)N(R)-Y or X- N(R)C(=0)-Y, unless the context clearly limits the orientation of the group within the molecular structure.
Alkyl groups include straight chain and branched alkyl groups and cycloalkyl groups having from 1 to about 20 carbon atoms, and typically from 1 to 12 carbons or, in some embodiments, from 1 to 8 carbon atoms. Examples of straight chain alkyl groups include those with from 1 to 8 carbon atoms such as methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, and n-octyl groups. Examples of branched alkyl groups include, but are not limited to, isopropyl, iso-butyl, sec-butyl, t-butyl, neopentyl, isopentyl, and 2,2-dimethylpropyl groups. Representative substituted alkyl groups can be substituted one or more times with any of the groups listed above, for example, amino, hydroxy, cyano, carboxy, nitro, thio, alkoxy, and halogen groups.
Cycloalkyl groups are cyclic alkyl groups such as, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups. In some embodiments, the cycloalkyl group can have 3 to about 8-12 ring members, whereas in other embodiments the number of ring carbon atoms range from 3 to 4, 5, 6, or 7. Cycloalkyl groups further include polycyclic cycloalkyl groups such as, but not limited to, norbornyl, adamantyl, bornyl, camphenyl, isocamphenyl, and carenyl groups, and fused rings such as, but not limited to, decalinyl, and the like. Cycloalkyl groups also include rings that are substituted with straight or branched chain alkyl groups as defined above.
Representative substituted cycloalkyl groups can be mono-substituted or substituted more than once, such as, but not limited to, 2,2-, 2,3-, 2,4- 2,5- or 2,6-disubstituted cyclohexyl groups or mono-, di- or tri-substituted norbornyl or cycloheptyl groups, which can be substituted with, for example, amino, hydroxy, cyano, carboxy, nitro, thio, alkoxy, and halogen groups. The term "cycloalkyl" as used herein can refer to a cycloalkenyl group comprising one or more double bond in the ring(s) thereof. The term "cycloalkenyl" alone or in combination denotes a cyclic alkenyl group.
The terms "carbocyclic," "carbocyclyl," and "carbocycle" denote a ring structure wherein the atoms of the ring are carbon, such as a cycloalkyl group or an aryl group. In some embodiments, the carbocycle has 3 to 8 ring members, whereas in other embodiments the number of ring carbon atoms is 4, 5, 6, or 7. Unless specifically indicated to the contrary, the carbocyclic ring can be substituted with as many as N- 1 substituents wherein N is the size of the carbocyclic ring with, for example, alkyl, alkenyl, alkynyl, amino, aryl, hydroxy, cyano, carboxy, heteroaryl, heterocyclyl, nitro, thio, alkoxy, and halogen groups, or other groups as are listed above. A carbocyclyl ring can be a cycloalkyl ring, a cycloalkenyl ring, or an aryl ring. A carbocyclyl can be monocyclic or polycyclic, and if polycyclic each ring can be independently be a cycloalkyl ring, a cycloalkenyl ring, or an aryl ring.
(Cycloalkyl)alkyl groups, also denoted cycloalkylalkyl, are alkyl groups as defined above in which a hydrogen or carbon bond of the alkyl group is replaced with a bond to a cycloalkyl group as defined above.
Alkenyl groups include straight and branched chain and cyclic alkyl groups as defined above, except that at least one double bond exists between two carbon atoms. Thus, alkenyl groups have from 2 to about 20 carbon atoms, and typically from 2 to 12 carbons or, in some embodiments, from 2 to 8 carbon atoms. Examples include, but are not limited to vinyl, -CH=CH(C]¾),
-CH=C(CH3)2, -C(CH3)=CH2, -C(CH3)=CH(CH3), -C(CH2CH3)=CH2, cyclohexenyl, cyclopentenyl, cyclohexadienyl, butadienyl, pentadienyl, and hexadienyl among others.
When a group is defined as =C, the term refers to a carbon atom double- bonded to its bonding partner, with other valences filled as is known in the art.
Cycloalkenyl groups include cycloalkyl groups having at least one double bond between 2 carbons. Thus for example, cycloalkenyl groups include but are not limited to cyclohexenyl, cyclopentenyl, and cyclohexadienyl groups. Cycloalkenyl groups can have from 3 to about 8-12 ring members, whereas in other embodiments the number of ring carbon atoms range from 3 to 5, 6, or 7. Cycloalkyl groups further include polycyclic cycloalkyl groups such as, but not limited to, norbornyl, adamantyl, bornyl, camphenyl, isocamphenyl, and carenyl groups, and fused rings such as, but not limited to, decalinyl, and the like, provided they include at least one double bond within a ring. Cycloalkenyl groups also include rings that are substituted with straight or branched chain alkyl groups as defined above. (Cycloalkenyl)alkyl groups are alkyl groups as defined above in which a hydrogen or carbon bond of the alkyl group is replaced with a bond to a cycloalkenyl group as defined above.
Alkynyl groups include straight and branched chain alkyl groups, except that at least one triple bond exists between two carbon atoms. Thus, alkynyl groups have from 2 to about 20 carbon atoms, and typically from 2 to 12 carbons or, in some embodiments, from 2 to 8 carbon atoms. Examples include, but are not limited to -C≡CH, -C≡C(CH3), -C≡C(CH2CH3), -CH2C≡CH,
-CH2C≡C(CH3), and -CH2C≡C(CH2CH3) among others.
The term "heteroalkyl" by itself or in combination with another term means, unless otherwise stated, a stable straight or branched chain alkyl group consisting of the stated number of carbon atoms and one or two heteroatoms selected from the group consisting of O, N, and S, and wherein the nitrogen and sulfur atoms may be optionally oxidized and the nitrogen heteroatom may be optionally quaternized. The heteroatom(s) may be placed at any position of the heteroalkyl group, including between the rest of the heteroalkyl group and the fragment to which it is attached, as well as attached to the most distal carbon atom in the heteroalkyl group. Examples include: -0-CH2-CH2-CH3,
-CH2-CH2CH2-OH, -CH2-CH2-NH-CH3, -CH2-S-CH2-CH3,
-CH2CH2-S(=0)-CH3, and -CH2CH2-0-CH2CH2-0-CH3. Up to two heteroatoms may be consecutive, such as, for example, -CH2-NH-OCH3, or - CH2-CH2-S-S-CH3.
A "cycloheteroalkyl" ring is a cycloalkyl ring containing at least one heteroatom. A cycloheteroalkyl ring can also be termed a "heterocyclyl," described below.
The term "heteroalkenyl" by itself or in combination with another term means, unless otherwise stated, a stable straight or branched chain
monounsaturated or di-unsaturated hydrocarbon group consisting of the stated number of carbon atoms and one or two heteroatoms selected from the group consisting of O, N, and S, and wherein the nitrogen and sulfur atoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized. Up to two heteroatoms may be placed consecutively. Examples include -CH=CH-0-CH3, -CH=CH-CH2-OH, -CH2-CH=N-OCH3, -CH=CH-N(CH3)-CH3, -CH2-CH=CH-CH2-SH, and and -CH=CH-0-CH2CH2- O-CH3.
Aryl groups are cyclic aromatic hydrocarbons that do not contain heteroatoms in the ring. Thus aryl groups include, but are not limited to, phenyl, azulenyl, heptalenyl, biphenyl, indacenyl, fluorenyl, phenanthrenyl, triphenylenyl, pyrenyl, naphthacenyl, chrysenyl, biphenylenyl, anthracenyl, and naphthyl groups. In some embodiments, aryl groups contain about 6 to about 14 carbons in the ring portions of the groups. Aryl groups can be unsubstituted or substituted, as defined above. Representative substituted aryl groups can be mono-substituted or substituted more than once, such as, but not limited to, 2-, 3-, 4-, 5-, or 6-substituted phenyl or 2-8 substituted naphthyl groups, which can be substituted with carbon or non-carbon groups such as those listed above.
Aralkyl groups are alkyl groups as defined above in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to an aryl group as defined above. Representative aralkyl groups include benzyl and phenylethyl groups and fused (cycloalkylaryl)alkyl groups such as 4-ethyl-indanyl.
Aralkenyl group are alkenyl groups as defined above in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to an aryl group as defined above.
Heterocyclyl groups or the term "heterocyclyl" includes aromatic and non-aromatic ring compounds containing 3 or more ring members, of which, one or more is a heteroatom such as, but not limited to, N, O, and S. Thus a heterocyclyl can be a cycloheteroalkyl, or a heteroaryl, or if polycyclic, any combination thereof. In some embodiments, heterocyclyl groups include 3 to about 20 ring members, whereas other such groups have 3 to about 15 ring members. A heterocyclyl group designated as a C2-heterocyclyl can be a 5-ring with two carbon atoms and three heteroatoms, a 6-ring with two carbon atoms and four heteroatoms and so forth. Likewise a C4-heterocyclyl can be a 5-ring with one heteroatom, a 6-ring with two heteroatoms, and so forth. The number of carbon atoms plus the number of heteroatoms sums up to equal the total number of ring atoms. A heterocyclyl ring can also include one or more double bonds. A heteroaryl ring is an embodiment of a heterocyclyl group. The phrase "heterocyclyl group" includes fused ring species including those comprising fused aromatic and non-aromatic groups. For example, a dioxolanyl ring and a benzdioxolanyl ring system (methylenedioxyphenyl ring system) are both heterocyclyl groups within the meaning herein. The phrase also includes polycyclic ring systems containing a heteroatom such as, but not limited to, quinuclidyl. Heterocyclyl groups can be unsubstituted, or can be substituted as discussed above. Heterocyclyl groups include, but are not limited to, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, thiophenyl,
benzothiophenyl, benzofuranyl, dihydrobenzofuranyl, indolyl, dihydroindolyl, azaindolyl, indazolyl, benzimidazolyl, azabenzimidazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, imidazopyridinyl, isoxazolopyridinyl, thianaphthalenyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl,
isoquinolinyl, tetrahydroquinolinyl, quinoxalinyl, and quinazolinyl groups. Representative substituted heterocyclyl groups can be mono-substituted or substituted more than once, such as, but not limited to, piperidinyl or quinolinyl groups, which are 2-, 3-, 4-, 5-, or 6-substituted, or disubstituted with groups such as those listed above.
Heteroaryl groups are aromatic ring compounds containing 5 or more ring members, of which, one or more is a heteroatom such as, but not limited to, N, O, and S; for instance, heteroaryl rings can have 5 to about 8-12 ring members. A heteroaryl group is a variety of a heterocyclyl group that possesses an aromatic electronic structure. A heteroaryl group designated as a C2- heteroaryl can be a 5-ring with two carbon atoms and three heteroatoms, a 6-ring with two carbon atoms and four heteroatoms and so forth. Likewise a C4- heteroaryl can be a 5-ring with one heteroatom, a 6-ring with two heteroatoms, and so forth. The number of carbon atoms plus the number of heteroatoms sums up to equal the total number of ring atoms. Heteroaryl groups include, but are not limited to, groups such as pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, thiophenyl, benzothiophenyl, benzofuranyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, azabenzimidazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, imidazopyridinyl, isoxazolopyridinyl, thianaphthalenyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl,
isoquinolinyl, tetrahydroquinolinyl, quinoxalinyl, and quinazolinyl groups. Heteroaryl groups can be unsubstituted, or can be substituted with groups as is discussed above. Representative substituted heteroaryl groups can be substituted one or more times with groups such as those listed above.
Additional examples of aryl and heteroaryl groups include but are not limited to phenyl, biphenyl, indenyl, naphthyl (1-naphthyl, 2-naphthyl), N- hydroxytetrazolyl, N-hydroxytriazolyl, N-hydroxyimidazolyl, anthracenyl (1- anthracenyl, 2- anthracenyl, 3-anthracenyl), thiophenyl (2-thienyl, 3-thienyl), furyl (2-furyl, 3-furyl), indolyl, oxadiazolyl, isoxazolyl, quinazolinyl, fluorenyl, xanthenyl, isoindanyl, benzhydryl, acridinyl, thiazolyl, pyrrolyl (2-pyrrolyl), pyrazolyl (3-pyrazolyl), imidazolyl (1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5- imidazolyl), triazolyl (1,2,3-triazol- l-yl, l,2,3-triazol-2-yl l,2,3-triazol-4-yl, l,2,4-triazol-3-yl), oxazolyl (2-oxazolyl, 4-oxazolyl, 5-oxazolyl), thiazolyl (2- thiazolyl, 4-thiazolyl, 5-thiazolyl), pyridyl (2-pyridyl, 3-pyridyl, 4-pyridyl), pyrimidinyl (2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl), pyrazinyl, pyridazinyl (3- pyridazinyl, 4-pyridazinyl, 5-pyridazinyl), quinolyl (2- quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 6-quinolyl, 7-quinolyl, 8-quinolyl), isoquinolyl (1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl, 6- isoquinolyl, 7-isoquinolyl, 8-isoquinolyl), benzo[b]furanyl (2-benzo[b]furanyl, 3-benzo[b]furanyl, 4-benzo[b]furanyl, 5-benzo[b]furanyl, 6-benzo[b]furanyl, 7- benzo[b]furanyl), 2,3-dihydro-benzo[b]furanyl (2-(2,3-dihydro- benzo[b]furanyl), 3-(2,3-dihydro-benzo[b]furanyl), 4-(2,3-dihydro- benzo[b]furanyl), 5-(2,3-dihydro-benzo[b]furanyl), 6-(2,3-dihydro- benzo[b]furanyl), 7-(2,3-dihydro-benzo[b]furanyl), benzo[b]thiophenyl (2- benzo[b]thiophenyl, 3-benzo[b]thiophenyl, 4-benzo[b]thiophenyl,
5 -benzo[b] thiophenyl, 6-benzo[b]thiophenyl, 7-benzo[b]thiophenyl),
2,3-dihydro-benzo[b]thiophenyl, (2-(2,3-dihydro-benzo[b]thiophenyl), 3-(2,3- dihydro-benzo[b]thiophenyl), 4-(2,3-dihydro-benzo[b]thiophenyl), 5-(2,3- dihydro-benzo[b]thiophenyl), 6-(2,3-dihydro-benzo[b]thiophenyl), 7-(2,3- dihydro-benzo[b]thiophenyl), indolyl (1 -indolyl, 2-indolyl, 3-indolyl, 4-indolyl, 5-indolyl, 6-indolyl, 7-indolyl), indazole (1-indazolyl, 3-indazolyl, 4-indazolyl, 5-indazolyl, 6-indazolyl, 7-indazolyl), benzimidazolyl (1-benzimidazolyl, 2-benzimidazolyl, 4-benzimidazolyl, 5-benzimidazolyl, 6-benzimidazolyl, 7-benzimidazolyl, 8-benzimidazolyl), benzoxazolyl (1-benzoxazolyl, 2- benzoxazolyl), benzothiazolyl (1-benzothiazolyl, 2-benzothiazolyl, 4- benzothiazolyl, 5-benzothiazolyl, 6-benzothiazolyl, 7-benzothiazolyl), carbazolyl (1-carbazolyl, 2-carbazolyl, 3-carbazolyl, 4-carbazolyl),
5H-dibenz[b,f]azepine (5H-dibenz[b,f]azepin- 1 -yl, 5H-dibenz[b,f]azepine-2-yl, 5H-dibenz[b,f]azepine-3-yl, 5H-dibenz[b,f]azepine-4-yl, 5H-dibenz[b,f]azepine- 5-yl), 10,l l-dihydro-5H-dibenz[b,f]azepine (10,1 l-dihydro-5H- dibenz[b,f]azepine-l-yl, 10, 1 l-dihydro-5H-dibenz[b,f]azepine-2-yl, 10,1 1- dihydro-5H-dibenz[b,f]azepine-3-yl, 10, 1 1 -dihydro-5H-dibenz[b,f]azepine-4-yl, 10,1 l-dihydro-5H-dibenz[b,f]azepine-5-yl), and the like.
Heterocyclylalkyl groups are alkyl groups as defined above in which a hydrogen or carbon bond of an alkyl group as defined above is replaced with a bond to a heterocyclyl group as defined above. Representative heterocyclyl alkyl groups include, but are not limited to, furan-2-yl methyl, furan-3-yl methyl, pyridine-3-yl methyl, tetrahydrofuran-2-yl ethyl, and indol-2-yl propyl.
Heteroarylalkyl groups are alkyl groups as defined above in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to a heteroaryl group as defined above.
The term "alkoxy" refers to an oxygen atom connected to an alkyl group, including a cycloalkyl group, as are defined above. Examples of linear alkoxy groups include but are not limited to methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, and the like. Examples of branched alkoxy include but are not limited to isopropoxy, sec-butoxy, tert-butoxy, isopentyloxy, isohexyloxy, and the like.Examples of cyclic alkoxy include but are not limited to cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like. An alkoxy group can include one to about 12-20 carbon atoms bonded to the oxygen atom, and can further include double or triple bonds, and can also include heteroatoms. For example, an allyloxy group is an alkoxy group within the meaning herein. A methoxyethoxy group is also an alkoxy group within the meaning herein, as is a methylenedioxy group in a context where two adjacent atoms of a structures are substituted therewith.
