# Patent

## Title
Certain alkylene diamine-substituted heterocycles

## Abstract

This invention relates to novel compounds, compositions, and methods for the treatment of physiological disorders associated with an excess of neuropeptide Y. The novel compounds encompassed by the present invention are those of the formula II, IV, V, VII–IX and XI

## Background
CROSS REFERENCE TO RELATED APPLICATION
This application is a divisional of U.S. patent application Ser. No. 10/291,446, filed on Nov. 8, 2002, now U.S. Pat. No. 6,696,445, issued Feb. 24, 2004, which is a divisional of U.S. patent application Ser. No. 09/676,941, filed on Sep. 29, 2000, now U.S. Pat. No. 6,506,762, issued Jan. 14, 2003. The non-provisional patent application designated above, namely U.S. patent application Ser. No. 09/676,941, filed on Sep. 29, 2000, claims the benefit of U.S. Provisional Patent Application Ser. No. 60/156,870, filed on Sep. 30, 1999, and incorporates the same by reference.


FIELD OF THE INVENTION
This invention relates to certain alkylene diamine-substituted heterocycles which selectively and potently bind mammalian neuropeptide Y (NPY) receptors. This invention also relates to pharmaceutical compositions comprising such compounds. It further relates to the use of such compounds in treating physiological disorders associated with an excess of neuropeptide Y, especially feeding disorders, some psychiatric disorders, and certain cardiovascular diseases.
BACKGROUND OF THE INVENTION
Neuropeptide Y (NPY) is a 36 amino acid peptide first isolated in 1982 and subsequently found to be largely conserved across species. It belongs to a large family of peptides that includes, among others, peptide YY (PYY) and pancreatic peptide (PP). NPY is believed to be the most abundant peptide in the mammalian brain. It is also found in sympathetic neurons, and NPY-containing fibers have been found in peripheral tissues, such as around the arteries in the heart, the respiratory tract, the gastrointestinal tract, and the genitourinary tract. Central injection of NPY elicits a multitude of physiological responses, such as stimulation of feeding, increase in fat storage, elevation of blood sugar and insulin, anxiolytic behaviors, reduction in locomotor activity, hormone release, increase in blood pressure, reduction in body temperature, and catalepsy. In the cardiovascular system, NPY is believed to be involved in the regulation of coronary tone, while in the gastrointestinal tract, PYY is reported to cause inhibition of gastric acid secretion, pancreatic exocrine secretion, and gastrointestinal motility. These effects appear to be selectively mediated by various NPY receptors which currently include the Y1, Y2, Y3, Y4, Y5, and Y6 subtypes, in addition to the hypothetical Y1-like subtype. Selective peptidic agonists and antagonists have been identified for most of the subtypes, but few selective non-peptidic antagonists have been reported. The Y1 and Y5 receptor subtypes appear to be involved in appetite regulation, but their relative contribution to the modulation of food intake and energy expenditure remains unclear. The discovery of non-peptidic antagonists of the Y1 and/or Y5 receptor provides novel therapeutic agents, that are less prone to the shortcomings of the peptide antagonists, namely, for example, poor metabolic stability, low oral bioavailability, and poor brain permeability, for the treatment of obesity and cardiovascular disease.
SUMMARY OF THE INVENTION
The present invention also provides a general method to whereby mono-, bi-, or tricyclic heterocycles may be modified to obtain potent antagonists at the NPY1 receptor.
The present invention provides novel, potent, non-peptidic antagonists of NPY receptors, particularly, the NPY1 receptors, designed from a selection of mono-, bi-, or tri-cyclic heterocyclic cores.
The heterocyclic cores encompassed by the compounds of formula II–XV (shown below) have been previously described. The modifications made to these heterocyclic cores to obtain potent and selective NPY1 antagonists are entirely novel.
Compounds that interact with the Y1 receptor and inhibit the activity of neuropeptide Y at those receptors are useful in treating physiological disorders associated with an excess of neuropeptide Y, including eating disorders, such as, for example, obesity and bulimia, and certain cardiovascular diseases, for example, hypertension.
This invention relates to novel compounds, compositions, and methods for the treatment of physiological disorders associated with an excess of neuropeptide Y. The novel compounds encompassed by the present invention are those of the formula I–XV.










wherein

    X is N or CR14;
    W is S, O, or NR15;
    Y is N or CR3;
    E, F, and G are each, independently, CR3 or N;
    I and J are each, independently,
    
        C═O, S, O, CR3R16 or NR15 when single bonded to both adjacent ring atoms, or
        N, or CR3 when double bonded to an adjacent ring atom;
    
    
    K is
    
        N or CR3 when double bonded to L or J, or
        O, S, C═O, CR3R16, or NR15 when single bonded to both adjacent ring atoms, or
        N or CR3 when double bonded to an adjacent ring atom;
    
    
    L is
    
        N or CR16 when single bonded to all atoms to which it is attached, or
        C (carbon) when double bonded to K;
    
    
    The 6- or 7-membered ring that contains I, J, K, and L may contain from 1 to 3 double bonds, from 0 to 2 heteroatoms, and from 0 to 2 C═O groups, wherein the carbon atom of such groups are part of the ring and the oxygen atom is a substituent on the ring;
    Q is O or NR15;
    R1 is selected from H, C1–C6 alkyl, C3–C10 cycloalkyl, (C3–C10 cycloalkyl) C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, cyano, halo, C1–C6 haloalkyl, OR7, C1–C6 alkyl-OR7; C1–C6 cyanoalkyl, NR8R9, C1–C6 alkyl-NR8R9;
    R2 is H,
    
        C1–C6 alkyl which optionally forms a C3–C6 aminocarbocycle or a C2–C5 aminoheterocycle with A or B, each optionally substituted at each occurrence with R7, C3–C10 cycloalkyl, or
        (C3–C10 cycloalkyl) C1–C6 alkyl;
        or R2 and R6 jointly form with the 2 nitrogen atoms to which they are bound a C2–C5 aminoheterocycle optionally substituted at each occurrence with R7;
    
    
    A is (CH2)m where m is 1,2 or 3 and is optionally mono- or di-substituted on each occurrence with C1–C6 alkyl, C3–C10 cycloalkyl, (C3–C10 cycloalkyl) C1–C6 alkyl, C1–C6 alkenyl, C1–C6 alkynyl, cyano, halo, C1–C6 haloalkyl, OR7, C1–C6 alkyl-OR7; C1–C6 cyanoalkyl, NR8R9, C1–C6 alkyl-NR8R9,
    
        or A and B jointly form a C3–C6 carbocycle, optionally substituted at each occurrence with R7 
        or, as mentioned above, A and R2 jointly form a C3–C6 aminocarbocycle or a C2–C5 aminoheterocycle optionally substituted at each occurrence with R7;
    
    
    B is (CH2)n where n is 1,2 or 3 and is optionally mono- or di-substituted on each occurrence with C1–C6 alkyl, C3–C10 cycloalkyl, (C3–C10 cycloalkyl) C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, cyano, halo, C1–C6 haloalkyl, OR7, C1–C6 alkyl-OR7; C1–C6 cyanoalkyl, NR8R9, C1–C6 alkyl-NR8R9,
    
        or, as mentioned above, B and A jointly form a C3–C6 carbocycle, optionally substituted at each occurrence with R7 
        or, as mentioned above, B and R2 jointly form a C3–C6 aminocarbocycle or a C2–C5 aminoheterocycle optionally substituted at each occurrence with R7;
    
    
    R3 and R16 are selected independently at each occurrence from H, C1–C6 alkyl, C3–C10 cycloalkyl, (C3–C10 cycloalkyl) C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, cyano, halogen, C1–C6 haloalkyl, OR7, C1–C6 alkyl-OR7, C1–C6 cyanoalkyl, NR8R9, C1–C6 alkyl-NR8R9;
    R4 is selected from aryl or heteroaryl, each optionally substituted with 1 to 5 substituents independently selected at each occurrence from C1–C6 alkyl, C3–C10 cycloalkyl, C3–C10 cycloalkenyl, (C3–C10 cycloalkyl) C1–C6 alkyl, C1–C6 alkenyl, halogen, C1–C6 haloalkyl, trifluromethylsulfonyl, OR7, C1–C6 alkyl-OR7, NR8R9, C1–C6 alkyl-NR8R9, CONR8R9, C1–C6 alkyl-CONR8R9, COOR7, C1–C6 alkyl-COOR7, CN, C1–C6 alkyl-CN, SO2NR8R9, SO2R7, aryl, heteroaryl, heterocycloalkyl, 3-, 4-, or 5-(2-oxo-1,3-oxazolidinyl), with the proviso that at least one of the positions ortho or para to the point of attachment of the aryl or heteroaryl ring to the heterocyclic core is substituted;
    R5 is selected from:
    
        C1–C6 alkyl, (C3–C10 cycloalkyl) C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, each of which is substituted with 1 to 5 groups independently selected at each occurrence from halo, C1–C2 haloalkyl, OR7, cyano, NR8R9, CONR8R9, COOR7, SO2NR8R9, SO2R7, NR11COR12, NR11SO2R7;
    
    
    C1–C6 arylalkyl, C1–C6 heteroarylalkyl, C5–C8 arylcycloalkyl, or C5–C8 heteroarylcycloalkyl, where aryl is phenyl or naphthyl, and heteroaryl is 2-,3-, or 4-pyridyl, 2-, 4- or 5-pyrimidinyl, triazinyl, 1-, 2- or 4-imidazolyl, 2-, 4-, or 5-oxazolyl, isoxazolyl, indolyl, pyrazolyl, quinolyl, isoquinolyl, 2-, 4-, or 5-thiazolyl, benzothiadiazolyl, 1-, 3- or 4-pyrazolyl, 1-, 3- or 4-triazolyl, 2-triazinyl, 2-pyrazinyl, 2-, or 3-furanyl, 2-, or 3-thienyl, 2-, or 3-benzothienyl, or 1-, 2- or 5-tetrazolyl, each of which is optionally substituted with 1 to 5 substituents independently selected at each occurrence from C1–C6 alkyl, C3–C10 cycloalkyl, C3–C10 cycloalkenyl, (C3–C10 cycloalkyl) C1–C6 alkyl, C1–C6 alkenyl, halogen, C1–C6 haloalkyl, trifluromethylsulfonyl, OR7, NR8R9, C1–C6 alkyl-OR7, C1–C6 alkyl-NR8R9, CONR8R9, COOR7, CN, SO2NR8R9, SO2R7, aryl, heteroaryl, heterocycloalkyl, 3-, 4-, or 5-(2-oxo-1,3-oxazolidinyl), with the proviso that 2 adjacent substituents can optionally form together a C3–C10 cycloalkyl ring, a C3–C10 cycloalkenyl ring or a heterocycloalkyl ring;
    C3–C10 cycloalkyl, (C3–C10 cycloalkyl) C1–C6 alkyl, C3–C10 cycloalkenyl, C2–C6 alkenyl, C2–C6 alkynyl, each of which is optionally with 1 to 6 substituents independently selected at each occurrence from C1–C6 alkyl, C3–C10 cycloalkyl, C3–C10 cycloalkenyl, (C3–C10 cycloalkyl) C1–C6 alkyl, C1–C6 alkenyl, halogen, C1–C6 haloalkyl, OR7, NR8R9, with the proviso that when two OR7 or NR8R9 substituents are geminally located on the same carbon R7 is not H and they can form together a C2–C4 ketal, oxazoline, oxazolidine, imidazoline, or imidazolidine heterocycle, C1–C6 alkyl-OR7, C1–C6 alkyl-NR8R9, CONR8R9, COOR7, CN, oxo, hydroximino, C1–C6 alkoximino, SO2NR8R9, SO2R7, heterocycloalkyl, aryl, heteroaryl, where aryl or heteroaryl is optionally substituted with 1 to 5 substituents independently selected at each occurrence from C1–C6 alkyl, C3–C10 cycloalkyl, C3–C10 cycloalkenyl, (C3–C10 cycloalkyl) C1–C6 alkyl, C1–C6 alkenyl, halogen, C1–C6 haloalkyl, trifluromethylsulfonyl, OR7, NR8R9, C1–C6 alkyl-OR7, C1–C6 alkyl-NR8R9, CONR8R9, COOR7, CN, SO2NR8R9, SO2R7, aryl, heteroaryl, heterocycloalkyl, 3-, 4-, or 5-(2-oxo-1,3-oxazolidinyl), with the proviso that 2 adjacent substituents can optionally form together a C3–C10 cycloalkyl ring, a C3–C10 cycloalkenyl ring or a heterocycloalkyl ring;
    aryl or heteroaryl, optionally substituted with 1 to 5 substituents independently selected at each occurrence from halogen, C1–C6 alkyl, C3–C10 cycloalkyl, C3–C10 cycloalkenyl, (C3–C10 cycloalkyl) C1–C6 alkyl, C1–C6 alkenyl, halogen, C1–C6 haloalkyl, trifluromethylsulfonyl, OR7, NR8R9, C1–C6 alkyl-OR7, C1–C6 alkyl-NR8R9, CONR8R9, COOR7, CN, SO2NR8R9, SO2R7, aryl, heteroaryl, heterocycloalkyl, 3-, 4-, or 5-(2-oxo-1,3-oxazolidinyl), with the proviso that 2 adjacent substituents can optionally form together a C3–C10 cycloalkyl ring, a C3–C10 cycloalkenyl ring or a heterocycloalkyl ring; or
    3- or 4-piperidinyl, 3-pyrrolidinyl, 3- or 4-tetrahydropyranyl; 3-tetrahydrofuranyl, 3- or 4-tetrahydropyranyl, 3-tetrahydrofuranyl, 3- or 4-tetrahydrothiopyranyl, 3- or 4-(1,1-dioxo)tetrahydrothiopyranyl, 1-azabicyclo[4.4.0]decyl, 8-azabicyclo[3.2.1]octanyl, norbornyl, quinuclidinyl, each optionally substituted with 1 to 5 substituents independently selected at each occurrence from R7, C1–C6 alkyl-OR7, C1–C6 alkyl-NR8R9, CONR8R9, COOR7;
    R6 is selected from H, C1–C6 alkyl, C3–C10 cycloalkyl, (C3–C10 cycloalkyl) C1–C6 alkyl, C2–C4 alkenyl, C1–C6 arylalkyl, C1–C6 heteroarylalkyl where aryl or heteroaryl are optionally substituted with 1 to 5 substituents independently selected at each occurrence from halogen, C1–C6 haloalkyl, OR13, NR8R9, C1–C6 alkyl-OR13, C1–C6 alkyl-NR8R9, CONR8R9, COOR7, CN, SO2NR8R9, SO2R7,
    
        or R6 and R2, as mentioned above, jointly form, with the 2 nitrogen atoms to which they are bound, a C2–C5 aminoheterocycle optionally substituted at each occurrence with R7;
    
    
    R7 is H, C1–C6 alkyl, C3–C10 cycloalkyl, C3–C10 cycloalkenyl, (C3–C10 cycloalkyl) C1–C6 alkyl, C1–C3 haloalkyl,
    
        or heterocycloalkyl, C1–C8 alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, C1–C8 alkanoyl, aroyl, heteroaroyl, aryl, heteroaryl, C1–C6 arylalkyl or C1–C6 heteroarylalkyl each optionally substituted with 1 to 5 substituents independently selected at each occurrence from halogen, C1–C6 haloalkyl, OR13, NR8R9, C1–C6 alkyl-OR13, C1–C6 alkyl-NR8R9, CONR8R9, COOR13, CN, SO2NR8R9, SO2R13, with the proviso that when R7 is SO2R13, R13 cannot be H;
    
    
    R8 and R9 are independently selected at each occurrence from H, C1–C6 alkyl, C3–C10 cycloalkyl, C2–C6 alkenyl, C3–C10 cycloalkenyl, C2–C6 alkynyl, heterocycloalkyl, C1–C8 alkanoyl, aroyl, heteroaroyl, aryl, heteroaryl, C1–C6 arylalkyl or C1–C6 heteroarylalkyl, or R8 and R9, taken together, can form a C3–C6 aminocarbocycle or a C2–C5 aminoheterocycle each optionally substituted at each occurrence with with C1–C6 alkyl, C3–C10 cycloalkyl, C3–C10 cycloalkenyl, (C3–C10 cycloalkyl) C1–C6 alkyl, C1–C3 haloalkyl, or heterocycloalkyl, C1–C8 alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, C1–C8 alkanoyl, aroyl, heteroaroyl, aryl, heteroaryl, C1–C6 arylalkyl or C1–C6 heteroarylalkyl;
    R11 is selected from H, C1–C6 alkyl, C3–C10 cycloalkyl, (C3–C10 cycloalkyl) C1–C6 alkyl;
    R12 is selected from H, aryl, heteroaryl, C1–C6 alkyl, C3–C10 cycloalkyl, (C3–C10 cycloalkyl) C1–C6 alkyl, optionally substituted with OR7, NR8R9, C3–C6 aminocarbocycle, or C2–C5 aminoheterocycle;
    R13 is independently selected at each occurrence from H, C1–C6 alkyl, C3–C10 cycloalkyl, (C3–C10 cycloalkyl) C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl, with the proviso that for SO2NR8R9, SO2R13, R13 cannot be H;
    R14 is H, C1–C6 alkyl, C3–C10 cycloalkyl, (C3–C10 cycloalkyl) C1–C6 alkyl, C2–C4 alkenyl, C2–C4 alkynyl, halo, or CN;
    R15 is selected at each occurrence from H, C1–C6 alkyl, C3–C10 cycloalkyl, (C3–C10 cycloalkyl) C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C2–C6 alkyl-OR7, C2–C6 cyanoalkyl, C2–C6 alkyl-NR8R9;
    or a pharmaceutically acceptable salt, hydrate, or prodrug thereof


Preferred compounds of the present invention are those where X is N or CH, R1 is H, C1–C6 alkyl, C3–C10 cycloalkyl, or (C3–C10 cycloalkyl) C1–C6 alkyl; and R6 is H, C1–C6 alkyl, C3–C10 cycloalkyl, or (C3–C10 cycloalkyl) C1–C6 alkyl. Additional prefered compounds are those wherein R6 is phenethyl optionally substituted with one or two substituents selected from alkyl and alkoxy, tetrahydropyranyl and piperidinyl optionally substituted by a heterocycle. Other preferred compounds are those wherein R4 is phenyl, optionally substituted in one, two or three positions by alkyl, alkoxy or halogen.
This invention also encompasses, in additional embodiments, the novel compounds of formula I–XV, and the salts and solvates thereof, as well as pharmaceutical formulations comprising a compound of formula I–XV, or a pharmaceutically acceptable salt or solvate thereof, in combination with one or more pharmaceutically acceptable carriers, excipients, or diluents thereof.
This invention also encompasses methods to treat physiological disorders associated with an excess of neuropeptide Y, such as eating and cardiovascular disorders, which method comprises administering to a mammal in need of said treatment an effective amount of a compound of the formula I–XV.
This invention also encompasses methods of selectively inhibiting binding of NPY1 receptors, which comprises contacting a compound of formula I–XV with neuronal cells, wherein the compound is present in an amount effective to produce a concentration sufficient to inhibit binding of NPY1 receptors in vitro.
As such, the present invention also provides a method to convert heterocyclic cores of formula Ia to XVa where X, E, F, G, W, I, J, K, L, Q, R1, R3, R4, R15 and R16 are defined above, into compounds that potently and selectively interact with NPY1 receptors by substituting the n-position of heterocycles of formula Ia–XVIa with a diamine group of formula N[R2]-A-B—N[R6]—R5 where R2, A, B, R6, and R5 are defined above.









DETAILED DESCRIPTION OF THE INVENTION
This invention relates to certain alkylene diamine-substituted heterocycles which selectively and potently bind mammalian neuropeptide Y (NPY) receptors., those of formula I–XV, which are novel and useful neuropeptide Y receptor antagonists.
In the present description, the compounds of formula I–XV may be generically described under formula A, where R1, R2, R4, R5, R6, X, Y, A, and B are defined above.




