US 7,598,255 B2Grant

Pyrimidine compounds as serotonin receptor modulators

Issue Date:2009-10-06

•11 Claims

Abstract

Certain pyrimidine-containing compounds are serotonin receptor modulators useful in the treatment of serotonin-mediated diseases.

Metadata

Assignee

Janssen Pharmaceutica NV

Inventor

Curt A. Dvorak

Application Information

Application Number:US 11/460,294

Filing Date:2006-07-27

Priority Date:2005-08-04

Art Unit:1624

Classifications

IPC:

A61K31/519C07D471/04C07D487/04C07D491/04C07D239/28C07D239/72C07D239/42C07D487/08C07D401/04C07D403/04C07D413/04C07D417/04C07D419/04

Patent Drawings

This patent does not have any drawings.

Description

RELATED APPLICATIONS

[0001] The present application claims the benefit under 35 U.S.C. §119(e) of provisional application Ser. No. 60/705,719, filed on Aug. 4, 2005, which is incorporated herein in its entirety.

FIELD OF THE INVENTION

[0002] There is provided by the present invention compounds that are serotonin receptor modulators. More particularly, there is provided by the present invention pyrimidine compounds that are serotonin receptor modulators useful for the treatment of disease states mediated by serotonin receptor activity.

BACKGROUND OF THE INVENTION

[0003] Serotonin (5-hydroxytryptamine, 5-HT) is a major neurotransmitter eliciting effects via a multiplicity of receptors. To date, at least fifteen different 5-HT receptors have been identified, largely as the result of cloning cDNA's, and these receptors have been grouped into seven families (5-HT₁through 5-HT₇) (Hoyer, D. et al. Pharmacol. Biochem. Behav. 2002, 71, 533-554). Fourteen of the fifteen cloned 5-HT receptors are expressed in the brain. 5-HT is implicated in many disease states, particularly conditions of the central nervous system including; depression, anxiety, schizophrenia, eating disorders, obsessive compulsive disorder, learning and memory dysfunction, migraine, chronic pain, sensory perception, motor activity, temperature regulation, nociception, sexual behavior, hormone secretion, and cognition. The identification of multiple 5-HT receptors has provided the opportunity to characterize existing therapeutic agents thought to act via the serotonergic system. Consequently, this has led to the realization that many drugs have non-selective properties (Roth, B. L. et al. Neuroscientist 2000, 6(4), 252-262). For example, the antipsychotic drugs, clozapine, chlorpromazine, haloperidol and olanzapine exhibit affinities for multiple serotonin receptors in addition to other families of receptors. Similar behavior has been noted for antidepressants, including imipramine, nortriptaline, fluoxetine and sertraline. Similarly, the anti-migraine agent sumatriptan exhibits high affinity for several serotonin receptors. While the lack of selectivity often contributes to a favorable therapeutic outcome, it can also cause undesirable and dose-limiting side effects (Stahl, S. M. Essential Psychopharmacology, 2^nded., Cambridge University Press, Cambridge, U.K., 2000). Thus, the inhibition of serotonin and norepinephrine uptake together with 5-HT₂receptor blockade is responsible for the therapeutic effects of the tricyclic antidepressants. In contrast, their blockade of histamine H₁, muscarinic and alpha-adrenergic receptors can lead to sedation, blurred vision and orthostatic hypertension respectively. Likewise, the atypical antipsychotics, including olanzapine and clozapine, are considered to have positive therapeutic effects attributable to their actions at 5-HT₂, D₂and 5-HT₇receptors. Conversely, their side effect liability is due to their affinities for a range of dopaminergic, serotonergic and adrenergic receptors.

[0004] More selective ligands therefore have the potential to ameliorate untoward pharmacologies and provide novel therapies. More importantly the ability to obtain compounds with known receptor selectivities affords the prospect to target multiple therapeutic mechanisms and improve clinical responses with a single drug.

[0005] 4-Phenyltetrahydropyrido[4,3-d]pyrimidines with utility in the treatment of gastrointestinal diseases have been described in U.S. Pat. No. 5,137,890 (Sanfilippo et al.):

[0006]

[0007] The features and advantages of the invention are apparent to one of ordinary skill in the art. Based on this disclosure, including the summary, detailed description, background, examples, and claims, one of ordinary skill in the art will be able to make modifications and adaptations to various conditions and usages. Publications described herein are incorporated by reference in their entirety.

[0008] Described herein is a series of pyrimidine compounds with the ability to modulate the activity of serotonin receptors.

SUMMARY OF THE INVENTION

[0009] The invention features a compound of Formulae (I) or (II):

[0010]