The terms "halo" or "halogen" or "halide" by themselves or as part of another substituent mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom, preferably, fluorine, chlorine, or bromine. A "haloalkyl" group includes mono-halo alkyl groups, poly-halo alkyl groups wherein all halo atoms can be the same or different, and per-halo alkyl groups, wherein all hydrogen atoms are replaced by halogen atoms, such as fluoro. Examples of haloalkyl include trifluoromethyl, 1, 1-dichloroethyl, 1,2- dichloroethyl, l,3-dibromo-3,3-difluoropropyl, perfluorobutyl, and the like.
A "haloalkoxy" group includes mono-halo alkoxy groups, poly-halo alkoxy groups wherein all halo atoms can be the same or different, and per-halo alkoxy groups, wherein all hydrogen atoms are replaced by halogen atoms, such as fluoro. Examples of haloalkoxy include trifluoromethoxy, 1,1 - dichloroethoxy, 1 ,2-dichloroethoxy, l,3-dibromo-3,3-difluoropropoxy, perfluorobutoxy, and the like.
The term "(Cx-Cy)perfluoroalkyl," wherein x < y, means an alkyl group with a minimum of x carbon atoms and a maximum of y carbon atoms, wherein all hydrogen atoms are replaced by fluorine atoms. Preferred is
-(Ci-C6)perfluoroalkyl, more preferred is -(Ci-C3)perfluoroalkyl, most preferred is -CF3.
The term "(Cx-Cy)perfluoroalkylene," wherein x < y, means an alkyl group with a minimum of x carbon atoms and a maximum of y carbon atoms, wherein all hydrogen atoms are replaced by fluorine atoms. Preferred is -(Ci-C6)perfluoroalkylene, more preferred is -(Ci-C3)perfluoroalkylene, most preferred is -CF2-
The terms "aryloxy" and "arylalkoxy" refer to, respectively, an aryl group bonded to an oxygen atom and an aralkyl group bonded to the oxygen atom at the alkyl moiety. Examples include but are not limited to phenoxy, naphthyloxy, and benzyloxy.
An "acyl" group as the term is used herein refers to a group containing a carbonyl moiety wherein the group is bonded via the carbonyl carbon atom. The carbonyl carbon atom is also bonded to another carbon atom, which can be part of an alkyl, aryl, aralkyl cycloalkyl, cycloalkylalkyl, heterocyclyl,
heterocyclylalkyl, heteroaryl, heteroarylalkyl group or the like. In the special case wherein the carbonyl carbon atom is bonded to a hydrogen, the group is a "formyl" group, an acyl group as the term is defined herein. An acyl group can include 0 to about 12-20 additional carbon atoms bonded to the carbonyl group. An acyl group can include double or triple bonds within the meaning herein. An acryloyl group is an example of an acyl group. An acyl group can also include heteroatoms within the meaning here. A nicotinoyl group (pyridyl-3-carbonyl) group is an example of an acyl group within the meaning herein. Other examples include acetyl, benzoyl, phenylacetyl, pyridylacetyl, cinnamoyl, and acryloyl groups and the like. When the group containing the carbon atom that is bonded to the carbonyl carbon atom contains a halogen, the group is termed a "haloacyl" group. An example is a trifluoroacetyl group.
The term "amine" includes primary, secondary, and tertiary amines having, e.g., the formula N(group)3 wherein each group can independently be H or non-H, such as alkyl, aryl, and the like. Amines include but are not limited to R-NH2, for example, alkylamines, arylamines, alkylarylamines; R2NH wherein each R is independently selected, such as dialkylamines, diarylamines, aralkylamines, heterocyclylamines and the like; and R3N wherein each R is independently selected, such as trialkylamines, dialkylarylamines,
alkyldiarylamines, triarylamines, and the like. The term "amine" also includes ammonium ions as used herein.
An "amino" group is a substituent of the form -N¾, -NHR, -NR2, -NR3 , wherein each R is independently selected, and protonated forms of each, except for -NR3 +, which cannot be protonated. Accordingly, any compound substituted with an amino group can be viewed as an amine. An "amino group" within the meaning herein can be a primary, secondary, tertiary or quaternary amino group. An "alkylamino" group includes a monoalkylamino, dialkylamino, and trialkylamino group.
An "ammonium" ion includes the unsubstituted ammonium ion NH4 +, but unless otherwise specified, it also includes any protonated or quaternarized forms of amines. Thus, trimethylammonium hydrochloride and
tetramethylammonium chloride are both ammonium ions, and amines, within the meaning herein.
The term "amide" (or "amido") includes C- and N-amide groups, i.e., -C(0)NR2, and -NRC(0)R groups, respectively. Amide groups therefore include but are not limited to primary carboxamide groups (-C(0)NH2) and formamide groups (-NHC(O)H). A "carboxamido" group is a group of the formula (ϋ(0)ΝΙ¾, wherein R can be H, alkyl, aryl, etc.
The term "azido" refers to an N3 group. An "azide" can be an organic azide or can be a salt of the azide (N3 ~) anion. The term "nitro" refers to an NO2 group bonded to an organic moiety. The term "nitroso" refers to an NO group bonded to an organic moiety. The term nitrate refers to an ONO2 group bonded to an organic moiety or to a salt of the nitrate (NO3 ) anion.
The term "urethane" ("carbamoyl" or "carbamyl") includes N- and O- urethane groups, i.e., -NRC(0)OR and -OC(0)NR2 groups, respectively.
The term "sulfonamide" (or "sulfonamido") includes S- and N- sulfonamide groups, i.e., -SO2NR2 and -NRSO2R groups, respectively.
Sulfonamide groups therefore include but are not limited to sulfamoyl groups (- SO2NH2). An organosulfur structure represented by the formula -S(0)(NR)- is understood to refer to a sulfoximine, wherein both the oxygen and the nitrogen atoms are bonded to the sulfur atom, which is also bonded to two carbon atoms.
The term "amidine" or "amidino" includes groups of the formula -C(NR)NR2. Typically, an amidino group is -C(NH)NH2.
The term "guanidine" or "guanidino" includes groups of the formula -NRC(NR)NR2. Typically, a guanidino group is -NHC(NH)NH2.
A "salt" as is well known in the art includes an organic compound such as a carboxylic acid, a sulfonic acid, or an amine, in ionic form, in combination with a counterion. For example, acids in their anionic form can form salts with cations such as metal cations, for example sodium, potassium, and the like; with ammonium salts such as NH4 + or the cations of various amines, including tetraalkyl ammonium salts such as tetramethylammonium, or other cations such as trimethylsulfonium, and the like. A "pharmaceutically acceptable" or "pharmacologically acceptable" salt is a salt formed from an ion that has been approved for human consumption and is generally non-toxic, such as a chloride salt or a sodium salt. A "zwitterion" is an internal salt such as can be formed in a molecule that has at least two ionizable groups, one forming an anion and the other a cation, which serve to balance each other. For example, amino acids such as glycine can exist in a zwitterionic form. A "zwitterion" is a salt within the meaning herein. The compounds of the present invention may take the form of salts. The term "salts" embraces addition salts of free acids or free bases which are compounds of the invention. Salts can be "pharmaceutically- acceptable salts." The term "pharmaceutically-acceptable salt" refers to salts which possess toxicity profiles within a range that affords utility in
pharmaceutical applications. Pharmaceutically unacceptable salts may nonetheless possess properties such as high crystallinity, which have utility in the practice of the present invention, such as for example utility in process of synthesis, purification or formulation of compounds of the invention.
Suitable pharmaceutically-acceptable acid addition salts may be prepared from an inorganic acid or from an organic acid. Examples of inorganic acids include hydrochloric, hydrobromic, hydriodic, nitric, carbonic, sulfuric, and phosphoric acids. Appropriate organic acids may be selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic and sulfonic classes of organic acids, examples of which include formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic,
4-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic, trifluoromethanesulfonic, 2-hydroxyethanesulfonic, p-toluenesulfonic, sulfanilic,
cyclohexylaminosulfonic, stearic, alginic, β-hydroxybutyric, salicylic, galactaric and galacturonic acid. Examples of pharmaceutically unacceptable acid addition salts include, for example, perchlorates and tetrafluoroborates.
Suitable pharmaceutically acceptable base addition salts of compounds of the invention include, for example, metallic salts including alkali metal, alkaline earth metal and transition metal salts such as, for example, calcium, magnesium, potassium, sodium and zinc salts. Pharmaceutically acceptable base addition salts also include organic salts made from basic amines such as, for example, N,N-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine. Examples of pharmaceutically unacceptable base addition salts include lithium salts and cyanate salts. Although pharmaceutically unacceptable salts are not generally useful as medicaments, such salts may be useful, for example as intermediates in the synthesis of Formula (I) compounds, for example in their purification by recrystallization. All of these salts may be prepared by conventional means from the corresponding compound according to Formula (I) by reacting, for example, the appropriate acid or base with the compound according to Formula (I). The term "pharmaceutically acceptable salts" refers to nontoxic inorganic or organic acid and/or base addition salts, see, for example, Lit et al., Salt Selection for Basic Drugs (1986), Int J. Pharm., 33, 201 -217, incorporated by reference herein.
A "hydrate" is a compound that exists in a composition with water molecules. The composition can include water in stoichiometric quantities, such as a monohydrate or a dihydrate, or can include water in random amounts. As the term is used herein a "hydrate" refers to a solid form, i.e., a compound in water solution, while it may be hydrated, is not a hydrate as the term is used herein.
A "solvate" is a similar composition except that a solvent other that water replaces the water. For example, methanol or ethanol can form an "alcoholate", which can again be stoichiometic or non-stoichiometric. As the term is used herein a "solvate" refers to a solid form, i.e., a compound in solution in a solvent, while it may be solvated, is not a solvate as the term is used herein.
A "prodrug" as is well known in the art is a substance that can be administered to a patient where the substance is converted in vivo by the action of biochemicals within the patients body, such as enzymes, to the active pharmaceutical ingredient. Examples of prodrugs include esters of carboxylic acid groups, which can be hydrolyzed by endogenous esterases as are found in the bloodstream of humans and other mammals. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs", ed. H. Bundgaard, Elsevier, 1985.
In addition, where features or aspects of the invention are described in terms of Markush groups, those skilled in the art will recognize that the invention is also thereby described in terms of any individual member or subgroup of members of the Markush group. For example, if X is described as selected from the group consisting of bromine, chlorine, and iodine, claims for X being bromine and claims for X being bromine and chlorine are fully described. Moreover, where features or aspects of the invention are described in terms of Markush groups, those skilled in the art will recognize that the invention is also thereby described in terms of any combination of individual members or subgroups of members of Markush groups. Thus, for example, if X is described as selected from the group consisting of bromine, chlorine, and iodine, and Y is described as selected from the group consisting of methyl, ethyl, and propyl, claims for X being bromine and Y being methyl are fully described.
In various embodiments, the compound or set of compounds, such as are used in the inventive methods, can be any one of any of the combinations and/or sub-combinations of the above-listed embodiments.
Isomerism and Tautomerism in Compounds of the Invention
Tautomerism
Within the present invention it is to be understood that a compound of the formula (I) or a salt thereof may exhibit the phenomenon of tautomerism whereby two chemical compounds that are capable of facile interconversion by exchanging a hydrogen atom between two atoms, to either of which it forms a covalent bond. Since the tautomeric compounds exist in mobile equilibrium with each other they may be regarded as different isomeric forms of the same compound. It is to be understood that the formulae drawings within this specification can represent only one of the possible tautomeric forms. However, it is also to be understood that the invention encompasses any tautomeric form, and is not to be limited merely to any one tautomeric form utilized within the formulae drawings. The formulae drawings within this specification can represent only one of the possible tautomeric forms and it is to be understood that the specification encompasses all possible tautomeric forms of the compounds drawn not just those forms which it has been convenient to show graphically herein. For example, tautomerism may be exhibited by a pyrazolyl group bonded as indicated by the wavy line. While both substituents would be termed a 3-methyl-4-pyrazolyl group, it is evident that a different nitrogen atom bears the hydrogen atom in each structure.
Figure imgf000040_0001
Such tautomerism can also occur with substituted pyrazoles such as 3- methyl, 5-methyl, or 3,5-dimethylpyrazoles, and the like. Another example of tautomerism is amido-imido (lactam-lactim when cyclic) tautomerism, such as is seen in heterocyclic compounds bearing a ring oxygen atom adjacent to a ring nitrogen atom. For example, the equilibrium:
Figure imgf000041_0001
is an example of tautomerism. Accordingly, a structure depicted herein as one tautomer is intended to also include the other tautomer.
Optical Isomerism
It will be understood that when compounds of the present invention contain one or more chiral centers, the compounds may exist in, and may be isolated as pure enantiomeric or diastereomeric forms or as racemic mixtures. The present invention therefore includes any possible enantiomers,
diastereomers, racemates or mixtures thereof of the compounds of the invention.
The isomers resulting from the presence of a chiral center comprise a pair of non-superimposable isomers that are called "enantiomers." Single enantiomers of a pure compound are optically active, i.e., they are capable of rotating the plane of plane polarized light. Single enantiomers are designated according to the Cahn-Ingold-Prelog system. The priority of substituents is ranked based on atomic weights, a higher atomic weight, as determined by the systematic procedure, having a higher priority ranking. Once the priority ranking of the four groups is determined, the molecule is oriented so that the lowest ranking group is pointed away from the viewer. Then, if the descending rank order of the other groups proceeds clockwise, the molecule is designated as having an (R) absolute configuration, and if the descending rank of the other groups proceeds counterclockwise, the molecule is designated as having an (S) absolute configuration. In the example in the Scheme below, the
Cahn-Ingold-Prelog ranking is A > B > C > D. The lowest ranking atom, D is oriented away from the viewer. The solid wedge indicates that the atom bonded thereby projects toward the viewer out of the plane of the paper, and a dashed wedge indicates that the atom bonded thereby projects away from the viewer out of the plan of the paper, i.e., the plane "of the paper" being defined by atoms A, C, and the chiral carbon atom for the (R) configuration shown below.
Figure imgf000042_0001
(R) configuration (S) configuration
A carbon atom bearing the A-D atoms as shown above is known as a "chiral" carbon atom, and the position of such a carbon atom in a molecule is termed a "chiral center." Compounds of the invention may contain more than one chiral center, and the configuration at each chiral center is described in the same fashion.
There are various conventions for depicting chiral structures using solid and dashed wedges. For example, for the (R) configuration shown above, the following two depictio equivalent:
Figure imgf000042_0002
The present invention is meant to encompass diastereomers as well as their racemic and resolved, diastereomerically and enantiomerically pure forms and salts thereof. Diastereomeric pairs may be resolved by known separation techniques including normal and reverse phase chromatography, and
crystallization.
"Isolated optical isomer" means a compound which has been
substantially purified from the corresponding optical isomer(s) of the same formula. Preferably, the isolated isomer is at least about 80%, more preferably at least 90% pure, even more preferably at least 98% pure, most preferably at least about 99% pure, by weight.
Isolated optical isomers may be purified from racemic mixtures by well-known chiral separation techniques. According to one such method, a racemic mixture of a compound of the invention, or a chiral intermediate thereof, is separated into 99% wt.% pure optical isomers by HPLC using a suitable chiral column, such as a member of the series of DAI CEL® CHIRALPAK® family of columns (Daicel Chemical Industries, Ltd., Tokyo, Japan). The column is operated according to the manufacturer instructions.
Rotational Isomerism
It is understood that due to chemical properties (i.e., resonance lending some double bond character to the C-N bond) of restricted rotation about the amide bond linkage (as illustrated below) it is possible to observe separate rotamer species and even, under some circumstances, to isolate such species (see below). It is further understood that certain structural elements, including steric bulk or substituents on the amide nitrogen, may enhance the stability of a rotamer to the extent that a compound may be isolated as, and exist indefinitely, as a single stable rotamer. The present invention therefore includes any possible stable rotamers of formula (I) which are biologically active in the treatment of cancer or other proliferative disease states.
Figure imgf000043_0001
Regioisomerism
The preferred compounds of the present invention have a particular spatial arrangement of substituents on the aromatic rings, which is related to the structure activity relationship demonstrated by the compound class. Often such substitution arrangement is denoted by a numbering system; however, numbering systems are often not consistent between different ring systems. In six-membered aromatic systems, the spatial arrangements are specified by the common nomenclature "para" for 1,4-substitution, "meta" for 1,3 -substitution and "ortho" for 1 ,2-substitution as shown below.
Figure imgf000043_0002
"para-" "meta-" "ortho-1 In various embodiments, the compound or set of compounds, such as are among the inventive compounds or are used in the inventive methods, can be any one of any of the combinations and/or sub-combinations of the above-listed embodiments.
In various embodiments, a compound as shown in any of the Examples, or among the exemplary compounds, is provided. Provisos may apply to any of the disclosed categories or embodiments wherein any one or more of the other above disclosed embodiments or species may be excluded from such categories or embodiments.