In certain situations, the compounds of formula I–XV may contain one or more asymmetric carbon atoms, so that the compounds can exist in different stereoisomeric forms. These compounds can be, for example, racemates or optically active forms. In these situations, the single enantiomers, i.e., optically active forms, can be obtained by asymmetric synthesis or by resolution of the racemates. Resolution of the racemates can be accomplished, for example, by conventional methods such as crystallization in the presence of a resolving agent, or chromatography, using, for example a chiral HPLC column.
Representative compounds of the present invention, which are encompassed by formula I–XV, include, but are not limited to the compounds in Examples 1–56 and their pharmaceutically acceptable acid addition salts. In addition, if the compound of the invention is obtained as an acid addition salt, the free base can be obtained by basifying a solution of the acid salt. Conversely, if the product is a free base, an addition salt, particularly a pharmaceutically acceptable addition salt, may be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, in accordance with conventional procedures for preparing acid addition salts from base compounds.
Non-toxic pharmaceutical salts include salts of acids such as hydrochloric, phosphoric, hydrobromic, sulfuric, sulfinic, formic, toluenesulfonic, methanesulfonic, nitric, benzoic, citric, tartaric, maleic, hydroiodic, alkanoic such as acetic, HOOC—(CH2)n-COOH where n is 0–4, and the like. Those skilled in the art will recognize a wide variety of non-toxic pharmaceutically acceptable addition salts.
The present invention also encompasses the acylated prodrugs of the compounds of formula I–XV. “Prodrugs” are considered to be any covalently bonded carriers which release the active parent drug of formula I–XV in vivo when such prodrug is administered to a mammalian subject. Prodrugs of the compounds of the invention are prepared by modifying functional groups present in the compounds in such a way that the modifications are cleaved, either in routine manipulation or in vivo to the parent compounds. Prodrugs include compounds wherein hydroxy, amine, or sulfhydryl groups are bonded to any group that, when administered to a mammalian subject, cleaves to form a free hydroxyl, amino, or sulfhydryl group, respectively. Examples of prodrugs include,.but are not limited to, acetate, formate, and benzoate derivatives of alcohol and amine functional groups in the compounds of formula I–XV; and the like. Those skilled in the art will recognize various synthetic methodologies which may be employed to prepare non-toxic pharmaceutically acceptable addition salts and acylated prodrugs of the compounds encompassed by formula I–XV.
Where a compound exists in various tautomeric forms, the invention is not limited to any one of the specific tautomers. The invention includes all tautomeric forms of a compound.
By “heteroatom” in the present invention is meant oxygen or sulfur, or a nitrogen atom optionally substituted by C1–C6 lower alkyl, C1–C6 arylalkyl, C1–C10 cycloalkyl, (C3–C10 cycloalkyl) C1–C6 alkyl, C2–C8 alkanoyl, C1–C6 sulfonyl.
By “alkyl”, “lower alkyl”, or “C1–C6 alkyl” in the present invention is meant straight or branched chain alkyl groups having 1–6 carbon atoms, such as, for example, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl.
By “cycloalkyl”, or “C3–C10 cycloalkyl” in the present invention is meant alkyl groups having 3–10 carbon atoms forming a mono-, bi-, or polycyclic ring system, such as, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, and, the like.
By “(cycloalkyl)alkyl”, “lower (cycloalkyl)alkyl” or (C3–C10 cycloalkyl) C1–C6 alkyl in the present invention is meant a straight or branched alkyl substituent formed of 1 to 6 carbon atoms attached to a mono-, bi, or polycyclic ring system having 3–10 carbon atoms, such as, for example, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, and the like.
The term “C2–C6 alkenyl” in the present invention means hydrocarbon chains having 2 to 6 carbons in a straight or branched arrangement and containing one or more unsaturated carbon-carbon double bonds which may occur in any stable point along the chain, such as, for example, ethenyl, allyl, isopropenyl, and the like.
By “cycloalkenyl” or “C3–C10 cycloalkenyl” in the present invention is meant alkyl groups having 3–10 carbon atoms forming a mono-, bi, or polycyclic ring system having 3–10 carbon atoms and containing one or more carbon-carbon double bonds which may occur in any stable point in the ring, such as, for example, cyclopentenyl, cyclohexenyl, or cycloheptenyl.
The term “C2–C6 alkynyl” in the present invention means hydrocarbon chains having 2 to 6 carbons in a straight or branched arrangement and containing one or more unsaturated carbon-carbon triple bonds which may occur in any stable point along the chain, such as, for example, ethynyl, propargyl, and the like.
The term “aryl” in the present invention means a monocyclic or bicyclic aromatic group having preferably 6 to 10 carbon atoms, such as, for example, phenyl or naphthyl.
The term “heteroaryl” in the present invention means an aryl group in which one or more of the ring(s) carbon atoms have been replaced with a heteroatom. Such groups preferably have 4 to 10 carbon atoms and 1 to 4 heteroatoms, such as, for example, pyridyl, pyrimidinyl, triazinyl, imidazolyl, oxazolyl, isoxazolyl, indolyl, pyrrolyl, pyrazolyl, quinolinyl, isoquinolinyl, thiazolyl, benzothiadiazolyl, triazolyl, triazinyl, pyrazinyl, furanyl, thienyl, benzothienyl, benzofuranyl, tetrazolyl.
The term “heterocyclyl”, “heterocycle” or “heterocycloalkyl” in the present invention means a saturated or partially saturated heteroaryl group.
By “C1–C6 arylalkyl” or “C1–C6 heteroarylalkyl” in the present invention is meant a branched or straight-chain alkyl group having 1–6 carbon atoms and substituted on one of the carbon atoms by an optionally substituted aryl or heteroaryl ring, such as, for example, benzyl, phenethyl, methylpyridyl, ethylpyridyl, and the like.
By “C5–C8 arylcycloalkyl” in the present invention is meant cycloalkyl groups having 5–8 carbon atoms and fused to an aryl group, such as, for example, 1,2,3,4 tetrahydronaphthalenyl, 2,3-dihydrobenzothienyl, or 2,3-dihydobenzofuranyl.
By “C5–C8 heteroarylcycloalkyl” in the present invention is meant cycloalkyl groups having 5–8 carbon atoms fused to a heteroaryl group, such as, for example, 1,2,3,4 tetrahydroquinolyl, 2,3-dihydrobenzothienyl, 2,3-dihydobenzofuranyl, or indolinyl.
By “alkoxy”, “C1–C6 alkoxy”, or “C1–C6 alkyloxy” in the present invention is meant straight or branched chain alkoxy groups having 1–6 carbon atoms, such as, for example, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, pentoxy, 2-pentyl, isopentoxy, neopentoxy, hexoxy, 2-hexoxy, 3-hexoxy, and 3-methylpentoxy.
By “cycloalkoxy”, “C3–C10 cycloalkoxy”, or “C3–C10 cycloalkyloxy” in the present invention is meant a group formed by an oxygen atom attached to a mono-, bi, or polycyclic ring system having 3–10 carbon atoms, such as, for example, cyclopropoxy, cyclobutoxy, cyclopentoxy, cyclohexoxy, or cycloheptoxy.
By “(cycloalkyl)alkyloxy”, “(C3–C10 cycloalkyl) C1–C6 alkoxy”, or “(C3–C10 cycloalkyl) C1–C6 alkyloxy” in the present invention is meant a group formed by an oxygen atom attached to a 1–6 carbon chain linked to a mono-, bi, or polycyclic ring system having 3–10 carbon atoms, such as, for example, cyclopropylmethyloxy, cyclobutylmethyloxy, cyclopentylmethyloxy, cyclohexylmethyloxy, cycloheptylmethyloxy, and the like.
By “C3–C6 aminocarbocycle” is meant a cyclic amino group formed by a nitrogen contained in a ring having 3 to 6 carbon atoms, such as, for example, azetidino, pyrrolidino, piperidino, perhydroazepino.
By “C2–C5 aminoheterocycle” is meant a cyclic amino group formed by a nitrogen contained in a ring having 2 to 5 carbon atoms and one other heteroatom, such as, for example, morpholino, thiomorpholino, piperazino.
By the terms “halo” or “halogen” in the present invention is meant fluoro, chloro, bromo, and iodo.
“Haloalkyl” is intended to include both branched and straight-chain alkyl having the specified number of carbon atoms substituted with 1 or more halogens.
The term “C2–C8 alkanoyl” means an acyl group with 2 to 8 carbon atoms in a linear, branched, or C3–C10 cycloalkyl arrangement, optionally substituted with 1 to 5 substituents independently selected at each occurrence from halogen, trifluoromethyl, OR7, NR8R9, CONR8R9, COOR7, or CN.
The term “C1–C6 alkyl sulfonyl” means an alkylsulfonyl group containing 1 to 6 carbon atoms in a linear, branched, or C3–C7 cycloalkyl arrangement.
The term “substituted” means that one or more hydrogen on the designated atom is replaced by the specified group, provided that the valence on the designated atom is not exceeded, and that a chemically stable compound results from the substitution.
A stable compound is defined herein as one that can be isolated, characterized, and tested for biological activity.
The term “oxo” (i.e. ═O) indicates that two geminal hydrogen atoms are replaced by a double-bond oxygen group.
By “heterocyclic core” in the present invention is meant one of the following structures of formula Ia to XVa, where X, E, F, G, W, I, J, K, L, Q, R1, R3, R4, R15 and R16 are defined above.







In the present invention, some of the groups specifically mentioned above are defined as follows
















2-one-1,3-oxazolidinyl is







 



1-aza-bicyclo[4.4.0]decyl is







 



8-azabicyclo[3.2.1]octanyl is







 



(1,1-dioxo)tetrahydrothiopyranyl is







 



norbornyl is







 



quinuclidinyl is














Unless specified, the point of attachment may occur in any stable point along the above-mentioned rings.
In the present invention, the term “potent” in the context of NPY1 receptor antagonists qualifies a binding affinity with a Ki of less than 10 micromolar, preferably less than 1 micromolar, and more preferably less than 100 nanomolar in the human NPY1 binding assay.
In the present invention, the term “selective” in the context of NPY1 receptor antagonists qualifies a binding affinity with a Ki in the human NPY1 binding assay that is 10-fold, preferably 100-fold, and more preferably 1000-fold, less than the Ki of the same compound measured in another receptor binding assay, in particular the NPY5 and CRF1 receptor binding assays. Binding assays for the NPY5 and CRF1 receptors have been described, for example, in J. Clin. Invest., 102, 2136 (1998) and in Endocrinology 116, 1653 (1985), respectively.
As the compounds of formula I–XV are antagonists of the Y1 receptor, they are of value in the treatment of a wide variety of clinical conditions which are characterized by the presence of an excess of neuropeptide Y. Thus, the invention provides methods for the treatment or prevention of a physiological disorder associated with an excess of neuropeptide Y, which method comprises administering to a mammal in need of said treatment an effective amount of a compound of formula I–XV or a pharmaceutically acceptable salt, solvate or prodrug thereof. The term “physiological disorder associated with an excess of neuropeptide Y” encompasses those disorders associated with an inappropriate stimulation of neuropeptide Y receptors, regardless of the actual amount of neuropeptide Y present locally. These physiological disorders may include: disorders or diseases pertaining to the heart, blood vessels or the renal system, such as vasospasm, heart failure, shock, cardiac hypertrophy increased blood pressure, angina, myocardial infarction, sudden cardiac death, arrhythmia, peripheral vascular disease,-and abnormal renal conditions such as impaired flow of fluid, abnormal mass transport, or renal failure; conditions related to increased sympathetic nerve activity for example, during or after coronary artery surgery, and operations and surgery in the gastrointestinal tract; cerebral diseases and diseases related to the central nervous system, such as cerebral infarction, neurodegeneration, epilepsy, stroke, and conditions related to stroke, cerebral vasospasm and hemorrhage, depression, anxiety, schizophrenia, and dementia; conditions related to pain or nociception; diseases related to abnormal gastrointestinal motility and secretion, such as different forms of ileus, urinary incontinence, and Crohn's disease; abnormal drink and food intake disorders, such as obesity, anorexia, bulimia, and metabolic disorders; diseases related to sexual dysfunction and reproductive disorders; conditions or disorders associated with inflammation; respiratory diseases, such as asthma and conditions related to asthma and bronchoconstriction; and diseases related to abnormal hormone release, such as leutinizing hormone, growth hormone, insulin, and prolactin. See U.S. Pat. No. 5,504,094.
Pharmaceutical Preparations
The compounds of general Formula I–XV may be administered orally, topically, parenterally, by inhalation or spray or rectally in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles. The term parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques. In addition, there is provided a pharmaceutical formulation comprising a compound of general Formula I–XV and a pharmaceutically acceptable carrier. One or more compounds of general Formula I–XV may be present in association with one or more non-toxic pharmaceutically acceptable carriers and/or diluents and/or adjuvants and if desired other active ingredients. The pharmaceutical compositions containing compounds of general Formula I–XV may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsion, hard or soft capsules, or syrups or elixirs.
Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed.
Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin or olive oil.
Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydropropylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example, lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.
Oily suspensions may be formulated by suspending the active ingredients in a vegetable oil, for example arachid oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide palatable oral preparations. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present.
Pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, for example olive oil or arachid oil, or a mineral oil, for example liquid paraffin or mixtures of these. Suitable emulsifying agents may be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol, anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavoring agents.
Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents. The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be sterile injectable solution or suspension in a non-toxic parentally acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotopic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.
The compounds of general Formula I–XV may also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols.
Compounds of general Formula I–XV may be administered parenterally in a sterile medium. The drug, depending on the vehicle and concentration used, can either be suspended or dissolved in the vehicle. Advantageously, adjuvants such as local anesthetics, preservatives and buffering agents can be dissolved in the vehicle.
Dosage levels of the order of from about 0.1 mg to about 50 mg per kilogram of body weight per day are useful in the treatment of the above-indicated conditions (about 0.5 mg to about 3 g per patient per day), although in some circumstances higher amoounts, fo example upto 140 mg/kg/day may be appropriate. The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. Dosage unit forms will generally contain between from about 1 mg to about 500 mg of an active ingredient.
Frequency of dosage may also vary depending on the compound used and the particular disease treated. However, for treatment of most eating disorders, a dosage regimen of 4 times daily or less is preferred. For the treatment of stress and depression a dosage regimen of 1 or 2 times daily is particularly preferred.
It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, and rate of excretion, drug combination and the severity of the particular disease undergoing therapy.
Preferred compounds of the invention will have certain pharmacological properties. Such properties include, but are not limited to oral bioavailability, low toxicity, low serum protein binding and desirable in vitro and in vivo half-lives. Penetration of the blood brain barrier for compounds used to treat CNS disorders is necessary, while low brain levels of compounds used to treat peripheral disorders are often preferred.
Assays may be used to predict these desirable pharmacological properties. Assays used to predict bioavailability include transport across human intestinal cell monolayers, including Caco-2 cell monolayers. Toxicity to cultured hepatocytes may be used to predict compound toxicity. Penetration of the blood brain barrier of a compound in humans may be predicted from the brain levels of the compound in laboratory animals given the compound intravenously.
Serum protein binding may be predicted from albumin binding assays. Such assays are described in a review by Oravcová, et al. (Journal of Chromatography B 1996, 677, 1–27).
Compound half-life is inversely proportional to the frequency of dosage of a compound. In vitro half-lives of compounds may be predicted from assays of microsomal half-life as described by Kuhnz and Gieschen (Drug Metabolism and Disposition 1998, 26, 1120–1127).
As discussed above, preferred compounds of the invention exhibit good activity in standard in vitro NPY receptor binding assays, specifically the assay as specified in Example 261, which follows. References herein to “standard in vitro receptor binding assay” are intended to refer to that protocol as defined in Example 261 which follows. Generally preferred compounds of the invention exhibit a Ki of about 1 micromolar or less, still more preferably and Ki of about 100 nanomolar or less even more preferably an Ki of about 10 nanomolar or less or even 1 nanomolar or less in such a defined standard in vitro NPY receptor binding assay as exemplified by Example 261 which follows.
In appropriate case, the compounds of the invention may be employed in combination with other active agents. The invention therefore also provides pharmaceutical combination compositions comprising a therapeutically effective amount of a composition comprising: (a) first compound, said first compound being a compound as described above a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug; and (b) a second compound, said second compound being a β3 agonist, a thyromimetic, an eating behavior modifying agent or a NPY antagonist; and a pharmaceutical carrier, vehicle, diluent. To this end therefore the invention also provides a kit comprising: (a) first compound, said first compound being a compound as described above, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug; (b) a second compound, said second compound being a β3 agonist, a thyromimetic, an eating behavior modifying agent or a NPY antagonist; and a pharmaceutical carrier, vehicle, diluent; and (c) means for containing said first and second unit dosage forms wherein the amounts of the first and second compounds result in a therapeutic effect.
Preparation of Alkylene Diamnine-Substituted Heterocycles of Formula I–XV
The preparation of these heterocyclic cores, identified in formula II–XV, can be carried out according to the methods described in the following references and those cited therein:

    Formula II: WO 9413676, WO 9534563, WO 9845295, EP 729758, J. Med. Chem., 40(11), 1749–1754 (1997), Bioorg. Med. Chem. Lett., 9(7), 967–972 (1999), J. Med. Chem., 42(5), 819–832 (1999); J. Med. Chem. 42(5), 833–848 (1999);
    Formula III: WO 9635689, WO 9729110, WO 9808847, WO 9847903, WO 9940091, U.S. Pat. No. 5,664,057;
    Formula IV: WO 9413677, WO 9534563, EP 0729758;
    Formula V: WO 9533750, J. Med. Chem. 42(5), 833–848 (1999); Bioorg. Med. Chem. Lett., 9(7), 967–972 (1999);
    Formula VI: WO 9808847, WO 9829397;
    Formula VII: EP 239191, U.S. Pat. No. 5,273,608;
    Formula VIII: U.S. Pat. No. 5,273,608;
    Formula IX: WO 9510506, WO 9735539, WO 9808847, WO 9842706, J. Med. Chem. 42(5), 833–848 (1999);
    Formula X: WO 9808847, WO 9835967;
    Formula XI: WO 9533750, Bioorg. Med. Chem. Lett., 9(7), 967–972 (1999);
    Formula XII: WO 9808847, WO 9835967;
    Formula XIII: WO 9744038;
    Formula XIV: WO 9808846; WO 9829397, WO 9835967, WO 9847874, WO 9912908;
    Formula XV: WO 9510506, WO 9533750, WO 9714684, WO 9735580, WO 9842699, EP 778277, J. Med. Chem. 39(22), 4358–4360 (1996), J. Med. Chem. 42(5), 805–818 (1999), J. Med. Chem. 42(5), 833–848 (1999);


An illustration of preparation methods of compounds of the present invention is given in the Schemes below. In particular displacement of a leaving group Z, as in formula 10 (scheme 1) by the appropriate substituted amine or appropriate substitution of an heterocyclic amino group, as in formula 21 (scheme 7), provides general methods to convert the heterocyclic cores of the present invention into compounds that potently interact with the NPY1 receptor. Such transformations may require several consecutive chemical steps. Those having skill in the art will recognize that the starting materials may be varied and additional steps employed to produce compounds encompassed by the present invention. The disclosures of all articles and references mentioned in this application, including patents, are incorporated herein by reference.




As illustrated in scheme 1, compounds of formula A can be prepared from intermediate compounds of formula 10, where Z is halogen (preferably chloro or bromo), alkane sulfonyloxy, aryl sulfonyloxy or haloalkane sulfonyloxy, and where R1, R2, R4, R5, R6, X, Y, A, and B are defined above, using the procedures outlined below.
Compounds of formula 10 react with an amine of formula H2N-A-B—N[R6]—R5, where A, B, R5 and R6 are defined as above, in the presence or absence of a base in the presence or absence of an inert solvent at reaction temperatures ranging from −78° C. to 250° C. to generate compounds of formula A. Bases may include, but are not limited to, alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides (1–6 carbons) (preferably sodium methoxide, sodium ethoxide, or sodium tert-butoxide), alkaline earth metal hydrides, alkali metal dialkylamides (preferably lithium diisopropylamide), alkali metal carbonates, alkali metal bicarbonates, alkali metal bis-(trialkylsilyl)amides (preferably lithium or sodium (trimethylsilyl)amide), trialkylamines (preferably N,N-di-isopropyl-N-ethyl amine or triethylamine), arylamines (preferably 4-dimethyl aniline), or heteroaromatic amines (preferably pyridine). Inert solvents may include, but are not limited to, alkyl alcohols (1–8 carbons) (preferably methanol, ethanol, or tert-butanol), lower alkanenitriles (1–6 carbons) (preferably acetonitrile), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N,N-dialkylformamides (preferably dimethyl formamide), N,N-dialkylacetamides (preferably dimethyl acetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferably dimethylsulfoxide), aromatic hydrocarbons (preferably benzene or toluene), or haloalkanes (1–10 carbons and 1–10 halogens) (preferably CH2Cl2). Preferred reaction temperatures range from 0° C. to 140° C.




Alternatively, as illustrate in scheme 2, compounds of formula A can be obtained by first reacting a compound of formula 10 with an amino alcohol of formula H2N-A-B—OH, where A and B are defined as above, in the presence or absence of a base in the presence or absence of an inert solvent at reaction temperatures ranging from −78° C. to 250° C. to generate intermediates of formula 11. Reacting a compound of formula 11 with a halogenating agent or sulfonylating agent in the presence or absence of a base in the presence or absence of an inert solvent at reaction temperatures ranging from −78° C. to 250° C. to afford products of formula 12a (where Z is halogen, alkane sulfonyloxy, aryl sulfonyloxy or haloalkane sulfonyloxy) or 12b when A and B are both CH2 and X is CR14. Halogenating agents include, but are not limited to, SOCl2, POCl3, PCl3, PCl5, POBr3, PBr3, PBr5., CCl4PPh3. Sulfonylating agents include, but are not limited to, alkanesulfonyl halides or anhydrides (preferably methanesulfonyl chloride or methanesulfonic anhydride), aryl sulfonyl halides or anhydrides (such as p-toluenesulfonyl chloride or anhydride), or haloalkylsulfonyl halides or anhydrides (preferably trifluoromethanesulfonic anhydride). Bases may include, but are not limited to, trialkylamines (preferably N,N-di-isopropyl-N-ethyl amine or triethylamine), bicyclic amidines (preferably DBU), anilines (preferably N-dimethyl aniline), or heteroaromatic amines (preferably pyridine). Inert solvents may include, but are not limited to, lower alkanenitriles (1–6 carbons) (preferably acetonitrile), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N,N-dialkylformamides (preferably dimethyl formamide), N,N-dialkylacetamides (preferably dimethyl acetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferably dimethylsulfoxide), aromatic hydrocarbons (preferably benzene or toluene), or haloalkanes with 1–10 carbons and 1–10 halogens (preferably CH2Cl2). Preferred reaction temperatures range from −20° C. to 100° C. Compounds of formula 12a or 12b can then be reacted with an amine of formula HN[R6]—R5, where R5 and R6 are defined as above, to give a compound of formula A Bases may include, but are not limited to, alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides (1–6 carbons) (preferably sodium methoxide, sodium ethoxide, or sodium tert-butoxide), alkaline earth metal hydrides, alkali metal dialkylamides (preferably lithium diisopropylamide), alkali metal carbonates, alkali metal bicarbonates, alkali metal bis-(trialkylsilyl)amides (preferably lithium or sodium (trimethylsilyl)amide), trialkylamines (preferably N,N-di-isopropyl-N-ethyl amine or triethylamine), arylamines (preferably 4-dimethyl aniline), or heteroaromatic amines (preferably pyridine). Inert solvents may include, but are not limited to, alkyl alcohols (1–8 carbons) (preferably methanol, ethanol, or tert-butanol), lower alkanenitriles (1–6 carbons) (preferably acetonitrile), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N,N-dialkylformamides (preferably dimethyl formamide), N,N-dialkylacetamides (preferably dimethyl acetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferably dimethylsulfoxide), aromatic hydrocarbons (preferably benzene or toluene), or haloalkanes (1–10 carbons and 1–10 halogens) (preferably CH2Cl2). Preferred reaction temperatures range from 0° C. to 140° C.