wherein

[0011] m is 1, 2, or 3;
[0012] n is 1, 2, or 3;
[0013] where when m and n are both present, m+n is greater than or equal to 2, and is less than or equal to 4;
[0014] R^aand R^bare independently —H, —C_1-7alkyl, or —C_3-7cycloalkyl, or R^aand R^btaken together with the nitrogen of attachment form piperidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, or piperazinyl, where each R^aand R^bis optionally and independently substituted with —C_1-4alkyl;
[0015] q is 0 or 1;
[0016] A is >NR¹, >CHNR^cR^d, >CHOH or —CH₂— wherein
- [0017] R¹is selected from the group consisting of —H, —C_1-7alkyl, —C_3-7cycloalkyl, and benzyl, where each alkyl, cycloalkyl, or benzyl is optionally mono-, di-, or tri-substituted with R^e;
  - [0018] R^eis selected from the group consisting of —C_1-4alkyl, —C_2-4alkenyl, —C_2-4alkynyl, —C_3-6cycloalkyl, halo, —CF₃, —OH, —OC_1-4alkyl, —OCF₃, —N(R^f)R^g(wherein R^fand R^gare independently —H or —C_1-4alkyl, or R^fand R^gtaken together with the nitrogen of attachment form piperidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, or piperazinyl), —C(O)N(R^f)R^g, —N(R^h)C(O)R^h, —N(R^h)SO₂C_1-7alkyl (wherein R^his —H or —C_1-4alkyl, or two R^hin the same substituent taken together with the amide of attachment form an otherwise aliphatic 4- to 6-membered ring), —S(O)_0-2—C_1-4alkyl, —SO₂N(R^f)R^g, —SCF₃, —C(O)C_1-4alkyl, —CN, —COOH, and —COOC_1-4alkyl;
- [0019] R^cand R^dare independently selected from the group consisting of —H, —C_1-7alkyl, —C_3-7alkenyl, —C_3-7alkynyl, —C_3-7cycloalkyl, —C_1-7alkylC_3-7cycloalkyl, and —C_3-7cycloalkylC_1-7alkyl, or R^cand R^dtaken together with the nitrogen of attachment form piperidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, or piperazinyl, where each R^cand R^dis optionally and independently substituted with R^e;
[0020] R³is —C_1-4alkyl, —C_1-4alkenyl, or benzyl, each optionally substituted with —C_1-3alkyl, —OH, or halo, or two R³substituents taken together form C_2-5alkylene optionally substituted with —C_1-3alkyl, —OH, or halo;
[0021] r is 0 or is an integer less than or equal to m+n+1;
[0022] Ar is an aryl or heteroaryl ring selected from the group consisting of:
- [0023] a) phenyl, optionally mono-, di-, or tri-substituted with Rⁱor di-substituted on adjacent carbons with —OC_1-4alkyleneO—, —(CH₂)_2-3NH—, —(CH₂)_1-2NH(CH₂)—, —(CH₂)_2-3N(C_1-4alkyl)—, or —(CH₂)_1-2N(C_1-4alkyl)(CH₂)—;
  - [0024] Rⁱis selected from the group consisting of —C_1-7alkyl, —C_2-7alkenyl, —C_2-7alkynyl, —C_3-7cycloalkyl, halo, —CF₃, —OH, —OC_1-7alkyl, —OCF₃, —OC_3-7alkenyl, —OC_3-7alkynyl, —N(R^j)R^k(wherein R^jand R^kare independently —H or —C_1-4alkyl), —C(O)N(R^j)R^k, —N(R^j)C(O)R^k, —N(R^j)SO₂C_1-6alkyl, —S(O)_0-2—C_1-6alkyl, —SO₂N(R^j)R^k, —SCF₃, —C(O)C_1-6alkyl, —NO₂, —CN, —COOH, and —COOC_1-7alkyl;
- [0025] b) a monocyclic aromatic hydrocarbon group having five ring atoms, having a carbon atom which is the point of attachment, having one carbon atom replaced by >O, >S, >NH, or >N(C_1-4alkyl), having up to two additional carbon atoms optionally replaced by —N═, optionally mono- or di-substituted with Rⁱ;
- [0026] c) a monocyclic aromatic hydrocarbon group having six ring atoms, having a carbon atom which is the point of attachment, having one or two carbon atoms replaced by —N═, optionally mono- or di-substituted with Rⁱ; and
- [0027] d) phenyl or pyridyl, substituted with a substituent selected from the group consisting of phenyl, phenoxy, pyridyl, thiophenyl, oxazolyl, and tetrazolyl, where the resultant substituted moiety is optionally further mono-, di-, or tri-substituted with Rⁱ;
[0028] ALK is a branched or unbranched C_1-7alkylene, C_2-7alkenylene, C_2-7alkynylene, C_3-7cycloalkylene, or C_3-7cycloalkenylene, optionally mono-, di-, or tri-substituted with R^m;
- [0029] R^mis selected from the group consisting of halo, —CF₃, —OH, —OC_1-7alkyl, —OC_3-7cycloalkyl, —OCF₃, —N(R^p)R^s(wherein R^pand R^sare independently —H or —C_1-7alkyl), —C(O)N(R^p)R^s, —N(R^t)C(O)R^t, —N(R^t)SO₂C_1-6alkyl (wherein R^tis —H or —C_1-7alkyl), —S(O)_0-2—C_1-6alkyl, —SO₂N(R^p)R^s, —SCF₃, —CN, —NO₂, —C(O)C_1-7alkyl, —COOH, and —COOC_1-7alkyl;
[0030] CYC is —H or is a ring system selected from the group consisting of:
- [0031] i) phenyl, optionally mono-, di-, or tri-substituted with R^uor di-substituted on adjacent carbons with —OC_1-4alkyleneO—, —(CH₂)_2-3NH—, —(CH₂)_1-2NH(CH₂)—, —(CH₂)_2-3N(C_1-4alkyl)-, or —(CH₂)_1-2N(C_1-4alkyl)(CH₂)—;
  - [0032] R^uis selected from the group consisting of —C_1-7alkyl, —C_3-7cycloalkyl, phenyl, benzyl, halo, —CF₃, —OH, —OC_1-7alkyl, —OC_3-7cycloalkyl, —Ophenyl, —Obenzyl, —OCF₃, —N(R^v)R^w(wherein R^vand R^ware independently —H or —C_1-7alkyl, or R^vand R^wtaken together with the nitrogen of attachment form piperidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, or piperazinyl, where each R^vand R^wis optionally and independently substituted with —OH or —C_1-7alkyl), —C(O)N(R^v)R^w, —N(R^x)C(O)R^x, —N(R^x)SO₂C_1-6alkyl (wherein R^xis —H or —C_1-7alkyl, or two R^xin the same substituent taken together with the amide of attachment form an otherwise aliphatic 4- to 6-membered ring), —N—(SO₂C_1-6alkyl)₂, —S(O)_0-2—C_1-6alkyl, —SO₂N(R^v)R^w, —SCF₃, —C(O)C_1-6alkyl, —NO₂, —CN, —COOH, and —COOC_1-7alkyl;
- [0033] ii) a monocyclic aromatic hydrocarbon group having five ring atoms, having a carbon atom which is the point of attachment, having one carbon atom replaced by >O, >S, >NH, or >N(C_1-4alkyl), having up to one additional carbon atoms optionally replaced by —N═, optionally mono- or di-substituted with R^u;
- [0034] iii) a monocyclic aromatic hydrocarbon group having six ring atoms, having a carbon atom which is the point of attachment, having one or two carbon atoms replaced by —N═, optionally mono- or di-substituted with R^u; and
- [0035] iv) a non-aromatic heterocyclic ring having 4 to 8 members, said ring having 0, 1, or 2 non-adjacent heteroatom members selected from the group consisting of O, S, —N═, >NH, and >N(C_1-4alkyl), having 0, 1, or 2 double bonds, having 0, 1, or 2 carbon members which is a carbonyl, optionally having one carbon member which forms a bridge, having 0 to 5 substituents R^u, and where when q is 0, said ring has a carbon atom which is the point of attachment;
[0036] and enantiomers, diastereomers, hydrates, solvates, and pharmaceutically acceptable salts, esters and amides thereof;
[0037] with the proviso that in Formula (I):
- [0038] (a) when ALK is methylene, ethylene, propylene, or isopropylene, CYC is —H, Ar is phenyl or mono-substituted phenyl, m is 2, n is 1, and A is >NR¹, then R¹is not —C_1-4alkyl or benzyl;
- [0039] (b) when q is 0, CYC is phenyl, Ar is phenyl or 3-chlorophenyl, m is 2, and n is 1, then A is not unsubstituted —CH₂—; and
- [0040] (c) when q is 0, CYC is 2-pyridyl, Ar is 2-pyridyl, m is 2, and n is 1, then A is not unsubstituted —CH₂—.

[0041] Isomeric forms of the compounds of Formulae (I) and (II) and of their pharmaceutically acceptable salts, esters, and amides, are encompassed within the present invention, and reference herein to one of such isomeric forms is meant to refer to at least one of such isomeric forms. One of ordinary skill in the art will recognize that compounds according to this invention may exist, for example in a single isomeric form whereas other compounds may exist in the form of a regioisomeric mixture.

[0042] The present invention provides methods of treating or preventing diseases and conditions mediated by the serotonin receptors, particularly, 5-HT₇and/or 5-HT₂receptor subtypes.

[0043] The invention also features pharmaceutical compositions containing such compounds and methods of using such compositions in the treatment or prevention of disease states mediated by the serotonin receptors, particularly, 5-HT₇and/or 5-HT₂receptor subtypes.

[0044] Compounds of the present invention are useful in combination with other therapeutic agents as a combination therapy method, including use in combination with selective serotonin reuptake inhibitors (SSRIs), anti-psychotics, norepinephrine reuptake inhibitors (NRIs), sedatives, monoamine oxidase inhibitors (MAOs), or tricyclic antidepressants (TCAs).

[0045] Additional features and advantages of the invention will become apparent from the detailed description and examples below, and the appended claims.

DETAILED DESCRIPTION

[0046] Particular preferred compounds of the invention comprise a compound of Formula (I) or (II), or an enantiomer, diastereomer, hydrate, solvate thereof, or a pharmaceutically acceptable salt, amide or ester thereof, wherein m, n, R^a, R^b, q, A, R³, r, Ar, ALK, and CYC have any of the meanings defined hereinabove and equivalents thereof, or at least one of the following assignments and equivalents thereof. Such assignments may be used where appropriate with any of the definitions, claims or embodiments defined herein:

[0047] Preferably, m is 1 and n is 1.

[0048] Preferably, m is 1 and n is 2.

[0049] Preferably, m is 2 and n is 1.

[0050] Preferably, m is 2 and n is 2.

[0051] Preferably, m is 1 and n is 3.

[0052] Preferably, m is 3 and n is 1.

[0053] Preferably, in Formula (II), n is 1.

[0054] Preferably, in Formula (II), n is 2.

[0055] Preferably, q is 1.

[0056] Preferably, —N(R^a)R^bis amino, methylamino, ethylamino, isopropylamino, dimethylamino, diethylamino, diisopropylamino, cyclopropylamino, cyclopentylamino, piperidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, or piperazinyl.

[0057] More preferably, —N(R^a)R^bis amino, methylamino, dimethylamino, or N-methylpiperazinyl.

[0058] Preferably, A is >NR¹.

[0059] Preferably, R¹is selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, butyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, and benzyl, each optionally mono-, di-, or tri-substituted with R^e.

[0060] More preferably, R¹, optionally R^esubstituted, is selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, and benzyl.

[0061] Even more preferably, R¹is hydrogen or methyl.

[0062] Preferably, R³, optionally substituted, is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, methylene, allyl, and benzyl. Alternatively, two R³substituents taken together form ethylene.

[0063] More preferably, R³is methyl.

[0064] Preferably, r is 0, 1, or 2.