The present invention further embraces isolated compounds according to any of formulas(I), (II), or (III). The expression "isolated compound" refers to a preparation of a compound of any of those formulas, or a mixture of compounds according to any of those formulas, wherein the isolated compound has been separated from the reagents used, and/or byproducts formed, in the synthesis of the compound or compounds. "Isolated" does not mean that the preparation is technically pure (homogeneous), but it is sufficiently pure to compound in a form in which it can be used therapeutically. Preferably an "isolated compound" refers to a preparation of a compound of formula (I), (II), or (III) or a mixture of compounds according to any of those formulas, which contains the named compound or mixture of compounds according to the respective formula in an amount of at least 10 percent by weight of the total weight. Preferably the preparation contains the named compound or mixture of compounds in an amount of at least 50 percent by weight of the total weight; more preferably at least 80 percent by weight of the total weight; and most preferably at least 90 percent, at least 95 percent or at least 98 percent by weight of the total weight of the preparation.
The compounds of the invention and intermediates may be isolated from their reaction mixtures and purified by standard techniques such as filtration, liquid-liquid extraction, solid phase extraction, distillation, recrystallization or chromatography, including flash column chromatography, or HPLC.
Description
The invention is directed, in various embodiments, to a compound that is a modulator of a neuropeptide Y (NPY) receptor. The NPY receptor can be Y2R or Y1R. In various embodiments, a compound of the invention is a selective modulator of Y2R. In various embodiments, the invention is directed to methods of making a compound of the invention. In various embodiments, the invention is directed to methods of using a compound of the invention, e.g., for therapeutic purposes for treatment of a medical condition.
In various embodiments, the invention provides a compound of formula
(III)
Figure imgf000045_0001
wherein
ring A comprises 0-2 nitrogen atoms; or, ring B comprises 0-2 nitrogen atoms; or, both; and, each of ring A and ring B is independently substituted with n independently selected J groups;
or, ring A is absent and the two carbon atoms connecting X1 and X3 are mutually double bonded and each independently bears hydrogen or (C 1 -
C6)alkyl, or the two carbon atoms are mutually single bonded and together with a methano bridge therebetween form a cyclopropyl, and ring B is substituted with n independently selected J groups;
or, ring B is absent and the two carbon atoms connecting X1 and X3 are mutually double bonded and each independently bears hydrogen or (C 1 -
C6)alkyl, or the two carbon atoms are mutually single bonded and together with a methano bridge therebetween form a cyclopropyl, and ring A is substituted with n independently selected J groups; and, Cyc is single -bonded or double -bonded to any one οίΧ', Χ2, or X3, provided that when X3 is C=0 or O, Cyc is bonded to X1 or X2; and, a single bond or a double bond is present between X1 and X2; such that,
when a single bond is present between X1 and X2,
X1 is CHRC, C=0, or NR', unless Cyc is single-bonded to X1, then X1 is
CRC or N, or unless Cyc is double-bonded to X1, then X1 is a carbon atom;
X2 is CHRC, C=0, or NR', unless Cyc is single-bonded to X2, then X2 is CRC or N, or unless Cyc is double-bonded to X2, then X2 is a carbon atom;
X3 is CHRC, NR', C=0, or O; unless Cyc is single-bonded to X3, then X3 is CRC or N, or unless Cyc is double-bonded to X3, then X3 is a carbon atom; provided that when one of X1 and X2 is C=0 and the other of X1 and X2 is NR', then X3 is CRC or N and Cyc is single-bonded to X3; or X3 is a carbon atom and Cyc is double-bonded thereto,
or, when a double bond is present between X1 and X2,
X1 is CRC or N, unless Cyc is bonded to X1, then X1 is a carbon atom;
X2 is CRC or N, unless Cyc is bonded to X2, then X2 is a carbon atom;
X3 is CRC, NR', C=0, or O; unless Cyc is single-bonded to X3, then X3 is CRC or N, or unless Cyc is double-bonded to X3, then X3 is a carbon atom; each n is independently 0, 1, 2, 3, or 4;
Cyc is
Figure imgf000046_0001
Figure imgf000047_0001
wherein W is CR or N, each Rcyc is independently selected halo, (Cl-C6)alkyl, or (C 1 -C6)alkoxyl; p is 0, 1, or 2; wherein wavy lines indicate points of bonding; or,
Figure imgf000047_0002
wavy lines indicate points of bonding; and,
Q is a bond, C(=NR)NR, C(=N-CN)NR, OC(=NR)NR, OC(=N-CN)NR, NRC(=NR)NR, NRC(=N-CN)NR, C(=0)NR, C(=0)0, OC(=0)0, OC(=0)NR, NRC(=0)NR, C(=S)NR, OC(=S)NR, NRC(=S)NR, C(=CR2)NR, OC(=CR2)NR, NRC(=CR2)NR, NR, C(=0)CHR"NRC(=0)OCH2,
C(=0)CHR"NRC(=0)NRCH2, C(=0)CHR"NRC(=S)NRCH2, C(=O)(CR2)0-3, or Q is
Figure imgf000047_0003
wherein wavy lines indicate points of bonding, or Q is S(0)q or NRS(0)q wherein q is 0, 1, or 2;
HA is aryl or heteroaryl substituted with 0, 1 , or 2 substituents independently selected from the group consisting of halo, cyano, (Cl-C6)alkyl, (Cl-C6)alkoxyl, and C02R', and further substituted with JHA;
JHA is (CH2)o-2RJ, (CH2)o-2ORJ, (CH2)0-2N(RJ)2, (CH2)0-2SRJ, (CH2)0- 2SORJ, (CH2)o-2S02RJ, (CH2)o-2S02N(RJ)2, (CH2)0-2SO3RJ, (CH2)0-2C(O)RJ, (CH2)o-2C(0)C(0)RJ, (CH2)o-2C(0)CH2C(0)RJ, (CH2)0-2C(O)ORJ, (CH2)0- 2OC(0)RJ, (CH2)o-2OC(0)ORJ, (CH2)0-2C(O)N(RJ)2, (CH2)0-2OC(O)N(RJ)2, (CH2)o-2N(RJ)C(0)RJ, (CH2)o-2N(RJ)C(0)ORJ, (CH2)0-2N(RJ)C(O)N(RJ)2, (CH2)o-2N(RJ)N(RJ)C(0)RJ, (CH2)0-2N(RJ)N(RJ)C(O)ORJ, (CH2)0- 2N(RJ)N(RJ)CON(RJ)2, (CH2)0-2N(RJ)SO2RJ, (CH2)0-2N(RJ)SO2N(RJ)2, (CH2)0- 2C(S)RJ, (CH2)o-2OC(S)RJ, (CH2)0-2N(RJ)C(S)RJ, (CH2)0-2N(RJ)C(S)N(RJ)2, (CH2)o-2C(S)N(RJ)2, (CH2)o-2N(CORJ)CORJ, (CH2)0-2N(ORJ)RJ, (CH2)0- 2C(=NRJ)N(RJ)2, (CH2)o-2C(0)N(ORJ)RJ, and (CH2)0-2C(=NORJ)RJ,
each independently selected R' is H or (C 1 -C6)alkyl, and n' = 0, 1, or 2; each independently selected R" is H, (C 1 -C6)alkyl, or (CH2)mNR2 wherein m is 1, 2, 3, or 4;
each independently selected Rc is H, halo, (Cl-C6)alkyl, OH, or (Cl- C6)alkoxyl;
R is independently at each occurrence hydrogen or an alkyl, acyl, cycloalkyl, cycloalkylalkyl, aryl, aroyl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, wherein any alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl is substituted with 0-3 J; or wherein two R groups together with a nitrogen atom or with two adjacent nitrogen atoms to which they are bonded can together form a (C3-C8)heterocyclyl substituted with 0-3 J; optionally further comprising 1-3 additional heteroatoms selected from the group consisting of O, N, and S(0)q; wherein any cycloalkyl, aryl, heterocyclyl, or heteroaryl can be fused, bridged, or in a spiro configuration with one or more additional optionally substituted cycloalkyl, aryl, heterocyclyl, and heteroaryl, monocyclic, bicyclic or polycyclic, saturated, partially unsaturated, or aromatic rings;
wherein J independently at each occurrence is selected from the group consisting of F, CI, Br, I, OR, CN, CF3, OCF3, O, S, C(O), S(O),
methylenedioxy, ethylenedioxy, (CH2)0-2N(RJ)2, (CH2)0-2SRJ, (CH2)0-2SORJ, (CH2)o-2S02RJ, (CH2)o-2S02N(RJ)2, (CH2)0-2SO3RJ, (CH2)0-2C(O)RJ, (CH2)0- 2C(0)C(0)RJ, (CH2)o-2C(0)CH2C(0)RJ, (CH2)0-2C(S)RJ, (CH2)0-2C(O)ORJ, (CH2)o-2OC(0)RJ, (CH2)o-2OC(0)ORJ, (CH2)0-2C(O)N(RJ)2, (CH2)0- 2OC(0)N(RJ)2, (CH2)o-2C(S)N(RJ)2, (CH2)0-2N(RJ)C(O)RJ, (CH2)0- 2N(RJ)N(RJ)C(0)RJ, (CH2)o-2N(RJ)N(RJ)C(0)ORJ, (CH2)0- 2N(RJ)N(RJ)CON(RJ)2, (CH2)0-2N(RJ)SO2RJ, (CH2)0-2N(RJ)SO2N(RJ)2, (CH2)0- 2N(RJ)C(0)ORJ, (CH2)o-2N(RJ)C(0)RJ, (CH2)0-2N(RJ)C(S)RJ, (CH2)0- 2N(RJ)C(0)N(RJ)2, (CH2)o-2N(RJ)C(S)N(RJ)2, (CH2)0-2N(CORJ)CORJ, (CH2)0- 2N(ORJ)RJ, (CH2)o-2C(=NRJ)N(RJ)2, (CH2)0-2C(O)N(ORJ)RJ, and (CH2)0- 2C(=NORJ)RJ, wherein RJ is independently at each occurrence selected from the group consisting of hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl, wherein any alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, is unsubstituted or is substituted with 1 , 2, or 3 substituents independently selected from the group consisting of (C 1 -C6)alkyl and (C6-C 10)aryl; or wherein two RJ groups together with a nitrogen atom or with two adjacent nitrogen atoms to which they are bonded can together form a (C3-C8)heterocyclyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of (Cl-C6)alkyl and (C6-
C10)aryl, and optionally further comprising 1-3 additional heteroatoms selected from the group consisting of O, N, S, S(O) and S(0)2;
or a pharmaceutically acceptable salt thereof.
In various embodiments^1 is C=0 and X2 is NH.
In various embodiments, a double bond is present between X1 and X2, and X3 is O.
In various embodiments, X1 and X2 are both C¾ and X3 is CH, Cyc being bonded to X3.
In various embodiments, X1 is C=0, X2 is NH or N(CH3), and X3 is CH, C-OH, or C-CH3, Cyc being bonded to X3.
In various embodiments, Cyc is piperidinyl or piperazinyl. In other embodiments, Cyc is
Figure imgf000049_0001
P
Figure imgf000050_0001
, wherein R y and p are as defined herein.
The Cyc group can be present in either orientation with respect to Q and to X .
In various embodiments, n = 1 and J is chloro or fluoro.
In various embodiments, Q is a bond, C(=S)NH, C(=0)NH, C(=0)0, NHC(=0)NH, or C(=NCN)NH.
In various embodiments, HA is phenyl. In various embodiments, an HA group can be substituted with cyano, fluoro, or methyl. In various embodiments JHA is a heterocyclyl or heteroaryl that is directly bonded to ring system HA. In other embodiments, the heterocyclyl or heteroaryl of JHA is linked to HA via an amide, sulfonamide, or urea bond. In various embodiments, a heterocyclyl or heteroaryl of is substituted with alkyl, such as methyl.
In various embodiments, the invention provides a compound of formula (III), wherein the compound is any of the compounds shown in Table 1 , below. Table 1 : Specific Compounds of Formula (III)
Figure imgf000050_0002
Figure imgf000051_0001
Figure imgf000052_0001
50
Figure imgf000053_0001
51
Figure imgf000054_0001
Figure imgf000055_0001
Figure imgf000056_0001
Figure imgf000057_0001
Figure imgf000058_0001
Figure imgf000059_0001
Figure imgf000060_0001
Figure imgf000061_0001

Figure imgf000062_0001
Figure imgf000063_0001
Figure imgf000064_0001
Figure imgf000065_0001
Figure imgf000066_0001
Figure imgf000067_0001
Figure imgf000069_0001
Figure imgf000070_0001
Figure imgf000071_0001
Figure imgf000072_0001
Figure imgf000073_0001
Figure imgf000074_0001
Figure imgf000075_0001
Figure imgf000076_0001
74
Figure imgf000077_0001
Figure imgf000078_0001
76
Figure imgf000079_0001
Figure imgf000080_0001
Figure imgf000081_0001
Figure imgf000082_0001
Figure imgf000083_0001
Figure imgf000084_0001
Figure imgf000085_0001
Figure imgf000086_0001
Figure imgf000087_0001
Figure imgf000088_0001
Figure imgf000089_0001
Figure imgf000090_0001
Figure imgf000091_0001
Figure imgf000092_0001
622
Figure imgf000093_0001
623
Figure imgf000093_0002
624
625
626
Figure imgf000093_0003
Figure imgf000094_0001
632
633
Figure imgf000095_0001
634
Figure imgf000095_0002
635
636
Figure imgf000095_0003
Figure imgf000096_0001
Figure imgf000097_0001
Figure imgf000098_0001
Figure imgf000099_0001
657
Figure imgf000100_0001
658
659
660
661
Figure imgf000100_0002
Figure imgf000101_0001
Figure imgf000102_0001
Figure imgf000103_0001
677
Figure imgf000104_0001
678
Figure imgf000104_0002
679
680
Figure imgf000104_0003
681
Figure imgf000104_0004
Figure imgf000105_0001
Figure imgf000106_0001
wherein Ar1, Ar2 and Ar3 each independently selected from the group consisting of cycloalkyl, aryl, heterocyclyl, and heteroaryl, provided that Ar3 can also be hydrogen, wherein any cycloalkyl, aryl, heterocyclyl, or heteroaryl is mono- or independently multi-substituted with J, (Ci-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (Ci-C6)haloalkyl, (Ci-C6)alkoxy, (Ci-C6)haloalkoxy, cycloalkyl(Co-C6)alkyl, heterocyclyl(Co-Ce) alkyl, aryl(Co-C6)alkyl, or heteroaryl(Co-Ce)alkyl; wherein any alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, aryl, heterocyclyl, or heteroaryl can be further substituted with J;
W and Y are each independently selected from the group consisting of a single bond, a double bond, ((CH2)o-2CR2(CH2)o-2, (CH2)o-20(CH2)o-2, (CH2)0- 2C(0)(CH2)o-2,
(CH2)o-2C(OR)(R)(CH2)o-2, (CH2)0-2N(R)C(O)(CH2)0-2, (CH2)0- 2N(R)C(S)(CH2)o-2R, 0(CR2)nO wherein n is 1 to 4, (CH2)0-2N(R)(CH2)0-2, (CH2)o-2S(0)q(CH2)o-2 wherein q = 0, 1 , or 2,
(CH2)o-2S02N(R)(CH2)o-2, (CH2)0-2SO3(CH2)0-2, (CH2)0-2C(O)C(O)(CH2)0-2, (CH2)o-2C(0)CH2C(0)(CH2)o-2, (CH2)0-2C(S)(CH2)0-2, (CH2)0-2C(O)O(CH2)0-2, (CH2)o-2C(0)C(R)2(CH2)o-2, (CH2)o-2OC(0)0(CH2)o-2, (CH2)0- 2OC(0)N(R)(CH2)o-2, (CH2)o-2N(R)C(0)N(R)(CH2)o-2, (CH2)0- 2N(R)C(S)N(R)(CH2)o-2, (CH2)0-2C(S)N(R)(CH2)0-2,
(CH2)o-2N(R)N(R)C(0)(CH2)o-2, (CH2)0-2N(R)N(R)C(O)O(CH2)0-2,
(CH2)o-2N(R)N(R)CON(R)(CH2)o-2, (CH2)0-2N(R)SO2(CH2)0-2, (CH2)0- 2N(R)S02N(R)(CH2)o-2,
(CH2)o-2N(COR)CO(CH2)o-2, (CH2)0-2N(OR)(CH2)0-2, (CH2)0- 2C(=NR)N(R)(CH2)o-2, (CH2)0-2C(=CR2)N(R)(CH2)0-2, (CH2)0- 2C(0)N(OR)(CH2)o-2, (CH2)o-2C(=NOR)(CH2)o-2 and thiazolyl;
or wherein an R group of Y together with Ar2 and the atom to which it is bonded together form a heterocyclyl or cycloalkyl ring; or wherein an R group of W together with Ar3 and the atom to which it is bonded together form a heterocyclyl or cycloalkyl ring; or both;
wherein R is independently at each occurrence selected from the group consisting of hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl, wherein any alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl is substituted with 0-3 J; or wherein two R groups together with a nitrogen atom or with two adjacent nitrogen atoms to which they are bonded can together form a (C3-C8)heterocyclyl substituted with 0-3 J; optionally further comprising 1 -3 additional heteroatoms selected from the group consisting of O, N, S, S(0) and S(0)2;
wherein any cycloalkyl, aryl, heterocyclyl, or heteroaryl can be fused, bridged, or in a spiro configuration with one or more additional optionally substituted cycloalkyl, aryl, heterocyclyl, and heteroaryl, monocyclic, bicyclic or polycyclic, saturated, partially unsaturated, or aromatic rings;
wherein J independently at each occurrence is selected from the group consisting of F, CI, Br, I, OR, CN, CF3, OCF3, O, S, C(O), S(O),
methylenedioxy, ethylenedioxy, N(RJ)2, SRJ, SORJ, S02RJ, S02N(RJ)2, S03RJ, C(0)RJ, C(0)C(0)RJ, C(0)CH2C(0)RJ, C(S)RJ, C(0)ORJ, OC(0)RJ,
OC(0)ORJ, C(0)N(RJ)2, OC(0)N(RJ)2, C(S)N(RJ)2, (CH2)0-2NHC(O)RJ,
N(RJ)N(RJ)C(0)RJ, N(RJ)N(RJ)C(0)ORJ, N(RJ)N(RJ)CON(RJ)2, N(RJ)S02RJ, N(RJ)S02N(RJ)2, N(RJ)C(0)ORJ, N(RJ)C(0)RJ, N(RJ)C(S)RJ, N(RJ)C(0)N(RJ)2, N(RJ)C(S)N(RJ)2, N(CORJ)CORJ, N(ORJ)RJ, C(=NRJ)N(RJ)2, C(0)N(ORJ)RJ, and C(=NORJ)RJ,
wherein RJ is independently at each occurrence selected from the group consisting of hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl, or wherein two RJ groups together with a nitrogen atom or with two adjacent nitrogen atoms to which they are bonded can together form a (C3-C8)heterocyclyl optionally further comprising 1 -3 additional heteroatoms selected from the group consisting of O, N, S, S(O) and S(0)2;
or a salt or hydrate thereof;
provided that the compound of formula (I) is not any of the following:
Figure imgf000109_0001
107
Figure imgf000110_0001
Figure imgf000111_0001
Groups W and Y, termed "linkers" herein, are atoms and groups that serve to bond together in defined spatial arrangements the three core cyclic groups Ar1, Ar2 and Ar3, which are cyclic groups as are defined herein.