A subset of compounds of formula A, described under formula A1 (scheme 3), can be obtained by first reacting a compound of formula 10 with a diamine of formula H2N-A-B—NH2, where A and B are defined as above, in the presence or absence of a base in the presence or absence of an inert solvent at reaction temperatures ranging from −78° C. to 250° C. to generate intermediates of formula 13. Reaction of a compound of formula 13 with a ketone of Formula Ra—C═O—Rb in the presence of a reducing agent provides a compound of formula A1, where the grouping Ra—CH—Rb corresponds to R5 in formula A, as defined above. Reducing agents include, but are not limited to, alkali metal or alkaline earth metal borohydrides (preferably lithium or sodium borohydride), borane (preferably complexed with dimethyl sulfide or tetrahydrofuran), dialkylboranes (such as di-isoamylborane), alkali metal aluminum hydrides (preferably lithium aluminum hydride), alkali metal (trialkoxy)aluminum hydrides (such as triethoxyaluminum hydride), dialkyl aluminum hydrides (such as di-isobutyl aluminum hydride), alane (preferably complexed with dimethyl amine). Inert solvents may include, but are not limited to, alkyl alcohols (1–6 carbons) (preferably methanol, ethanol, or tert-butanol), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), aromatic hydrocarbons (preferably benzene or toluene). Preferred reaction temperatures range from −78° C. to 100° C.




Alternatively, a subset of compounds of formula A, described under formula A2 (scheme 4), can be obtained by first reacting a compound of formula 13 with an activated acid of formula Rc—C═O-Z, where Z is halo (preferably chloro), O-acyl (preferably O—C═O—Rc), in the presence or absence of a base in the presence or absence of an inert solvent at reaction temperatures ranging from −78° C. to 250° C. to generate an amide intermediate of formula 14. Reaction of a compound of formula 14 with a reducing agent provides a compound of formula A2, where the grouping Rc—CH2 corresponds to R5 in formula A, as defined above. Reducing agents include, but are not limited to, alkali metal or alkaline earth metal borohydrides (preferably lithium or sodium borohydride), borane (preferably complexed with dimethyl sulfide or tetrahydrofuran), dialkylboranes (such as di-isoamylborane), alkali metal aluminum hydrides (preferably lithium aluminum hydride), alkali metal (trialkoxy)aluminum hydrides (such as triethoxyaluminum hydride), dialkyl aluminum hydrides (such as di-isobutyl aluminum hydride), alane (preferably complexed with dimethyl amine). Inert solvents may include, but are not limited to, alkyl alcohols (1–6 carbons) (preferably methanol, ethanol, or tert-butanol), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), aromatic hydrocarbons (preferably benzene or toluene). Preferred reaction temperatures range from −78° C. to 100° C.




Alternatively, a subset of compounds of formula A, described under formula A3 (scheme 5), can be obtained by first reacting a compound of formula 10 with an amine of formula H2N-A-CH(ORc)(ORd), where A is defined above, and Rc and Rd are C1–C6 lower alkyls or, taken together, complete a ketal group, such as, for example a dioxane or dioxolane group, in the presence or absence of a base in the presence or absence of an inert solvent at reaction temperatures ranging from −78° C. to 250° C. to generate compounds of formula 15. Bases may include, but are not limited to, alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides (1–6 carbons) (preferably sodium methoxide, sodium ethoxide, or sodium tert-butoxide), alkaline earth metal hydrides, alkali metal dialkylamides (preferably lithium diisopropylamide), alkali metal carbonates, alkali metal bicarbonates, alkali metal bis-(trialkylsilyl)amides (preferably lithium or sodium (trimethylsilyl)amide), trialkylamines (preferably N,N-di-isopropyl-N-ethyl amine or triethylamine), arylamines (preferably 4-dimethyl aniline), or heteroaromatic amines (preferably pyridine). Inert solvents may include, but are not limited to, alkyl alcohols (1–8 carbons) (preferably methanol, ethanol, or tert-butanol), lower alkanenitriles (1–6 carbons) (preferably acetonitrile), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N,N-dialkylformamides (preferably dimethyl formamide), N,N-dialkylacetamides (preferably dimethyl acetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferably dimethylsulfoxide), aromatic hydrocarbons (preferably benzene or toluene), or haloalkanes (1–10 carbons and 1–10 halogens) (preferably CH2Cl2). Compounds of formula 15 react with a protic acid in the presence or absence of an inert solvent at reaction temperatures ranging from −78° C. to 250° C., followed by aqueous work-up to generate compounds of formula 16. Inert solvents may include, but are not limited to dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N,N-dialkylformamides (preferably dimethyl formamide), N,N-dialkylacetamides (preferably dimethyl acetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferably dimethylsulfoxide), aromatic hydrocarbons (preferably benzene or toluene), or haloalkanes (1–10 carbons and 1–10 halogens) (preferably CH2Cl2). Protic acids include, but are not limited to, formic acid, acetic acid, trifluoroacetic acid, hydrochloric acid, methane sulfonic acid. Alternatively, compounds of formula 16 can be obtained by oxidation of compounds of formula 11 where B═CH2. Oxidizing agents include, but are not limited to, transition metal oxides, such as CrO3 or MnO2, pyridine-chromium complexes, such as CrO3.C5H5N, pyridinium dichromate or pyridinium chlorochromate, or an oxalyl chloride-DMSO-triethylamine reagent (Swern oxidation). Compounds of formula 16 react with amines of formula H2N—R5, where R5 is defined above, in the presence of a reducing agent in the presence or absence of an inert solvent in the presence or absence of a protic acid at temperatures ranging from −78° C. to 100° C., to give compounds of formula A3. Reducing agents include, but are not limited to, alkali metal or alkaline earth metal borohydrides (preferably lithium or sodium borohydride), borane (preferably complexed with dimethyl sulfide or tetrahydrofuran), dialkylboranes (such as di-isoamylborane), alkali metal aluminum hydrides (preferably lithium aluminum hydride), alkali metal (trialkoxy)aluminum hydrides (such as triethoxyaluminum hydride), dialkyl aluminum hydrides (such as di-isobutyl aluminum hydride), alane (preferably complexed with dimethyl amine). Inert solvents may include, but are not limited to, alkyl alcohols (1–6 carbons) (preferably methanol, ethanol, or tert-butanol), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), aromatic hydrocarbons (preferably benzene or toluene).
Compounds of formula 10, encompassing the heterocyclic cores of formula I–XV, are prepared according to procedures described in the references listed below.
Compounds of formula 10a, used as starting material for the preparation of compounds of formula 1, can be obtained according to scheme 6.




Compounds of formula 17, where E, F, and G are defined above and Z is a halogen, react with a compound of formula R4—CH2—CN, where R4 is defined above, in the presence of base, in the presence or absence of an inert solvent, at reaction temperatures ranging from −78° C. to 100° C., to generate compounds of formula 18. Bases may include, but are not limited to, alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides (1–6 carbons) (preferably sodium methoxide, sodium ethoxide, or sodium tert-butoxide), alkaline earth metal hydrides, alkali metal dialkylamides (preferably lithium diisopropylamide), alkali metal carbonates, alkali metal bicarbonates, alkali metal bis-(trialkylsilyl)amides (preferably lithium or sodium (trimethylsilyl)amide), trialkylamines (preferably N,N-di-isopropyl-N-ethyl amine or triethylamine), arylamines (preferably 4-dimethyl aniline), or heteroaromatic amines (preferably pyridine). Inert solvents may include, but are not limited to, alkyl alcohols (1–8 carbons) (preferably methanol, ethanol, or tert-butanol), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), or dialkylsulfoxides (preferably dimethylsulfoxide). Preferred reaction temperatures range from 0° C. to 100° C. Compounds of formula 18 then react with a compound of formula Z-CH2—COORc, where Z is halogen (preferably chloro or bromo), alkane sulfonyloxy, aryl sulfonyloxy or haloalkane sulfonyloxy and Rc is C1–C6 alkyl in the presence of base, in the presence or absence of an inert solvent, at reaction temperatures ranging from −78° C. to 100° C., to generate compounds of formula 19. Bases may include, but are not limited to, alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides (1–6 carbons) (preferably sodium methoxide, sodium ethoxide, or sodium tert-butoxide), alkaline earth metal hydrides, alkali metal dialkylamides (preferably lithium diisopropylamide), alkali metal carbonates, alkali metal bicarbonates, alkali metal bis-(trialkylsilyl)amides (preferably lithium or sodium (trimethylsilyl)amide), trialkylamines (preferably N,N-di-isopropyl-N-ethyl amine or triethylamine), arylamines (preferably 4-dimethyl aniline), or heteroaromatic amines (preferably pyridine). Inert solvents may include, but are not limited to, alkyl alcohols (1–8 carbons) (preferably methanol, ethanol, or tert-butanol), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), or dialkylsulfoxides (preferably dimethylsulfoxide). Preferred reaction temperatures range from 0° C. to 100° C. Compounds of formula 20, where X is CR14 and R1 is defined above, can be obtained in two consecutive steps from compounds of formula 19 can be first reacted with a compound of formula R1C(ORc)—CH2—R14, where Rc is methyl or ethyl, in the presence of base, in the presence or absence of an inert solvent, at reaction temperatures ranging from −78° C. to 100° C., to generate an non-isolated imine intermediate. Bases may include, but are not limited to, alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides (1–6 carbons) (preferably sodium methoxide, sodium ethoxide, or sodium tert-butoxide), alkaline earth metal hydrides, alkali metal dialkylamides (preferably lithium diisopropylamide), alkali metal carbonates, alkali metal bicarbonates, alkali metal bis-(trialkylsilyl)amides (preferably lithium or sodium (trimethylsilyl)amide), trialkylamines (preferably N,N-di-isopropyl-N-ethyl amine or triethylamine), arylamines (preferably 4-dimethyl aniline), or heteroaromatic amines (preferably pyridine). Inert solvents may include, but are not limited to, alkyl alcohols (1–8 carbons) (preferably methanol, ethanol, or tert-butanol), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), or dialkylsulfoxides (preferably dimethylsulfoxide). Preferred reaction temperatures range from 0° C. to 100° C. In a second step, the imine intermediates are cyclized to a compound of formula 20 (X═CR14) in the presence of base, in the presence or absence of an inert solvent, at reaction temperatures ranging from −78° C. to 100° C. Bases may include, but are not limited to, alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides (1–6 carbons) (preferably sodium methoxide, sodium ethoxide, or sodium tert-butoxide), alkaline earth metal hydrides, alkali metal dialkylamides (preferably lithium diisopropylamide), alkali metal carbonates, alkali metal bicarbonates, alkali metal bis-(trialkylsilyl)amides (preferably lithium or sodium (trimethylsilyl)amide), trialkylamines (preferably N,N-di-isopropyl-N-ethyl amine or triethylamine), arylamines (preferably 4-dimethyl aniline), or heteroaromatic amines (preferably pyridine). Inert solvents may include, but are not limited to, alkyl alcohols (1–8 carbons) (preferably methanol, ethanol, or tert-butanol), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), or, dialkylsulfoxides (preferably dimethylsulfoxide). Preferred reaction temperatures range from 0° C. to 100° C.
Compounds of formula 20, where X is N and R1 is defined above, can be obtained by reacting compounds of formula 19 with a compound of formula R1—C═O—Rc, and Rc is halogen, cyano, lower alkoxy (1–6 carbons), or lower alkanoyloxy (1–6 carbons), in the presence of a base in an inert solvent at reaction temperatures ranging from −78° C. to 200° C. Bases may include, but are not limited to, alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides (1–6 carbons) (preferably sodium methoxide, sodium ethoxide, or sodium tert-butoxide), alkaline earth metal hydrides, alkali metal dialkylamides (preferably lithium diisopropylamide), alkali metal carbonates, alkali metal hydroxides, alkali metal bis-(trialkylsilyl)amides (preferably lithium or sodium (trimethylsilyl)amide), trialkylamines (preferably N,N-di-isopropyl-N-ethyl amine or triethylamine), bicyclic amidines (preferably DBU), or heteroaromatic amines (preferably pyridine). Inert solvents may include, but are not limited to, alkyl alcohols (1–8 carbons) (preferably methanol, ethanol, or tert-butanol), lower alkanenitriles (1–6 carbons) (preferably acetonitrile), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N,N-dialkylformamides (preferably dimethyl formamide), N,N-dialkylacetamides (preferably dimethyl acetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferably dimethylsulfoxide), aromatic hydrocarbons (preferably benzene or toluene). Compounds of formula 10a, where Z is halogen, alkane sulfonyloxy, aryl sulfonyloxy or haloalkane sulfonyloxy and X is N, can be prepared by reacting a compound of formula 20 with a halogenating agent or sulfonylating agent in the presence or absence of a base in the presence or absence of an inert solvent at reaction temperatures ranging from −78° C. to 250° C. Halogenating agents include, but are not limited to, SOCl2, POCl3, PCl3, PCl5, POBr3, PBr3, or PBr5. Sulfonylating agents include, but are not limited to, alkanesulfonyl halides or anhydrides (preferably methanesulfonyl chloride or methanesulfonic anhydride), aryl sulfonyl halides or anhydrides (such as p-toluenesulfonyl chloride or anhydride), or haloalkylsulfonyl halides or anhydrides (preferably trifluoromethanesulfonic anhydride). Bases may include, but are not limited to, trialkylamines (preferably N,N-di-isopropyl-N-ethyl amine or triethylamine), bicyclic amidines (preferably DBU), anilines (preferably N-dimethyl aniline), or heteroaromatic amines (preferably pyridine). Inert solvents may include, but are not limited to, lower alkanenitriles (1–6 carbons) (preferably acetonitrile), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N,N-dialkylformamides (preferably dimethyl formamide), N,N-dialkylacetamides (preferably dimethyl acetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferably dimethylsulfoxide), aromatic hydrocarbons (preferably benzene or toluene), or haloalkanes with 1–10 carbons and 1–10 halogens (preferably CH2Cl2). Preferred reaction temperatures range from −20° C. to 100° C.
Alternatively, some of the compounds of formula A can be obtained from compounds of formula 21, as illustrated in scheme 7.




Compounds of formula 21, where X, R1 and R4 are defined above, react with a compound of formula Z-B—(C═O)—Rc, where B is defined above, Z is halogen (preferably chloro or bromo), alkane sulfonyloxy, aryl sulfonyloxy or haloalkane sulfonyloxy, and Rc is halogen, cyano, lower alkoxy (1–6 carbons), or lower alkanoyloxy (1–6 carbons), in the presence or absence of a base, in the presence or absence of an inert solvent at reaction temperatures ranging from −78° C. to 200° C., to produce compounds of formula 22. Bases may include, but are not limited to, trialkylamines (preferably N,N-di-isopropyl-N-ethyl amine or triethylamine), bicyclic amidines (preferably DBU), anilines (preferably N-dimethyl aniline), or heteroaromatic amines (preferably pyridine). Inert solvents may include, but are not limited to, lower alkanenitriles (1–6 carbons) (preferably acetonitrile), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N,N-dialkylformamides (preferably dimethyl formamide), N,N-dialkylacetamides (preferably dimethyl acetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferably dimethylsulfoxide), aromatic hydrocarbons (preferably benzene or toluene), or haloalkanes with 1–10 carbons and 1–10 halogens (preferably CH2Cl2). Preferred reaction temperatures range from −20° C. to 100° C.
Amides of formula 22 can be reacted with an amine of formula NH[R6]R5, where R6 and R5 are defined above, in the presence or absence of a base, in the presence or absence of an inert solvent at reaction temperatures ranging from −78° C. to 200° C., to produce compounds of formula 23. Bases may include, but are not limited to, alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides (1–6 carbons) (preferably sodium methoxide, sodium ethoxide, or sodium tert-butoxide), alkaline earth metal hydrides, alkali metal dialkylamides (preferably lithium diisopropylamide), alkali metal carbonates, alkali metal bicarbonates, alkali metal bis-(trialkylsilyl)amides (preferably lithium or sodium (trimethylsilyl)amide), trialkylamines (preferably N,N-di-isopropyl-N-ethyl amine or triethylamine), arylamines (preferably 4-dimethyl aniline), or heteroaromatic amines (preferably pyridine). Inert solvents may include, but are not limited to, alkyl alcohols (1–8 carbons) (preferably methanol, ethanol, or tert-butanol), lower alkanenitriles (1–6 carbons) (preferably acetonitrile), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N,N-dialkylformamides (preferably dimethyl formamide), N,N-dialkylacetamides (preferably dimethyl acetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferably dimethylsulfoxide), aromatic hydrocarbons (preferably benzene or toluene), or haloalkanes (1–10 carbons and 1–10 halogens) (preferably CH2Cl2). Preferred reaction temperatures range from 0° C. to 140° C.
Compounds of formula 23 can be reacted with a reducing agent in the presence or absence of an inert solvent to provide compounds of formula A, as defined above. Reducing agents include, but are not limited to, alkali metal or alkaline earth metal borohydrides (preferably lithium or sodium borohydride), borane (preferably complexed with dimethyl sulfide or tetrahydrofuran), dialkylboranes (such as di-isoamylborane), alkali metal aluminum hydrides (preferably lithium aluminum hydride), alkali metal (trialkoxy)aluminum hydrides (such as triethoxyaluminum hydride), dialkyl aluminum hydrides (such as di-isobutyl aluminum hydride), alane (preferably complexed with dimethyl amine). Inert solvents may include, but are not limited to, alkyl alcohols (1–6 carbons) (preferably methanol, ethanol, or tert-butanol), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), aromatic hydrocarbons (preferably benzene or toluene). Preferred reaction temperatures range from −78° C. to 100° C.
Alternatively, compounds of formula 22 can be reduced first, under experimental conditions similar to those used for the conversion of compounds of formula 23 to compounds of formula A, to generate compounds of formula 24. Compounds of formula 24 can then be reacted with compounds of formula NH[R6]R5, as defined above, under experimental conditions similar to those used for the conversion of compounds of formula 22 to compounds of formula 23, to generate compounds of formula A.
Other compounds of formula 10 and of formula 21, used as starting material for the preparation of compounds of formula II–XV, can be obtained according to procedures described in the following references:

    Formula II: WO 9413676, WO 9534563, WO 9845295, EP 729758, J. Med. Chem., 40(11), 1749–1754 (1997), Bioorg. Med. Chem. Lett., 9(7), 967–972 (1999), J. Med. Chem., 42(5), 819–832 (1999); J. Med. Chem. 42(5), 833–848 (1999);
    Formula III: WO 9635689, WO 9729110, WO 9808847, WO 9847903, WO 9940091, U.S. Pat. No. 5,664,057;
    Formula IV: WO 9413677, WO 9534563, EP 0729758;
    Formula V: WO 9533750, J. Med. Chem. 42(5), 833–848 (1999); Bioorg. Med. Chem. Lett., 9(7), 967–972 (1999);
    Formula VI: WO 9808847, WO 9829397;
    Formula VII: EP 239191, U.S. Pat. No. 5,273,608;
    Formula VIII: U.S. Pat. No.5,273,608;
    Formula IX: WO 9510506, WO 9735539, WO 9808847, WO 9842706, J. Med. Chem. 42(5), 833–848 (1999);
    Formula X: WO 9808847, WO 9835967;
    Formula XI: WO 9533750, Bioorg. Med. Chem. Lett., 9(7), 967–972 (1999);
    Formula XII: WO 9808847, WO 9835967;
    Formula XIII: WO 9744038;
    Formula XIV: WO 9808846; WO 9829397, WO 9835967, WO 9847874, WO 9912908;
    Formula XV: WO 9510506, WO 9533750, WO 9714684, WO 9735580, WO 9842699, EP 778277, J. Med. Chem. 39(22), 4358–4360 (1996), J. Med. Chem. 42(5), 805–818 (1999), J. Med. Chem. 42(5), 833–848 (1999).