[0065] Preferably Ar, optionally substituted, is selected from the group consisting of:

[0066] a) phenyl, 5-, 6-, 7-, 8-benzo-1,4-dioxanyl, 4-, 5-, 6-, 7-benzo-1,3-dioxolyl, 4-, 5-, 6-, 7-indolinyl, 4-, 5-, 6-, 7-isoindolinyl, 1,2,3,4-tetrahydro-quinolin-4,5,6 or 7-yl, 1,2,3,4-tetrahydro-isoquinolin-4,5,6 or 7-yl,

[0067] b) furanyl, oxazolyl, isoxazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, thiophenyl, thiazolyl, isothiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl,

[0068] c) pyridinyl, pyridinyl-N-oxide, pyrazinyl, pyrimidinyl, pyridazinyl, and

[0069] d) biphenyl, and 4-tetrazolylphenyl.

[0070] More preferably, Ar, optionally substituted, is selected from the group consisting of phenyl, pyridyl, thiophen-2-yl, and thiophen-3-yl.

[0071] Specific Ar may be selected from the group consisting of phenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 4-ethylphenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 3-trifluoromethoxyphenyl, 4-trifluoromethoxyphenyl, 3-cyanophenyl, 4-cyanophenyl, 3-acetylphenyl, 4-acetylphenyl, 3,4-difluorophenyl, 3,4-dichlorophenyl, 2,3-difluorophenyl, 2,3-dichlorophenyl, 2,4-difluorophenyl, 2,4-dichlorophenyl, 3-nitrophenyl, 4-nitrophenyl, 3-chloro-4-fluorophenyl, 3-fluoro-4-chlorophenyl, benzo[1,3]dioxol-4 or 5-yl, 3-hydroxyphenyl, 4-hydroxyphenyl, 4-hydroxy-2-methylphenyl, 4-hydroxy-3-fluorophenyl, 3,4-dihydroxyphenyl, 4-dimethylaminophenyl, 4-carbamoylphenyl, 4-fluoro-3-methylphenyl, 2-phenoxyphenyl, furan-2-yl, furan-3-yl, 5-methyl-furan-2-yl, thiophen-2-yl, thiophen-3-yl, 5-chlorothiophen-2-yl, 5-methylthiophen-2-yl, 5-chlorothiophen-3-yl, 5-methylthiophen-3-yl, oxazol-2-yl, 4,5-dimethyl-oxazol-2-yl, thiazol-2-yl, 3H-[1,2,3]triazol-4-yl, 2H-pyrazol-3-yl, 1H-pyrazol-4-yl, 4-pyridyl, 5-fluoro-pyridin-2-yl, 4′-chlorobiphenyl, and 4-tetrazolylphenyl.

[0072] Preferably, ALK, optionally substituted, is selected from the group consisting of methylene, ethylene, propylene, butylene, sec-butylene, tert-butylene, pentylene, 1-ethylpropylene, 2-ethylpropylene, 2-ethylbutylene, isopropylene, but-3-enylene, isobutylene, 3-methylbutylene, allylene, prop-2-ynylene, cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, and cycloheptylene.

[0073] Specific ALK may be selected from the group consisting of methylene, hydroxymethylene, fluoromethylene, difluoromethylene, trifluoromethylmethylene, 2,2,2-trifluoro-1-trifluoromethyl-ethylene, methoxycarbonylmethyl, methylcarbamoylmethyl, ethylene, 2-dimethylaminoethylene, 2-cyanoethylene, 2-methoxyethylene, 1-carboxy-ethylene, propylene, 3-methoxycarbonyl propylene, 3-carboxy propylene, isopropylene, 1-fluoro-1-methyl-ethylene, 1-hydroxy-1-methyl-ethylene, 1-carboxy-1-methyl-ethylene, 1-ethylpropylene, 2-ethylpropylene, butylene, tert-butylene, sec-butylene, isobutylene, 4-hydroxybutylene, 4-methoxycarbonyl butylene, 4-carboxy butylene, 2-ethylbutylene, isobutylene, 3-methylbutylene, prop-2-ynylene, but-3-enylene, pentylene, 5-hydroxypentylene, cyclopropylene, cyclobutylene, cyclopentylene, cyclopentenylene, 3,3-difluoro-cyclopentylene, 3-hydroxy-cyclohexylene, 4-fluorocyclohexylene, 4,4-difluoro-cyclohexylene, and 1-methyl-cyclopropylene.

[0074] Preferably CYC, optionally substituted, is hydrogen or is a ring system selected from the group consisting of:

[0075] i) phenyl, 5-, 6-, 7-, 8-benzo-1,4-dioxanyl, 4-, 5-, 6-, 7-benzo-1,3-dioxolyl, 4-, 5-, 6-, 7-indolinyl, 4-, 5-, 6-, 7-isoindolinyl, 1,2,3,4-tetrahydro-quinolin-4,5,6 or 7-yl, 1,2,3,4-tetrahydro-isoquinolin-4,5,6 or 7-yl,

- [0076] ii) furanyl, oxazolyl, isoxazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, thiophenyl, thiazolyl, isothiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl,
- [0077] iii) pyridinyl, pyridinyl-N-oxide, pyrazinyl, pyrimidinyl, pyridazinyl, and
- [0078] iv) pyrrolinyl, pyrrolidinyl, pyrazolinyl, piperidinyl, homopiperidinyl, azepanyl, tetrahydrofuranyl, tetrahydropyranyl, piperazinyl, morpholinyl, thiomorpholinyl, and piperidinonyl.

[0079] More preferably, CYC, optionally substituted, is selected from the group consisting of hydrogen, phenyl, thiophen-2-yl, thiophen-3-yl, furan-2-yl, furan-3-yl, pyridinyl, piperidin-1,2,3 or 4-yl, 2-pyrrolin-2,3,4, or 5-yl, 3-pyrrolin-2 or 3-yl, 2-pyrazolin-3,4 or 5-yl, tetrahydrofuran-3-yl, tetrahydropyran-4-yl, morpholin-2,3, or 4-yl, thiomorpholin-2,3, or 4-yl, piperazin-1,2,3, or 4-yl, pyrrolidin-1,2, or 3-yl, and homopiperidinyl.

[0080] Most preferably, CYC, optionally substituted, is selected from the group consisting of hydrogen, phenyl, pyridyl, thiophen-2-yl, thiophen-3-yl, tetrahydropyranyl, furan-2-yl, furan-3-yl, tetrahydrofuran-3-yl, and piperidinyl.

[0081] Specific CYC may be selected from the group consisting of hydrogen, phenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 4-ethylphenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 3-trifluoromethoxyphenyl, 4-trifluoromethoxyphenyl, 2-cyanophenyl, 3-cyanophenyl, 4-cyanophenyl, 3-acetylphenyl, 4-acetylphenyl, 3,4-difluorophenyl, 3,4-dichlorophenyl, 2,3-difluorophenyl, 2,3-dichlorophenyl, 2,4-difluorophenyl, 2,4-dichlorophenyl, 2,6-difluorophenyl, 2,6-dichlorophenyl, 2,6-dimethylphenyl, 2,4,6-trifluorophenyl, 2,4,6-trichlorophenyl, 3,4,5-trimethoxyphenyl, 4-fluoro-3-methylphenyl, 3-nitrophenyl, 4-nitrophenyl, 4-methyl-3-fluorophenyl, 3,4-dimethylphenyl, 4-methoxy-3-fluorophenyl, 4-methoxy-2-methylphenyl, 3-aminophenyl, 4-aminophenyl, 4-carbomethoxyphenyl, 3-methanesulfonylamino-phenyl, 4-methanesulfonylamino-phenyl, 3-dimethanesulfonylamino-phenyl, 4-dimethanesulfonylamino-phenyl, thiophen-2-yl, thiophen-3-yl, 5-chlorothiophen-2-yl, benzo[1,3]dioxol-4 or 5-yl, tetrahydrofuran-3-yl, tetrahydropyran-2,3 or 4-yl, furan-2-yl, furan-3-yl, 5-carboxyethyl-furan-2-yl, piperidinyl, 3,4-bisbenzyloxyphenyl, 2-hydroxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 4-hydroxy-2-methylphenyl, 4-hydroxy-3-fluorophenyl, 3,4-dihydroxyphenyl, 1-piperidinyl, 4-piperidinyl, and 1-methyl-4-piperidinyl.