In various embodiments, Ar1 can be aryl or heteroaryl. For example, Ar1 can be phenyl, pyrrolyl, thiazolyl, or thiophenyl.
In other embodiments, Ar1 can be cycloalkyl or heterocyclyl. For example, Ar1 can be piperidinyl or piperazinyl.
In various embodiments, Ar2, Ar3, or both, can be aryl or heteroaryl. For example, Ar2, Ar3, or both, can be phenyl, biphenyl, phenanthridinyl, pyrazolylphenyl, pyridylphenyl, or thiophenylphenyl.
In other embodiments, Ar2, Ar3, or both, can be cycloalkyl or heterocyclyl. For example, Ar2, Ar3, or both, can be piperidinyl, or piperazinyl.
In various embodiments, the linkers W, Y, or both, can be a
carboxamido, thiocarboxamido, or a sulfonamido group. More specifically, one of W and Y can be a carboxamido or thiocarboxamido group and the other of W and Y can be a sulfonamido group. In certain embodiments, W or Y bonded to Ar1 can form a urea or a thiourea moiety, e.g., wherein one of the nitrogen atoms of the urea or thiourea moiety is a member of the Ar1 ring.
In various embodiments, all of Ar1, Ar2 and Ar3 are aryl or heteroaryl. In other embodiments, each of Ar1, Ar2 and Ar3 can independently be cycloalkyl or saturated heterocyclyl groups.
In various embodiments, the invention comprises a compound of formula (IA)
Figure imgf000112_0001
wherein nl is 0-3, Ar2, Ar3, each independently selected R, and each independently selected J, are as defined for formula (I).
In various embodiments, the invention comprises a compound of formula (IB)
Figure imgf000112_0002
wherein m is 0 or 1, nl, n2, and n3 is each independently 0-3, and each independently selected J and each independently selected R is as defined for formula (I).
In various embodiments, the invention comprises a compound of formula
(IC)
Figure imgf000112_0003
wherein a ring "het" is a heterocyclyl or heteroaryl wherein the carboxamido and sulfonamido groups can be disposed at any two positions thereupon, and wherein m is 0 or 1, and nl, n2, and n3 is each independently 0- 3, each independently selected R and each independently selected J is as defined in claim 1.
In various embodiments, the invention comprises a compound of formula
(ID1)
or of formula (ID2)
Figure imgf000113_0001
wherein X, R and Ar are as defined for formula (I).
In other embodiments, the invention comprises a compound of formula (IE1)
or of formula (IE2)
Figure imgf000113_0002
or of formula (IF 1 ) of of formula (1F2)
Figure imgf000114_0001
wherein X, R and Ar3 are as defined for formula (I).
In various embodiments, the invention comprises a compound of
(IG1)
or of formula (IG2)
Figure imgf000114_0002
wherein X, R and Ar3 are as defined for formula (I).
In various embodiments, the invention comprises a compound of of formula (IH1) or of formula (IH2)
Figure imgf000115_0001
wherein X, Y, R, and Ar are as defined for formula (I).
In various embodiments, the invention comprises a compound of
Figure imgf000115_0002
wherein Ar , each R, and each X are independently selected as defined in claim 1.
In various embodiments, the invention comprises a compound of formula (IK1 or IK2)
Figure imgf000115_0003
(IK2)
wherein R, X, Ar2, and Ar3 are as defined for formula (I).
In various embodiments, the invention comprises a compound of formula
(IL)
Figure imgf000116_0001
wherein J is H or OH and Z is CH or N, and Ar3 is as defined for formula (I).
In various embodiments, the invention comprises a compound of formula (IM1 or IM2)
Figure imgf000116_0002
(IM2)
wherein each independently selected R, each independently selected X, Ar2, and Ar3, is as defined for formula (I).
In various embodiments, the invention provides any of the compounds listed below in Table 2: Specific Compounds of Formula (I), all of which have been synthesized and characterized. Many of the compounds in Table 1 have been tested with respect to bioactivity as a modulator of an NPY receptor or as a selective modulator of Y2R, and many have been found to have bioactivity at concentrations which indicate potential of the compounds as therapeutic agents for treatment of malconditions in humans for which modulation of an NPY receptor is medically indicated.
Table 2: Specific Compounds of Formula (I)
(Ph = phenyl, Bn = benzyl)
Compound Structure
Number
Figure imgf000117_0001
Figure imgf000118_0001
Figure imgf000119_0001
Figure imgf000120_0001
118
Figure imgf000121_0001
Figure imgf000122_0001
120
Figure imgf000123_0001
Figure imgf000124_0001
Figure imgf000125_0001

Figure imgf000126_0001
Figure imgf000127_0001
Figure imgf000128_0001
Figure imgf000129_0001
Figure imgf000130_0001
Figure imgf000131_0001
Figure imgf000132_0001
Figure imgf000133_0001
Figure imgf000134_0001
Figure imgf000135_0001
ı33
Figure imgf000136_0001
Figure imgf000137_0001

Figure imgf000138_0001
In various embodiments, the invention provides a compound of formula
(Π)
Figure imgf000139_0001
wherein
each independently selected R1 is H, aryl, or heteroaryl;
each independently selected R2 is H, OH, (Cl-C6)alkoxy, NR2, (Cl- C6)alkoxycarbonyl, -N(R)C(=0)(Cl-C6)alkyl,or -C(=0)NR2;
k is 0, 1, or 2;
n is 0, 1, 2, 3, or 4;
Cyc is f wherein W is CH or N, and wavy lines indicate points of bonding, or,
Cyc is
Figure imgf000139_0002
, and wavy lines indicate points of bonding, or,
Cyc is absent;
Q is a bond, C(=NR)NR, OC(=NR)NR, NRC(=NR)NR, C(=0)NR, C(=0)0, OC(=0)0, OC(=0)NR, NRC(=0)NR, C(=S)NR, OC(=S)NR, NRC(=S)NR, C(=CR2)NR, OC(=CR2)NR, NRC(=CR2)NR, NR,
C(=0)CHR"NRC(=0)OCH2, C(=0)CHR"NRC(=0)NRCH2,
C(=0)CHR"NRC(=S)NRCH2, C(=O)(CHR)0-3,C(=C(CN)(CO2CH3))NH, or Q
Figure imgf000139_0003
wherein a wavy line indicated a point of attachment, or, Q is S(0)q or NRS(0)q wherein q is 0, 1, or 2; HA is aryl or heteroaryl, wherein any aryl or heteroaryl is substituted with O, 1, 2, 3, or 4 J;
each independently selected R" is H, (C 1 -C6)alkyl, or (CH2)mNR2 wherein m is 1, 2, 3, or 4;
R is independently at each occurrence hydrogen or an alkyl, acyl, cycloalkyl, cycloalkylalkyl, aryl, aroyl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, wherein any alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl is substituted with 0-3 J; or wherein two R groups together with a nitrogen atom or with two adjacent nitrogen atoms to which they are bonded can together form a (C3-C8)heterocyclyl substituted with 0-3 J; optionally further comprising 1-3 additional heteroatoms selected from the group consisting of O, N, and S(0)q; wherein any cycloalkyl, aryl, heterocyclyl, or heteroaryl can be fused, bridged, or in a spiro configuration with one or more additional optionally substituted cycloalkyl, aryl, heterocyclyl, and heteroaryl, monocyclic, bicyclic or polycyclic, saturated, partially unsaturated, or aromatic rings;
wherein J independently at each occurrence is selected from the group consisting of F, CI, Br, I, OR, CN, CF3, OCF3, O, S, C(O), S(O),
methylenedioxy, ethylenedioxy, N(RJ)2, SRJ, SORJ, S02RJ, S02N(RJ)2, S03RJ, C(0)RJ, C(0)C(0)RJ, C(0)CH2C(0)RJ, C(S)RJ, C(0)ORJ, OC(0)RJ,
OC(0)ORJ, C(0)N(RJ)2, OC(0)N(RJ)2, C(S)N(RJ)2, (CH2)0-2NHC(O)RJ, N(RJ)N(RJ)C(0)RJ, N(RJ)N(RJ)C(0)ORJ, N(RJ)N(RJ)CON(RJ)2, N(RJ)S02RJ, N(RJ)S02N(RJ)2, N(RJ)C(0)ORJ, N(RJ)C(0)RJ, N(RJ)C(S)RJ, N(RJ)C(0)N(RJ)2, N(RJ)C(S)N(RJ)2, N(CORJ)CORJ, N(ORJ)RJ, C(=NRJ)N(RJ)2, C(0)N(ORJ)RJ, and C(=NORJ)RJ,
wherein RJ is independently at each occurrence selected from the group consisting of hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl, or wherein two RJ groups together with a nitrogen atom or with two adjacent nitrogen atoms to which they are bonded can together form a (C3-C8)heterocyclyl optionally further comprising 1 -3 additional heteroatoms selected from the group consisting of O, N, S, S(0) and S(0)2;
or a salt or hydrate thereof, e following:
Figure imgf000141_0001
Figure imgf000142_0001
Figure imgf000143_0001
For example, in various embodiments, Cyc is
For example, in various embodiments, W is CH.
For example, in various embodiments, W is N.
For example, in various embodiments, Cyc is
Figure imgf000143_0002
For example, in various embodiments, Cyc is absent.
For example, in various embodiments, R1 is optionally substituted phenyl.
For example, in various embodiments, R2 is OH.
For example, in various embodiments, the compound is any of those of Table 3, below.
Table 3: Specific Compounds of Formula (II)
k = 1 unless otherwise stated
Figure imgf000143_0003
Figure imgf000144_0001
Figure imgf000145_0001
Figure imgf000146_0001
Figure imgf000147_0001

Figure imgf000148_0001
Figure imgf000149_0001
Figure imgf000150_0001
Figure imgf000151_0001
Figure imgf000152_0001
Figure imgf000153_0001
Figure imgf000154_0001
Figure imgf000155_0001
Figure imgf000156_0001
Figure imgf000157_0001
Figure imgf000158_0001
Figure imgf000159_0001
Figure imgf000160_0001
Figure imgf000161_0001
Figure imgf000162_0001
Figure imgf000163_0001
Figure imgf000164_0001
Figure imgf000165_0001
Figure imgf000166_0001
Figure imgf000167_0001
Figure imgf000168_0001
Figure imgf000169_0001
Figure imgf000170_0001
Figure imgf000171_0001
Figure imgf000172_0001
Figure imgf000173_0001
171
Figure imgf000174_0001
Figure imgf000175_0001
Figure imgf000176_0001
Figure imgf000177_0001
Figure imgf000178_0001
Figure imgf000179_0001
ı77
Figure imgf000180_0001

Figure imgf000181_0001

Figure imgf000182_0001
Figure imgf000183_0001
Figure imgf000184_0001
Figure imgf000185_0001
Figure imgf000186_0001
ı84
Figure imgf000187_0001
Figure imgf000188_0001
Figure imgf000189_0001
Figure imgf000190_0001
Figure imgf000191_0001

Figure imgf000192_0001
Figure imgf000193_0001
Figure imgf000194_0001
ı92
Figure imgf000195_0001
Figure imgf000196_0001
Figure imgf000197_0001
Figure imgf000198_0001
Figure imgf000199_0001
ı97
Figure imgf000200_0001
Figure imgf000201_0001
ı99
Figure imgf000202_0001
Figure imgf000203_0001
Figure imgf000204_0001
In various embodiments of the invention, a compound of the invention is a modulator of a neuropeptide Y (NPY) receptor. The NPY receptor can be Y2R or Y1R. In various embodiments, a compound of the invention is a selective modulator of Y2R.
In various embodiments, the invention provides a pharmaceutical composition comprising a compound of the invention and a pharmaceutically acceptable excipient, as discussed below.
In various embodiments, the invention provides a method of modulation a neuropeptide Y receptor comprising contacting the receptor with an effective amount or concentration of a compound of the invention. A compound of the invention can be an agonist or activator when it acts on the receptor to stimulate the function of the receptor, such as is done by an endogenous agonist ligand. A compound of the invention can be an antagonist or inhibitor when the compound blocks the effect of an endogenous receptor ligand, preventing functioning of the receptor. A compound of the invention can be a "selective modulator" when it modulates one class or subclass of receptor, for example Y2R, at a concentration or in an amount that is not effective to modulate a different class or subclass of receptor, for example Y1R. A compound of the invention can displace a known ligand bound to an NPY receptor.
In various embodiments, the NPY receptor can be contacted by a compound of the inventions vivo in a human patient, at a concentration or in an amount that is effective to modulate the receptor. In various embodiments, the amount or concentration of the compound can be effective to selectively modulate the NPY receptor Y2R.
Accordingly, in various embodiments the invention provides a method of treatment of a malcondition in a patient for which modulation of a neuropeptide Y receptor is medically indicated, comprising administering to the patient a compound of the invention in a dose, at a frequency, and for a duration sufficient to provide a beneficial effect to the patient. For example, the malcondition can comprise drug or alcohol abuse, anxiety disorders, depression, stress-related disorders, neurological disorders, nerve degeneration, osteoporosis or bone loss, sleep/wake disorders, cardiovascular diseases, obesity, anorexia, inovulation, fertility disorders, angiogenesis, cell proliferation, learning and memory disorders, migraine and pain., or any disorder that involves activation or inhibition of the effect or function of an NPY receptor.
In various embodiments, the invention provides a use of a compound of the invention in treatment of a malcondition in a human patient. Modulation of one or more NPY receptors modulated by the inventive compound can be medically indicated for treatment of the malcondition. The malcondition can comprise drug or alcohol abuse, anxiety disorders, depression, stress-related disorders, neurological disorders, nerve degernation, osteoporosis or bone loss, sleep/wake disorders, cardiovascular diseases, obesity, anorexia, inovulation, or fertility disorders, or any disorder that involves activation or inhibition of the effect or function of an NPY receptor. Another aspect of an embodiment of the invention provides compositions of the compounds of the invention, alone or in combination with another neuropeptide Y receptor modulator or another type of therapeutic agent, or both. As set forth herein, compounds of the invention include stereoisomers, tautomers, solvates, hydrates, salts including pharmaceutically acceptable salts, and mixtures thereof. Compositions containing a compound of the invention can be prepared by conventional techniques, e.g. as described in Remington: The Science and Practice of Pharmacy, 19th Ed., 1995, incorporated by reference herein. The compositions can appear in conventional forms, for example capsules, tablets, aerosols, solutions, suspensions or topical applications.
Typical compositions include a compound of the invention and a pharmaceutically acceptable excipient which can be a carrier or a diluent. For example, the active compound will usually be mixed with a carrier, or diluted by a carrier, or enclosed within a carrier which can be in the form of an ampoule, capsule, sachet, paper, or other container. When the active compound is mixed with a carrier, or when the carrier serves as a diluent, it can be solid, semi-solid, or liquid material that acts as a vehicle, excipient, or medium for the active compound. The active compound can be adsorbed on a granular solid carrier, for example contained in a sachet. Some examples of suitable carriers are water, salt solutions, alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil, peanut oil, olive oil, gelatin, lactose, terra alba, sucrose, dextrin, magnesium carbonate, sugar, cyclodextrin, amylose, magnesium stearate, talc, gelatin, agar, pectin, acacia, stearic acid or lower alkyl ethers of cellulose, silicic acid, fatty acids, fatty acid amines, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters, polyoxyethylene, hydroxymethylcellulose and polyvinylpyrrolidone. Similarly, the carrier or diluent can include any sustained release material known in the art, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax.