EXAMPLES
The following examples are which a provided to further illustrate the reaction schemes are not to be construed as limiting the invention.
The preparation of the compounds of the present invention by the above-mentioned methods is illustrated further by the following examples and those delineated in the Tables which are not to be construed as limiting the invention in scope or spirit to the specific procedures and compounds described in them. Commercial reagents were used without further purification. THF refers to tetrahydrofuran. LDA refers to lithium diisopropylamide and DBU refers to 1,8-diazabicyclo[5.4.0]undec-7-ene. Room or ambient temperature refers to 20° C. to 25° C. Concentration implies the use of a rotary evaporator. TLC refers to thin layer chromatography. Mass spectral data were obtained either by CI or APCI methods. Commonly used abbreviations are: Ph is phenyl, Me is methyl, Et is ethyl, Pr is n-propyl, iPr is isopropyl, Bu is butyl, iBu is isobutyl (CH2—CHMe2), tBu is tert-butyl, cBu is cyclobutyl, Pent is n-pentyl, cPent is cyclopentyl, cHex is cyclohexyl, Py is pyridyl, MeOH means methanol, EtOH means ethanol, EtOAc means ethyl acetate, Et2O means diethyl ether, CH2Cl2 means methylene chloride, DMSO means dimethyl sulfoxide, NMP means N-methyl pyrrolidone, THF means tetrahydrofuran, DMF means dimethyl formamide, EX means example. The specific heterocyclic cores, generically described under formula A, are indicated in the table under Formula, which refers to the heterocyclic core defined in formula I–XV.
Example 1
A. 2-(2-Pyridinyl)-2-(2,4,6-trimethylphenyl)ethanenitrile




Add dropwise over a 1-hour period a mixed solution of 2-(2,4,6-trimethylphenyl)ethanenitrile (20 g; 0.126 mol) and 2-bromopyridine (35 g; 0.22 mol) in DMSO (25 mL) to a solution of potassium t-butoxide (35 g; 0.31 mol) dissolved in DMSO (125 mL). After the addition, stir the mixture for 4 h at ambient temperature and slowly pour into a stirred, ice-cold solution of NH4Cl with vigorous stirring. Filter the resulting tan precipitate, wash with MeOH, and air-dry to obtain the title compound as a pale yellow solid: 1H NMR (400 MHz, CDCl3) δ 2.30 (s, 6H), 2.32 (s, 3H), 5.76 (s, 1H), 6.93 (s, 2H), 7.12 (d, 1H), 7.21 (dd, 1H), 7.63 (t, 1H), 8.63 (d, 1H).
B. Ethyl 2-amino-1-(2,4,6-trimethylphenyl)indolizine-3-carboxylate




Slowly add dropwise ethyl bromoacetate (23 mL; 0.21 mol) over a 3-hour period to a mixture of 2-(2-pyridinyl)-2-(2,4,6-trimethylphenyl)-ethanenitrile (22.3 g; 0.094 mol) and potassium carbonate (78 g; 0.57 mol) suspended in DMSO (100 mL). Stir the mixture for 1 day, pour into an aqueous NH4Cl solution (ca. 1 L), and extract with 3×200 mL of Et2O. Wash the combined extracts with saturated brine, dry over Na2SO4, filter, and concentrate in vacuo. Dissolve the residue in THF (200 mL), cool to 0° C., and add slowly in portions potassium t-butoxide (12 g; 0.11 mol) over a 10-minute period. After 30 minutes at 0° C., dilute the mixture with aqueous NH4Cl and extract with 2×150 mL of 50% Et2O in hexane. Wash the combined extracts with saturated brine, dry over Na2SO4, filter, concentrate in vacuo, and purify by column chromatography on silica gel (eluent: 5 to 10% EtOAc in hexane) to obtain the title compound as an oil: 1H NMR (400 MHz, CDCl3) δ 1.47 (t, 3H), 2.06 (s, 6H), 2.35 (s, 3H), 4.46 (br q, 2H), 6.6 (br t, 1H), 6.75 (d, 1H), 6.9 (br t, 1H), 7.00 (s, 2H), 9.4 (1H).
C. 2-Methyl-9-(2,4.6-trimethylphenyl)pyrido[2,3-b]-indolizin-4-ol




To a solution of 2-ethyl 2-amino-1-(2,4,6-trimethylphenyl)indolizine-3-carboxylate (19.2 g; 59.6 mmol) in 2,2-dimethoxypropane (100 mL), add dl-camphorsulfonic acid (0.2 g). Stir the mixture at reflux for 30 min and then distill slowly to remove ca. 60 mL of volatiles over a 30-minute period. Cool the solution to ambient temperature under inert atmosphere, dilute with anhydrous toluene (50 mL), and concentrate in vacuo. Dissolve the residue in toluene (50 mL) and add dropwise over a 1-hour period a 0.5 M solution of potassium bis(trimethylsilyl)amide in toluene (250 mL; 125 mmol) to the stirred solution. After the addition, stir the mixture for 2 h at ambient temperature, concentrate in vacuo to a small volume and dilute with aqueous NH4Cl. Filter the resulting biphasic mixture and wash successively with water, MeOH, and Et2O. Dry under vacuum to obtain the title compound as a pale yellow solid.
D. 4-Chloro-2-methyl-9-(2,4,6-trimethylphenyl)pyridino[2,3-b]-indolizine




Heat at 100° C. for 1 h a solution of 4-hydroxy-2-methyl-10-(2,4,6-trimethylphenyl)pyridino-[2,3-b]indolizine 2-methyl-9-(2,4,6-trimethylphenyl)pyrido[2,3-b]-indolizin-4-ol (10.1 g; 32 mmol) in phosphorus oxychloride (60 mL), cool to ambient temperature, and concentrate in vacuo. Partition the residue into ice water and CH2Cl2. Separate the aqueous phase, extract twice with CH2Cl2, and wash the combined organic extracts with a 1 N aqueous sodium hydroxide solution and then with water. Dry the solution over Na2SO4, filter, and concentrate in vacuo. Filter the dark residue through a short pad of silica gel and wash with 25% EtOAc in hexane. Concentrate the filtrate in vacuo to obtain the title compound as a yellow solid: 1H NMR (400 MHz, CDCl3) δ 2.00 (s, 6H), 2.37 (s, 3H), 2.64 (s, 3H), 6.58 (t, 1H), 6.95 (dd, 1H), 7.00 (s, 2H), 7.07 (s, 1H), 7.08 (d, 1H), 9.26 (d, 1H).
E. (2-Aminoethyl)[2-methyl-9-(2,4,6-trimethylphenyl)-pyridino[2,3-b]indolizin-4-yl]amine




Heat a solution of 4-chloro-2-methyl-9-(2,4,6-trimethylphenyl)pyridino[2,3-b]-indolizine (0.35 g, 1.04 mmol), and ethylene diamine (0.32 g, 1.04 mmol) in dry NMP (3 mL) at 100° C. for 5 h. Pour the cooled mixture onto water (30 mL) and extract twice with EtOAc (30 mL). Wash the combined extract with brine (30 mL), dry, and evaporate in vacuo. Purify by preparative TLC (20% MeOH in CH2Cl2 with 1% ammonium hydroxide) to obtain the title compound as a colorless oil.
F. 2-(4-Ethoxy-3-methoxy-phenyl)-N-{2-[2-methyl-9-(2,4,6-trimethyl-phenyl)-pyridino[2,3-b]indolizin-4-ylamino]-ethyl}-acetamide




Treat a solution of (2-aminoethyl)[2-methyl-9-(2,4,6-trimethylphenyl)-pyridino[2,3-b]indolizin-4-yl]amine (0.08 g, 0.22 mmol), 4-ethoxy, 3 methoxy phenylacetic acid (0.05 g, 0.22 mmol) and N,N diisopropylethyl amine (0.04 mL, 0.24 mmol) in CH2Cl2 (10 mL) with benzotriazol-1-yloxy-tris-(dimethylamino)phosphonium hexafluorophosphate (0.1 g, 0.24 mmol) and stir at ambient temperature for 14 h. Dilute the resulting mixture with CH2Cl2 (20 mL), water (20 mL), and saturated aq NaCl (20 mL). Dry the organic layer over Na2SO4, filter and concentrate in vacuo. Purify by preparative TLC (10% MeOH in CH2Cl2) to obtain the title compound as a solid.
G. (2-{[2-(4-Ethoxy-3-methoxyphenyl)ethyl]amino}ethyl)[2-methyl-9-(2,4,6-trimethylphenyl)pyridino[2,3-b]indolizin-4-yl]amine




Treat a solution of 2-(4-ethoxy-3-methoxy-phenyl)-N-{2-[2-methyl-9-(2,4,6-trimethyl-phenyl)-pyridino[2,3-b]indolizin-4-ylamino]-ethyl}-acetamide (0.08 g, 0.145 mmol) in THF (5 mL) with AlH3.NMe2Et (3 mL, 1.45 mmol) and heat to reflux for 14 h. Cool the resulting mixture to ambient temperature, quench with Na2CO3.10H2O (0.3 g) and stir at ambient temperature for 15 min. Filter the solution through Celite and wash with several portions of CH2Cl2. Concentrate the filtrate in vacuo to dryness and purify by preparative TLC (10% MeOH in CH2Cl2 with 0.5% ammonium hydroxide) to the title compound as a solid.
Example 2
A. 2-Methyl-9-(2,4,6-trimethylphenyl)pyrimidino[4,5-b]indolizin-4-ol




Heat to 100° C. for 1 h a solution of 2-amino-3-cyano-1-(2,4,6-trimethylphenyl)indolizine (220 mg) in an acetic anhydride (0.5 mL)—acetic acid (2 mL) mixture. Cool the mixture to ambient temperature before concentrating in vacuo. Heat the residue in 85% phosphoric acid (5 mL) at 100° C. for 1.5 h, allow to cool to ambient temperature, dilute with water, and neutralize to pH 7 by adding aqueous NaOH. Extract the resulting yellow suspension twice with CH2Cl2 and dry the combined extracts on Na2SO4, filter, concentrate, and purify by column chromatography on silica gel (eluent: 50% EtOAc in hexane to 10% MeOH in EtOAc) to obtain the title compound as a yellow solid.
B. 4-Chloro-2-methyl-9-(2,4,6-trimethylphenyl)pyrimidino[4,5-b]indolizine




Heat at 100° C. for 2 h a solution of 2-methyl-9-(2,4,6-trimethylphenyl)pyrimidino[4,5-b]indolizin-4-ol (120 mg) in phosphorus oxychloride (2 mL), cool to ambient temperature, and concentrate in vacuo. Partition the residue into ice water and CH2Cl2. Extract the aqueous phase twice with CH2Cl2 and wash the combined organic extracts with a saturated NaHCO3 solution. Dry the solution over Na2SO4, filter, and concentrate in vacuo. Purify the dark residue by column chromatography on silica gel (eluent: 10% to 20% EtOAc in hexane) to obtain the title compound as a greenish yellow foam: 1H NMR (400 MHz, CDCl3) δ 1.99 (s, 6H), 2.38 (s, 3H), 2.79 (s, 3H), 6.80 (m, 1H), 7.00 (s, 2H), 7.19 (m, 2H), 9.27 (d, 1H).
C. (2-Aminoethyl)[2-methyl-9-(2,4,6-trimethylphenyl)pyrimidino[4,5-b]indolizin-4-yl]amine




Heat a solution of 4-chloro-2-methyl-9-(2,4,6-trimethylphenyl)pyrimidino[4,5-b]indolizine (0.3 g, 0.89 mmol), and ethylene diamine (0.6 mL, 8.93 mmol) in dry NMP (3 mL) at 100° C. for 14 h. Pour the cooled mixture onto water (30 mL) and extracte twice with EtOAc (30 mL). Wash the combined extracts with brine (30 mL), dry, and evaporate in vacuo. Purify by preparative TLC (20% MeOH in CH2Cl2 with 0.5% ammonium hydroxide) to obtain the title compound as a yellow oil.
D. [2-(Cyclopentylamino)ethyl][2-methyl-9-(2,4,6-trimethylphenyl)pyrimidino[4,5-b]indolizin-4-yl]amine




Treat a solution of (2-aminoethyl)[2-methyl-9-(2,4,6-trimethylphenyl)pyrimidino[4,5-b]indolizin-4-yl]amine (0.07 g, 0.19 mmol), cyclopentanone (0.02 mL, 0.19 mmol) and acetic acid (0.01 mL, 0.19 mmol) in dry dichloroethane (3 mL) with sodium triacetoxyborohydride (0.06 g, 0.27 mmol) and stir at ambient temperature for 14 h. Dilute the resulting mixture with CH2Cl2 (20 mL) and wash with saturated aq NaCl (50 mL). Dry the organic portion over Na2SO4, filter, and concentrate under reduced pressure. Purify by preparative TLC (10% MeOH in CH2Cl2 with 0.5% ammonium hydroxide) to obtain the title compound as a yellow solid.
Example 3
A. N-(2-Amino-ethyl)-2-(4-ethoxy-3-methoxy-phenyl)-acetamide




Dissolve 4-ethoxy-3-methoxy-phenyl acetic acid (26 g, 119 mol) in dichloroethane (300 mL, anhydrous) and cool to 0° C. Dropwise add oxalyl chloride (130 mL, 2.0 M in CH2Cl2) and DMF (2 mL), then allow to warm to ambient temperature for 14 h. Concentrate under reduced pressure to a tan oil. Dissolve in dichloroethane (200 mL) and cool to 0° C. while stirring under N2. Dropwise, over 45 minutes, add a second solution of N-tBOC-ethylenediamine (20 g) and triethylamine (20 mL) in dichloroethane (100 mL). Partition between CH2Cl2 (500 mL) and 1.0 N HCl (200 mL), separate the layers, and wash the organic phase with 1.0 N HCl (200 mL). Wash the organic layer with saturated K2CO3 (2×200 mL), then dry the CH2Cl2 layer over Na2SO4, filter, and evaporate to tan solid. Triturate with Et2O (200 mL) and stir vigorously to fragment solid, then filter and wash copiously with Et2O to obtain a white solid. Dissolve the white solid (3.0 g, 8.52 mmol) in a 1:1 mixture of trifluoracetic acid and CH2Cl2 (10 mL) and stir at ambient temperature 1 h. Concentrate under reduced pressure and partition between CH2Cl2 (25 mL) and 1.0 N NaOH (25 mL), then separate the layers, and extract the aqueous layer with CH2Cl2 (25 mL). Pool the organic layers, dry over Na2SO4, filter and concentrate in vacuo to a white solid.
B. N-(4-Ethoxy-3-methoxy-phenethyl)-ethylenediamine




Treat a solution of N-(2-amino-ethyl)-2-(4-ethoxy-3-methoxy-phenyl)acetamide (0.7 g, 2.77 mmol) in THF (10 mL) with AlH3.NMe2Et (55 mL, 27.74 mmol) and heat to reflux for 14 h. Cool the resulting mixture to ambient temperature, quench with Na2CO3.10H2O (0.5 g) and stir at ambient temperature for 15 min. Filter the solution through Celite and wash with several portions of CH2Cl2. Concentrate the filtrate in vacuoo and purify by preparative TLC (10% MeOH in CH2Cl2) to obtain the title compound as a white oil.
C. (2-{[2-(4-Ethoxy-3-methoxyphenyl)ethyl]aminol}ethyl)[2,5,6-trimethyl-7-(2,4,6-trimethylphenyl)pyrrolo[3,2-e]pyrimidin-4-yl]amine




Heat a solution of 4-chloro-2,5,6-trimethyl-7-(2,4,6-trimethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidine (340 mg, 1.1 mmol) and N-(4-ethoxy-3-methoxy-phenethyl)-ethylenediamine in NMP (2 mL) for 14 h at 130° C. Pour into water (5 mL) and extract with EtOAc (2×10 mL). Dry the combined organic extracts over Na2SO4, filter, and concentrate under reduced pressure. Purify by preparative TLC, eluting with 10% MeOH in CH2Cl2. Dissolve the residue in a minimum amount of MeOH then add HCl in EtOAc (2 mL) and triturate with Et2O to obtain the title-compound as a solid (HCl salt).
Example 4
A. 2-(4-Methoxyphenyl)-N-(2-{[7-(4-methoxy-2,6-dimethylphenyl)-2,5-dimethylpyrrolo[2,3-e]pyrimidin-4-yl]amino}ethyl)acetamide




Heat a solution of 4-chloro-7-(4-methoxy-2,6-dimethyl-phenyl)-2,5-dimethyl-5H-pyrrolo[3,2-d]pyrimidine (120 mg, 0.38 mmol) and N-(2-amino-ethyl)-2-(4-methoxyphenyl)-acetamide (125 mg) in NMP (2 mL) for 14 h at 130° C. Pour into water (5 mL) and extract with EtOAc (2×10 mL). Dry the combined organic extracts over Na2SO4, filter, and concentrate under reduced pressure to obtain the title compound which is used without further purification.
B. (2-{[2-(4-Methoxyphenyl)ethyl]amino}ethyl)[7-(4-methoxy-2,6-dimethylphenyl)-2,5-dimethylpyrrolor[2,3-e]pyrimidin-4-yl]amine




Dissolve 2-(4-methoxyphenyl)-N-(2-{[7-(4-methoxy-2,6-dimethylphenyl)-2,5-dimethylpyrrolo[2,3-e]pyrimidin-4-yl]aminoethyl)acetamide in anhydrous THF (5 mL) and stir under N2. Add borane-dimethylsulfide complex (0.2 mL, 10.0 M in THF) and heat to reflux for 14 h. Quench by addition of N,N′-dimethyl-1,2-ethylenediamine (0.21 mL) in MeOH (5 mL) and stir for 1 h at ambient temperature. Concentrate under reduced pressure and purify the residue by preparative TLC, eluting with 10% MeOH in CH2Cl2. Dissolve the residue in a minimum amount of MeOH then add HCl in EtOAc (2 mL) and triturate with Et2O to obtain the title compound as a solid (HCl salt).
Example 5
A. 4-Chloro-6-methyl-3-nitro-pyridin-2-ol




Add 1-ethylpropylamine (9.00 g, 76.4 mmol) to a solution of 4-hydroxy-6-methyl-3-nitropyridone (10.0 g, 58.8 mmol) in anhydrous MeOH (20 mL). Stir the mixture until clear, then concentrated in vacuo. Add the residue portionwise to phosphorus oxychloride (70 mL), Stir at ambient temperature for 10 h, and pour onto ice-water. After stirring for 20 min, filter the precipitate, and dry over Na2SO4 to obtain the title compound as a yellow solid.
B. 4-Benzylamino-6-methyl-3-nitro-pyridin-2-ol




Stir a solution of 4-chloro-6-methyl-3-nitro-pyridin-2-ol (10.0 g, 53.0 mmol) and benzyl amine (17.3 g, 159 mmol) in EtOH (30 mL) at ambient temperature for 12 h, then concentrate in vacuo. Pour the resulting residue into water, acidify to pH 3 with 1N HCl and filter. Wash the precipitate several times with water to obtain the title compound as a yellow solid.
C. 4-Benzylamino-6-methyl-3-nitro-2-chloro-pyridine




Heat a solution of 4-benzylamino-6-methyl-3-nitro-pyridin-2-ol (13.70 g, 52.8 mmol) and tetramethylammonium chloride (6.0 g, 52.8 mmol) to reflux in phosphorus oxychloride (15 mL) for 5 h. After cooling, remove the excess phosphorus oxychloride in vacuo. Triturate the residue in ice-water (400 mL) to obtain the title compound as a brown solid.
D. 6-Methyl-3-nitro-4-[benzylamino](2-pyridyl)}(2,4,6-trimethylphenyl)amine




Add p-toluene sulfonic acid (11.0 g, 56.3 mmol) to a solution of 4-benzylamino-6-methyl-3-nitro-2-chloro-pyridine (13.0 g, 46.8 mmol) and 2,4,6-trimethylaniline (6.58 g, 46.8 mmol) in 350 mL of toluene. Heat the resulting mixture for 14 h under reflux using a Dean-Stark trap. After cooling to ambient temperature, dilute the solution with EtOAc (200 mL) and wash successively with saturated aq NaHCO3 and saturated aq NaCl. Separate the organic layer, dry over Na2SO4, filter, and concentrate in vacuo. Purify by flash column chromatography (2% methanol in CH2Cl2) to obtain obtain the title compound as a dark yellow solid.
E. 3-Amino-6-methyl-4-[benzylamino](2-pyridyl)(2,4,6-trimethylphenyl)amine




Add iron powder (7.0 g) to a solution of 6-methyl-3-nitro-4-[benzylamino](2-pyridyl)(2,4,6-trimethylphenyl)amine (8.75 g, 23.2 mmol) in acetic acid (14 mL) and MeOH (70 mL). Heat the resulting mixture at 70° C. for 1 h, cool to ambient temperature, and filter through a pad of celite. Evaporate the filtrate to dryness under reduced pressure. Treat he residue with 1N aq NaOH and extract with EtOAc. Wash the EtOAc extract with water and saturated aq NaCl. Separate the organic layer, dry over Na2SO4, filter, and concentrate to obtain the title compound as a brown solid which is used without further purification.
F. [5-methyl-3-(2,4,6-trimethylphenyl)imidazolo[5,4-b]pyridin-7-yl]benzylamine




Treat a solution of 3-amino-6-methyl-4-[benzylamino](2-pyridyl)(2,4,6-trimethylphenyl)amine (0.80 g, 2.31 mmol) and triethyl orthoformate (8.0 mL, 48.5 mmol) in dimethylacetamide (9 mL) with 12 M HCl (0.4 mL). Stir the mixture at ambient temperature for 14 h, dilute with EtOAc (50 mL), and wash with aq NaHCO3 (50 mL) and saturated aq NaCl (50 mL). Dry the organic layer over Na2SO4, filter, and concentrate. Purify by preparative TLC (10% methanol in CH2Cl2 with 0.1% ammonium hydroxide) to obtain the title compound as a solid.
G. 5-methyl-3-(2,4,6-trimethylphenyl)imidazolo[5,4-b]pyridin-7-ylamine




Add palladium hydroxide (0.05 g) to a solution of [2,5-dimethyl-3-(2,4,6-trimethylphenyl)imidazolo[5,4-b]pyridin-7-yl]benzylamine (0.15 g, 0.42 mmol) in acetic acid (10 mL). Hydrogenate the mixture at a pressure of 50 psi for 20 hr. Filter the reaction mixture through celite, evaporate to dryness under reduced pressure, dilute with EtOAc and successively wash with aq NaHCO3 and aq NaCl. Dry the organic layer over Na2SO4, filter, and concentrate. Purify by flash column chromatography (3% MeOH in CH2Cl2) to obtain the title compound as a brown solid.
H. N-[5-methyl-3-(2,4,6-trimethylphenyl)imidazolo[5,4-b]pyridin-7-yl]-2-chloroacetamide




Treat a solution of 5-methyl-3-(2,4,6-trimethylphenyl)imidazolo[5,4-b]pyridin-7-ylamine (0.05 g, 1.9 mmol), and N,N-diisopropylethylamine, (0.04 mL, 0.21 mmol) in 1,2-dichloroethane (5 mL) with chloroacetyl chloride (0.017 mL, 0.21 mmol). Heat the solution to reflux for 3 h, cool to ambient temperature, and pour into an aqueous potassium carbonate solution. Extract the resulting mixture with CH2Cl2 and wash with saturated aq NaCl. Separate the organic layer, dry over Na2SO4, filter, and concentrate. Purify by preparative TLC (5% MeOH in CH2Cl2) to obtain the title compound as a yellow solid.
I. (2-Chloroethyl)[5-methyl-3-(2,4,6-trimethylphenyl)imidazolo[5,4-b]pyridin-7-yl]-amine