[0082] In one embodiment of Formula (I), CYC-(ALK)_q- is —C_3-8cycloalkyl.

[0083] In another embodiment of Formula (I), CYC-(ALK)_q- is not methyl, ethyl, propyl, or isopropyl where A is >NR¹. In another embodiment of Formula (I), CYC-(ALK)_q- is not methyl, ethyl, propyl, or isopropyl. In another embodiment of Formula (I), m is not 2. In another embodiment of Formula (I), A is not unsubstituted —CH₂— where q is 0.

[0084] Compounds of Formulae (I) and (II) comprise compounds that satisfy any one of the combinations of definitions given herein and equivalents thereof.

[0085] It is understood that the symbol “>” when used herein immediately prior to an atom means that the atom immediately following this symbol is divalent.

[0086] It is understood that some compounds referred to herein are chiral and/or have geometric isomeric centers, for example E- and Z-isomers. The present invention encompasses all such optical isomers, including diastereomers and racemic mixtures, atropisomers, and geometric isomers, and mixtures thereof, that possess the activity that characterizes the compounds of this invention. In addition, certain compounds referred to herein can exist in solvated as well as unsolvated forms. It is understood that this invention encompasses all such solvated and unsolvated forms that possess the activity that characterizes the compounds of this invention.

[0087] Compounds according to the present invention that have been modified to be detectable by some analytic technique are also within the scope of this invention. The compounds of the present invention may be labeled with radioactive elements such as ¹²⁵I, ¹⁸F, ¹¹C, ⁶⁴Cu, ³H, ¹⁴C, and the like for use in imaging or for radioactive treatment of patients. An example of such compounds is an isotopically labeled compound, such as an ¹⁸F isotopically labeled compound that may be used as a probe in detection and/or imaging techniques, such as positron emission tomography (PET) and single-photon emission computed tomography (SPECT). Preferably, compounds of the present invention labeled with ¹⁸F or ¹¹C may be used as a positron emission tomography (PET) molecular probe for studying serotonin-mediated disorders. Alternatively, compounds of the present invention labeled with ¹⁴C may be used in metabolic studies. Another example of such compounds is an isotopically labeled compound, such as a deuterium and/or tritium labeled compound, that may be used in reaction kinetic studies. The compounds described herein may be reacted with an appropriate functionalized radioactive reagent using conventional chemistry to provide radiolabeled compounds.

[0088] Preferred compounds, which are pyrimidines, are selected from the group consisting of:

[0089]