The formulations can be mixed with auxiliary agents which do not deleteriously react with the active compounds. Such additives can include wetting agents, emulsifying and suspending agents, salt for influencing osmotic pressure, buffers and/or coloring substances preserving agents, sweetening agents or flavoring agents. The compositions can also be sterilized if desired. The route of administration can be any route which effectively transports the active compound of the invention to the appropriate or desired site of action, such as oral, nasal, pulmonary, buccal, subdermal, intradermal, transdermal or parenteral, e.g., rectal, depot, subcutaneous, intravenous, intraurethral, intramuscular, intranasal, ophthalmic solution or an ointment, the oral route being preferred.
If a solid carrier is used for oral administration, the preparation can be tabletted, placed in a hard gelatin capsule in powder or pellet form or it can be in the form of a troche or lozenge. If a liquid carrier is used, the preparation can be in the form of a syrup, emulsion, soft gelatin capsule or sterile injectable liquid such as an aqueous or non-aqueous liquid suspension or solution.
Injectable dosage forms generally include aqueous suspensions or oil suspensions which can be prepared using a suitable dispersant or wetting agent and a suspending agent Injectable forms can be in solution phase or in the form of a suspension, which is prepared with a solvent or diluent. Acceptable solvents or vehicles include sterilized water, Ringer's solution, or an isotonic aqueous saline solution. Alternatively, sterile oils can be employed as solvents or suspending agents. Preferably, the oil or fatty acid is non-volatile, including natural or synthetic oils, fatty acids, mono-, di- or tri-glycerides.
For injection, the formulation can also be a powder suitable for reconstitution with an appropriate solution as described above. Examples of these include, but are not limited to, freeze dried, rotary dried or spray dried powders, amorphous powders, granules, precipitates, or particulates. For injection, the formulations can optionally contain stabilizers, pH modifiers, surfactants, bioavailability modifiers and combinations of these. The compounds can be formulated for parenteral administration by injection such as by bolus injection or continuous infusion. A unit dosage form for injection can be in ampoules or in multi-dose containers.
The formulations of the invention can be designed to provide quick, sustained, or delayed release of the active ingredient after administration to the patient by employing procedures well known in the art. Thus, the formulations can also be formulated for controlled release or for slow release. Compositions contemplated by the present invention can include, for example, micelles or liposomes, or some other encapsulated form, or can be administered in an extended release form to provide a prolonged storage and/or delivery effect. Therefore, the formulations can be compressed into pellets or cylinders and implanted intramuscularly or subcutaneously as depot injections. Such implants can employ known inert materials such as silicones and biodegradable polymers, e.g., polylactide-polyglycolide. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides).
For nasal administration, the preparation can contain a compound of the invention, dissolved or suspended in a liquid carrier, preferably an aqueous carrier, for aerosol application. The carrier can contain additives such as solubilizing agents, e.g., propylene glycol, surfactants, absorption enhancers such as lecithin (phosphatidylcholine) or cyclodextrin, or preservatives such as parabens.
For parenteral application, particularly suitable are injectable solutions or suspensions, preferably aqueous solutions with the active compound dissolved in polyhydroxylated castor oil.
Tablets, dragees, or capsules having talc and/or a carbohydrate carrier or binder or the like are particularly suitable for oral application. Preferable carriers for tablets, dragees, or capsules include lactose, corn starch, and/or potato starch. A syrup or elixir can be used in cases where a sweetened vehicle can be employed.
A typical tablet that can be prepared by conventional tabletting techniques can contain:
Core:
Active compound (as free compound or salt thereof) 250 mg
Colloidal silicon dioxide (Aerosil)® 1.5 mg Cellulose, microcryst. (Avicel)® 70 mg
Modified cellulose gum (Ac-Di-Sol)® 7.5 mg
Magnesium stearate Ad.
Coating:
HPMC approx. 9 mg *Mywacett 9-40 T approx. 0.9 mg
*Acylated monoglyceride used as plasticizer for film coating.
A typical capsule for oral administration contains compounds of the invention (250 mg), lactose (75 mg) and magnesium stearate (15 mg). The mixture is passed through a 60 mesh sieve and packed into a No. 1 gelatin capsule. A typical injectable preparation is produced by aseptically placing 250 mg of compounds of the invention into a vial, aseptically freeze-drying and sealing. For use, the contents of the vial are mixed with 2 mL of sterile physiological saline, to produce an injectable preparation.
The compounds of the invention can be administered to a human in need of such treatment, prevention, elimination, alleviation or amelioration of a malcondition that is mediated through the action of a neuropeptide Y receptor such as Y1R or Y2R, for example, drug or alcohol abuse, anxiety disorders, depression, neurological disorders, nerve degeneration, osteoporosis or bone loss, sleep/wake disorders, cardiovascular diseases, obesity, anorexia, inovulation, or fertility disorders.
The compounds of the invention are effective over a wide dosage range. For example, in the treatment of adult humans, dosages from about 0.05 to about 5000 mg, preferably from about 1 to about 2000 mg, and more preferably between about 2 and about 2000 mg per day can be used. A typical dosage is about 10 mg to about 1000 mg per day. In choosing a regimen for patients it can frequently be necessary to begin with a higher dosage and when the condition is under control to reduce the dosage. The exact dosage will depend upon the activity of the compound, mode of administration, on the therapy desired, form in which administered, the subject to be treated and the body weight of the subject to be treated, and the preference and experience of the physician or veterinarian in charge. NPY receptor modulation bioactivity of the compounds of the invention can be determined by use of an in vitro assay system which measures the displacement of a known ligand of NPY receptors, e.g., compound BIIE0246, which can be expressed as IC50 values, as are well known in the art inhibitors of the invention can be determined by the method described in the Examples.
Generally, the compounds of the invention are dispensed in unit dosage form including from about 0.05 mg to about 1000 mg of active ingredient together with a pharmaceutically acceptable carrier per unit dosage.
Usually, dosage forms suitable for oral, nasal, pulmonal or transdermal administration include from about 125 μg to about 1250 mg, preferably from about 250 μg to about 500 mg, and more preferably from about 2.5 mg to about 250 mg, of the compounds admixed with a pharmaceutically acceptable carrier or diluent.
Dosage forms can be administered daily, or more than once a day, such as twice or thrice daily. Alternatively dosage forms can be administered less frequently than daily, such as every other day, or weekly, if found to be advisable by a prescribing physician.
An embodiment of the invention also encompasses prodrugs of a compound of the invention which on administration undergo chemical conversion by metabolic or other physiological processes before becoming active pharmacological substances. Conversion by metabolic or other physiological processes includes without limitation enzymatic (e.g, specific enzymatically catalyzed) and non-enzymatic (e.g., general or specific acid or base induced) chemical transformation of the prodrug into the active pharmacological substance. In general, such prodrugs will be functional derivatives of a compound of the invention which are readily convertible in vivo into a compound of the invention. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in Design of Prodrugs, ed. H. Bundgaard, Elsevier, 1985. In another embodiment, there are provided methods of making a composition of a compound described herein including formulating a compound of the invention with a pharmaceutically acceptable carrier or diluent. In some embodiments, the pharmaceutically acceptable carrier or diluent is suitable for oral administration. In some such embodiments, the methods can further include the step of formulating the composition into a tablet or capsule. In other embodiments, the pharmaceutically acceptable carrier or diluent is suitable for parenteral administration. In some such embodiments, the methods further include the step of lyophilizing the composition to form a lyophilized preparation.
In various embodiments, the invention provides a method of synthesis of a compound of formula (I), contacting a compound of formula (IPA)
Figure imgf000211_0001
wherein a ring labeled Ar1 is as defined for Ar1 herein,
and chlorosulfonic acid to provide a compound of formula (IIB)
Figure imgf000211_0002
then,
contacting the compound of formula (IPB) and an amine of formula (IPC)
N H2 (AT¾
(IPC),
wherein a ring labeled Ar3 is as defined for Ar3 herein, under conditions suitable to bring about formation of a sulfonamide bond;
to provide a compound of formula (IPD);
@-S02 -©
O H (no);
then,
contacting the compound of formula (IPD) and a compound of formula (IPE)
Figure imgf000212_0001
wherein a ring labeled Ar2 is as defined for Ar2 in herein,
under conditions suitable to bring about formation of a carboxamide bond; to provide a compound of the invention
Figure imgf000212_0002
Examples
The activity of compounds of the invention were evaluated in comparison to BIIE0246. The compounds were initially tested at 10 μΜ using a cAMP biosensor approach. The cAMP biosensor assay cell lines containing either the Y2R or the Y1R were purchased from BD Biosciences (Rockville, MD) as HEK293 cells stably expressing a cyclic nucleotide-gated (CNG) channel and either Y2R (catalog # BD344870) or Y1R (catalog # BD344869). Cells were cultured in T-175 cm2 flasks at 37 C and 95% relative humidity. Cells were plated and maintained in growth medium consisting of DMEM (Invitrogen catalog #11965) supplemented with 10% fetal bovine serum, 250 μg/mL geneticin and 1 μg /mL puromycin (growth medium).
For Y2R and Y1R assays, HEK293-CNG cells were diluted in growth medium and dispensed into 384-well black- wall, clear-bottom, PDL-coated plates (final concentration: 14,000 cells/well in 20 μί) and allowed to incubate for 24 hours at 37 C. Next, 20 μΐ^ of 2.5x concentrated membrane potential dye, prepared according to manufacturer instructions, was dispensed into each well. After incubating for 3 hours at room temperature, an initial fluorescent measurement (TO) was performed (510-545 nm excitation and 565-625 nm emission) using a EnVision fluorescence plate reader (Perkin Elmer, Turku,
Finland). Test compounds (10 μΜ final concentration), DMSO alone (2% final concentration), or BIIE0246 (10 μΜ final concentration) was added to sample or appropriate control wells, respectively along with NPY (50 nM final concentration), NECA (400 tiM final concentration; an al adrenergic receptor agonist that is used in all experiments to initiate a cAMP response that can then be modulated by Y2R ligands) and the phosphodiesterase inhibitor Ro-20- 1724 (25 μΜ final concentration).
The plates were incubated for 45 minutes (Y2R) or 30 minutes (Y1R) at room temperature before the final fluorescence measurement (T45 or T30) was taken. The T45 or T30 value was divided by the background (TO). Then, "% antagonist activity" scores were then calculated by averaging replicate wells, subtracting background fluorescence (obtained in 1 μΜ NPY alone treated wells) and then dividing by BIIE0246 treatment values, also tested at 10 μΜ and after subtracting background.
See, for example, S.P. Brothers, et al., Mol. Pharmacol, 77:46-57, 2010.
BIIE0246 has the followin formula:
Figure imgf000213_0001
The antagonist activity percentage scores were calculated by averaging replicate wells, subtracting background fluorescence and then dividing by BIIE0246 treatment values, also tested at 10 μΜ and after subtracting background (Tables 4-12).
Table 4. Y2R and Y1R, activity (% control) and IC50 values for the indicated compounds.
Figure imgf000213_0002
% % Y2 Yl
Cpd
X R control control
# ic50 ic50
Y2 Yl μΜ μΜ s
(Std.l) OEt 107.3 0 0.199 NA
(Std.2) s OMe 79.1 0 2.94 NA
49 s H 34.9 0 NA nt
50 s OiPr 57.1 0.4 1.77 NA
51 0 H 10.4 0 NA nt
52 0 CN 12.9 0 NA nt
53 0 Me 14.4 0 NA nt
54 0 OMe 2.9 1.2 NA nt
55 0 OEt 39.3 0 NA nt
2,4-
56 0 5.6 2.5 NA nt
OMe
57 0 OiPr 28 2.2 NA nt
"Std." = standard compound; NA: not active, nt: not tested.
Table 5. Y2R and Y1R, activity (% control) and IC50 values for the indicated compounds.
Figure imgf000215_0001
59 S OMe 9.7 7.7 NA nt
60 S OEt 10.2 0 NA nt
61 S OiPr 3.3 5.8 NA nt
62 O OEt 54.3 31 NA 48
63 O OMe 10 4.2 NA nt
64 O Me 3.6 5.5 NA nt
65 O CN 11.6 1 1 NA nt
66 O OiPr 2.9 2.8 NA nt
67 O 2,4-OMe 94.10 40.9 9.04 18
NA: not active, nt: not tested.
Table 6. Y2R and Y1R, activity (% control) and IC50 values for the indicated compounds.
Figure imgf000215_0002
69 S H 13.4 1.1 NA nt 0.37
70 S OEt 50.6 0.7 NA
2
71 S OiPr 3.3 5.8 NA nt
72 O OMe 0.2 1.4 NA nt
73 O H 1.9 0 NA nt
74 O OEt 3.4 0 NA nt
75 O CN 0 NA nt
76 O Me 0 NA nt
77 O OiPr 13.0 19.9 NA nt
2,4-
78 O 49.6 27.9 NA nt
OMe
NA: not active, nt: not tested.
Table 7. Y2R and YIR. activity (% control) and IC50 values for the indicated compounds.
Figure imgf000216_0001
97 l_ ~ l Et 99.2 nt NA nt
99 MeO-^- | Et 1.9 0 NA nt
100 — ί /hi Et 1 1.5 9.2 NA nt 101 NC0-| Et 2.4 1.9 NA nt
102 Ph-Q-| Et 67.9 62.8 2.22 2.38
103 >4-0-| Et 11.4 4.6 NA nt
Figure imgf000217_0001
106 l_ ~l |^_^N°2 0 nt NA nt
107 l-0~l l"Ph 3 33·3 NA nt
108 -O-l i l i-Q \= 55.9 41.5 NA nt
cCiN
109 l-0~l I"00 7·9 nt NA nt
110 l- ~l l^,^^ 8.6 0 NA nt
NA: not active, nt: not tested.
Table 8. Mean displacement percentages of BIIE 0246 produced at the fixed 10 μΜ concentration on Y2R cells by sulfamoyl benzamides modified on the sulfonamide portion.
Figure imgf000217_0002
Compound NRiX
Figure imgf000218_0001
/ N 22.6
k
Figure imgf000218_0002
Table 9. Mean displacement percentages of BIIE 0246 produced at the fixed 10 μΜ concentration on Y2R cells by sulfamoyl benzamides modified on the amide portion.
Figure imgf000219_0001
Figure imgf000220_0001
Figure imgf000220_0002
standard compound
Table 10. Mean displacement percentages of BIIE 0246 produced at the fixed 10 μΜ concentration on Y2R cells by sulfamoyl benzamides modified on the central aryl ring.
Figure imgf000220_0003
Cpd. # R X %
34 2'4'6" ΥΥ 7 9
(CH3)3
Figure imgf000220_0004
Figure imgf000221_0001
4-isopropyl '^}Γ^ ' ^·3
Figure imgf000221_0002
43 4-bromo A /¾SQ) 33.0
44 4-bromo /YY 20-2
Figure imgf000221_0003
46 S, CH3 '^ 3·4
47 S, CH; 3 A
Selected compounds that produced high antagonism of the Y2R, were further tested to determine IC5o values at both the Y2R and YIR (Table 8). Compounds were serial diluted (1 :3 dilutions; 30 μΜ starting concentration) and dispensed to cells as describe above. The results are summarized in Table 4. The selected compounds displayed promising activity profile with Y2R IC50 values ranging from 0.47 μΜ and 2.03 μΜ. Submicromolar IC50 values were found for 2,4- and 2,5-dimethoxyphenyl derivatives (compounds 3 and 4), a
methylpyridine analog(Cpd. #13) as well as for a pyridine derivative (Cpd. # 29). Notably, all the tested compounds were found to be selective over YlRs, as evaluated by their dose-response curves and compared to BIBP3226, a selective Y 1R antagonist control.Figure 1 shows the dose-response curves for compoundsat Y2R and Y1R. Table 11. Y2R IC50 values (uM)
Compound IC50 (uM)
2 1.57
3 0.47
4 0.59
5 0.98
6 1.65
13 0.79
19 1.34
28 2.03
29 0.60
Table 12: Bioactivity Data for Compounds of Formula (III)
Figure imgf000222_0001
Figure imgf000223_0001
Figure imgf000224_0001
Figure imgf000225_0001
Figure imgf000226_0001
Figure imgf000227_0001
Figure imgf000228_0001
Figure imgf000229_0001
Figure imgf000230_0001
Figure imgf000231_0001
Figure imgf000232_0001
Figure imgf000233_0001
Figure imgf000234_0001
556, 578
Figure imgf000235_0001
Figure imgf000236_0001
Figure imgf000237_0001
Figure imgf000238_0001
Figure imgf000239_0001
Figure imgf000240_0001
Figure imgf000241_0001
Figure imgf000242_0001
Figure imgf000243_0001
Figure imgf000244_0001
Figure imgf000245_0001
Figure imgf000246_0001
Figure imgf000247_0001
Figure imgf000248_0001
NPY
Observe
Cpd. Y2
Structure M.Wt d Mass
# IC50
(LC-MS) (nM)
633 67 475.6 476
634 64 489.6 490
635 3412 515.0 515
Ph = phenyl; Me = methyl; Ac = acetyl
It is within ordinary skill, using the structures of the compounds disclosed herein, the disclosed methods of manufacture, and the disclosed methods of testing and evaluation, for the person of ordinary skill in the art to prepare and test inventive compounds for efficacy in medical therapy.