Treat a solution of N-[5-methyl-3-(2,4,6-trimethylphenyl)imidazolo[5,4-b]pyridin-7-yl]-2-chloroacetamide (0.04 g, 0.10 mmol) in THF (5 mL) with borane-methyl sulfide complex (0.03 mL, 0.30 mmol). Heat the mixture to reflux for 8 h and quench at ambient temperature with a large excess of MeOH, followed by 6 N HCl (2 mL). Re-heat the mixture to reflux for 1 h, then concentrate under reduced pressure to obtain the title compound as a yellow solid.
J. (2-{[2-(4-Ethoxy-3-methoxyphenyl)ethyl]amino}ethyl[5-methyl-3-(2,4,6-trimethylphenyl)imidazolo[5,4-b]pyridin-7-yl]amine




Heat a solution of (2-chloroethyl)[5-methyl-3-(2,4,6-trimethylphenyl)imidazolo[5,4-b]pyridin-7-yl]-amine (0.030 g, 0.09 mmol) and 4-ethoxy-3-methoxy phenethylamine (0.10 g, 0.55 mmol) in dry NMP (2 mL) at 110° C. for 16 h. Pour the cooled mixture onto water (20 mL) and extract twice with EtOAc (20 mL). Wash the combined extracts with brine (30 mL), dry, and evaporate in vacuo. Purify by flash column chromatography (10% MeOH in CH2Cl2 with 0.1% ammonium hydroxide) to obtain the title compound as a solid.
Example 6
A. [2,5-dimethyl-3-(2,4,6-trimethylphenyl)imidazolo[5,4-b]pyridin-7-yl]benzylamine




Heat a solution of 3-amino-6-methyl-4-[benzylamino](2-pyridyl)(2,4,6-trimethylphenyl)amine (2.50 g, 7.21 mmol), triethyl orthoacetate (2.6 mL, 14.4 mmol) and camphorsulfonic acid (250 mg) in toluene (50 mL) to reflux for 14 h. After cooling to ambient temperature, concentrate the mixture in vacuo, dilute with water (100 mL), and extract with EtOAc. Wash the EtOAc extract successively with water and saturated aq NaCl, dry over Na2SO4, filter, and concentrate. Purify by flash column chromatography (5% methanol in CH2Cl2) to obtain the title compound as a white solid.
B. 2,5-Dimethyl-3-(2,4,6-trimethylphenyl)imidazolo[5,4-b]pyridine-7-ylamine




Add palladium hydroxide (2.0 g) to a solution of [2,5-dimethyl-3-(2,4,6-trimethylphenyl)imidazolo[5,4-b]pyridin-7-yl]benzylamine (1.50 g, 4.05 mmol) in acetic acid (10 mL). Hydrogenate the mixture at a pressure of 40 psi for 20 hr. Filter the reaction mixture through celite, evaporate to dryness under reduced pressure, dilute with EtOAc and successively wash with aq. NaHCO3 and aq NaCl. Dry the organic layer over Na2SO4, filter, and concentrate. Purify by flash column chromatography (3% MeoH in CH2Cl2) to obtain the title compound as a white solid.
C. N-[2,5-Dimethyl-3-(2,4,6-trimethylphenyl)imidazolo[5,4-b]pyridin-7-yl]-2-chloroacetamide




Treat a solution of 2,5-dimethyl-3-(2,4,6-trimethylphenyl)imidazolo[5,4-b]pyridine-7-ylamine (0.8 g, 2.85 mmol), and N,N-diisopropylethylamine, (0.54 mL, 3.13 mmol) in 1,2-dichloroethane (10 mL) with chloroacetyl chloride (0.25 mL, 3.13 mmol). Heat the solution to reflux for 5 h, cool to ambient temperature, and pour into an aqueous potassium carbonate solution. Extract the resulting mixture with CH2Cl2 and wash with saturated aq NaCl. Separate the organic layer, dry over Na2SO4, filter and concentrate. Purify by preparative TLC (5% MeOH in CH2Cl2) to obtain the title compound as a brown solid.
D. [2,5-Dimethyl-3-(2,4,6-trimethylphenyl)imidazolo[5,4-b]pyridin-7-yl](2-chloroethyl)amine




Treat a solution of N-[2,5-dimethyl-3-(2,4,6-trimethylphenyl)imidazolo[5,4-b]pyridin-7-yl]-2-chloroacetamide (0.91 g, 2.55 mmol) in THF (5 mL) with borane-methyl sulfide complex (0.8 mL, 7.65 mmol). Heat the mixture to reflux for 18 h and quench at ambient temperature with a large excess of MeOH, followed by 6N HCl (5 mL). Re-heat the mixture to reflux for 1 h, then concentrate under reduced pressure to obtain the title compound as a white crystalline solid.
E. [2,5-Dimethyl-3-(2,4,6-trimethylphenyl)imidazolo[5,4-b]pyridin-7-yl][2-(cyclohexylamino)ethyl]amine




Heat a solution of [2,5-dimethyl-3-(2,4,6-trimethylphenyl)imidazolo[5,4-b]pyridin-7-yl](2-chloroethyl)amine (0.04 g, 0.12 mmol), and cyclohexyl amine (0.13 mL g, 1.16 mmol) in dry NMP (2 mL) at 80° C. for 20 h. Pour the cooled mixture onto water (20 mL) and extract twice with ethyl acetate (20 mL). Wash the combined extracts with brine (20 mL), dry, and evaporate in vacuo. Purify by flash column chromatography (10% methanol in CH2Cl2 with 0.1% ammonium hydroxide) to obtain the title compound as a white solid.
Example 7
A. 3-(2,4-dichlorophenyl)-2,5-dimethylimidazolo[5,4-b]pyridin-7-ylamine




Stir a solution of [3-(2,4-dichlorophenyl)-2,5-dimethylimidazolo[5,4-b]pyridin-7-yl](4-methoxybenzyl)amine (4.23 g, 10 mmol), anisole (3.2 mL, 29.6 mmol), trifluoroacetic acid (80 mL), and concentrated sulfuric acid (2 mL) at ambient temperature for 14 h. Add the resulting mixture dropwise to ice-water and dilute with NaHCO3. Filter the resulting precipitate and wash thoroughly with water to obtain the title compound as a brown solid.
B. N-[3-(2,4-dichlorophenyl)-2,5-dimethylimidazolo[5,4-b]pyridin-7-yl]-2-chloroacetamide




Treat a solution of 3-(2,4-dichlorophenyl)-2,5-dimethylimidazolo[5,4-b]pyridin-7-ylamine (0.2 g, 0.65 mmol), and N,N-diisopropylethylamine, (0.12 mL, 0.72 mmol) in 1,2-dichloroethane (10 mL) with chloroacetyl chloride (0.06 mL, 30.72 mmol). Heat the solution to reflux for 2 h, cool to ambient temperature, and pour into an aqueous potassium carbonate solution. Extract the resulting mixture with CH2Cl2 and wash with saturated aq NaCl. Separate the organic layer, dry over Na2SO4, filter, and concentrate. Purify by preparative TLC (5% methanol in CH2Cl2) to obtain the title compound as a yellow solid.
C. [3-(2,4-dichlorophenyl)-2,5-dimethylimidazolo[5,4-b]pyridin-7-yl](2-chloroethyl)amine




Treat a solution of N-[3-(2,4-dichlorophenyl)-2,5-dimethylimidazolo[5,4-b]pyridin-7-yl]-2-chloroacetamide (1.0 g, 2.6 mmol) in THF (5 mL) with borane-methyl sulfide complex (0.8 mL, 7.8 mmol). Heat the mixture to reflux for 3 h and quench at ambient temperature with a large excess of MeOH followed by 5 N HCl (2 mL). Re-heat the mixture to reflux for 1 h, then concentrate under reduced pressure. Purify by flash column chromatography (50% EtOAc-hexane) to obtain the title compound as a beige solid.
D. [3-(2,4-dichlorophenyl)-2,5-dimethylimidazolo[5,4-b]pyridin-7-yl][2-(cyclopentylamino)ethyl]amine




Heat a solution of [3-(2,4-dichlorophenyl)-2,5-dimethylimidazolo[5,4-b]pyridin-7-yl](2-chloroethyl)amine (0.08 g, 0.22 mmol), and cyclopentyl amine (0.2 mL g, 0.22 mmol) in dry NMP (3 mL) at 80° C. for 20 h. Pour the cooled mixture onto water (30 mL) and extract twice with EtOAc (50 mL). Wash the combined extracts with brine (50 mL), dry, and evaporate in vacuo. Purify by preparative TLC (10% MeOH in CH2Cl2) to obtain the title compound as a yellow oil.
Example 8
A. Ethyl 4-(2,6-dichlorophenyl)-2,4-dioxobutanoate




To a solution of 2′,6′-dichloroacetophenone (12.5 g, 66 mmol) and diethyl oxalate (14.6 g, 100 mmol) in 450 mL of anhydrous toluene, cautiously add sodium hydride (60% dispersion in mineral oil, 2.8 g, 70 mmol). Cautiously heat the reaction mixture to reflux under N2 for 1 h, cool to ambient temperature and pour onto ice-cold 1M HCl. Separate the layers and extract the aqueous phase with EtOAc (2×200 mL). Wash the combined organic extracts with brine, dry over MgSO4 and evaporate to obtain the title compound which is used in the next step without further purification.
B. Ethyl 4-(2,6-dichlorophenyl)-3-(hydroxyimino)-2,4-dioxobutanoate




Slowly bubble N2O3 gas (generated by the dropwise addition of concentrated HCl into an aqueous solution of sodium nitrite) into a stirred solution of ethyl 4-(2,6-dichlorophenyl)-2,4-dioxobutanoate (14.4 g, 50 mmol) in EtOH (300 mL) until the reaction is complete (as determined by TLC). Remove the EtOH by evaporation under reduced pressure and partition the residue between EtOAc and water. Dry the organic extract over MgSO4 and evaporate in vacuo to obtain the title compound which is used in the next step without further purification.
C. Ethyl 4-amino-5-(2,6-dichlorophenyl)-1-methylpyrazole-3-carboxylate




To a solution of ethyl 4-(2,6-dichlorophenyl)-3-(hydroxyimino)-2,4-dioxobutanoate (14 g, 44 mmol) in MeOH (400 mL) at 0° C., add dropwise-concentrated HCl (10 mL) followed by methyl hydrazine (2.02 g, 44 mmol). Stir the reaction mixture at ambient temperature for 8 h and concentrate in vacuo. Partition the residue between EtOAc (400 mL) and saturated aqueous NaHCO3 (150 mL) and separate the layers. Add water (200 mL) to the organic layer, followed by sodium hydrosulfite (150 g) and stir the resulting mixture vigorously for 4 h. Separate the organic phase, wash with water (200 mL), brine (200 mL), dry over MgSO4 and evaporate to obtain the title compound.
D. 3-(2,6-Dichlorophenyl)-2.5-dimethyl-6-hydropyrazolo[4,3-d]pyrimidin-7-one




Saturate a solution of ethyl 4-amino-5-(2,6-dichlorophenyl)-1-methylpyrazole-3-carboxylate (6 g, 20 mmol) in acetonitrile (150 mL) with HCl gas, stir at ambient temperature for 14 h and then concentrate. Partition the residue partition between EtOAc (150 mL) and aqueous NaHCO3 (150 mL) and separate the layers. Wash the organic layer with brine (100 mL), dry over MgSO4 and concentrate. Triturate the residue with Et2O, and collect the yellow solid by filtration to obtain the title compound.
E. 3-(2,6-Dichlorophenyl)-7-chloro-2,5-dimethylpyrazolo[4,3-d]pyrimidine




Heat a solution of 3-(2,6-dichlorophenyl)-2,5-dimethyl-6-hydropyrazolo[4,3-d]pyrimidin-7-one (3.09 g, 10 mmol), POCl3 (35 mL) and N,N-dimethylaniline (1.44 g, 12 mmol) at 90° C. for 8 h. Remove the volatiles by evaporation, re-dissolve the residue in CH2Cl2 (100 mL) and wash with aqueous NaHCO3 (2×50 mL). Dry the organic layer over MgSO4 and concentrate under reduced pressure. Purify the residue by flash column chromatography (silica, eluent 50% Et2O in hexane) to obtain the title compound.
F. (2-Aminoethyl)[3-(2,6-dichlorophenyl)-2,5-dimethylpyrazolo[3,4-e]pyrimidin-7-yl]amine




To a stirred solution of 3-(2,6-dichlorophenyl)-7-chloro-2,5-dimethylpyrazolo[4,3-d]pyrimidine (652 mg, 2.0 mmol) in acetonitrile (50 mL) at 50° C., add ethylene diamine (2.4 g, 40 mmol) in one portion. Maintain the reaction at 50° C. for 2 h, cool to ambient temperature and remove the volatiles by evaporation. Partition the residue between CH2Cl2 (50 mL) and 1N NaOH (50 mL) and extract the aqueous layer with CH2Cl2 (2×30 mL). Wash the combined organic extracts with water (30 mL), brine (30 mL), dry over MgSO4 and evaporate to obtain the title compound.
G. [3-(2,6-Dichlorophenyl)-2,5-dimethylpyrazolo[3,4-e]pyrimidin-7-yl][2-cyclopentylamino)ethyl]amine




To (2-aminoethyl)[3-(2,6-dichlorophenyl)-2,5-dimethylpyrazolo[3,4-e]pyrimidin-7-yl]amine (140 mg, 0.4 mmol) in dichloroethane (5 mL), add cyclopentanone (34 mg, 0.4 mmol), sodium triacetoxyborohydride (106 mg, 0.5 mmol) and glacial acetic acid (24 mg, 0.4 mmol). Stir the reaction mixture at ambient temperature for 2 h and pour into 1N NaOH (10 mL). Separate the layers and extract the aqueous phase with CH2Cl2 (2×10 mL). Wash the combined organic extracts with water (10 mL), brine (10 mL), dry over MgSO4 and evaporate in vacuo. Purify by preparative TLC (eluent 10% MeOH in chloroform) to obtain the title compound.
Example 9
A. N-(2-{[3-(2,6-Dichlorophenyl)-2,5-dimethylpyrazolo[3,4-e]pyrimidin-7-yl]amino}-2-(4-ethoxy-3-methoxyphenyl)acetamide




To a stirred solution of (2-aminoethyl)[3-(2,6-dichlorophenyl)-2,5-dimethylpyrazolo[3,4-e]pyrimidin-7-yl]amine (175 mg, 0.5 mmol) in N,N-dimethylacetamide (5 mL), add 4-methylmorpholine (101 mg, 1.0 mmol), 2-(4-ethoxy-3-methoxyphenyl)acetic acid (115 mg, 0.55 mmol) and bis(2-oxo-3-oxazolidinyl)phosphinic chloride (331 mg, 0.75 mmol). Stir the reaction mixture at ambient temperature for 14 h and dilute with EtOAc (15 mL). Wash the organic extracts successively with water (10 mL), brine (10 mL), saturated NH4Cl (10 mL), 2N NaOH (10 mL), brine (10 mL), dry over MgSO4 and evaporate under reduced pressure to obtain the title compound.
B. [3-(2,6-dichlorophenyl)-2,5-dimethylpyrazolo[3,4-e]pyrimidin-7-yl](2-{[2-(4-ethoxy-3-methoxyphenyl)ethyl]amino}ethyl)amine




To a stirred solution of N-(2-{[3-(2,6-dichlorophenyl)-2,5-dimethylpyrazolo[3,4-e]pyrimidin-7-yl]amino}-2-(4-ethoxy-3-methoxyphenyl)acetamide (175 mg, 0.5 mmol) in THF (5 mL), add borane-dimethylsulfide complex (1M in THF, 0.25 mL, 2.5 mmol). Heat the reaction mixture to reflux for 14 h, cool to ambient temperature and quench by careful addition of MeOH (3 mL). Remove the volatile by evaporation and re-dissolve the residue in MeOH (5 mL). Add HCl in Et2O (1M, 2 mL) and heat the solution to reflux for 1 h. Remove the volatiles by evaporation under reduced pressure, dissolve the residue in CH2Cl2 (20 mL) and wash with saturated NaHCO3 (20 mL) and brine (10 mL). Dry the organic layer over MgSO4 and concentrate in vacuo. Purify of the residue by preparative TLC (eluent 20% MeOH in chloroform) to obtain the title compound.
Example 10
A. [5-Methyl-3-(2,4,6-trimethylphenyl)(1,2,3-triazolino[5,4-b]pyridin-7-yl)]benzylamine




Treat a solution of 3-amino-6-methyl-4-[benzylamino](2-pyridyl)(2,4,6-trimethylphenyl)amine (1.70 g, 4.91 mmol) in THF (25 mL) with tetrafluoroboric acid (0.86 g, 9.81 mmol) at 0° C. Add dropwise isoamyl nitrite (0.86 g, 7.36 mmol) to the reaction mixture, stir at ambient temperature for 30 min, dilute with EtOAc (30 mL), wash with aq NaHCO3 (40 mL), then with saturated aq NaCl (30 mL). Dry the organic layer over Na2SO4, filter, and concentrate in vacuo. Purify by flash column chromatography (50% ethyl acetate-hexane) to obtain the title compound as a solid.
B. 5-Methyl-3-(2,4,6-trimethylphenyl)-1,2,3-triazolino[5,4-b]pyridine-7-ylamine




Add palladium hydroxide (0.5 g) to a solution of [5-methyl-3-(2,4,6-trimethylphenyl)(1,2,3-triazolino[5,4-b]pyridin-7-yl)]benzylamine (0.75 g, 2.10 mmol) in acetic acid (10 mL). Hydrogenate the mixture at a pressure of 50 psi for 17 h. Filter the mixture through celite, evaporate to dryness under reduced pressure, dilute with EtOAc and successively wash with aq NaHCO3 and aq NaCl. Dry the organic layer over Na2SO4, filter, and concentrate in vacuo. Purify by flash column chromatography (3% MeOH in CH2Cl2) to obtain the title compound as a solid.
C. 2-Chloro-N-[5-methyl-3-(2,4,6-trimethylphenyl)(1,2,3-triazolino[5,4-b]pyridin-7-yl)]acetamide




Treat a solution of 5-methyl-3-(2,4,6-trimethylphenyl)-1,2,3-triazolino[5,4-b]pyridine-7-ylamine (1.0 g, 3.74 mmol), and N,N-diisopropylethylamine, (0.7 mL, 4.11 mmol) in 1,2-dichloroethane (10 mL) with chloroacetyl chloride (0.33 mL, 4.11 mmol). Heat the solution to reflux for 3 h, cool to ambient temperature, and pour into an aqueous potassium carbonate solution. Extract the resulting mixture with CH2Cl2 and wash with saturated aq NaCl. Separate the organic layer, dry over Na2SO4, filter and concentrate. Purify by flash column chromatography (30% ethyl acetate-hexane)to obtain the title compound as a white crystalline solid.
D. (2-Chloroethyl)[5-methyl-3-(2,4,6-trimethylphenyl)(1,2,3-triazolino[5,4-b]pyridin-7-yl)]amine




Treat a solution of 2-chloro-N-[5-methyl-3-(2,4,6-trimethylphenyl)(1,2,3-triazolino[5,4-b]pyridin-7-yl)]acetamide (0.80 g, 2.33 mmol) in THF (7 mL) with borane-methyl sulfide complex (0.7 mL, 7.0 mmol). Heat the mixture to reflux for 8 h and quench at ambient temperature with a large excess of methanol. Re-heat the mixture to reflux for 1 h, then concentrate under reduced pressure to obtain the title compound as a yellow solid.
E. (2-{[2-(4-Ethoxy-3-methoxyphenyl)ethyl]amino}ethyl)[5-methyl-3-(2,4,6-trimethylphenyl)(1,2,3-triazolino[5,4-b]pyridin-7-yl)]amine




Heat a solution of (2-chloroethyl)[5-methyl-3-(2,4,6-trimethylphenyl)(1,2,3-triazolino[5,4-b]pyridin-7-yl)]amine (0.150 g, 0.45 mmol) and 4-ethoxy-3-methoxy phenethylamine (0.53 g, 2.73 mmol) in dry NMP (3 mL) at 80° C. for 14 h. Pour the cooled mixture onto water (50 mL) and extract twice with EtOAc (30 mL). Wash the combined extracts with brine (30 mL), dry, and evaporate in vacuo. Purify by flash column chromatography (10% MeOH in CH2Cl2–0.1% ammonium hydroxide) to obtain the title compound as a solid.
Example 11
A. [2-(Cyclopentylamino)ethyl][5-methyl-3-(2,4,6-trimethylphenyl)(1,2,3-triazolino[5,4-b]pyridin-7-yl)]amine




Heat a solution of (2-chloroethyl)[5-methyl-3-(2,4,6-trimethylphenyl)(1,2,3-triazolino[5,4-b]pyridin-7-yl)]amine (0.06 g, 0.18 mmol), and cyclopentyl amine (0.53 g, 1.82 mmol) in dry NMP (3 mL) at 80° C. for 14 h. Pour the cooled mixture onto water (30 mL) and extract twice with EtOAc (20 mL). Wash the combined extracts with brine (20 mL), dry, and evaporate in vacuo. Purify by flash column chromatography (10% methanol-CH2Cl2–0.1% ammonium hydroxide) to obtain the title compound as a solid.
Example 12
A. 4,6-Dichloro-2-methyl-5-amino-pyrimidine