Ex.	Chemical Name


1	2-tert-Butyl-4-(4-fluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;
2	2-Benzyl-4-(4-fluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;
3	2-sec-Butyl-4-(4-fluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine hydrochloride;
4	2-sec-Butyl-4-p-totyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine hydrochloride;
5	2-Cyclobutyl-4-(4-fluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine hydrochloride;
6	2-Cyclobutyl-4-p-tolyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;
7	2-Cyclopropyl-4-(4-fluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;
8	2-Benzyl-4-p-tolyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;
9	2-Benzyl-4-(4-trifluoromethyl-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;
10	2-Benzyl-4-(3,4-difluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;
11	2-Benzyl-4-phenyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;
12	2-Benzyl-4-(3-fluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;
13	2-(4-Fluoro-benzyl)-4-(4-fluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;
14	2-(4-Fluoro-benzyl)-4-(4-fluoro-phenyl)-6-methyl-5,6,7,8-tetrahydro-
	pyrido[4,3-d]pyrimidine;
15	4-[2-(4-Fluoro-benzyl)-6-methyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-
	yl]-benzonitrile;
16	4-[2-(4-Fluoro-benzyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yl]-benzonitrile;
17	2-Cyclopentyl-4-(4-fluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;
18	2-Cyclopentyl-4-p-tolyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;
19	2-Cyclopentyl-4-(4-methoxy-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;
20	4-(2-Cyclopentyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yl)-benzonitrile;
21	4-(4-Fluoro-phenyl)-2-isopropyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine hydrochloride;
22	4-(4-Fluoro-phenyl)-2-isopropyl-6-methyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;
23	4-(3,4-Dichloro-phenyl)-2-isopropyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine
	hydrochloride;
24	4-(3,4-Difluoro-phenyl)-2-isopropyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine
	hydrochloride;
25	4-(3-Fluoro-phenyl)-2-isopropyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;
26	4-(2-Fluoro-phenyl)-2-isopropyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;
27	4-(2,4-Difluoro-phenyl)-2-isopropyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;
28	2-Isopropyl-4-p-tolyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;
29	4-(4-Chloro-phenyl)-2-isopropyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;
30	2-Isopropyl-4-(4-methoxy-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;
31	2-Isopropyl-4-phenyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;
32	2-Isopropyl-4-(4-trifluoromethyl-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;
33	2-Isopropyl-4-(2-phenoxy-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;
34	2-Isobutyl-4-thiophen-3-yl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;
35	2-Isobutyl-4-thiophen-2-yl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;
36	2-Isobutyl-4-pyridin-4-yl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;
37	4-(4-Fluoro-phenyl)-2-isobutyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;
38	2-Isobutyl-4-p-tolyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;
39	4-(4-Fluoro-3-methyl-phenyl)-2-isobutyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;
40	4-(2-Isobutyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yl)-benzonitrile;
41	2-Isobutyl-4-(4-methoxy-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;
42	2-sec-Butyl-4-(2-fluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine hydrochloride;
43	2-sec-Butyl-4-(3-fluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;
44	2-sec-Butyl-4-(4-methoxy-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;
45	2-sec-Butyl-4-(4-trifluoromethoxy-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;
46	2-Cyclopentyl-4-(4-fluoro-phenyl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine;
47	2-Cyclopentyl-4-p-tolyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine;
48	2-Cyclopentyl-4-(4-methoxy-phenyl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine;
49	4-(2-Cyclopentyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl)-benzonitrile;
50	4-(4-Fluoro-phenyl)-2-isopropyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine
	hydrochloride;
51	4-(4-Chloro-phenyl)-2-methyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine;
52	2-Methyl-4-phenyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine;
53	4-(3-Chloro-phenyl)-2-methyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine;
54	2-Benzyl-4-(4-fluoro-phenyl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine;
55	2-Benzyl-4-p-tolyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine;
56	2-Benzyl-4-(4-trifluoromethyl-phenyl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine;
57	2-(4-Fluoro-benzyl)-4-(4-fluoro-phenyl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine;
58	2-Cyclopentyl-4-(4-fluoro-phenyl)-7-methyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine;
59	2-Cyclopentyl-7-methyl-4-p-tolyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine;
60	2-Cyclopentyl-4-(4-methoxy-phenyl)-7-methyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]
	azepine;
61	2-Benzyl-7-methyl-4-p-tolyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine;
62	2-(4-Fluoro-benzyl)-4-(4-fluoro-phenyl)-7-methyl-6,7,8,9-tetrahydro-5H-
	pyrimido[4,5-d]azepine;
63	2-(4-Fluoro-benzyl)-4-(4-fluoro-phenyl)-7-methyl-9-methylene-6,7,8,9-tetrahydro-
	5H-pyrimido[4,5-d]azepine;
64	2-Benzyl-4-(4-fluoro-phenyl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-c]azepine
	hydrochloride;
65	4-(4-Fluoro-phenyl)-2-isopropyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-c]azepine
	hydrochloride;
66	2-Isopropyl-4-p-tolyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-c]azepine hydrochloride;
67	2-Isopropyl-4-(4-methoxy-phenyl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-c]azepine;
68	2-Isopropyl-4-phenyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-c]azepine;
69	2-Benzyl-4-(4-fluoro-phenyl)-6,7,8,9-tetrahydro-5H-1,3,6-triaza-
	benzocycloheptene hydrochloride;
70	2,7-Dibenzyl-4-(4-fluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidine hydrochloride;
71	2,7-Dibenzyl-4-p-tolyl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidine;
72	2,7-Dibenzyl-4-phenyl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidine;
73	2,7-Dibenzyl-4-(4-methoxy-phenyl)-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidine;
74	7-Benzyl-4-(4-fluoro-phenyl)-2-isopropyl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidine;
75	7-Benzyl-2-isopropyl-4-phenyl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidine;
76	2-Benzyl-4-(4-fluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidine
	hydrochloride;
77	2-Benzyl-4-p-tolyl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidine hydrochloride;
78	2-Benzyl-4-phenyl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidine;
79	2-Benzyl-4-(4-methoxy-phenyl)-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidine;
80	4-(4-Fluoro-phenyl)-2-isopropyl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidine
	hydrochloride;
81	2-Isopropyl-4-phenyl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidine;
82	2-Benzyl-4-(4-fluoro-phenyl)-7-methyl-5,6,7,8-tetrahydro-pyrido[3,4-
	d]pyrimidine hydrochloride;
83	2-Benzyl-4-(4-fluoro-phenyl)-7-isopropyl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidine;
84	4-(4-Fluoro-phenyl)-2-isopropyl-7-methyl-5,6,7,8-tetrahydro-pyrido[3,4-
	d]pyrimidine hydrochloride;
85	2-Isopropyl-7-methyl-4-phenyl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidine;
86	7-Benzyl-2-isopropyl-4-(5-methyl-thiophen-3-yl)-5,6,7,8-tetrahydro-
	pyrido[3,4-d]pyrimidine hydrochloride;
87	7-Benzyl-2-isopropyl-4-thiophen-3-yl-5,6,7,8-tetrahydro-pyrido[3,4-
	d]pyrimidine hydrochloride;
88	2-Isopropyl-4-(5-methyl-thiophen-3-yl)-5,6,7,8-tetrahydro-pyrido[3,4-
	d]pyrimidine hydrochloride;
89	2-Isopropyl-4-thiophen-3-yl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidine
	hydrochloride;
90	2-Isopropyl-7-methyl-4-(5-methyl-thiophen-3-yl)-5,6,7,8-tetrahydro-
	pyrido[3,4-d]pyrimidine hydrochloride;
91	2-Isopropyl-7-methyl-4-thiophen-3-yl-5,6,7,8-tetrahydro-pyrido[3,4-
	d]pyrimidine hydrochloride;
92	6-Benzyl-4-(4-fluoro-phenyl)-2-isopropyl-8-methyl-5,6,7,8-tetrahydro-pyrido[4,3-d]
	pyrimidine;
93	6-Benzyl-4-(3-chloro-4-fluoro-phenyl)-2-isopropyl-8-methyl-5,6,7,8-tetrahydro-pyrido
	[4,3-d]pyrimidine;
94	6-Benzyl-2-isopropyl-8-methyl-4-p-tolyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;
95	6-Benzyl-2-isopropyl-8-methyl-4-phenyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;
96	6-Benzyl-2-isopropyl-8-methyl-4-(4-trifluoromethyl-phenyl)-5,6,7,8-
	tetrahydro-pyrido[4,3-d]pyrimidine;
97	6-Benzyl-4-(4-chloro-phenyl)-2-isopropyl-8-methyl-5,6,7,8-tetrahydro-pyrido[4,3-d]
	pyrimidine;
98	6-Benzyl-2-isopropyl-8-methyl-4-thiophen-3-yl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;
99	6-Benzyl-4-(4′-chloro-biphenyl-4-yl)-2-isopropyl-8-methyl-5,6,7,8-tetrahydro-
	pyrido[4,3-d]pyrimidine;
100	4-(4-Fluoro-phenyl)-2-isopropyl-8-methyl-5,6,7,8-tetrahydro-pyrido[4,3-
	d]pyrimidine hydrochloride;
101	4-(3-Chloro-4-fluoro-phenyl)-2-isopropyl-8-methyl-5,6,7,8-tetrahydro-pyrido[4,3-d]
	pyrimidine hydrochloride;
102	2-Isopropyl-8-methyl-4-p-tolyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine
	hydrochloride;
103	2-Isopropyl-8-methyl-4-phenyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;
104	2-Isopropyl-8-methyl-4-(4-trifluoromethyl-phenyl)-5,6,7,8-tetrahydro-
	pyrido[4,3-d]pyrimidine;
105	2-Isopropyl-8-methyl-4-thiophen-3-yl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;
106	4-(4-Fluoro-phenyl)-2-isopropyl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidine
	hydrochloride;
107	4-(4-Fluoro-phenyl)-2-isopropyl-7-pyrrolidin-1-yl-5,6,7,8-tetrahydro-quinazoline;
108	[4-(4-Fluoro-phenyl)-2-isopropyl-5,6,7,8-tetrahydro-quinazolin-7-yl]-methyl-
	amine hydrochloride;
109	[4-(4-Fluoro-phenyl)-2-isopropyl-5,6,7,8-tetrahydro-quinazolin-6-yl]-methyl-
	amine hydrochloride;
110	4-(4-Fluoro-phenyl)-2-isopropyl-5,6,7,8-tetrahydro-quinazolin-7-ol;
111	4-(4-Fluoro-phenyl)-2-isopropyl-5,6,7,8-tetrahydro-quinazoline;
112	(2-Benzyl-6-p-tolyl-pyrimidin-4-ylmethyl)-dimethyl-amine;
113	2-Benzyl-4-(4-methyl-piperazin-1-ylmethyl)-6-p-tolyl-pyrimidine;
114	[6-(4-Fluoro-phenyl)-2-isopropyl-pyrimidin-4-ylmethyl]-methyl-amine;
115	2-(2-Benzyl-6-p-tolyl-pyrimidin-4-yl)-ethylamine;
116	[2-(4-Fluoro-benzyl)-4-p-tolyl-pyrimidin-5-ylmethyl]-dimethyl-amine;
117	4-(4-Fluoro-phenyl)-2-phenyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;
118	2-(3,3-Difluoro-cyclopentyl)-4-(4-fluoro-phenyl)-5,6,7,8-tetrahydro-
	pyrido[4,3-d]pyrimidine;
119	4-(4-Fluoro-phenyl)-2-(tetrahydro-furan-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;
120	4-(4-Fluoro-phenyl)-2-(2-piperidin-1-yl-ethyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;
121	2-(1-Fluoro-1-methyl-ethyl)-4-(4-fluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]
	pyrimidine;
122	3-(4-Fluoro-phenyl)-5-isopropyl-4,6,12-triaza-tricyclo[7.2.1.0^2,7]dodeca-
	2,4,6-triene;
123	7-(4-Fluoro-phenyl)-5-isopropyl-4,6,13-triaza-tricyclo[8.2.1.0^3,8]trideca-3,5,7-
	triene;
124	4-(4-Fluoro-phenyl)-2-(tetrahydro-pyran-4-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;
125	4-(4-Fluoro-phenyl)-2-(tetrahydro-pyran-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;
126	4-(4-Fluoro-phenyl)-2-(2-methoxy-ethyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;
127	2-[4-(4-Fluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-2-yl]-propan-2-ol;
128	4-(4-Fluoro-phenyl)-2-(1-methyl-1-phenyl-ethyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]
	pyrimidine;
129	2-Cyclopent-3-enyl-4-(4-fluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;
130	3-[4-(4-Fluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-2-yl]-cyclohexanol;
131	4-(4-Fluoro-phenyl)-2-piperidin-4-yl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;
132	4-(4-Fluoro-phenyl)-2-(1-methyl-piperidin-4-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;
133	[4-(4-Fluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-2-yl]-phenyl-methanol;
134	4-(4-Fluoro-phenyl)-2-(fluoro-phenyl-methyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;
135	2-(Difluoro-phenyl-methyl)-4-(4-fluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;
136	4-(4-Fluoro-phenyl)-2-phenyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;
137	4-(4-Fluoro-phenyl)-2-(3-fluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;
138	4-(4-Fluoro-phenyl)-2-(4-methoxy-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;
139	4-(4-Fluoro-phenyl)-2-o-tolyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;
140	3-[4-(4-Fluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-2-yl]-benzonitrile;
141	4-(4-Fluoro-phenyl)-2-(2,2,2-trifluoro-1-trifluoromethyl-ethyl)-5,6,7,8-tetrahydro-
	pyrido[4,3-d]pyrimidine;
142	4-(4-Fluoro-phenyl)-2-(1-methyl-cyclopropyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;
143	2-[4-(4-Fluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-2-yl]-2-methyl-propionic
	acid;
144	2-[4-(4-Fluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-2-yl]-propionic acid;
145	2-(4-Fluoro-cyclohexyl)-4-(4-fluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;
146	2-(4,4-Difluoro-cyclohexyl)-4-(4-fluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]
	pyrimidine;
147	4-(4-Fluoro-phenyl)-2-phenethyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;
148	4-Furan-2-yl-2-isopropyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;
149	2-Isopropyl-4-(5-methyl-furan-2-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;
150	4-Furan-3-yl-2-isopropyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;
151	4-(5-Fluoro-pyridin-2-yl)-2-isopropyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;
152	2-Isopropyl-4-oxazol-2-yl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;
153	4-(4,5-Dimethyl-oxazol-2-yl)-2-isopropyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;
154	2-Isopropyl-4-thiazol-2-yl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;
155	2-Isopropyl-4-(3H-[1,2,3]triazol-4-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;
156	2-Isopropyl-4-(2H-pyrazol-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;
157	2-Isopropyl-4-(1H-pyrazol-4-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;
158	4-(4-Fluoro-phenyl)-2,6-diisopropyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;
159	6-Ethyl-4-(4-fluoro-phenyl)-2-isopropyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;
160	6-Cyclopropyl-4-(4-fluoro-phenyl)-2-isopropyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;
161	6-Cyclobutyl-4-(4-fluoro-phenyl)-2-isopropyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;
162	6-Cyclopentyl-4-(4-fluoro-phenyl)-2-isopropyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;
163	6-Butyl-4-(4-fluoro-phenyl)-2-isopropyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;
165	4-(4-Fluoro-phenyl)-2-isopropyl-5,6,7,8-tetrahydro-pyrido[4,3]pyrimidine, citrate salt;
166	{2-[2-tert-Butyl-6-(4-fluoro-phenyl)-pyrimidin-4-yl]-ethyl}-methyl-amine; and
167	{2-[2-tert-Butyl-6-(4-fluoro-phenyl)-pyrimidin-4-yl]-ethyl}-dimethyl-amine.