It is further within ordinary skill for the practitioner to carry a compound so identified through the necessary testing and evaluation for use in human therapy, wherein it can be prescribed by a physician for use by a patient based upon the skill, knowledge, and experience of the physician.
Figure 2 shows the effect of NPY Y2 antagonist compound 518 (see Table 1) on alcohol intake behaviors in rats. A) Drinking In the Dark: Limited access for four hours per day. Ethanol-concentration increases over training time with the final concentration being 10%. B) Operant self-administration at FR-1, 10% ethanol-solution.
Figure 3 shows data supporting that NPY Y2 antagonist compound 518 (i.c.v.) blocks tumor-induced bone loss and tactile hypersensitivity. A.
Representative images of contralateral (control) and ipsilateral (tumor) bones 15 days following implantation of cancer cells. Tumor growth produced bone loss in the proximal end of the tumor bearing bone in the vehicle treated rats (arrow). compound 518 administration (i.c.v.) blocked the tumor induced bone loss. B.
Injection of tumor into the bone produced tactile hypersensitivity within 15 days in the vehicle treated rats. This was blocked in the compound 518 treated rats.
Graphs mean ± SEM, n=4-6.
Methods of Synthesis
Generalized synthetic schemes:
Refluxing 4-methylbenzoic acid in chlorosulfonic acid, followed by reaction of the corresponding sulfonyl chloride intermediate with 2,5-dimethyl aniline gave the sulfamoyl carboxylic acid derivative (1), that was finally reacted with 2-aminobiphenyl under standard amide coupling conditions to afford the desired product (3).
Figure imgf000250_0001
Reagents and conditions: (i) HSO3CI, reflux, overnight (general yields 70-90%); (ii) Py, 2,5-dimethyl aniline, DCM, rt, overnight (general yields 22-93%); (iii) 2- aminobiphenyl, HOBt, EDC1, DMF, rt, overnight (general yields 20-72%). Pyridine was not used for the synthesis of intermediates of certain members of the series.
Scheme 2.
Figure imgf000251_0001
Reagents and conditions: (i) Pd(OAc)2, PCy3, Toluene, ¾0, 100°C, 6h; (general yields 10-40%), (ii) BDS, THF, reflux, 24 h; (yield 20%), (iii) NaBH4, silica gel, EtOH, rt, 2h (yield 60%).
Scheme 3.
Figure imgf000251_0002
Reagents and conditions: (i) CH3I, K2CO3, CH3CN, DMF, reflux, overnight (yield 42%); (ii) LiOH, MeOH, THF, H20 (yield 95%); (iii) 2-aminobiphenyl, HOBt, EDCl, DMF, rt, overnight (yield 22%); (iv) CH3I, t-BuOK, 18-crown-6, THF, rt, overnight (yield 47%).
Scheme 4.
Figure imgf000251_0003
14' a-c 13' a-c Reagents and conditions: (i) a for 12g: cyclopropylboronic acid, Pd(OAc)2, PCy3, H3PO4, toluene, H20, 100°C, 6h (yield 14%); b for 12h: phenylboronic acid, Pd(Ph3)4, Na2C03, toluene, EtOH, 80°C, overnight (yield 18%);(ii) HSO3CI, reflux, overnight ; (iii) Py, N¾X, DCM, rt, overnight ; (iv) 2-aminobiphenyl, HOBt, EDC1, DMF, rt, overnight.
Scheme 5.
e (3f) X = O R = CH3 (3g) x = o R = OMe Pr(3h) X = O R = OEt (3i)X = O R = 2,4-OMe (3j) X = O R = O /-Pr
Figure imgf000252_0001
Reagents and conditions: (a) toluene, 2h, rt, (general yields 68-98%).
The a,a-diphenyl-4-piperidinemethanol (azacyclonol) analogues (3a-j), as shown in Table 4, above, were synthesized following the protocol described in scheme 5. Piperidine and the appropriate isocyanate or isothiocyanate were stirred for two hours in toluene.
Scheme 6.
OH (4a) X = S R = H (4f) X = O R = OMe
Ph-†-Ph R (4b) x = s R = OMe (4g) X = O R = CH3 , a, b R-f VlMH Ph (4c) X = S R = OEt (4h) X = O R = CN V ψ x¾~N^ =<ph (4d) X = S = 0 -Pr (4i)x= O R = 0 -Pr H NCX (4e) X - O R - OEt (4j) X = O R = 2, 4-OMe
(a) TFA, DCM, overnight, rt, quant; (b) toluene, 2h, rt, (general yields 10-82%).
The azacyclonol was dehydrated in acidic condition followed by a coupling with isocyanate to produce compounds4a-jas shown in Table 5, above. Scheme 7.
Figure imgf000252_0002
Reagents and conditions: (a) toluene, 2h, rt, (general yields 88-96%).
Piperazine compounds (5a-k) were prepared according to Scheme 7similarly to procedures described for 3a-j; an iso(thio)cyanate was reacted with 1-benzhydrylpiperazine in toluene to form the corresponding (thio)urea in two hours.
Scheme 8. _ (7a) X = S R = H r> Ph R_f 7-NCX (7b) X = S R = OEt
O H (7c) X = O R = H i ] , — R_0¾ Ph (7d) X = O R = CN
^N ^ NH (7e) X = O R = OMe
Boc H (7f) X = O R = CH3
6 (7g) X = O R = OEt
Reagents and conditions: (a) NaBH(OAc)3, AcOH, aniline, DCE, overnight, rt, (yield 84%); (b) TFA, DCM, lh, rt, quant; (c) toluene, 2h, rt, (general yields 5- 23%).
In Scheme 8, the reductive amination of aniline with 1 -boc-4-piperidone followed by deprotection in acidic condition afforded compound 6 which was reacted with appropriate isocyanates or isothiocyanates to produce the 4- anilinopiperidine series 7a-g.
Scheme 9.
Figure imgf000253_0001
Reagents and conditions: (a) B0C2O, 1,4-dioxane, H2O, NaOH, overnight, rt, (yield 94%); (b) HOBt, EDCl, TEA,DMF, NHMeOMe-HCl, overnight, rt, (yield 42%); (c) BuLi, 2-bromobiphenyl, TMEDA, THF, 3h, -78°C, (yield 35%) ; (d) TFA, DCM , lh, rt, (yield quant); (e) toluene, 2h, (yield 24%), (f) NaBH4, THF, MeOH, overnight, rt, (yield 25%).
Compounds 8-9 were synthesized from isonipecotic acid. The amine function was first protected with tert-butyl carbamate group followed by the formation of the Weinreb amide using HOBt and EDCl. Then, the lithium anion of 2-bromobiphenyl reacted on the Weinreb amide and Boc deprotection to give compounds 8. Addition reaction on iso(thio)cyanate with the piperidine in toluene afforded (thio)urea 9a-9b, followed by a reduction of the ketone group give the alcohol derivatives lOa-lOb.
Scheme 10.
Figure imgf000254_0001
Reagents and conditions: (a) HOBt, EDCl, DCM, overnight, rt, (yield 69%); (b) TFA, DCM, lh, rt, (yield quant); (c) isothiocyanate, toluene, 2h, (yield 10%).
Amidesll were synthesized from a coupling between diphenylacetic acid and 1 -boc-4-aminopiperidine in the presence of HOBt and EDCl. After a deprotection, the piperidine reacted on the iso(thio)cyanate to give the corresponding (thio)urea lla-llb.
Figure imgf000254_0002
Reagents and conditions: (a) NaSCN, EtOH, 2h, reflux, (yield 83%); (b) HCl, THF, overnight, reflux, (yield 28%); (c) Pd2(dba)3, (t-Bu)PHBF3, Cs2C03, dioxane, 24h, 120°C, (yield 30%).
Compound wherein the group Ar1 comprises a thiazole were also prepared. 2-bromo-2',4-dimethoxy-acetophenone or 2-bromo-4-ethoxy- acetophenone reacted with sodium thiocyanate to give respectively, 2- thiocyanate-2' ,4-dimethoxy-acetophenone and 2-thiocyanate-4-ethoxy- acetophenone which were cyclized under acidic condition at reflux to produce the thiazole moety 12a and 12b. These two molecules were coupled on the different cores in the presence of Pd2(dba)3, tri-tert-butyl-phosphonium tetrafluoroborate and cesium carbonate to afford the two azacyclonol 13a and 13b, and the benzhydrylpiperazine 14.
Scheme 12.
Figure imgf000255_0001
Reagents and conditions: (a) Ri-NH2,NaBH(OAc)3, AcOH, DCE, overnight, rt, (general yields 39-95%); (b) R2C0C1, TEA, DCM, overnight, rt, (general yields 25-89%).
4-(N-acetylanilino)- 1 -benzylpiperidine compounds were using a reductive amination followed by reaction with acyl chloride to afford compounds 15a-h, 16a-c, 17a-c and 18a-c. Treatment of commercial acid (3- Nitrocinnamic acid and benzo[b]thiophene-2-carboxylic acid) with
thionylchloride by a conventional method produced the acyl chloride derivatives. Scheme 13.
Figure imgf000255_0002
eagents and conditions: (a) TFA, DCM, rt, (yield quant); (b) MeS02Cl, TEA, DCM, 2h, 0°C, (yield quant); (c) K2C03, DMF, rt, (yield 70%); (d) 4- iodoaniline, NaBH(OAc)3, AcOH, DCE, overnight, rt, (yield 15%); (e)
CICOCH2CH3, TEA, DCM, overnight, rt, (yield 75%).
Compound 19 was synthesized from a coupling between the deprotected piperidone derivative and cyclopentylethanol which was first mesylated by a treatment with methansulfonylchloride. Then, in a similar manner as compound 15, 16, 17, 18, reductive animation followed by acetylation produced expected compound 20.
Further examples include compounds of the general structures:
Figure imgf000256_0001
wherein W is a linker as defined above, and core cyclic groups Ar2 and Ar3 are as defined above, the indole or indoline corresponding to group Ar1.
All compounds synthesized were characterized by !Η NMR (Varian Mercury-300, Varian Inova -400) and LC-MS (Shimadzu 210A).
General Schemes and Procedures for Synthesis of Compounds of Formula
Scheme 14:
Figure imgf000256_0002
Intermediate 1
H, )-Me, )-Me
Figure imgf000256_0003
Reagents and conditions: i) K2C03, DMF, 80 °C, 5 h; (ii) TFA/CH2C12, rt, 2 h; (iii) l l-chloro-5H-dibenzo[b,e]azepin-6(HH)-one (or) 1 l-chloro-5-methyl-5H- dibenzo[b,e]azepin-6(l lH)-one, DIEA, CH3CN, 1 10 °C, 1 h, microwave; (iv) SnCi2.2H20, EtOH, 4 h; (V) RCOCl, Et3N, CH2C12, 3 h (or) RNCO, CH2C12, 3 h (or) RCOOH, EDCI, HOBt, CH2C12, 18 h.
General procedure for the preparation of intermediate 1 (Scheme 14; step i):
A mixture of N-Boc protected piperazine (1 equiv.), l-fluoro-2- substituted-4-nitrobenzene (1 equiv.) and solid K2C03 (2 equiv.) in dry DMF was heated to 80 °C for 5 hrs. The reaction mixture was cooled to r.t., added to ¾0 and stirred for 2 hrs. The resulting solids were collected by filtration, washed with a mixture of EtOAc/hexanes and dried in vacuo to obtain the desired product which was used for next step without purification. In case, the precipitation was not observed, the solvents were concentrated in vacuo, the residue partitioned between ethyl acetate and water, organic layer was separated, washed with satbrine solution, dried over anhyd.Na2S04, solvents removed in vacuo and the crude was crystallized from EtOAc/hexanes.
General procedure (Scheme 14; step ii):
To a stirred solution of intermediate 1 (1 mmol) in dry CH2CI2 (1 mL) was added 1 mL of TFA and the mixture was stirred for 2-3 hrs (monitored by LC-MS) at r.t. The solvents were removed in vacuo, co-evaporated with toluene couple of times and the residue was dried under high vacuo. The crude product was used for next step without purification.
General procedure for the preparation of intermediate 2 (Scheme 14; step iii):
A mixture of N-Boc deprotected intermediate 1 (1.1 equiv.), 1 1-chloro-
5H-dibenzo[b,e]azepin-6(l lH)-one (1 equiv. ; prepared following the procedure described in DE 19816929 [Chem. Abstr. 1999, 131, 286 832]) or 1 l-chloro-5- methyl-5H-dibenzo[b,e]azepin-6(l lH)-one and DIEA (3 equiv.) in dry DMF or dry CH3CN was heated to 1 10 °C for 1 h under microwave irradiation. The reaction mixture was diluted with ethyl acetate and washed with sat. NaHC03, H2O and sat. brine solution. The organic layer was separated, dried over anhyd.Na2S04, solvents removed in vacuo and the crude was purified by column chromatography.
General procedure for the preparation of intermediate 3 (Scheme 14; step iv):
A mixture of intermediate 2 (1 equiv.) and SnCi2.2H20 (5 equiv.) in
EtOH was heated to reflux for 4-6 h (monitored by LC-MS). The solvents were removed in vacuo, the residue taken in ¾0, basified with IN aq.NaOH and CH2CI2 was added. The mixture was stirred for 2 h, transferred into a separating funnel; organic layer was separated, washed with ¾0 and sat.brine solution. The organic layer was separated, dried over anhyd.Na2S04, solvents removed in vacuo and the crude product was used for next step without purification.
General procedure (Scheme 14; step v): To a stirred solution of intermediate 3 (1 equiv.) in dry CH2CI2 was added Et3N (2 equiv.) followed by the addition of RCOCl (1 equiv.) or RNCO (1 equiv.) in CH2CI2 and the mixture was stirred for 3 h at r.t. The mixture was diluted with CH2CI2, washed with ¾0, sat. NaHC03 and sat. brine solution. The organic layer was separated, dried over anhyd.Na2S04, solvents removed in vacuo and the crude was purified by column chromatography.
OR
A mixture of R-COOH (1 equiv.), EDCI (1.1 equiv.) and HOBt (1 equiv.) in dry CH2CI2 was stirred at r.t. for 30-60 min. Then, intermediate 3 (1 equiv.) in dry CH2CI2 was added and the mixture was stirred for 18 h. The mixture was diluted with CH2CI2, washed with ¾0, sat. NaHC03 and sat. brine solution. The organic layer was separated, dried over anhyd.Na2S04, solvents removed in vacuo and the crude was purified by column chromatography. Scheme 15
Figure imgf000258_0001
Intermediate 1 Intermediate 4 Intermediate 5
Figure imgf000258_0002
Reagents and conditions: i) K2C03, DMF, 80 °C, 5 h; (ii) SnCl2.2H20, EtOH, 4 h or 10%Pd-C, H2, MeOH, 4 h; (iii) RCOCl, Et3N, CH2C12, 3 h (or) RCOOH, EDCI, HOBt, CH2C12, 18 h; (iv) TFA/CH2C12, rt, 2 h; (v) Ar2CHCl or
Ar(R)CHCl, DIEA, CH3CN, 1 10 °C, 1 h, microwave.
General procedure for the preparation of intermediate 4 (Scheme 15; step ii):
A mixture of intermediate 1 and 10% Pd-C in MeOH or a mixture
EtOAc/MeOH was stirred under ¾ atmosphere (balloons) for 4 h at r.t. The reaction mixture was filtered through celite, washed with MeOH, the filtrates were concentrated in vacuo to obtain intermediate 4 which was used for next step without purification. General procedure for the preparation of intermediate 5 (Scheme 15; step iii):
To a stirred solution of intermediate 4 (1 equiv.) in dry CH2CI2 was added Et3N (2 equiv.) followed by the addition of RCOC1 (1 equiv.) in CH2C12 and the mixture was stirred for 3 h at r.t. The mixture was diluted with CH2CI2, washed with ¾0, sat. NaHCC>3 and sat. brine solution. The organic layer was separated, dried over anhyd.Na2S04, solvents removed in vacuo and the crude was purified by column chromatography.
OR
A mixture of R-COOH (1 equiv.), EDCI (1.1 equiv.) and HOBt (1.1 equiv.) in dry CH2CI2 was stirred at r.t. for 30-60 min. Then, intermediate 4 (1 equiv.) in dry CH2CI2 was added and the mixture was stirred for 18 h. The mixture was diluted with CH2CI2, washed with ¾0, sat. NaHCC>3 and sat. brine solution. The organic layer was separated, dried over anhyd.Na2S04, solvents removed in vacuo and the crude was purified by column chromatography.
General procedure (Scheme 15; step iv):
To a stirred solution of intermediate 5 (1 mmol) in dry CH2CI2 (1 mL) was added 1 mL of TFA and the mixture was stirred for 2-3 h (monitored by LC- MS) at r.t. The solvents were removed in vacuo, the residue was taken in CH2CI2, washed with sat.NaHC03 (2 x), ¾0 and sat.brine solution. The organic layer was separated, dried over anhyd.Na2S04, solvents removed in vacuo and the crude product was used for next step without purification.