Add iron powder (6.0 g) to a solution of 4,6 dichloro-2-methyl-5-nitro-pyrimidine (6.50 g, 31 mmol) in acetic acid (11 mL) and MeOH (50 mL). Heat the resulting mixture at 65° C. for 1 h. After cooling, to ambient temperature, filter the mixture through a pad of celite, and evaporate the filtrate to dryness under reduced pressure. Treat the residue with 1N aq NaOH, and extract with EtOAc. Wash the EtOAc extract with water and saturated aq NaCl, dry over Na2SO4, filter, and concentrate in vacuo to obtain the title compound as a solid.
B. (5-Amino-6-chloro-2-methylpyrimidin-4-yl)[(2-bromo-4-isopropyl)phenyl]amine




Heat a solution of 4,6-dichloro-2-methyl-5-amino-pyrimidine (2.0 g, 11.2 mmol) and 2-bromo-4-isopropylamine (2.4 g, 11.2 mmol) at 140° C. for 1 h. After cooling to ambient temperature, dilute the mixture with EtOAc (25 mL), and wash with 1N NaOH (50 mL) and saturated aq NaCl (20 mL). Dry the organic layer over Na2SO4, filter, and concentrate under reduced pressure to obtain the title compound as a dark oil which is used without further purification.
C. 9-[(2-Bromo-4-isopropyl)-phenyl]-6-chloro-2-methyl-7-hydropurin-8-one




Treat a solution of (5-amino-6-chloro-2-methylpyrimidin-4-yl)[(2-bromo-4-isopropyl)phenyl]amine (1.0 g, 2.88 mmol) and triethyl amine (0.27 mL, 1.97 mmol) in THF (10 mL) with triphosgene (0.3 g, 0.98 mmol) and stir at ambient temperature for 14 h.
Quench the reaction mixture with water and dilute with EtOAc (20 mL). Separate the organic layer, wash with brine (20 mL), dry over Na2SO4, filter, and concentrate under reduced pressure. Purify by flash column chromatography (50% EtOAc-hexane) to obtain the title compound as a dark brown solid.
D. 6-[(2-Aminoethyl)amino]-9-[(2-bromo-4-isopropyl)phenyl]-2-methyl-7-hydropurin-8-one




Heat a solution of 9-[(2-bromo-4-isopropyl)-phenyl]-6-chloro-2-methyl-7-hydropurin-8-one. (0.34 g, 0.89 mmol), and ethylenediamine (0.32 g, 5.37 mmol) in dry NMP (2 mL) at 85° C. for 14 h. Pour the cooled mixture onto water (50 mL) and extract twice with EtOAc (30 mL). Wash the combined extracts with brine (30 mL), dry, and evaporate in vacuo to obtain the title compound which is used without further purification.
E. 9-[(2-Bromo-4-isopropyl)phenyl]-6-{[2-(cyclohexylamino)ethyl]amino}-2-methyl-7-hydropurin-8-one




Treat a solution of 6-[(2-aminoethyl)amino]-9-[(2-bromo-4-isopropyl)phenyl]-2-methyl-7-hydropurin-8-one (0.100 g, 0.248 mmol), cyclohexanone (0.03 mL, 0.248 mmol) and acetic acid (0.01 mL, 0.248 mmol) in dry dichloroethane (3 mL) with sodium triacetoxyborohydride (0.07 g, 0.347 mmol) and stir at ambient temperature for 10 h. Dilute the resulting mixture with CH2Cl2 (20 mL) and wash with saturated aq NaCl (50 mL). Dry the organic phase over Na2SO4, filter, and concentrate under reduced pressure. Purify by preparative TLC (10% methanol in CH2Cl2 with 0.5% ammonium hydroxide) to obtain the title compound as a yellow solid.
Example 13
A. (2-Aminoethyl)[2-methyl-8-(2,4,6-trimethylphenyl)(4-quinolyl)]amine




In a sealed tube, heat 4-bromo-2-methyl-8-(2,4,6-trimethyl-phenyl)-quinoline (100 mg, 0.29 mmol) at 140° C. in a mixture of ethylene glycol (1 mL) and ethylene diamine (0.3 mL). After 4 h, cool the reaction mixture and partition between saturated aqueous NaHCO3 and chloroform. Dry the combined organic extracts on Na2SO4 and concentrate under reduced pressure to obtain the title compound as a yellow glass: +APcI MS (M+1)+ 320; 1H NMR (methanol-d4) δ: 7.78 (dd, 1H), 7.39 (t, 1H), 7.34 (dd, 1H), 6.95 (s, 2H), 6.31 (s, 1H), 3.34 (t, 2H), 3.11 (t, 2H), 2.43 (s, 3H), 2.34 (s, 3H), 1.89 (s, 6H).
B. [2-Methyl-8-(2,4,6-trimethylphenyl)(4-quinolyl)][2-(2-1,2,3,4-tetrahydronaphthylamino)ethyl]amine hydrochloride




To a stirred solution of (2-aminoethyl)[2-methyl-8-(2,4,6-trimethylphenyl)(4-quinolyl)]amine (21 mg, 0.066 mmol) and 1,2,3,4-tetrahydro-2-naphthalenone (42 mg, 0.29 mmol) in MeOH (1 mL)/acetic acid (0.01 mL), add sodium cyanoborohydride (4 mg, 0.3 mmol). After stirring 4 h, concentrate the reaction mixture under reduced pressure and partition between saturated aqueous NaHCO3 and chloroform. Dry the combined organic extracts on Na2SO4, concentrate under reduced pressure, and purify by column chromatography on silica gel (eluent: 32:1 EtOAc/triethylamine) to obtain the title compound as a colorless glass. Treat a methanolic solution of the product with concentrated aqueous hydrochloric acid to generate the hydrochloride salt. Concentrate the solution under reduced pressure and triturate the residue in Et2O to obtain the title compound as a colorless solid: +APcI MS (M+1)+ 450; 1H NMR (methanol-d4) δ: 8.52 (dd, 1H), 7.78 (t, 1H), 7.62 (dd, 1H), 7.15–7.00 (m, 7H), 4.06 (t, 2H), 2.66 (s, 3H), 2.38 (s, 3H), 1.87 (s, 6H).
Example 14
A. 2-(3,4-Dimethoxyphenyl)-N-(2-{[3,6-dimethyl-2-(2,4,6-trimethylphenoxy)(4-pyridyl)]amino}ethyl)acetamide




Stir a solution of [3,6-dimethyl-2-(2,4,6-trimethyl-phenoxy)-4-pyridyl][2-(methylamino)ethyl]amine (68 mg, 0.23 mmol), 3,4-dimethoxyphenylacetic acid (59 mg, 0.3 mmol), EDC (59 mg, 0.3 mmol) and HOBT (41 mg, 0.3 mmol) in DMF (1.0 mL) for 12 h. Dilute the reaction mixture with EtOAc (10 mL) and wash with saturated aq NaHCO3 (2×10 mL) and saturated aq brine (2×10 mL), dry and concentrate in vacuo to obtain the title compound as an oily residue. M+1: 478.
B. (2-{[2-(3,4-Dimethoxyphenyl)ethyl]amino}ethyl)[3,6-dimethyl-2-(2,4,6-trimethylphenoxy)(4-pyridyl)]amine




Add BH3 in THF (1 M solution, 0.3 mmol, 0.3 mL) to a solution of the crude 2-(3,4-dimethoxyphenyl)-N-(2-{[3,6-dimethyl-2-(2,4,6-trimethylphenoxy)(4-pyridyl)]amino}ethyl) acetamide in THF (2.0 mL) at ambient temperature. Heat the reaction mixture under reflux for 15 h, dilute with a solution of 10% aq HCV/MeOH (1:1, 2 mL) and heat again under reflux (1 h). Dilute the reaction mixture with CHCl3 (10 mL), wash with saturated aq NaHCO3 (1×5 mL), dry and concentrate in vacuo. Chromatograph the crude residue on SiO2-gel using a gradient of 100% EtOAc to 10% Et2NH/EtOAc to obtain the title compound as a colorless oil. Immediately dissolve the product in Et2O (1 mL), treat with excess 4 M HCl/dioxane and concentrate in vacuo to obtain the hydrochloride salt of the title compound as a colorless solid. 1H NMR (d4-MeOH, Unity 400): d 6.99–6.77 (6H, m), 3.81 (3H, s), 3.78 (3H, s), 3.62 (2H, m), 2.98 (2H, t), 2.39 (3H, s), 2.29 (3H, s), 2.16 (3H, s), 2.07 (6H, s). M+1: 464.
Example 15
A. (2-Aminoethyl){2-methyl-6-[(2,4,6-trimethylphenyl)amino]pyrimidin-4-yl}amine




Heat a solution of 6-chloro-2-methyl-pyrimidin-4-yl)-(2,4,6-trimethyl-phenyl)-amine (0.50 g, 1.91 mmol), and ethylenediamine (1.28 mL, 19.10 mmol) in dry NMP (5 mL) at 100° C. for 14 h. Pour the cooled mixture onto water (50 mL) and extract twice with EtOAc (30 mL). Wash the combined extracts with brine (30 mL), dry, and evaporate in vacuo. Purify by preparative TLC (10% methanol-CH2Cl2–0.5% ammonium hydroxide) to obtain the title compound.
B. 2-(4-Ethoxy-3-methoxy-phenyl)-N-{2-[2-methyl-6-(2,4,6-trimethyl-phenylamino)-pyrimidin-4-ylamino]ethyl}-acetamide




To a solution of (2-aminoethyl){2-methyl-6-[(2,4,6-trimethylphenyl)amino]pyrimidin-4-yl}amine (0.36 g, 1.26 mmol), 4-ethoxy-3-methoxyphenethylamine (0.26 g, 1.26 mmol)) and N,N diisopropylethyl amine (0.24 ml, 1.38 mmol in CH2Cl2 (5 mL), add benzotriazol-1-yloxytris-(dimethylamino)phosphonium hexafluorophosphate (0.61 g, 1.38 mmol) and stir at ambient temperature for 14 h. Dilute the resulting mixture with CH2Cl2 (20 mL), and wash with water (20 mL) and saturated aq NaCl (20 mL). Dry the organic layer over Na2SO4, filter and concentrate in vacuo. Purify by preparative TLC (7% methanol-CH2Cl2) to obtain the title compound.
C. (2-{[2-(4-Ethoxy-3-methoxyphenyl)ethyl]amino}ethyl){2-methyl-6-[(2,4,6-trimethylphenyl)amino]pyrimidin-4-yl}amine




Heat a solution of 2-(4-ethoxy-3-methoxy-phenyl)-N-{2-[2-methyl-6-(2,4,6-trimethyl-phenylamino)-pyrimidin-4-ylamino]ethyl}-acetamide (0.324 g, 0.68 mmol) in THF (10 mL) with AlH3.NMe2Et (14 mL, 6.78 mmol) to reflux for 14 h. Cool the resulting mixture to ambient temperature, quench with Na2CO3.10H2O (1.0 g) and stir at ambient temperature for 15 min. Filter the solution through Celite and wash with several portions of CH2Cl2. Concentrate the filtrate in vacuo to dryness and purify by preparative TLC (10% MeOH in CH2Cl2) to obtain the title compound.
The preparation of the compounds of the present invention by the above-mentioned methods is illustrated further by the following examples, delineated in the TABLE which are not to be construed as limiting the invention in scope or spirit to the specific procedures and compounds described in them. Commonly used abbreviations are: Ph is phenyl, Me is methyl, Et is ethyl, Pr is n-propyl, iPr is isopropyl, cPr is cyclopropyl, Bu is butyl, iBu is isobutyl (CH2—CHMe2), tBu is tert-butyl, cBu is cyclobutyl, Pent is n-pentyl, cPent is cyclopentyl, cHex is cyclohexyl, Py is pyridyl, Bn is benzyl (CH2Ph), Ac is acetyl (CH3—(C═O)), tBOC is tert-butyloxycarbonyl (tBuO—(C═O)). EX means example.







TABLE 1







Tables of Examples


 








 















EX
X
R1
R2
E
F
G
R4
A—B—N[R6]—R5





16.
CH
Me
H
CH
CH
CH
2,6-diMe-4-OMe—Ph
(CH2)2—NH—(CH2)2—(3,4-diOMe—Ph)


17.
CH
Me
H
CH
CH
CH
2,4,6-triMe—Ph
(CH2)2—NH—(CH2)2—(3,4-diOMe—Ph)


18.
CH
Me
H
CH
CH
CH
2,4,6-triMe—Ph
(CH2)2—NH—(CH2)2—(4-OCF3—Ph)


19.
CH
Me
H
CH
CH
CH
2,4,6-triMe—Ph
(CH2)2—NH-cPent


20.
CH
Me
H
CH
CH
CH
2,4,6-triMe—Ph
(CH2)2—NH-cHex


21.
CH
Me
H
CH
CH
CH
2,4,6-triMe—Ph
(CH2)2—NH-(4-OH-cHex)


22.
CH
Me
H
CH
CH
CH
2,4,6-triMe—Ph
(CH2)2—NH-(tetrahydropyran-4-yl)


23.
CH
Me
H
CH
CH
CH
2,4,6-triMe—Ph
(CH2)2—NH-(1-(pyrimidin-2-yl)-piperidin-4-yl)


24.
CH
Me
H
CH
CH
CH
2,6-diCl-4-OMe—Ph
(CH2)2—NH-cPent


25.
CH
Me
H
CH
CH
CH
2,6-diCl-4-OMe—Ph
(CH2)2—NH-cHex


26.
CH
Me
H
CH
CH
CH
2,6-diCl-4-OMe—Ph
(CH2)2—NH-(4-OH-cHex)


27.
CH
Me
H
CH
CH
CH
2,6-diCl-4-OMe—Ph
(CH2)2—NH-(tetrahydropyran-4-yl)


28.
CH
Me
H
CH
CH
CH
2,6-diCl-4-OMe—Ph
(CH2)2—NH-(1-(pyrimidin-2-yl)-piperidin-4-yl)


29.
CH
Me
H
CH
CH
CH
2,6-diCl-4-OMe—Ph
(CH2)2—NH—(CH2)2—(3-OMe-4-EtO—Ph)


30.
N
Me
H
CH
CH
CH
2,4,6-triMe—Ph
(CH2)2—N(cPent)2


31.
N
Me
H
CH
CH
CH
2,4,6-triMe—Ph
(CH2)2—NH—(CH2)2—(3,4-diOMe—Ph)


32.
N
Me
H
CH
CH
CH
2,4,6-triMe—Ph
(CH2)2—NH—(CH2)2—(3-OMe-4-EtO—Ph)


33.
N
Me
H
CH
CH
CH
2,4,6-triMe—Ph
(CH2)2—NH-cHex


34.
N
Me
H
CH
CH
CH
2,4,6-triMe—Ph
(CH2)2—NH-(4-OH-cHex)


35.
N
Me
H
CH
CH
CH
2,4,6-triMe—Ph
(CH2)2—NH-(tetrahydropyran-4-yl)


36.
N
Me
H
CH
CH
CH
2,4,6-triMe—Ph
(CH2)2—NH-(1-(pyrimidin-2-yl)-piperidin-4-yl)


37.
N
Me
H
CH
CH
CH
2,6-diCl-4-OMe—Ph
(CH2)2—NH-cPent


38.
N
Me
H
CH
CH
CH
2,6-diCl-4-OMe—Ph
(CH2)2—NH-cHex


39.
N
Me
H
CH
CH
CH
2,6-diCl-4-OMe—Ph
(CH2)2—NH-(4-OH-cHex)


40.
N
Me
H
CH
CH
CH
2,6-diCl-4-OMe—Ph
(CH2)2—NH-(tetrahydropyran-4-yl)


41.
N
Me
H
CH
CH
CH
2,6-diCl-4-OMe—Ph
(CH2)2—NH-(1-(pyrimidin-2-yl)-piperidin-4-yl)


42.
N
Me
H
CH
CH
CH
2,6-diCl-4-OMe—Ph
(CH2)2—NH—(CH2)2—(3-OMe-4-EtO—Ph)


43.
N
Me
H
CH
CH
CH
2,6-diCl-4-OEt—Ph
(CH2)2—NH-cPent


44.
N
Me
H
CH
CH
CH
2,6-diCl-4-OEt—Ph
(CH2)2—NH-cHex


45.
N
Me
H
CH
CH
CH
2,6-diCl-4-OEt—Ph
(CH2)2—NH-(4-OH-cHex)


46.
N
Me
H
CH
CH
CH
2,6-diCl-4-OEt—Ph
(CH2)2—NH-(tetrahydropyran-4-yl)


47.
N
Me
H
CH
CH
CH
2,6-diCl-4-OEt—Ph
(CH2)2—NH-(1-(pyrimidin-2-yl)-piperidin-4-yl)


48.
N
Me
H
CH
CH
CH
2,6-diCl-4-OEt—Ph
(CH2)2—NH—(CH2)2—(3-OMe-4-EtO—Ph)
















TABLE 2













 













EX
X
R1
R2
R3
R16
R4





49.
CH
Me
H
Me
H
2,4,6-triMe—Ph


50.
CH
Me
H
Me
H
2,4,6-triMe—Ph


51.
CH
Me
H
Me
H
2,4,6-triMe—Ph


52.
CH
Me
H
Me
H
2,4;6-triMe—Ph


53.
CH
Me
H
Me
H
2,4,6-triMe—Ph


54.
CH
Me
H
Me
H
2,4,6-triMe—Ph


55.
CH
Me
H
Me
H
2,4,6-triMe—Ph


56.
CH
Me
H
Me
H
2,6-diCl-4-OMe—Ph


57.
CH
Me
H
Me
H
2,6-diCl-4-OMe—Ph


58.
CH
Me
H
Me
H
2,6-diCl-4-OMe—Ph


59.
CH
Me
H
Me
H
2,6-diCl-4-OMe—Ph


60.
CH
Me
H
Me
H
2,6-diCl-4-OMe—Ph


61.
CH
Me
H
Me
H
2,6-diCl-4-OEt—Ph


62.
CH
Me
H
Me
H
2,6-diCl-4-OEt—Ph


63.
CH
Me
H
Me
H
2,6-diCl-4-OEt—Ph


64.
CH
Me
H
Me
H
2,6-diCl-4-OEt—Ph


65.
CH
Me
H
Me
H
2,6-diCl-4-OEt—Ph


66.
N
Me
H
Me
H
2,4,-diMe-4-Br—Ph


67.
N
Me
H
Me
Me
2,4,6-triMe—Ph


68.
N
Me
H
Me
H
2,4,6-triMe—Ph


69.
N
Me
H
Me
Me
2,4,6-triMe—Ph


70.
N
Me
H
Me
H
2,4,6-triMe—Ph


71.
N
Me
H
Me
H
2,4,6-triMe—Ph
















TABLE 3













 














EX
X
W
R1
R2
R3
R4
A—B—N[R6]—R5





72.
N
NMe
Me
H
H
2,4,6-triMe—Ph
(CH2)2—NH—(CH2)2—(4-OMe—Ph)


73.
N
NMe
Me
H
H
2,4,6-triMe—Ph
(CH2)2—NH-cPent


74.
N
NMe
Me
H
H
2,4,6-triMe—Ph
(CH2)2—NH-cHex


75.
N
NMe
Me
H
H
2,4,6-triMe—Ph
(CH2)2—NH-(4-OH-cHex)


76.
N
NMe
Me
H
H
2,4,6-triMe—Ph
(CH2)2—NH-(tetrahydropyran-4-yl)


77.
N
NMe
Me
H
H
2,4,6-triMe—Ph
(CH2)2—NH-(1-(pyrimidin-2-yl)-piperidin-4-yl)


78.
N
NMe
Me
H
H
2,4,6-triMe—Ph
(CH2)2—NH—(CH2)2—(3-OMe-4-EtO—Ph)


79.
N
S
Me
H
H
2,4,6-triMe—Ph
(CH2)2—NH—(CH2)2—(4-OMe—Ph)


80.
N
S
Me
H
H
2,4,6-triMe—Ph
(CH2)2—NH-cPent


81.
N
S
Me
H
H
2,4,6-triMe—Ph
(CH2)2—NH-cHex


82.
N
S
Me
H
H
2,4,6-triMe—Ph
(CH2)2—NH-(4-OH-cHex)


83.
N
S
Me
H
H
2,4,6-triMe—Ph
(CH2)2—NH-(tetrahydropyran-4-yl)


84.
N
S
Me
H
H
2,4,6-triMe—Ph
(CH2)2—NH-(1-(pyrimidin-2-yl)-piperidin-4-yl)


85.
N
S
Me
H
H
2,4,6-triMe—Ph
(CH2)2—NH—(CH2)2—(3-OMe-4-EtO—Ph)
















TABLE 4













 













#
EX
X
R1
R2
R3
R4

















86.
N
Me
H
H
2,4,6-triMe—Ph



87.
N
Me
H
H
2,4,6-triMe—Ph



88.
N
Me
H
H
2,4,6-triMe—Ph



89.
N
Me
H
H
2,4,6-triMe—Ph



90.
N
Me
H
H
2,4,6-triMe—Ph



91.
N
Me
H
H
2,4,6-triMe—Ph



92.
N
Me
H
H
2,4,6-triMe—Ph

















TABLE 5













 