[0090] Preferably, the compound is 4-(4-fluoro-phenyl)-2-isopropyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine or a pharmaceutically acceptable salt thereof.

[0091] The features and advantages of the invention are apparent to one of ordinary skill in the art. Based on this disclosure, including the summary, detailed description, background, examples, and claims, one of ordinary skill in the art will be able to make modifications and adaptations to various conditions and usages. Publications described herein are incorporated by reference in their entirety. Where chemical symbols are used, it is understood that they are read from left to right, and that otherwise their spatial orientation has no significance.

[0092] The compounds as described above may be made according to processes within the skill of the art and/or that are described in the schemes and examples that follow. To obtain the various compounds herein, starting materials may be employed that carry the ultimately desired substituents though the reaction scheme with or without protection as appropriate. This may be achieved by means of conventional protecting groups, such as those described in “Protective Groups in Organic Chemistry”, ed. J. F. W. McOmie, Plenum Press, 1973; and T. W. Greene & P. G. M. Wuts, “Protective Groups in Organic Synthesis”, 3^rded., John Wiley & Sons, 1999. The protecting groups may be removed at a convenient subsequent stage using methods known from the art. Alternatively, it may be necessary to employ, in the place of the ultimately desired substituent, a suitable group that may be carried through the reaction scheme and replaced as appropriate with the desired substituent. Such compounds, precursors, or prodrugs are also within the scope of the invention. Reactions may be performed between the melting point and the reflux temperature of the solvent, and preferably between 0° C. and the reflux temperature of the solvent.

[0093] The pyrimidine compounds of Formulae (I) and (II) may be prepared by a number of reaction schemes. Access to compounds of Formulae (I) and (II) is described in Schemes 1-5. Persons skilled in the art will recognize that certain compounds are more advantageously produced by one scheme as compared to the other. In addition to the Schemes shown below, alternative methods may be used to prepare compounds of Formulae (I) or (II). Such methods are described in U.S. patent application Ser. No. 10/941,664 (Carruthers et al.), which is hereby incorporated by reference.

[0094]


Table of Acronyms
	Term	Acronym

	Tetrahydrofuran	THF
	N,N-Dimethylformamide	DMF
	N,N-Dimethylacetamide	DMA
	Dimethyl sulfoxide	DMSO
	tert-Butylcarbamoyl	Boc
	High-pressure liquid chromatography	HPLC
	Thin layer chromatography	TLC
	N,N-Diisopropylethylamine	DIEA
	1,2-Dichloroethane	DCE
	Ethylene glycol dimethyl ether	DME
	Acetyl	Ac
	Diisobutylaluminum hydride	DIBAL-H
	Ethyl acetate	EtOAc
	Trifluoroacetic acid	TFA
	Methanesulfonyl chloride	MsCl

[0095]

[0096] Referring to Scheme 1, compounds of Formula (I) may be preprared from beta-ketoesters (V), where G may be A or a protected form of A. Where A contains an amine group, the amine moiety may be suitably protected as an alkyl or benzyl amine, amide, carbamate, or other suitable group. Preferred protecting groups for amines include the t-butyl carbamate (Boc) or benzyl groups. Beta-ketoesters (V) are available according to methods known to one skilled in the art. Compounds of formula (V) are reacted with amidines (VI), prepared, for example, in the presence of KOtBu or a tertiary amine base such as Et₃N, in a solvent such as tBuOH, at temperatures ranging from room temperature to the reflux temperature of the solvent, to form hydroxy pyrimidines (VII). (See also: U.S. Patent Appl. 60/326,662; Tetrahedron 1989, 45(20), 6511). Pyrimidines (VII) can be converted into precursors for transition metal-catalyzed cross-coupling reactions, such as Stille, Suzuki, Negishi or other such coupling reactions known to one skilled in the art. For example, treatment with POCl₃, PCl₃, PCl₅, PBr₃or POBr₃can afford the corresponding halopyrimidines, where Y is bromide or chloride. Preferably, pyrimidines (VII) are treated with a triflating agent such as trifluoromethane-sulfonic anhydride or N-phenyl-bis(trifluoromethane-sulfonimide) in DCE, CH₂Cl₂, THF, or the like, in the presence of a base such as pyridine, Et₃N, DIEA, or KOtBu, to provide triflates of formula (VII) where Y is OTf. Coupling of halides or triflates (VIII) with aryl boronic acids (IX), or their boronic ester analogs, in the presence of a catalyst such as Pd(PPh₃)₄, PdCl₂(PPh₃)₂, PdCl₂(Pot-ol₃)₂, PdCl₂(dppe) or PdCl₂(dppf), in a solvent such as THF, 1,4-dioxane, DMA, DMF, DME, toluene, toluene/ethanol, or toluene/H₂O mixtures, in the presence of a base such as Na₂CO₃, K₂CO₃, Cs₂CO₃, K₃PO₄, KF, CsF, or KOAc, affords pyrimidines (X). Preferred catalysts are Pd(PPh₃)₄and PdCl₂(dppf), with or without additives such as dppf and catalytic Bu₄NBr. Preferred conditions include PdCl₂(dppf), catalytic dppf, and K₃PO₄in 1,4-dioxane.

[0097] Where G contains a protecting group, it may be removed using generally accepted methods, or may be otherwise converted into A of Formula (I). More specifically, a group such as a t-butyl carbamate may be removed with an acid such as trifluoroacetic acid or HCl, in a solvent such as CH₂Cl₂, dioxane, EtOH, or MeOH to afford compounds of Formula (I). Where G contains a benzyl group, said group may be removed according to standard methods, including hydrogenation in the presence of a palladium catalyst such as Pd/C, in a solvent such as EtOH, or through reaction with 1-chloroethylchloroformate in DCE.

[0098] Compounds of formula (X) where G is >NH may be further converted into additional embodiments of Formula (I) wherein A is >NR¹using conventional synthetic methods such as reductive amination or alkylation protocols. Thus, treatment of amines (X) with a suitable aldehyde in the presence of a reductant such as NaBH₄, NaBH₃CN, NaBH(OAc)₃, or H_2(g), in the presence of a catalyst, in a solvent such as CH₂Cl₂, DCE, THF, EtOH, or MeOH affords compounds of Formula (I) where A is >NR¹. One skilled in the art will recognize that the addition of an acid such as AcOH, Ti(O-iPr)₄, trifluoroacetic acid, or HCl, may be required. Alternatively, compounds (X) where G is >NH may be treated with an alkylating agent, such as an alkyl chloride, bromide, iodide, mesylate or tosylate, in a solvent such as DMF, DMA, THF, or EtOH, and in the presence of a base such as NaHCO₃, Na₂CO₃, K₂CO₃or Cs₂CO₃will produce compounds of Formula (I) where A is >NR¹.