General procedure (Scheme 15; step v):
A mixture of N-Boc deprotected intermediate 5 (1.1 equiv.), tricyclic or bicyclic chloride (1 equiv.) and DIEA (2 equiv.) in dry DMF or dry CH3CN was heated to 1 10 °C for 1 h under microwave irradiation. The reaction mixture was diluted with ethyl acetate and washed with sat. NaHCC>3, H2O and sat. brine solution. The organic layer was separated, dried over anhyd.Na2S04, solvents removed in vacuo and the crude was purified by column chromatography.
Scheme 16:
Figure imgf000260_0001
Figure imgf000260_0002
Intermediate 8
Reagents and conditions: i) dry THF, 2-3 h, rt, when R = C¾ (or) dry THF, reflux, 2-3 hr, when R = H; (ii) 10%Pd-C, H2, MeOH, 16 h; (iii) K2C03, DMF, 80 °C, 5 h; (iv) 10%Pd-C, H2, MeOH, overnight, when Ri = CN (or)
SnCl2.2H20, EtOH, 4 h, when Rj = CI; (v) RCOC1, Et3N, CH2C12, 3 h (or) RNCO, CH2C12, 3 h (or) RCOOH, EDCI, HOBt, CH2C12, 18 h.
General procedure for the preparation of intermediate 6 (Scheme 16; step i):
A freshly prepared (l-benzylpiperidin-4-yl) magnesium bromide, from 1 -benzyl-4-bromopiperidine, in dry THF was added drop wise to a stirred suspension of 5H-dibenzo[Z?,e]azepine-6,l 1-dioneor a stirred solution of 5- methyl-5H-dibenzo[Z?,e]azepine-6, l 1-dione in dry THF and the mixture was stirred at r.t. 2-3 h (monitored by LC-MS). In case of 5H-dibenzo[Z?,e]azepine- 6, 1 1-dione, the mixture was heated to reflux for 2-3 h. After completion of the starting material tricyclic ketone, the reaction mixture was quenched with IN HCl, the mixture was partitioned between ethyl acetate and water, organic layer was separated, washed with satbrine solution, dried over anhyd.Na2S04, solvents removed in vacuo and the crude was purified by column
chromatography.
General procedure (Scheme 16; step ii):
A mixture of intermediate 6 and 10% Pd-C in MeOH was stirred under H2 atmosphere (balloons) for 16 h at r.t. The reaction mixture was filtered through celite, washed with MeOH, the filtrates were concentrated in vacuo to obtain N-benzyl deprotected intermediate 6, which was used for next step without purification. General procedure for the preparation of intermediate 7 (Scheme 16; step iii):
A mixture of N-benzyl deprotected intermediate 6 (1 equiv.), l-fluoro-2- substituted-4-nitrobenzene (1 equiv.) and solid K2CO3 (2 equiv.) in dry DMF was heated to 80 °C for 5 hrs. The solvents were concentrated in vacuo, the residue partitioned between ethyl acetate and water, organic layer was separated, washed with satbrine solution, dried over anhyd.Na2S04, solvents removed in vacuo and the crude was purified by column chromatography.
General procedure for the preparation of intermediate 8 (Scheme 16; step iv):
A mixture of intermediate 7 and 10% Pd-C in MeOH was stirred under ¾ atmosphere (balloons) overnight at r.t. The reaction mixture was filtered through celite, washed with MeOH, the filtrates were concentrated in vacuo to obtain intermediate 8, which was used for next step without purification.
OR
A mixture of intermediate 7 (1 equiv.) and SnC¾.2H20 (5 equiv.) in EtOH was heated to reflux for 4 h (monitored by LC-MS). The solvents were removed in vacuo, the residue taken in ¾0, basified with IN aq.NaOH and CH2CI2 was added. The mixture was stirred for 2 h, transferred into separating funnel; organic layer was separated, washed with ¾0 and sat.brine solution. The organic layer was separated, dried over anhyd.Na2S04, solvents removed in vacuo and the crude product was used for next step without purification.
General procedure (Scheme 16; step v):
To a stirred solution of intermediate 8 (1 equiv.) in dry CH2CI2 was added Et3N (2 equiv.) followed by the addition of RCOCl (1 equiv.) or RNCO (1 equiv.) in CH2CI2 and the mixture was stirred for 3 h at r.t. The mixture was diluted with CH2CI2, washed with ¾0, sat. NaHC03 and sat. brine solution. The organic layer was separated, dried over anhyd.Na2S04, solvents removed in vacuo and the crude was purified by column chromatography.
OR
A mixture of R-COOH (1 equiv.), EDCI (1.1 equiv.) and HOBt (1 equiv.) in dry CH2CI2 was stirred at r.t. for 30-60 min. Then, intermediate 8 (1 equiv.) in dry CH2CI2 was added and the mixture was stirred for 18 h. The mixture was diluted with CH2CI2, washed with ¾0, sat. NaHC03 and sat. brine solution. The organic layer was separated, dried over anhyd.Na2S04, solvents removed in vacuo and the crude was purified by column chromatography.
Figure imgf000262_0001
Intermediate 11
Reagents and conditions: i) DMSO, 80 °C, 5 h; (ii) DMF, 1 10 °C, 1 h, microwave; (iii) 2N aq.NaOH, MeOH, 50 °C, 4 h; (iv) RNH2, EDCI, HOBt, Et3N, DMF, 18 h.
General procedure for the preparation of intermediate 9 (Scheme 17; step i):
A mixture of piperazine (1 equiv.), methyl-3-cyano-4-fluoro benzoate (1 equiv.) in DMSO was heated to 80 °C for 5 h. The mixture was cooled, DIEA added and then the mixture poured into water and extracted with EtOAc. The organic layer was separated, washed with ¾0 and sat. brine solution, dried over anhyd.Na2S04, solvents removed in vacuo to obtain intermediate 9, which was used for next step without purification.
General procedure for the preparation of intermediate 10 (Scheme 17; step ii):
A mixture of intermediate 9 (1 equiv.), 1 l-chloro-5H- dibenzo[b,e]azepin-6(HH)-one (1 equiv.; prepared following the literature procedure) and DIEA (2 equiv.) in dry DMF was heated to 1 10 °C for 1 h under microwave irradiation. The reaction mixture was added to ί¾0 and extracted with with ethyl acetate. The organic layer was separated, washed with i¾0 and sat. brine solution. The organic layer was separated, dried over anhyd.Na2S04, solvents removed in vacuo and the crude was purified by column
chromatography.
General procedure for the preparation of intermediate 1 1 (Scheme 17; step iii): To a stirred solution of intermediate 10 (1 equiv.) in MeOH was added 2N aq.NaOH (2 equiv.) and the mixture was heated to 50 °C for 4 h. The reaction mixture was cooled to r.t., solvents removed in vacuo, the residue taken in H20, neutralized with IR-120H resin. The aqueous layer was separated, resin washed with H20 and the combined aqueous layers were concentrated to dryness in vacuo. The resulting solids were suspended in EtOAc, collected by filtration and dried to obtain pure intermediate 1 1.
General procedure (Scheme 17; step iv):
A mixture of intermediate 1 1 (1 equiv.), EDCI (1.2 equiv.) and HOBt (1.2 equiv.) and Et3N (3 equiv.) in dry DMF was stirred at r.t. for 1 h. Then, amine (1.2 equiv.) was added and the mixture was stirred for 18 h. The mixture was diluted with EtOAc, washed with H20, sat. NaHCC>3 and sat. brine solution. The organic layer was separated, dried over anhyd.Na2S04, solvents removed in vacuo and the crude was purified by column chromatography.
Figure imgf000263_0001
Reagents and conditions: i) dry THF, reflux, 2-4 h; (ii) CHCI3, H2S04, reflux, 3 h; (iii) 10%Pd-C, H2, MeOH/CH2Cl2, overnight; (iv) K2C03, DMF, 80 °C, overnight; (iv) 10%Pd-C, H2, MeOH, overnight; (v) RCOC1, Et3N, CH2C12, 3 h (or) RNCO, CH2C12, 3 h (or) RCOOH, EDCI, HOBt, CH2C12, 18 h.
General procedure for the preparation of intermediate 12 (Scheme 18; step ii):
To a stirred solution of intermediate 6 in 4 mL of CHCI3 was added 1 mL of conc.H2S04 and the reaction mixture was heated to reflux for 3 h. The solvents were concentrated in vacuo, the residue taken in H20 and basified with IN NaOH. The aqueous layer was extracted with CH2CI2, organic layers were combined, washed with satbrine solution, dried over anhyd.Na2S04, solvents removed in vacuo to obtain intermediate 12, which was used for next step without purification.
General procedure (Scheme 18; step in):
A mixture of intermediate 12 and 10% Pd-C in MeOH was stirred under ¾ atmosphere (balloons) for 16 h at r.t. The reaction mixture was filtered through celite, washed with MeOH, the filtrates were concentrated to obtain N- benzyl deprotected intermediate 12, which was used for next step without purification.
General procedure for the preparation of intermediate 13 (Scheme 18; step iv):
A mixture of N-benzyl deprotected intermediate 6 (1 equiv.), 2-fluoro-5- nitrobenzonitrile (1 equiv.) and solid K2CO3 (2 equiv.) in dry DMF was heated to 80 °C for 5 hrs. The solvents were concentrated in vacuo, the residue partitioned between ethyl acetate and water, organic layer was separated, washed with satbrine solution, dried over anhyd.Na2S04, solvents removed in vacuo and the crude was purified by column chromatography.
General procedure for the preparation of intermediate 14 (Scheme 18; step v):
A mixture of intermediate 13 and 10% Pd-C in MeOH was stirred under ¾ atmosphere (balloons) overnight at r.t. The reaction mixture was filtered through celite, washed with MeOH, the filtrates were concentrated to obtain intermediate 14, which was used for next step without purification.
General procedure (Scheme 18; step vi):
To a stirred solution of intermediate 14 (1 equiv.) in dry CH2CI2 was added Et3N (2 equiv.) followed by the addition of RCOC1 (1 equiv.) or RNCO (1 equiv.) in CH2CI2 and the mixture was stirred for 3 h at r.t. The mixture was diluted with CH2CI2, washed with ¾0, sat. NaHC03 and sat. brine solution. The organic layer was separated, dried over anhyd.Na2S04, solvents removed in vacuo and the crude was purified by column chromatography. OR
A mixture of R-COOH (1 equiv.), EDCI (1.1 equiv.) and HOBt (1 equiv.) in dry CH2CI2 was stirred at r.t. for 1 h. Then, intermediate 8 (1 equiv.) in dry CH2CI2 was added and the mixture was stirred for 18 h. The mixture was diluted with CH2CI2, washed with ¾0, sat. NaHCC>3 and sat. brine solution. The organic layer was separated, dried over anhyd.Na2S04, solvents removed in vacuo and the crude was purified by column chromatography.
Figure imgf000265_0001
intermediate 15 intermediate 16
Figure imgf000265_0002
Reagents and conditions: i) Pd(PPh3)4, K2CO3, dioxane, ¾0, microwave, 150 °C, 1 h; (ii) 10%Pd-C, H2, MeOH, 2-5 h; (iii) RCOC1, Et3N, CH2C12, 3 h (or) RCOOH, EDCI, HOBt, CH2C12, 18 h; (iv) TFA/CH2C12, rt, 3 h; (v) Ar-Cl, DIEA, DMF, 1 10 °C, 1 h, microwave.
General procedure for the preparation of intermediate 15 (Scheme 19; step i):
A sample of 4-bromo-2-substituted-nitrobenzene (1 equiv.), boronic acid pinacol ester (1.5 equiv.), K2CO3 (3 equiv.), Pd(PPh3)4 (0.1 equiv.), was taken in 2-5 mL of microwave vial and was added dioxane and ¾0. The N2 gas was bubbled into the reaction mixture for 5 min, then sealed and the mixture was heated to 150 °C for 1 h. The mixture was diluted with EtOAc, washed with H2O and sat. brine solution. The organic layer was dried over anhyd.Na2S04, solvents removed in vacuo and the crude product was purified by column chromatography.
General procedure for the preparation of intermediate 16 (Scheme 19; step ii):
A mixture of intermediate 15 and 10% Pd-C in MeOH was stirred under
¾ atmosphere (balloons) 2-5 h at r.t. The reaction mixture was filtered through celite, washed with MeOH, the filtrates were concentrated to obtain intermediate 16, which was used for next step without purification.
General procedure for the preparation of intermediate 17 (Scheme 19; step iii): To a stirred solution of intermediate 16 (1 equiv.) in dry CH2CI2 was added Et3N (2 equiv.) followed by the addition of RCOC1 (1 equiv.) in CH2C12 and the mixture was stirred for 3 h at r.t. The mixture was diluted with CH2CI2, washed with ¾0, sat. NaHCC>3 and sat. brine solution. The organic layer was separated, dried over anhyd.Na2S04, solvents removed in vacuo and the crude was purified by column chromatography.
OR
A mixture of R-COOH (1 equiv.), EDCI (1.1 equiv.) and HOBt (1.1 equiv.) in dry CH2CI2 was stirred at r.t. for 30-60 min. Then, intermediate 16 (1 equiv.) in dry CH2CI2 was added and the mixture was stirred for 18 h. The mixture was diluted with CH2CI2, washed with ¾0, sat. NaHCC>3 and sat. brine solution. The organic layer was separated, dried over anhyd.Na2S04, solvents removed in vacuo and the crude was purified by column chromatography. General procedure (Scheme 19; step iv):
To a stirred solution of intermediate 17 (1 mmol) in dry CH2CI2 (1 mL) was added 1 mL of TFA and the mixture was stirred for 2-3 hrs (monitored by LC-MS) at r.t. The solvents were removed in vacuo, the residue was taken in CH2CI2, washed with sat.NaHC03 (2 x), ¾0 and sat.brine solution. The organic layer was separated, dried over anhyd.Na2S04, solvents removed in vacuo and the crude product was used for next step without purification.
General procedure (Scheme 19; step v):
A mixture of N-Boc deprotected intermediate 17 (1.1 equiv.), tricyclic or bicyclic chloride (1 equiv.; prepared following the literature procedure) and DIEA (3 equiv.) in dry DMF or dry CH3CN was heated to 1 10 °C for 1 h under microwave irradiation. The reaction mixture was diluted with ethyl acetate and washed with sat. NaHCC>3, ¾0 and sat. brine solution. The organic layer was separated, dried over anhyd.Na2S04, solvents removed in vacuo and the crude was purified by column chromatography.
Scheme 20:
Figure imgf000267_0001
Reagents and conditions: i) K2CO3, DMF, 80 °C, overnight.
General procedure for the preparation of intermediate 18 (Scheme 20):
A mixture of 3-chloro-4-fluoro benzoic acid (1 equiv.), EDCI (1.1 equiv.) and HOBt (1.1 equiv.) in dry DMF was stirred at r.t. for 1 h. Then, alkylamide oxime (1.2 equiv.) in dry DMF was added and the mixture was stirred at r.t 4 h and then at 80 °C overnight. The solvents were concentrated in vacuo, the residue partitioned between ethyl acetate and water, organic layer was separated, washed with satbrine solution, dried over anhyd.Na2S04, solvents removed in vacuo and the crude was purified by column chromatography.
General procedure (Scheme 20. step i):
A mixture of 1 l -hydroxy-5-methyl- l l -(piperidin-4-yl)-5H- dibenzo[b,e]azepin-6(l lH)-one (0.1 mmol; for preparation see Scheme 3, step ii), intermediate 18 (1 equiv.) and solid K2CO3 (2 equiv.) in dry DMF was heated to 80 °C overnight. The reaction mixture was cooled to r.t., added to H2O and extracted with EtOAc. The organic layer was separated, washed with sat.brine solution, dried over anhyd.Na2S04, solvents removed in vacuo and the crude was purified by preparative TLC.
Scheme 21 :
Figure imgf000267_0002
Intermediate 19 Intermediate 20
Figure imgf000267_0003
n erme a e Reagents and conditions: i) K2C03, DMF, 80 °C, overnight; (ii) 2N aq.NaOH, MeOH, 50 °C, 2 h; (iii) EDCI, HOBt, dry DMF, lh, then alkylamide oxime 4 h at r.t. and overnight at 50 °C; (iv) TFA/CH2C12, rt, 2-3 h; (v) Ar2CH-Cl, DIEA, CH3CN, 1 10 °C, 1 h, microwave.
General procedure for the preparation of intermediate 19 (Scheme 21 ; step i):
A mixture of N-Boc piperazine (1.2 equiv.), methyl-3-substitutued-4- fluoro benzoate (1 equiv.) in dry DMF was heated to 80 °C for overnight. The solvents were concentrated in vacuo, the residue partitioned between ethyl acetate and water, organic layer was separated, washed with sat.brine solution, dried over anhyd.Na2S04, solvents removed in vacuo and the crude was purified by column chromatography.