R1 is methyl












EX
X
R2
R3
R4
A—B—N[R6]—R5





93.
CH
H
Me
2,4,-diCl—Ph
(CH2)2—NH—(CH2)2—(2-OiPr-5-pyridyl)


94.
CH
H
Me
2,4,-diCl—Ph
(CH2)2—NH-cHex


95.
CH
H
Me
2,4-diCl—Ph
(CH2)2—NH—(CH2)2—((3-OMe-4-OiPr)-Ph)


96.
CH
H
Me
2,4,6-triMe-3-Py
(CH2)2—NH—(CH2)2—(3-OMe-4-iPrO—Ph)


97.
CH
H
Me
2,4,6-triMe—Ph
(CH2)2—NH-cBu


98.
CH
H
Me
2,4,6-triMe—Ph
(CH2)2—NH-cPent


99.
CH
H
Me
2,4,6-triMe—Ph
(CH2)2—NH-(4-OH-cHex)


100.
CH
H
Me
2,4,6-triMe—Ph
(CH2)2—NH-(tetahydropyran-4-yl)


101.
CH
H
Me
2,4,6-triMe—Ph
(CH2)2—NH-(1-pyrimidin-2-yl)-pipendin-4-yl)


102.
CH
H
Me
2,4,6-triMe—Ph
(CH2)2—NH—(CH2)2—(2-OiPr-5-pyridyl)


103.
CH
H
Me
2,4,6-triMe—Ph
(CH2)2—NH—(CH2)2—(3-OMe-4-EtO—Ph)


104.
CH
H
Me
2,4,6-triMe—Ph
(CH2)2—NH—(CH2)2—(3-OMe-4-iPrO—Ph)


105.
CH
H
Me
2,6-diCl-4-OMe—Ph
(CH2)2—NH-cPent


106.
CH
H
Me
2,6-diCl-4-OMe—Ph
(CH2)2—NH-cHex


107.
CH
H
Me
2,6-diCl-4-OMe—Ph
(CH2)2—NH-(4-OH-cHex)


108.
CH
H
Me
2,6-diCl-4-OMe—Ph
(CH2)2—NH-(tetrahydropyran-4-yl)


109.
CH
H
Me
2,6-diCl-4-OMe—Ph
(CH2)2—NH-(1-(pyrimidin-2-yl)-piperidin-4-yl)


110.
CH
H
Me
2,6-diCl-4-OMe—Ph
(CH2)2—NH—(CH2)2—(3-OMe-4-EtO—Ph)


111.
N
H
Me
2-Br-4-iPr—Ph
(CH2)2—NH-cPent


112.
N
H
Cl
2,4,6-triMe—Ph
(CH2)2—NH-cPent


113.
N
H
Me
2,4,6-triMe—Ph
(CH2)2—NH-cPent


114.
N
H
Me
2,4,6-triMe—Ph
(CH2)2—NH-cHex


115.
N
H
Me
2,4,6-triMe—Ph
(CH2)2—NH-(4-OH-cHex)


116.
N
H
Me
2,4,6-triMe—Ph
(CH2)2—NH-(tetrahydropyran-4-yl)


117.
N
H
Me
2,4,6-triMe—Ph
(CH2)2—NH-(1-(pyrimidin-2-yl)-piperidin-4-yl)


118.
N
H
Me
2,4,6-triMe—Ph
(CH2)2—NH—(CH2)2—(3-OMe-4-EtO—Ph)


119.
N
H
Me
2,4,6-triMe—Ph
(CH2)2—NH—(CH2)2—(3-OMe-4-iPrO—Ph)


120.
N
H
Cl
2,4,6-triMe—Ph
(CH2)2-NH-cPent


121.
N
H
Cl
2,4,6-triMe—Ph
(CH2)2—NH—(CH2)2—(3-OMe-4-EtO—Ph)


122.
N
H
Me
2,6-diCl-4-OMe—Ph
(CH2)2—NH-cPent


123.
N
H
Me
2,6-diCl-4-OMe—Ph
(CH2)2—NH-cHex


124.
N
N
Me
2,6-diCl-4-OMe—Ph
(CH2)2—NH-(4-OH-cHex)


125.
N
H
Me
2,6-diCl-4-OMe—Ph
(CH2)2—NH-(tetahydropyran-4-yl)


126.
N
H
Me
2,6-diCl-4-OMe—Ph
(CH2)2—NH—(CH2)2—(3-OMe-4-EtO—Ph)
















TABLE 6













 


R1 is mrthyl












EX
X1
R2
R3
R4
A—B—N[R6]—R5





127.
CH
H
Me
2,4,6-triMe—Ph
(CH2)2—NH-cPent


128.
CH
H
Me
2,4,6-triMe—Ph
(CH2)2—NH-cHex


129.
CH
H
Me
2,4,6-triMe—Ph
(CH2)2—NH-(4-OH-cHex)


130.
CH
H
Me
2,4,6-triMe—Ph
(CH2)2—NH-(tetrahydropyran-4-yl)


131.
CH
H
Me
2,4,6-triMe—Ph
(CH2)2—NH-(1-(pyrimidin-2-yl)-piperidin-4-yl)


132.
CH
H
Me
2,4,6-triMe—Ph
(CH2)2—NH—(CH2)2—(3-OMe-4-EtO—Ph)
















TABLE 7













 













EX
X
R1
R2
R15







133.
N
Me
H
Me



134.
N
Me
H
Me



135.
N
Me
H
Me



136.
N
Me
H
Me



137.
N
Me
H
Me



138.
N
Me
H
Me



139.
N
Me
H
Me



140.
N
Me
H
Me



141.
N
Me
H
Me



142.
N
Me
H
Me



143.
N
Me
H
Me



144.
N
Me
H
Me



145.
N
Me
H
Me



146.
N
Me
H
Me



147.
N
Me
H
Me



148.
N
Me
H
Me



149.
N
Me
H
Me

















TABLE 8













 













EX
X
R1
R2
R15
R4
A—B—N[R6]—R5





150.
N
Me
H
Me
2,4,6-triMe—Ph
(CH2)2—NH-cPent


151.
N
Me
H
Me
2,4,6-triMe—Ph
(CH2)2—NH-cHex


152.
N
Me
H
Me
2,4,6-triMe—Ph
(CH2)2—NH-(4-OH-cHex)


153.
N
Me
H
Me
2,4,6-triMe—Ph
(CH2)2—NH-(tetrahydropyran-4-yl)


154.
N
Me
H
Me
2,4,6-triMe—Ph
(CH2)2—NH-(1-(pyrimidin-2-yl)-piperidin-4-yl)


155.
N
Me
H
Me
2,4,6-triMe—Ph
(CH2)2—NH—(CH2)2—(3-OMe-4-EtO—Ph)


156.
N
Me
H
Me
2,6-diCl-4-OMe—Ph
(CH2)2—NH-cPent


157.
N
Me
H
Me
2,6-diCl-4-OMe—Ph
(CH2)2—NH-cHex


158.
N
Me
H
Me
2,6-diCl-4-OMe—Ph
(CH2)2—NH-(4-OH-cHex)


159.
N
Me
H
Me
2,6-diCl-4-OMe—Ph
(CH2)2—NH-(tetahydropyran-4-yl)


160.
N
Me
H
Me
2,6-diCl-4-OMe—Ph
(CH2)2—NH-(1-(pyrimidin-2-yl)-piperidin-4-yl)


161.
N
Me
H
Me
2,6-diCl-4-OMe—Ph
(CH2)2—NH—(CH2)2—(3-OMe-4-EtO—Ph)
















TABLE 9













 