[0099] In the following Schemes, the R³substituents of Formula (I) and intermediates have been removed to simplify the structural depictions, but one skilled in the art will recognize that the procedures shown provide access to compounds of Formula (I) containing the R³substituents.

[0100]

[0101] Referring to Scheme 2, compounds of formula (X′), where PG is a ketone protecting group, may be prepared according to the methods described in Scheme 1. Compounds (X′) may subsequently be converted into additional embodiments of Formula (I), exemplified by compounds (XII), (XIII), and (XIV). Reductive amination of ketones (XI) may be accomplished as described in Scheme 1. Alternatively, ketones (XI) may be reduced using conventional methods such as NaBH₄in EtOH or DIBAL-H in THF to the corresponding secondary alcohols (XIV), or reduced completely via hydrogenation, Wolff-Kishner reduction, or other protocols to form carbocycles (XIII).

[0102]

[0103] Compounds of Formula (II) may be accessed according to Scheme 3. Alkynes (XV) where R is a suitable protected alcohol or amine are first coupled with a suitable acid chloride (XVI), in the presence of a palladium catalyst such as Pd(PPh₃)₂Cl₂, a base such as Et₃N, an additive such as CuI, in a solvent such as THF to form intermediate alkynyl ketones. Said ketones are reacted in situ with amidines (VI), under conditions as described in Scheme 1, to form pyrimidines (XVII). Alcohol and amino protecting groups may then be removed under standard conditions. The resulting free amines are themselves compounds of Formula (II), but may be further processed to additional embodiments of Formula (II) via reductive amination as described in Scheme 2. Where a free alcohol is liberated, said alcohol may be converted to —N(R^a)R^bby: 1) formation of a suitable leaving group (an alkyl halide, mesylate, or tosylate); and 2) displacement with HN(R^a)R^b. Alternatively, the leaving group may be displaced by treatment with sodium azide. Subsequent reduction of the azido group under Staudinger conditions gives a free amine. In another embodiment, the free alcohol may be oxidized to the corresponding aldehyde using, for example, Dess-Martin periodinane or Swern oxidation conditions, and the resulting aldehyde converted to —N(R^a)R^busing reductive amination methods as described in Scheme 1.

[0104]

[0105] Alternatively, compounds of Formula (II) may be prepared according to Scheme 4. Acrylate esters (XVIII) may be condensed with amidines (VI) as described in Scheme 1 to form pyrimidines (XIX). The pendant ester group may be transformed into amines where n=1 by reduction to the alcohol, and either: 1) oxidizing to the corresponding aldehyde, and performing a reductive amination to install the —N(R^a)R^bsubstituent; or 2) activating the alcohol as a leaving group such as a tosylate, bromide, or chloride, and displacing with a suitable —HN(R^a)R^breagent. For n=2, the ester may be converted to an amide through peptide coupling methods, and the amide reduced to the corresponding amine. For n=3, homologation procedures known to one skilled in the art may be used to install two carbon units.

[0106]

[0107] Compounds of Formula (I) where A is >NH, and m and n are as defined in Formula (I), may be prepared according to Scheme 5. Ketones (XX) are commercially available or may be prepared using methods known to one skilled in the art. The nitrogen protecting group may be an acyl group or carbamoyl group (such as a Boc group). Preferably, the nitrogen protecting group is acetyl. Conversion to enamines of formula (XXI) is performed by reaction with a secondary amine under standard water removal conditions. Preferably, the reaction is done with piperidine as the secondary amine, and using a Dean Stark trap, with a catalyst such as p-toluenesulfonic acid, in a solvent such as toluene. Elevated temperatures are preferred. Enamines are transformed into 1,3-diketones (XXII) by reaction with acyl chlorides (XVI), in the presence of a suitable base such as Et₃N, in a solvent such as CH₂Cl₂. See also: Breitenbucher, et al. PCT Intl. Appl. WO02/014314. Condensation with amidines of formula (VI) to form pyrimidines (XXIII) may be accomplished as described in Scheme 1. Preferably, condensations are accomplished in the presence of Et₃N, in a solvent such as t-amyl alcohol, at temperatures between room temperature and reflux temperature of the solvent. Deprotection of the nitrogen protecting group may be effected using conditions known to one skilled in the art. Preferably, where the protecting group is acetyl, deprotection is done in the presence of 10% aqueous HCl at reflux temperature. One skilled in the art will recognize that compounds of Formula (I) prepared in Scheme 5 may be subsequently converted to other embodiments where A is >NR²as described in Scheme 1.

[0108] Compounds of Formulae (I) or (II) may be converted to their corresponding salts using methods known to those skilled in the art. For example, amines of Formulae (I) or (II) may be treated with trifluoroacetic acid, HCl, or citric acid in a solvent such as MeOH to provide the corresponding salt forms.

[0109] Compounds prepared according to the schemes described above may be obtained as single enantiomers, diastereomers, or regioisomers, or as racemic mixtures or mixtures of enantiomers, diastereomers, or regioisomers. Where regioisomeric or diastereomeric mixtures are obtained, isomers may be separated using conventional methods such as chromatography or crystallization. Where racemic (1:1) and non-racemic (not 1:1) mixtures of enantiomers are obtained, single enantiomers may be isolated using conventional separation methods known to one skilled in the art. Particularly useful separation methods may include chiral chromatography, recrystallization, resolution, diastereomeric salt formation, or derivatization into diastereomeric adducts followed by separation.

[0110] The present invention includes within its scope prodrugs of the compounds of this invention. In general, such prodrugs will be functional derivatives of the compounds that are readily convertible in vivo into the required compound. Thus, in the methods of treatment of the present invention, the term “administering” shall encompass the treatment of the various disorders described with a compound of Formula (I) or (II) or with a compound that converts to a compound of Formula (I) or (II) in vivo after administration to the patient. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in “Design of Prodrugs”, ed. H. Bundgaard, Elsevier, 1985. In addition to salts, the invention provides the esters, amides, and other protected or derivatized forms of the described compounds.

[0111] For therapeutic use, salts of the compounds of the present invention are those that are pharmaceutically acceptable. However, salts of acids and bases that are non-pharmaceutically acceptable may also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound. All salts, whether pharmaceutically acceptable or not are included within the ambit of the present invention.

[0112] Pharmaceutically acceptable salts, esters, and amides of compounds according to the present invention refer to those salt, ester, and amide forms of the compounds of the present invention which would be apparent to the pharmaceutical chemist, i.e., those that are non-toxic and that would favorably affect the pharmacokinetic properties of said compounds of the present invention. Those compounds having favorable pharmacokinetic properties would be apparent to the pharmaceutical chemist, i.e., those which are non-toxic and which possess such pharmacokinetic properties to provide sufficient palatability, absorption, distribution, metabolism and excretion. Other factors, more practical in nature, which are also important in the selection, are cost of raw materials, ease of crystallization, yield, stability, hygroscopicity and flowability of the resulting bulk drug.

[0113] Examples of acids that may be used in the preparation of pharmaceutically acceptable salts include the following: acetic acid, 2,2-dichloroacetic acid, acylated amino acids, adipic acid, alginic acid, ascorbic acid, L-aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, boric acid, (+)-camphoric acid, camphorsulfonic acid, (+)-(1S)-camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclamic acid, cyclohexanesulfamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxy-ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, D-gluconic acid, D-glucuronic acid, L-glutamic acid, α-oxo-glutaric acid, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, (+)-L-lactic acid, (±)-DL-lactic acid, lactobionic acid, lauric acid, maleic acid, (−)-L-malic acid, malonic acid, (±)-DL-mandelic acid, methanesulfonic acid, naphthalene-2-sulfonic acid, naphthalene-1,5-disulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, nitric acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, perchloric acid, phosphoric acid, L-pyroglutamic acid, saccharic acid, salicylic acid, 4-amino-salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tannic acid, (+)-L-tartaric acid, thiocyanic acid, p-toluenesulfonic acid, undecylenic acid, and valeric acid.