General procedure for the preparation of intermediate 20 (Scheme 21 ; step ii):
To a stirred solution of intermediate 19 (1 equiv.) in MeOH was added 2N aq.NaOH (2 equiv.) and the mixture was heated to 50 °C for 2 h. The reaction mixture was cooled to r.t., solvents removed in vacuo, the residue taken in H20, neutralized with IN HC1. The aqueous layer was extracted with EtOAc, organic layer separated, washed with H20 and satbrine solution, dried over anhyd.Na2S04, solvents removed in vacuo and the crude product was used for next step without purification.
General procedure for the preparation of intermediate 21 (Scheme 21 ; step iii):
A mixture of intermediate 20 (1 equiv.), EDCI (1.1 equiv.) and HOBt (1.1 equiv.) in dry DMF was stirred at r.t. for 1 h. Then, alkylamide oxime (1.2 equiv.) in dry DMF was added and the mixture was stirred at r.t for 4 h and then at 80 °C overnight. The solvents were concentrated in vacuo, the residue partitioned between ethyl acetate and water, organic layer was separated, washed with satbrine solution, dried over anhyd.Na2S04, solvents removed in vacuo and the crude was purified by column chromatography.
General procedure (Scheme 21 ; step iv):
To a stirred solution of intermediate 21 (1 mmol) in dry CH2C12 (1 mL) was added 1 mL of TFA and the mixture was stirred for 2-3 h (monitored by LC- MS) at r.t. The solvents were removed in vacuo, the residue was taken in CH2C12, washed with sat.NaHC03 (2 x), H20 and sat.brine solution. The organic layer was separated, dried over anhyd.Na2S04, solvents removed in vacuo and the crude product was used for next step without purification.
General procedure (Scheme 21 ; step V):
A mixture of N-Boc deprotected intermediate 21 (1.1 equiv.), 1 1-chloro- 5H-dibenzo[b,e]azepin-6(l lH)-one or 1 l-chloro-5-methyl-5H- dibenzo[b,e]azepin-6(l lH)-one and DIEA (2 equiv.) in dry C¾CN was heated to 1 10 °C for 1 h under microwave irradiation. The solvents were concentrated in vacuo, the residue partitioned between ethyl acetate and water, organic layer was separated, washed with satbrine solution, dried over anhyd.Na2S04, solvents removed in vacuo and the crude was purified by preparative TLC. Documents Cited
1. (a) Rahardio, G.L.; Huang, X.F.; Tan Y. Y.; Deng, C. Endocrinology2007 , 148, 4704. (b) Vrang, N.; Madsen, AN.; Tang-Christensen, M.; Hansen, G.; Larsen, PJ. Am. J. Physiol.2006, 291, R367-375.
2. Greco, B.; Carli, M. Behavioural Brain Research2006, 169, 325.
3. Dvorak, C. et al. WO 2009/006185 Al, 2009.
4. Heilig M.; Widerlov E. Acta Psychiatr Scandl990, 82, 95.
5. Kalra, S.P. et al. Front Neuroendocrinal. 1992, 13, 1.
6. Clarke, I.J.; Backholer, K.; Tilbrook, A.J. Endocrinology2005, 146 (2), 769. 7. Baldock, P.A. J. Clin. Invest. 2002, 109, 915.
8. (a) Thiele, T.E. et al. Neuropeptides2004, 38 (4), 235. (b) Peptides2004, 25 (6), 975.
9. Kuo, L.E.; Zukowska, Z. Peptides 2007, 28, 435.
10. Brumovsky P.et alTrends Pharmacol SW2007, 28, 93-102
1 1. Balasubramaniam, A. et al. Peptides 2007, 28, 235.
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While the invention has been described and exemplified in sufficient detail for those skilled in this art to make and use it, various alternatives, modifications, and improvements will be apparent to those skilled in the art without departing from the spirit and scope of the claims.
All patents and publications referred to herein are incorporated by reference herein to the same extent as if each individual publication was specifically and individually indicated to be incorporated by reference in its entirety.
The terms and expressions which have been employed are used as terms of description and not of limitation, and there is no intention that in the use of such terms and expressions of excluding any equivalents of the features shown and described or portions thereof, but it is recognized that various modifications are possible within the scope of the invention claimed. Thus, it should be understood that although the present invention has been specifically disclosed by preferred embodiments and optional features, modification and variation of the concepts herein disclosed may be resorted to by those skilled in the art, and that such modifications and variations are considered to be within the scope of this invention as defined by the appended.

Claims

CLAIMS What is claimed is:
1. A compound of formula (III)
Figure imgf000271_0001
wherein
ring A comprises 0-2 nitrogen atoms; or, ring B comprises 0-2 nitrogen atoms; or, both; and, each of ring A and ring B is independently substituted with n independently selected J groups;
or, ring A is absent and the two carbon atoms connecting X1 and X3 are mutually double bonded and each independently bears hydrogen or (C 1 - C6)alkyl, or the two carbon atoms are mutually single bonded and together with a methano bridge therebetween form a cyclopropyl, and ring B is substituted with n independently selected J groups;
or, ring B is absent and the two carbon atoms connecting X1 and X3 are mutually double bonded and each independently bears hydrogen or (C 1 - C6)alkyl, or the two carbon atoms are mutually single bonded and together with a methano bridge therebetween form a cyclopropyl, and ring A is substituted with n independently selected J groups; and,
Cyc is single -bonded or double -bonded to any one of X1, X2, or X3, provided that when X3 is C=0 or O, Cyc is bonded to X1 or X2; and, a single bond or a double bond is present between X1 and X2; such that, when a single bond is present between X1 and X2,
X1 is CHRC, C=0, or NR', unless Cyc is single-bonded to X1, then X1 is CRC or N, or unless Cyc is double-bonded to X1, then X1 is a carbon atom;
X2 is CHRC, C=0, or NR', unless Cyc is single-bonded to X2, then X2 is CRC or N, or unless Cyc is double-bonded to X2, then X2 is a carbon atom;
X3 is CHRC, NR', C=0, or O; unless Cyc is single-bonded to X3, then X3 is CRC or N, or unless Cyc is double-bonded to X3, then X3 is a carbon atom; provided that when one of X1 and X2 is C=0 and the other of X1 and X2 is NR', then X3 is CRC or N and Cyc is single-bonded to X3; or X3 is a carbon atom and Cyc is double-bonded thereto,
or, when a double bond is present between X1 and X2,
X1 is CRC or N, unless Cyc is bonded to X1, then X1 is a carbon atom;
X2 is CRC or N, unless Cyc is bonded to X2, then X2 is a carbon atom;
X3 is CRC, NR', C=0, or O; unless Cyc is single-bonded to X3, then X3 is CRC or N, or unless Cyc is double-bonded to X3, then X3 is a carbon atom; each n is independently 0, 1, 2, 3, or 4;
Cyc is
Figure imgf000272_0001
wherein W is CR or N, each Rcyc is independently selected halo, (C 1 -C6)alkyl, or (C 1 -C6)alkoxyl; p is 0, 1, or 2; wherein wavy lines indicate points of bonding; or,
Figure imgf000273_0001
wavy lines indicate points of bonding; and,
Q is a bond, C(=NR)NR, C(=N-CN)NR, OC(=NR)NR, OC(=N-CN)NR, NRC(=NR)NR, NRC(=N-CN)NR, C(=0)NR, C(=0)0, OC(=0)0, OC(=0)NR, NRC(=0)NR, C(=S)NR, OC(=S)NR, NRC(=S)NR, C(=CR2)NR, OC(=CR2)NR, NRC(=CR2)NR, NR, C(=0)CHR"NRC(=0)OCH2,
C(=0)CHR"NRC(=0)NRCH2, C(=0)CHR"NRC(=S)NRCH2, C(=O)(CR2)0-3, or Q is
Figure imgf000273_0002
wherein wavy lines indicate points of bonding, or Q is S(0)q or
NRS(0)q wherein q is 0, 1, or 2;
HA is aryl or heteroaryl substituted with 0, 1, or 2 substituents independently selected from the group consisting of halo, cyano, (C 1 -C6)alkyl, (Cl-C6)alkoxyl, and C02R', and further substituted with JHA;
JHA is (CH2)o-2RJ, (CH2)o-2ORJ, (CH2)0-2N(RJ)2, (CH2)0-2SRJ, (CH2)0- 2SORJ, (CH2)o-2S02RJ, (CH2)o-2S02N(RJ)2, (CH2)0-2SO3RJ, (CH2)0-2C(O)RJ, (CH2)o-2C(0)C(0)RJ, (CH2)o-2C(0)CH2C(0)RJ, (CH2)0-2C(O)ORJ, (CH2)0- 2OC(0)RJ, (CH2)o-2OC(0)ORJ, (CH2)0-2C(O)N(RJ)2, (CH2)0-2OC(O)N(RJ)2, (CH2)o-2N(RJ)C(0)RJ, (CH2)o-2N(RJ)C(0)ORJ, (CH2)0-2N(RJ)C(O)N(RJ)2, (CH2)o-2N(RJ)N(RJ)C(0)RJ, (CH2)0-2N(RJ)N(RJ)C(O)ORJ, (CH2)0- 2N(RJ)N(RJ)CON(RJ)2, (CH2)0-2N(RJ)SO2RJ, (CH2)0-2N(RJ)SO2N(RJ)2, (CH2)0- 2C(S)RJ, (CH2)o-2OC(S)RJ, (CH2)o-2N(RJ)C(S)RJ, (CH2)0-2N(RJ)C(S)N(RJ)2, (CH2)o-2C(S)N(RJ)2, (CH2y2N(CORJ)CORJ, (CH2)0-2N(ORJ)RJ, (CH2)0- 2C(=NRJ)N(RJ)2, (CH2)o-2C(0)N(ORJ)RJ, and (CH2)0-2C(=NORJ)RJ,
each independently selected R' is H or (C 1 -C6)alkyl, and n' = 0, 1, or 2; each independently selected R" is H, (C 1 -C6)alkyl, or (CH2)mNR2 wherein m is 1, 2, 3, or 4; each independently selected R is H, halo, (Cl-C6)alkyl, OH, or (Cl- C6)alkoxyl;
R is independently at each occurrence hydrogen or an alkyl, acyl, cycloalkyl, cycloalkylalkyl, aryl, aroyl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, wherein any alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl is substituted with 0-3 J; or wherein two R groups together with a nitrogen atom or with two adjacent nitrogen atoms to which they are bonded can together form a (C3-C8)heterocyclyl substituted with 0-3 J; optionally further comprising 1-3 additional heteroatoms selected from the group consisting of O, N, and S(0)q; wherein any cycloalkyl, aryl, heterocyclyl, or heteroaryl can be fused, bridged, or in a spiro configuration with one or more additional optionally substituted cycloalkyl, aryl, heterocyclyl, and heteroaryl, monocyclic, bicyclic or polycyclic, saturated, partially unsaturated, or aromatic rings;
wherein J independently at each occurrence is selected from the group consisting of F, CI, Br, I, OR, CN, CF3, OCF3, O, S, C(O), S(O),
methylenedioxy, ethylenedioxy, (CH2)o-2N(RJ)2, (CH2)0-2SRJ, (CH2)0-2SORJ, (CH2)o-2S02RJ, (CH2)o-2S02N(RJ)2, (CH2)0-2SO3RJ, (CH2)0-2C(O)RJ, (CH2)0- 2C(0)C(0)RJ, (CH2)o-2C(0)CH2C(0)RJ, (CH2)0-2C(S)RJ, (CH2)0-2C(O)ORJ, (CH2)o-2OC(0)RJ, (CH2)o-2OC(0)ORJ, (CH2)0-2C(O)N(RJ)2, (CH2)0- 2OC(0)N(RJ)2, (CH2)o-2C(S)N(RJ)2, (CH2)0-2N(RJ)C(O)RJ, (CH2)0- 2N(RJ)N(RJ)C(0)RJ, (CH2)o-2N(RJ)N(RJ)C(0)ORJ, (CH2)0- 2N(RJ)N(RJ)CON(RJ)2, (CH2)0-2N(RJ)SO2RJ, (CH2)0-2N(RJ)SO2N(RJ)2, (CH2)0- 2N(RJ)C(0)ORJ, (CH2)o-2N(RJ)C(0)RJ, (CH2)0-2N(RJ)C(S)RJ, (CH2)o- 2N(RJ)C(0)N(RJ)2, (CH2)o-2N(RJ)C(S)N(RJ)2, (CH2)0-2N(CORJ)CORJ, (CH2)0- 2N(ORJ)RJ, (CH2)o-2C(=NRJ)N(RJ)2, (CH2)0-2C(O)N(ORJ)RJ, and (CH2)0- 2C(=NORJ)RJ,
wherein RJ is independently at each occurrence selected from the group consisting of hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl, wherein any alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, is unsubstituted or is substituted with 1 , 2, or 3 substituents independently selected from the group consisting of (C 1 -C6)alkyl and (C6-C 10)aryl; or wherein two RJ groups together with a nitrogen atom or with two adjacent nitrogen atoms to which they are bonded can together form a (C3-C8)heterocyclyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of (Cl-C6)alkyl and (C6- C10)aryl, and optionally further comprising 1-3 additional heteroatoms selected from the group consisting of O, N, S, S(O) and S(0)2;
or a pharmaceutically acceptable salt thereof.
2. The compound of claim 1, wherein X1 is C=0 and X2 is NH.
3. The compound of claim 1 wherein a double bond is present between X1 and X2, and X3 is O.
4. The compound of claim 1 wherein X1 and X2 are both C¾ and X3 is CH, Cyc being bonded to X3'
5. The compound of claim 1 wherein X1 is C=0, X2 is NH or N(CH3), and X3 is CH, C-OH, or C-CH3, Cyc being bonded to X3.
6. The compound of claim 1 wherein Cyc is piperidinyl or piperazinyl, either of which is optionally substituted with oxo or methyl.
7. The compound of claim 1 wherein n = 1 and J is chloro or fluoro.
8. The compound of claim 1 wherein Q is a bond, C(=S)NH, C(=0)NH, C(=0)0, NHC(=0)NH, or C(=NCN)NH.
9. The compound of claim 1 wherein the compound is any of the following:
Figure imgf000276_0001
Figure imgf000277_0001
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Figure imgf000278_0001
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Figure imgf000279_0001
Figure imgf000280_0001
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Figure imgf000281_0001
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Figure imgf000288_0001
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Figure imgf000296_0001
WO 2014/116684
Figure imgf000297_0001
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Figure imgf000299_0001
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Figure imgf000300_0001
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Figure imgf000301_0001
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Figure imgf000305_0001
Figure imgf000306_0001
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Figure imgf000316_0001
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Figure imgf000319_0001
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Figure imgf000320_0001
Figure imgf000321_0001
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Figure imgf000322_0001
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Figure imgf000323_0001
10. The compound of claim 1 wherein the compound is a modulator of a neuropeptide Y receptor.
1 1. The compound of claim 10 wherein the neuropeptide Y receptor is Y 1 R or Y2R.
12. The compound of claim 10 wherein the compound is selective for modulation of Y2R.
13. A pharmaceutical composition comprising a compound of any one of claims 1-12 and a pharmaceutically acceptable excipient.
14. A method of modulation a neuropeptide Y receptor comprising contacting the receptor with an effective amount or concentration of a compound of any one of claims 1-12.
15. The method of claim 14 wherein the contacting is in vivo in a human patient.
16. The method of claim 14 wherein the amount or concentration of the compound is effective to selectively modulate Y2R.
17. A method of treatment of a malcondition in a patient for which modulation of a neuropeptide Y receptor is medically indicated, comprising administering to the patient a compound of any one of claims 1- 12 in a dose, at a frequency, and for a duration sufficient to provide a beneficial effect to the patient.
18. The method of claim 17 wherein the malcondition comprises drug or alcohol abuse, anxiety disorder, depression, stress-related disorder, neurological disorder, nerve degeneration, osteoporosis or bone loss, sleep/wake disorder, cardiovascular disease, obesity, anorexia, inovulation, fertility disorder, angiogenesis, cell proliferation, learning and memory disorder, migraine, or pain.
19. Use of a compound of any one of claims 1- 12 in treatment of a malcondition in a human patient.
20. The use of claim 19 wherein modulation of any NPY receptor is medically indicated for treatment of the malcondition.
21. The use of claim 19 wherein the malcondition comprises drug or alcohol abuse, anxiety disorder, depression, stress-releated disorder, neurological disorder, nerve degeneration, osteoporosis or bone loss, sleep/wake disorder, cardiovascular disease, obesity, anorexia, inovulation, fertility disorder, angiogenesis, cell proliferation, learning and memory disorder, migraine, or pain.
PCT/US2014/012521 2013-01-22 2014-01-22 Non-peptidic neuropeptide y receptor modulators WO2014116684A1 (en)

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JP2020183405A (en) * 2015-04-07 2020-11-12 イーエルエイ ファーマ リミテッドＥｌａ Ｐｈａｒｍａ Ｌｔｄ Compositions for treating and/or preventing cell and/or tissue necrosis specifically targeting cathepsin c and/or cela1 and/or cela3a and/or enzymes structurally related to them
WO2018202524A1 (en) 2017-05-04 2018-11-08 Bayer Cropscience Aktiengesellschaft 2-{[2-(phenyloxymethyl)pyridin-5-yl]oxy}-ethanamin-derivatives and related compounds as pest-control agents e.g. for the protection of plants
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