EX
X
R1
R2
R4
A—B—N[R6]—R5





162.
CH
Me
H
2,4,6-triMe—Ph
(CH2)2—NH—(CH2)2-(3-OMe-4-iPrO—Ph)


163.
CH
Me
H
2,4,6-triMe—Ph
(CH2)2—NH-cBu


164.
CH
Me
H
2,4,6-triMe—Ph
(CH2)2—NH-cHex


165.
CH
Me
H
2,4,6-triMe—Ph
(CH2)2—NH-(4-OH-cHex)


166.
CH
Me
H
2,4,6-triMe—Ph
(CH2)2—NH-(tetrahydropyran-4-yl)


167.
CH
Me
H
2,4,6-triMe—Ph
(CH2)2—NH-(1-(pyrimidin-2-yl)-piperidin-4-yl)


168.
CH
Me
H
2,4,6-triMe—Ph
(CH2)2—NH—(CH2)2—(3-OMe-4-EtO—Ph)


169.
CH
Me
H
2,6-diCl-4-OMe—Ph
(CH2)2—NH-cPent


170.
CH
Me
H
2,6-diCl-4-OMe—Ph
(CH2)2—NH-cHex


171.
CH
Me
H
2,6-diCl-4-OMe—Ph
(CH2)2—NH-(4-OH-cHex)


172.
CH
Me
H
2,6-diCl-4-OMe—Ph
(CH2)2—NH-(tetrahydropyran-4-yl)


173.
CH
Me
H
2,6-diCl-4-OMe—Ph
(CH2)2—NH-(1-(pyrimidin-2-yl)-piperidin-4-yl)


174.
CH
Me
H
2,6-diCl-4-OMe—Ph
(CH2)2—NH—(CH2)2—(3-OMe-4-EtO—Ph)
















TABLE 10

























EX
X
R1
R2
R3
R4







175.
CH
Me
H
Me
2,4,6-triMe—Ph



176.
CH
Me
H
Me
2,4,6-triMe—Ph



177.
CH
Me
H
Me
2,4,6-triMe—Ph



178.
CH
Me
H
Me
2,4,6-triMe—Ph



179.
CH
Me
H
Me
2,4,6-triMe—Ph



180.
CH
Me
H
Me
2,4,6-triMe—Ph

















TABLE 11






















EX
X
R1
R2
R15





181.
CH
CH
H
Me


182.
CH
CH
H
Me


183.
CH
CH
H
Me


184.
CH
CH
H
Me


185.
CH
CH
H
Me


186.
N
CH
H
Me


187.
N
CH
H
Me


188.
N
CH
H
Me


189.
N
CH
H
Me


190.
N
CH
H
Me


191.
N
CH
H
Me
















TABLE 12

























EX
X
R1
R2
R3
R16
R4
A—B—N[R6]—R5





192.
CH
Me
H
Me
H
2,4,6-triMe—Ph
(CH2)2—NH-cPent


193.
CH
Me
H
Me
H
2,4,6-triMe-Ph
(CH2)2—NH-cHex


194.
CH
Me
H
Me
H
2,4,6-triMe-Ph
(CH2)2—NH-(4-OH-cHex)


195.
CH
Me
H
Me
H
2,4,6-triMe-Ph
(CH2)2—NH-(tetrahydropyran-4-yl)


196.
CH
Me
H
Me
H
2,4,6-triMe-Ph
(CH2)2—NH-(1-(pyrimidin-2-yl)-piperidin-4-yl)


197.
CH
Me
H
Me
H
2,6-diCl-4-OMe—Ph
(CH2)2—NH-cPent


198.
CH
Me
H
Me
H
2,6-diCl-4-OMe—Ph
(CH2)2—NH-cHex


199.
CH
Me
H
Me
H
2,6-diCl-4-OMe—Ph
(CH2)2—NH-(4-OH-cHex)


200.
CH
Me
H
Me
H
2,6-diCl-4-OMe—Ph
(CH2)2—NH-(tetrahydropyran-4-yl)


201.
CH
Me
H
Me
H
2,6-diCl-4-OMe—Ph
(CH2)2—NH-(1-(pyrimidin-2-yl)-piperidin-4-yl)


202.
N
Me
H
Me
Me
2,4,6-triMe—Ph
(CH2)2—NH—(CH2)2-(4-OMe—Ph)


203.
N
Me
H
Me
H
2,4,6-triMe—Ph
(CH2)2-NH-cPent


204.
N
Me
H
Me
Me
2,4,6-triMe—Ph
(CH2)2-NH-cPent


205.
N
Me
H
Me
H
2,4,6-triMe—Ph
(CH2)2-NH-Et


206.
N
Me
H
Me
H
2,4,6-triMe—Ph
(CH2)2—NH-(1-(pyrimidin-2-yl)-piperidin-4-yl)


207.
N
Me
H
Me
Me
2,4,6-triMe—Ph
(CH2)2—NH—(CH2)2-(3-OMe-4-EtO—Ph)
















TABLE 13

























EX
X
W
R1
R2
R3
R16
R4





208.
CH
NH
Me
H
Me
H
2,4,6-triMe—Ph


209.
CH
NH
Me
H
Me
H
2,4,6-triMe—Ph


210.
CH
NH
Me
H
Me
H
2,4,6-triMe—Ph


211.
CH
NH
Me
H
Me
H
2,4,6-triMe—Ph


212.
CH
NH
Me
H
Me
H
2,4,6-triMe—Ph


213.
CH
NH
Me
H
Me
H
2,4,6-triMe—Ph


214.
CH
NH
Me
H
Me
H
2,6-diCl-4-OMe—Ph


215.
CH
NH
Me
H
Me
H
2,6-diCl-4-OMe—Ph


216.
CH
NH
Me
H
Me
H
2,6-diCl-4-OMe—Ph


217.
CH
NH
Me
H
Me
H
2,6-diCl-4-OMe—Ph


218.
CH
NH
Me
H
Me
H
2,6-diCl-4-OMe—Ph


219.
N
NH
Me
H
Me
H
2,4,6-triMe—Ph


220.
N
NH
Me
H
Me
H
2,4,6-triMe—Ph


221.
N
NH
Me
H
Me
H
2,4,6-triMe—Ph


222.
N
NH
Me
H
Me
H
2,4,6-triMe—Ph


223.
N
NH
Me
H
Me
H
2,4,6-triMe—Ph


224.
N
NH
Me
H
Me
H
2,4,6-triMe—Ph
















TABLE 14
























EX
X
R1
R2
I
J
K





225.
CH
Me
H
CH
CH
CH


226.
CH
Me
H
CH
CH
CH


227.
CH
Me
H
CH
CH
CH


228.
CH
Me
H
CH
CH
CH


229.
CH
Me
H
CH
CH
CH


230.
CH
Me
H
CH
CH
CH


231.
CH
Me
H
CH
CH
CH
















TABLE 15

























EX
X
Y
R1
R2
Q
R4
A—B—N[R6]—R5





232.
CH
CMe
Me
H
O
2,4,6-triMe—Ph
(CH2)2—NcPent-(tetrahydropyran-4-yl)


233.
CH
CMe
Me
H
O
2,4,6-triMe—Ph
(CH2)2—NH-(1-(pyrimidin-2-yl)-piperidin-4-yl)


234.
CH
CMe
Me
H
O
2,4,6-triMe—Ph
(CH2)2—NH-cPent


235.
CH
CMe
Me
H
O
2,4,6-triMe—Ph
(CH2)3—NH-(1-Ac-piperidin-4-yl)


236.
CH
CMe
Me
H
O
2,4,6-triMe—Ph
(CH2)3—NH-(1,2,3,4-tetrahydro-naphthalen-2-yl)


237.
CH
CMe
Me
H
O
2,4,6-triMe—Ph
(CH2)4—NH-(1-(pyrimidin-2-yl)-piperidin-4-yl)


238.
CH
CMe
Me
H
O
2,4,6-triMe—Ph
(CH2)4—NH-(1-Ac-piperidin-4-yl)


239.
CH
CMe
Me
H
O
2,4,6-triMe—Ph
(CH2)4—NH-(1,2,3,4-tetrahydro-naphthalen-2-yl)


240.
CH
CMe
Me
H
O
2,4,6-triMe—Ph
CH2—CHMe—NH-(1-(pyrimidin-2-yl)-piperidin-4-yl)


241.
CH
CMe
Me
H
O
2,4,6-triMe—Ph
(CH2)2—NH-cHex


242.
CH
CMe
Me
H
O
2,4,6-triMe—Ph
(CH2)2—NH-(4-OH-cHex)


243.
CH
CMe
Me
H
O
2,4,6-triMe—Ph
(CH2)2—NH-(tetrahydropyran-4-yl)


244.
N
CH
Me
H
NH
2,4,6-triMe—Ph
(CH2)2—NH-cPent


245.
N
CH
Me
H
NH
2,4,6-triMe—Ph
(CH2)2—NH-cHex


246.
N
CH
Me
H
NH
2,4,6-triMe—Ph
(CH2)2—NH-(4-OH-cHex)


247.
N
CH
Me
H
NH
2,4,6-triMe—Ph
(CH2)2—NH-(tetrahydropyran-4-yl)


248.
N
CH
Me
H
NH
2,4,6-triMe—Ph
(CH2)2—NH-(1-(pyrimidin-2-yl)-piperidin-4-yl)


249.
CH
N
Me
H
NEt
2,4,6-triMe—Ph
(CH2)2—NH-cPent


250.
CH
N
Me
H
NEt
2,4,6-triMe—Ph
(CH2)2—NH-cHex


251.
CH
N
Me
H
NEt
2,4,6-triMe—Ph
(CH2)2—NH-(4-OH-cHex)


252.
CH
N
Me
H
NEt
2,4,6-triMe—Ph
(CH2)2—NH-(tetrahydropyran-4-yl)


253.
CH
N
Me
H
NEt
2,4,6-triMe—Ph
(CH2)2—NH-(1-(pyrimidin-2-yl)-piperidin-4-yl)


254.
CH
N
Me
H
NEt
2,4,6-triMe—Ph
(CH2)2—NH—(CH2)2-(3-OMe-4-EtO—Ph)


255.
N
N
Me
H
NEt
2,4,6-triMe—Ph
(CH2)2—NH-cPent


256.
N
N
Me
H
NEt
2,4,6-triMe—Ph
(CH2)2—NH-cHex


257.
N
N
Me
H
NEt
2,4,6-triMe—Ph
(CH2)2—NH-(4-OH-cHex)


258.
N
N
Me
H
NEt
2,4,6-triMe—Ph
(CH2)2—NH-(tetrahydropyran-4-yl)


259.
N
N
Me
H
NEt
2,4,6-triMe—Ph
(CH2)2—NH-(1-(pyrimidin-2-yl)-piperidin-4-yl)


260.
N
N
Me
H
NEt
2,4,6-triMe—Ph
(CH2)2—NH—(CH2)2-(3-OMe-4-EtO—Ph)









Example 261
Characterization of NPY Receptor Interactions and In Vivo Function
A. Assay for Human NPY1 Receptor Binding Activity: Compounds are assayed for activity using the following method: A cDNA encoding human NPY1 (SEQ ID NO:1) is ligated in the appropriate orientation for expression into the commercial expression vector pBacPAK9 (Clontech, Palo Alto, Calif.) for expression in SF9 cells. Each Baculoviral expression vector is co-transfected along with BACULOGOLD DNA (BD PharMingen, San Diego, Calif.) into Sf9 cells. The Sf9 cell culture supernatant is harvested three days post-transfection. The recombinant virus-containing supernatant is serially diluted in Hink's TNM-FH insect medium (JRH Biosciences, Kansas City) supplemented Grace's salts and with 4.1 mM L-Gln, 3.3 g/L LAH, 3.3 g/L ultrafiltered yeastolate and 10% heat-inactivated fetal bovine serum (hereinafter “insect medium”) and plaque assayed for recombinant plaques. After four days, recombinant plaques are selected and harvested into 1 ml of insect medium for amplification. Each 1 ml volume of recombinant baculovirus (at passage 0) is used to infect a separate T25 flask containing 2×106 Sf9 cells in 5 mL of insect medium. After five days of incubation at 27° C., supernatant medium is harvested from each of the T25 infections for use as passage 1 inoculum. Recombinant baculoviral clones are then subjected to a second round of amplification, using 1 ml of passage 1 stock to infect 1×108 cells in 100 ml of insect medium divided into 2 T175 flasks. Forty-eight h post infection, passage 2 medium is harvested from each 100 ml prep and plaque assayed for titer. The cell pellets from the second round of amplification are assayed for affinity binding of radiolabeled ligand (see below) to verify recombinant receptor expression. A third round of amplification is then initiated using an M.O.I. of 0.1 to infect a liter of Sf9 cells. Forty h post-infection the supernatant medium is harvested to yield passage 3 baculoviral stock and the cell pellet assayed for affinity binding. Titer of the passage 3 baculoviral stock is determined by plaque assay and an M.O.I. and Incubation Time Course experiment is carried out to determine conditions for optimal receptor expression.
Log-phase Sf9 cells are infected with stocks of recombinant baculovirus encoding the proteins of interest (e.g., human NPY1 and three g-proteins), followed by culturing in insect medium at 27° C. 72 h post-infection, a sample of cell suspension is analyzed for viability by trypan blue dye exclusion, and the remaining Sf9 cells are harvested via centrifugation (3000 rpm/10 minutes/4° C.).
B. Preparation of purified membranes: Sf9 cell pellets are resuspended in homogenization buffer (10 mM HEPES, 250 mM sucrose, 0.5 □g/ml leupeptin, 2 □g/ml Aprotinin, 200 □M PMSF, and 2.5 mM EDTA, pH 7.4) and homogenized using a POLYTRON homogenizer (setting 5 for 30 seconds). The homogenate is centrifuged (536×g/10 minutes/4° C.) to pellet the nuclei. The supernatant containing isolated membranes is decanted to a clean centrifuge tube, centrifuged (48,000×g/30 minutes, 4° C.) and resuspended in 30 ml, or preferably 20 ml of homogenization buffer. This centrifugation and resuspension step is repeated twice. The final pellet is resuspended in ice cold Dulbecco's PBS containing 5 mM EDTA and stored in frozen aliquots until needed at −80° C. The protein concentration of the resulting membrane preparation is measured using the Bradford protein assay (Bio-Rad Laboratories, Hercules, Calif.). By this measure, a 1-liter culture of cells typically yields 50–100 mg of total membrane protein.
CO-infection for GTPγ35S binding assay: Four baculoviral expression vector stocks are used to infect a culture of Sf9 cells with an MOI of 1:1:1:1. These four consisted of one vector encoding the human NPY1 receptor and a different commercially obtained baculoviral expression vector stock encoding each of the three subunits of a heterotrimeric G-protein, in particular, the G-protein-encoding virus stocks are obtained from BIOSIGNAL Inc., Montreal, and are 1) a Gα G-protein subunit-encoding virus stock (either the rat Gαi2 G-protein-encoding virus stock BIOSIGNAL #V5J008 or the rat Gα0 G-protein-encoding virus stock BIOSIGNAL #V5H010), 2) a bovine β1 G-protein-encoding virus stock (BIOSIGNAL #V5H012), and 3) a human γ2 G-protein-encoding virus stock (BIOSIGNAL #V6B003). Agonist-stimulated GTPγ35S binding on purified membranes is assessed using hNPY 1–36 (American Peptide Co., Sunnyvale, Calif.) as agonist in order to ascertain functional activity as measured by GTPγ35S binding.
GTPγ35S binding assay: Purified Sf9 cell membranes are resuspended by Dounce homogenization (tight pestle) in GTPγ35S binding assay buffer (50 mM Tris pH 7.0, 120 mM NaCl, 2 mM MgCl2, 2 mM EGTA, 0.1% BSA, 0.1 mM bacitracin, 100 KIU/mL Aprotinin, 5 μM GDP) and added to reaction tubes at a concentration of 30 μg/reaction tube. After adding increasing doses of the agonist hNPY 1–36 (American Peptide Co., Sunnyvale, Calif.), reactions are initiated by the addition of 100 pM GTPγ35S. Following a 30-minute incubation at ambient temperature, the reactions are terminated by vacuum filtration over GF/C filters (presoaked in wash buffer, 0.1% BSA) followed by washing with ice-cold wash buffer (50 mM Tris pH 7.0, 120 mM NaCl).
Bound GTPγ35S is determined by liquid scintillation spectrometry of the washed filters. Nonspecific binding is determined using 10 mM GTPγS. Data are generally expressed as % maximal response and are derived by determining the maximal agonist stimulated % above basal stimulation. Computer analysis may be conveniently used to calculate estimated EC50, IC50 and Ki values from GTPγ35S binding experiment data, e.g., using SigmaPlot software. The binding affinity for the preferred compounds of the invention, expressed as Ki values, ranges from about 0.1 nanomolar to about 5 micromolar. Particularly preferred compounds yield a Ki value of less than 100 nanomolar, most preferably less than 10 nanomolar.
Assay for affinity binding of radiolabeled ligand: Purified membranes are washed with PBS and re-suspended by gentle pipetting in binding buffer (50 mM Tris(HCl), 5 mM KCl, 120 mM NaCl, 2 mM CaCl2, 1 mM MgCl2, 0.1% bovine serum albumin (BSA), pH 7.4). Membranes (5 μg) are added to siliconized (Sigmacote, Sigma) polypropylene tubes in addition to 0.050 nM [125I]NPY (porcine, New England Nuclear Corp., Boston, Mass.) for competition analysis or 0.010–0.500 nM [125I]NPY (porcine) for saturation analysis. For evaluation of guanine nucleotide effects on receptor affinity, GTP is added at a final concentration of 100 μM. Cold displacers are added at concentrations ranging from 10–12 M to 10–6 M to yield a final volume of 0.250 mL. Nonspecific binding is determined in the presence of 1 μM NPY (human, American Peptide Co., Sunnyvale, Calif.) and accounts for less than 10% of total binding. Following a 2-hour incubation at ambient temperature, the reaction is terminated by rapid vacuum filtration. Samples are filtered over presoaked GF/C Whatman filters (1.0% polyethyleneimine for 2 hours) and rinsed 2 times with 5 mL cold binding buffer lacking BSA. Remaining bound radioactivity is measured by gamma counting. To estimate the Bmax, Kd and Ki, the results of binding experiments are analyzed using SigmaPlot software (SPSS Science, Chicago, Ill.). The binding affinity for the compounds of the invention, expressed as a Ki value, ranges from about 0.1 nanomolar to about 10 micromolar. The most preferred compounds of the invention have a Ki of less than 100 nanomolar and a binding selectivity of >100-fold relative to other G-protein coupled receptors, including NPY5 and CRF1 receptors.
C. In Vivo Analysis—Food Deprivation
Subjects. Experimentally naive and experienced male Sprague-Dawley rats (Sasco, St. Louis, Mo.) weighing 210–300 g at the beginning of the experiment are used. Animals are triple-housed in stainless steel hanging cages in a temperature (22 C±2) and humidity (40–70% RH) controlled animal facility with a 12:12 hour light-dark cycle. Food (Standard Rat Chow, PMI Feeds Inc., #5012) and water are available ad libitum.
Apparatus. Consumption data is collected while the animals are housed in Nalgene Metabolic cages (Model #650–0100). Each cage is comprised of subassemblies made of clear polymethlypentene (PMP), polycarbonate (PC), or stainless steel (SS). All parts disassemble for quick and accurate data collection and for cleaning. The entire cylinder-shaped plastic and SS cage rests on a SS stand and houses one animal.
The animal is contained in the round Upper Chamber (PC) assembly (12 cm high and 20 cm in diameter) and rests on a SS floor. Two subassemblies are attached to the Upper Chamber. The first assembly consists of a SS feeding chamber (10 cm long, 5 cm high and 5 cm wide) with a PC feeding drawer attached to the bottom. The feeding drawer has two compartments: a food storage compartment with the capacity for approximately 50 g of pulverized rat chow, and a food spillage compartment. The animal is allowed access to the pulverized chow by an opening in the SS floor of the feeding chamber. The floor of the feeding chamber does not allow access to the food dropped into the spillage compartment.
The second assembly includes a water bottle support, a PC water bottle (100 ml capacity) and a graduated water spillage collection tube. The water bottle support funnels any spilled water into the water spillage collection tube.
The lower chamber consists of a PMP separating cone, PMP collection funnel, PMP fluid (urine) collection tube, and a PMP solid (feces) collection tube. The separating cone is attached to the top of the collection funnel, which in turn is attached to the bottom of the Upper Chamber. The urine runs off the separating cone onto the walls of the collection funnel and into the urine collection tube. The separating cone also separates the feces and funnels it into the feces collection tube.
Food consumption, water consumption, and body weight may be measured with an Ohaus Portable Advanced scale (±0.1 g accuracy).
Procedure. Prior to the day of testing, animals are habituated to the testing apparatus by placing each animal in a Metabolic cage for 1 hour. On the, day of the experiment, animals that have been food deprived the previous night are weighed and assigned to treatment groups. Assignments are made using a quasi-random method utilizing the body weights to assure that the treatment groups had similar average body weight. Animals are then administered either vehicle (0.5% methyl cellulose) or drug (a compound of the invention). At that time, the feeding drawer is filled with pulverized chow, the filled water bottle, and the empty urine and feces collection tubes are weighed. Two h after drug treatment, each animal is weighed and placed in a Metabolic Cage. Following a one-hour test session, animals are removed and body weight obtained. The food and water containers are then weighed and the food and water consumption data recorded.
Drugs. Drug suspended in vehicle, or vehicle alone as a control, is administered orally (PO) using a gavage tube connected to a 3 or 5 ml syringe at a volume of 10 ml/kg. Drug is made into a homogenous suspension by stirring and ultrasonicating for at least 1 hour prior to dosing.
Statistical Analyses. The means and standard errors of the mean (SEM) for food consumption, water consumption, and body weight change are obtained. One-way analysis of variance using Systat (5.2.1) is used to test for group differences. A significant effect is defined as having a p value of <0.05.
The following parameters are defined: Body weight change is the difference between the body weight of the animal immediately prior to placement in the metabolic cage and its body weight at the end of the one hour test session. Food consumption is the difference in the weight of the food drawer prior to testing and the weight following the 1-hour test session. Water consumption is the difference in the weight of the water bottle prior to testing and the weight following the 1-hour test session. Preferred compounds of the invention reduce food intake and body weight gain, preferably to a statistically significant degree as determined by standard parametric analysis such as a student's T-test.
Example 262
Preparation of Radiolabeled Probe Compounds of the Invention
The compounds of the invention are prepared as radiolabeled probes by carrying out their synthesis using precursors comprising at least one atom that is a radioisotope. The radioisotope is preferably selected from of at least one of carbon (preferably 14C), hydrogen (preferably 3H), sulfur (preferably 35S), or iodine (preferably 125I). Such radiolabeled probes are conveniently synthesized by a radioisotope supplier specializing in custom synthesis of radiolabeled probe compounds. Such suppliers include Amersham Corporation, Arlington Heights, Ill.; Cambridge Isotope Laboratories, Inc. Andover, Mass.; SRI International, Menlo Park, Calif.; Wizard Laboratories, West Sacramento, Calif.; ChemSyn Laboratories, Lexena, Kans.; American Radiolabeled Chemicals, Inc., St. Louis, Mo.; and Moravek Biochemicals Inc., Brea, Calif.
Tritium labeled probe compounds are also conveniently prepared catalytically via platinum-catalyzed exchange in tritiated acetic acid, acid-catalyzed exchange in tritiated trifluoroacetic acid, or heterogeneous-catalyzed exchange with tritium gas. Such preparations are also conveniently carried out as a custom radiolabeling by any of the suppliers listed in the preceding paragraph using the compound of the invention as substrate. In addition, certain precursors may be subjected to tritium-halogen exchange with tritium gas, tritium gas reduction of unsaturated bonds, or reduction using sodium borotritide, as appropriate.
Example 263
Receptor Autoradiography
Receptor autoradiography (receptor mapping) is carried out in vitro as described by Kuhar in sections 8.1.1 to 8.1.9 of Current Protocols in Pharmacology (1998) John Wiley & Sons, New York, using radiolabeled compounds of the invention prepared as described in the preceding Example.
The invention and the manner and process of making and using it, are now described in such full, clear, concise and exact terms as to enable any person skilled in the art to which it pertains, to make and use the same. It is to be understood that the foregoing describes preferred embodiments of the present invention and that modifications may be made therein without departing from the spirit or scope of the present invention as set forth in the claims. To particularly point out and distinctly claim the subject matter regarded as invention, the following claims conclude this specification.

## Claims

1. A compound selected from Formulae II, IV, V, VII–IX and XI










or a pharmaceutically acceptable salt thereof, wherein
X is C (carbon);
R1 is selected from H, C1–C6 alkyl, C3–C10 cycloalkyl, (C3–C10 cycloalkyl) C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, cyano, halo, C1–C6 haloalkyl, OR7, C1–C6 alkyl-OR7; C1–C6 cyanoalkyl, NR8R9, C1–C6 alkyl-NR8R9;
R2 is H,
C1–C6 alkyl which optionally forms a C3–C6 aminocarbocycle or a C2–C5 aminoheterocycle with A or B, each optionally substituted at each occurrence with R7, C3–C10 cycloalkyl, or
(C3–C10 cycloalkyl) C1–C6 alkyl;
or R2 and R6 jointly form with the 2 nitrogen atoms to which they are bound a C2–C5 aminoheterocycle optionally substituted at each position with R7;

A is (CH2)m where m is 1, 2 or 3 and is optionally mono- or di-substituted on each occurrence with C1–C6 alkyl, C3–C10 cycloalkyl, (C3–C10 cycloalkyl) C1–C6 alkyl, C1–C6 alkenyl, C1–C6 alkynyl, cyano, halo, C1–C6 haloalkyl, OR7, C1–C6 alkyl-OR7; C1–C6 cyanoalkyl, NR8R9, C1–C6 alkyl-NR8R9, or
A and B jointly form a C3–C6 carbocycle, optionally substituted at each position with R7 or,
A and R2 jointly form a C3–C6 aminocarbocycle or a C2–C5 aminoheterocycle optionally substituted at each position with R7;
B is (CH2)n where n is 1, 2 or 3 and is optionally mono- or di-substituted on each carbon atom with C1–C6 alkyl, C3–C10 cycloalkyl, (C3–C10 cycloalkyl) C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, cyano, halo, C1–C6 haloalkyl, OR7, C1–C6 alkyl-OR7; C1–C6 cyanoalkyl, NR8R9, C1–C6 alkyl-NR8R9, or
B and R2 jointly form a C3–C6 aminocarbocycle or a C2–C5 aminoheterocycle optionally substituted at each carbon occurrence with R7;
R3 and R16 are independently selected at each occurrence from H, C1–C6 alkyl, C3–C10 cycloalkyl, (C3–C10 cycloalkyl) C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, cyano, halogen, C1–C6 haloalkyl, OR7, C1–C6 alkyl-OR7, C1–C6 cyanoalkyl, NR8R9, C1–C6 alkyl-NR8R9;
R4 is selected from aryl or heteroaryl, each optionally substituted with 1 to 5 substituents independently selected at each occurrence from C1–C6 alkyl, C3–C10 cycloalkyl, C3–C10 cycloalkenyl, (C3–C10 cycloalkyl) C1–C6 alkyl, C1–C6 alkenyl, halogen, C1–C6 haloalkyl, trifluromethylsulfonyl, OR7, C1–C6 alkyl-OR7, NR8R9, C1–C6 alkyl-NR8R9, CONR8R9, C1–C6 alkyl-CONR8R9, COOR7, C1–C6 alkyl-COOR7, CN, C1–C6 alkyl-CN, SO2NR8R9, SO2R7, aryl, heteroaryl, heterocycloalkyl, 3-, 4-, or 5-(2-oxo-1,3-oxazolidinyl), with the proviso that at least one of the positions ortho or para to the point of attachment of the aryl or heteroaryl ring to the heterocyclic core is substituted;
R5 is selected from:
C1–C6 alkyl, (C3–C10 cycloalkyl) C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, each of which is substituted with 1 to 5 groups independently selected at each occurrence from halo, C1–C2 haloalkyl, OR7, cyano, NR8R9, CONR8R9, COOR7, SO2NR8R9, SO2R7, NR11COR12, NR11SO2R7;

C1–C6 arylalkyl, C1–C6 heteroarylalkyl, C5–C8 arylcycloalkyl, or C5–C8 heteroarylcycloalkyl, where aryl is phenyl or naphthyl, and heteroaryl is 2-,3-, or 4-pyridyl, 2-, 4- or 5-pyrimidinyl, triazinyl, 1-, 2- or 4-imidazolyl, 2-, 4-, or 5-oxazolyl, isoxazolyl, indolyl, pyrazolyl, quinolyl, isoquinolyl, 2-, 4-, or 5-thiazolyl, benzothiadiazolyl, 1-, 3- or 4-pyrazolyl, 1-, 3- or 4-triazolyl, 2-triazinyl, 2-pyrazinyl, 2-, or 3-furanyl, 2-, or 3-thienyl, 2-, or 3-benzothienyl, or 1-, 2- or 5-tetrazolyl, each of which is optionally substituted with 1 to 5 substituents independently selected at each occurrence from C1–C6 alkyl, C3–C10 cycloalkyl, C3–C10 cycloalkenyl, (C3–C10 cycloalkyl) C1–C6 alkyl, C1–C6 alkenyl, halogen, C1–C6 haloalkyl, trifluromethylsulfonyl, OR7, NR8R9, C1–C6 alkyl-OR7, C1–C6 alkyl-NR8R9, CONR8R9, COOR7, CN, SO2NR8R9, SO2R7, aryl, heteroaryl, heterocycloalkyl, 3-, 4-, or 5-(2-oxo-1,3-oxazolidinyl), wherein 2 adjacent alkyl substituents can optionally form together a C3–C10 cycloalkyl ring, a C3–C10 cycloalkenyl ring or a heterocycloalkyl ring;
C3–C10 cycloalkyl, (C3–C10 cycloalkyl) C1–C6 alkyl, C3–C10 cycloalkenyl, C2–C6 alkenyl, C2–C6 alkynyl, each of which is optionally with 1 to 6 substituents independently selected at each occurrence from C1–C6 alkyl, C3–C10 cycloalkyl, C3–C10 cycloalkenyl, (C3–C10 cycloalkyl) C1–C6 alkyl, C1–C6 alkenyl, halogen, C1–C6 haloalkyl, OR7, NR8R9, with the proviso that when two OR7 or NR8R9 substituents are geminally located on the same carbon R7 is not H and they can form together a C2–C4 ketal, oxazoline, oxazolidine, imidazoline, or imidazolidine heterocycle, C1–C6 alkyl-OR7, C1–C6 alkyl-NR8R9, CONR8R9, COOR7, CN, oxo, hydroximino, C1–C6 alkoximino, SO2NR8R9, SO2R7, heterocycloalkyl, aryl, heteroaryl, where aryl or heteroaryl is optionally substituted with 1 to 5 substituents independently selected at each occurrence from C1–C6 alkyl, C3–C10 cycloalkyl, C3–C10 cycloalkenyl, (C3–C10 cycloalkyl) C1–C6 alkyl, C1–C6 alkenyl, halogen, C1–C6 haloalkyl, trifluromethylsulfonyl, OR7, NR8R9, C1–C6 alkyl-OR7, C1–C6 alkyl-NR8R9, CONR8R9, COOR7, CN, SO2NR8R9, SO2R7, aryl, heteroaryl, heterocycloalkyl, 3-, 4-, or 5-(2-oxo-1,3-oxazolidinyl), wherein 2 adjacent alkyl substituents can optionally form together a C3–C10 cycloalkyl ring, C3–C10 cycloalkenyl ring or a heterocycloalkyl ring;
aryl or heteroaryl, optionally substituted with 1 to 5 substituents independently selected at each occurrence from halogen, C1–C6 alkyl, C3–C10 cycloalkyl, C3–C10 cycloalkenyl, (C3–C10 cycloalkyl) C1–C6 alkyl, C1–C6 alkenyl, halogen, C1–C6 haloalkyl, trifluromethylsulfonyl, OR7, NR8R9, C1–C6 alkyl-OR7, C1–C6 alkyl-NR8R9, CONR8R9, COOR7, CN, SO2NR8R9, SO2R7, aryl, heteroaryl, heterocycloalkyl, 3-, 4-, or 5-(2-oxo-1,3-oxazolidinyl), wherein 2 adjacent alkyl substituents can optionally form together a C3–C10 cycloalkyl ring, a C3–C10 cycloalkenyl ring or a heterocycloalkyl ring; or
3- or 4-piperidinyl, 3-pyrrolidinyl, 3- or 4-tetrahydropyranyl, 3-tetrahydrofuranyl, 3- or 4-tetrahydropyranyl, 3-tetrahydrofuranyl, 3- or 4-tetrahydrothiopyranyl, 3- or 4-(1,1-dioxo)tetrahydrothiopyranyl, 1-azabicyclo[4.4.0]decyl, 8-azabicyclo[3.2.1]octanyl, norbornyl, quinuclidinyl, each optionally substituted with 1 to 5 substituents independently selected at each occurrence from R7, C1–C6 alkyl-OR7, C1–C6 alkyl-NR8R9, CONR8R9, COOR7;
R6 is selected from H, C1–C6 alkyl, C3–C10 cycloalkyl, (C3–C10 cycloalkyl) C1–C6 alkyl, C2–C4 alkenyl, C1–C6 arylalkyl, C1–C6 heteroarylalkyl where aryl or heteroaryl are optionally substituted with 1 to 5 substituents independently selected at each occurrence from halogen, C1–C6 haloalkyl, OR13, NR8R9, C1–C6 alkyl-OR13, C1–C6 alkyl-NR8R9, CONR8R9, COOR7, CN, SO2NR8R9, SO2R7,
or R6 and R2, as mentioned above, jointly form, with the 2 nitrogen atoms to which they are bound, a C2–C5 aminoheterocycle optionally substituted at each position with R7;

R7 is H, C1–C6 alkyl, C3–C10 cycloalkyl, C3–C10 cycloalkenyl, (C3–C10 cycloalkyl) C1–C6 alkyl, C1–C3 haloalkyl,
or heterocycloalkyl, C1–C8 alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, C1–C8 alkanoyl, aroyl, heteroaroyl, aryl, heteroaryl, C1–C6 arylalkyl or C1–C6 heteroarylalkyl each optionally substituted with 1 to 5 substituents independently selected at each occurrence from halogen, C1–C6 haloalkyl, OR13, NR8R9, C1–C6 alkyl-OR13, C1–C6 alkyl-NR8R9, CONR8R9, COOR13, CN, SO2NR8R9, SO2R13, with the proviso that when R7 is SO2R13, R13 cannot be H;

R8 and R9 are independently selected at each occurrence from H, C1–C6 alkyl, C3–C10 cycloalkyl, C2–C6 alkenyl, C3–C10 cycloalkenyl, C2–C6 alkynyl, heterocycloalkyl, C1–C8 alkanoyl, aroyl, heteroaroyl, aryl, heteroaryl, C1–C6 arylalkyl or C1–C6 heteroarylalkyl, or R8 and R9, taken together, can form a C3–C6 aminocarbocycle or a C2–C5 aminoheterocycle each optionally substituted at each occurrence with C1–C6 alkyl, C3–C10 cycloalkyl, C3–C10 cycloalkenyl, (C3–C10 cycloalkyl) C1–C6 alkyl, C1–C3 haloalkyl, or heterocycloalkyl, C1–C8 alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, C1–C8 alkanoyl, aroyl, heteroaroyl, aryl, heteroaryl, C1–C6 arylalkyl or C1–C6 heteroarylalkyl;
R11 is selected from H, C1–C6 alkyl, C3–C10 cycloalkyl, (C3–C10 cycloalkyl) C1–C6 alkyl;
R12 is selected from H, aryl, heteroaryl, C1–C6 alkyl, C3–C10 cycloalkyl, (C3–C10 cycloalkyl) C1–C6 alkyl, optionally substituted with OR7, NR8R9, C3–C6 aminocarbocycle, or C2–C5 aminoheterocycle;
R13 is independently selected at each occurrence from H, C1–C6 alkyl, C3–C10 cycloalkyl, (C3–C10 cycloalkyl) C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 haloalkyl, with the proviso that for SO2NR8R9, SO2R13, R13 cannot be H; and
R15 is selected at each occurrence from H, C1–C6 alkyl, C3–C10 cycloalkyl, (C3–C10 cycloalkyl) C1–C6 alkyl, C2–C6 alkenyl, C2–C6 alkynyl, C2–C6 alkyl-OR7, C2–C6 cyanoalkyl, C2–C6 alkyl-NR8R9.