[0114] Compounds of the present invention containing acidic protons may be converted into their therapeutically active non-toxic metal or amine addition salt forms by treatment with appropriate organic and inorganic bases. Appropriate base salt forms comprise, for example, the ammonium salts; the alkali and earth alkaline metal salts (e.g. lithium, sodium, potassium, magnesium, calcium salts, which may be prepared by treatment with, for example, magnesium hydroxide, calcium hydroxide, potassium hydroxide, zinc hydroxide, or sodium hydroxide); and amine salts made with organic bases (e.g. primary, secondary and tertiary aliphatic and aromatic amines such as L-arginine, benethamine, benzathine, choline, deanol, diethanolamine, diethylamine, dimethylamine, dipropylamine, diisopropylamine, 2-(diethylamino)-ethanol, ethanolamine, ethylamine, ethylenediamine, isopropylamine, N-methyl-glucamine, hydrabamine, 1H-imidazole, L-lysine, morpholine, 4-(2-hydroxyethyl)-morpholine, methylamine, piperidine, piperazine, propylamine, pyrrolidine, 1-(2-hydroxyethyl)-pyrrolidine, pyridine, quinuclidine, quinoline, isoquinoline, secondary amines, triethanolamine, trimethylamine, triethylamine, N-methyl-D-glucamine, 2-amino-2-(hydroxymethyl)-1,3-propanediol, and tromethamine). See, e.g., S. M. Berge, et al., “Pharmaceutical Salts”, J. Pharm. Sci., 1977, 66:1-19, and Handbook of Pharmaceutical Salts, Propertions, Selection, and Use; Stahl, P. H., Wermuth, C. G., Eds.; Wiley-VCH and VHCA: Zurich, 2002, which are incorporated herein by reference.

[0115] Pharmaceutically acceptable esters and amides are those that are within a reasonable benefit/risk ratio, pharmacologically effective and suitable for contact with the tissues of patients without undue toxicity, irritation, or allergic response. Representative pharmaceutically acceptable amides of the invention include those derived from ammonia, primary C_1-6alkyl amines and secondary di(C_1-6alkyl)amines. Secondary amines include 5- or 6-membered heterocyclic or heteroaromatic ring moieties containing at least one nitrogen atom and optionally between 1 and 2 additional heteroatoms. Preferred amides are derived from ammonia, C_1-3alkyl primary amines, and di(C_1-12alkyl)amines.

[0116] Representative pharmaceutically acceptable esters of the invention include C_1-7alkyl, C_5-7cycloalkyl, phenyl, substituted phenyl, and phenylC_1-6alkyl-esters. Preferred esters include methyl esters. Furthermore, examples of suitable esters include such esters where one or more carboxyl substituents is replaced with p-methoxybenzyloxy-carbonyl, 2,4,6-trimethylbenzyloxy-carbonyl, 9-anthryloxycarbonyl, CH₃SCH₂COO—, tetrahydrofur-2-yloxycarbonyl, tetrahydropyran-2-yloxy-carbonyl, fur-2-yloxycarbonyl, benzoylmethoxy-carbonyl, p-nitrobenzyloxy-carbonyl, 4-pyridylmethoxycarbonyl, 2,2,2-trichloro-ethoxycarbonyl, 2,2,2-tribromoethoxycarbonyl, t-butyloxycarbonyl, t-amyloxy-carbonyl, diphenylmethoxycarbonyl, triphenylmethoxycarbonyl, adamantyloxy-carbonyl, 2-benzyloxyphenyloxycarbonyl, 4-methylthiophenyloxycarbonyl, or tetrahydropyran-2-yloxycarbonyl.

[0117] The compounds of the present invention are serotonin receptor modulators, and as such, the compounds are useful in the treatment of serotonin-mediated disease states. Particularly, the compounds may be used in methods for treating or preventing CNS disorders, such as sleep disorders, depression/anxiety, generalized anxiety disorder, schizophrenia, bipolar disorders, cognitive disorders, mild cognitive impairment, Alzheimer's disease, Parkinson's disease, psychotic disorders, phobic disorders, obsessive-compulsive disorder, mood disorders, post-traumatic stress and other stress-related disorders, migraine, pain, eating disorders, obesity, sexual dysfunction, metabolic disturbances, hormonal imbalance, hot flushes associated with menopause, alcohol abuse, drug abuse, addictive disorders including drug addiction and alcohol addiction, nausea, inflammation, centrally mediated hypertension, sleep/wake disturbances, jetlag, and circadian rhythm abnormalities. The compounds may also be used in the treatment and prevention of hypotension, peripheral vascular disorders, cardiovascular shock, renal disorders, gastric motility, diarrhea, spastic colon, irritable bowel disorders, ischemias, septic shock, urinary incontinence, and other disorders related to the gastrointestinal and vascular systems. In addition, compounds of the present invention may be used in methods for treating or preventing a range of ocular disorders including glaucoma, optic neuritis, diabetic retinopathy, retinal edema, and age-related macular degeneration.

[0118] The compounds of the present invention are 5-HT₇modulators and many are 5-HT₇antagonists. As such, the compounds are useful in methods for treating or preventing 5-HT₇-mediated disease states. Where the compounds possess substantial 5-HT₇antagonist activity, they may be particularly useful in methods for treating or preventing depression/anxiety, sleep/wake disturbances, jetlag, migraine, urinary incontinence, gastric motility, and irritable bowel disorders.

[0119] Many of the compounds of the present invention are 5-HT₂modulators and many are 5-HT₂antagonists. As such, the compounds are useful in methods for treating or preventing 5-HT₂-mediated diseases and conditions. Where the compounds possess substantial 5-HT₂antagonist activity, they may be particularly useful in methods for treating or preventing depression/anxiety, generalized anxiety disorder, schizophrenia, bipolar disorders, psychotic disorders, obsessive-compulsive disorder, mood disorders, post-traumatic stress disorders, sleep disturbances, sexual dysfunction, hot flushes associated with menopause, eating disorders, migraine, addictive disorders, and peripheral vascular disorders.

[0120] The compounds of the present invention are 5-HT₆modulators and many are 5-HT₆antagonists. As such, the compounds are useful in methods for treating or preventing 5-HT₆-mediated disease states. Where the compounds possess substantial 5-HT₆antagonist activity, they may be particularly useful in methods for treating or preventing schizophrenia, cognitive disorders, mild cognitive impairment, Alzheimer's disease, and Parkinson's disease.

[0121] Said methods of treating and preventing comprise the step of administering to a mammal suffering therefrom an effective amount of at least one compound of the present invention.

[0122] The present invention also contemplates a method of treating or preventing a serotonin-mediated disease or condition with a combination therapy, comprising administering at least one compound of the present invention in combination with one or more neuroactive agents. Suitable neuroactive agents include: selective serotonin reuptake inhibitors (SSRIs), anti-psychotics, norepinephrine reuptake inhibitors (NRIs), sedatives, monoamine oxidase inhibitors (MAOs), and tricyclic antidepressants (TCAs). In another embodiment, the present invention includes compositions comprising at least one compound of the present invention and one or more neuroactive agent.

[0123] Compounds of the present invention may be administered in pharmaceutical compositions to treat patients (humans and other mammals) with disorders mediated by the serotonin receptor. Thus, the invention features pharmaceutical compositions containing at least one compound of the present invention and a pharmaceutically acceptable carrier. A composition of the invention may further include at least one other therapeutic agent (for example, a combination formulation or combination of differently formulated active agents for use in a combination therapy method).

[0124] The present invention also features methods of using or preparing or formulating such pharmaceutical compositions. The pharmaceutical compositions can be prepared using conventional pharmaceutical excipients and compounding techniques known to those skilled in the art of preparing dosage forms. It is anticipated that the compounds of the invention can be administered by oral, parenteral, rectal, topical, or ocular routes, or by inhalation. Preparations may also be designed to give slow release of the active ingredient. The preparation may be in the form of tablets, capsules, sachets, vials, powders, granules, lozenges, powders for reconstitution, liquid preparations, or suppositories. Preferably, compounds may be administered by intravenous infusion or topical administration, but more preferably by oral administration.

[0125] For oral administration, the compounds of the invention can be provided in the form of tablets or capsules, or as a solution, emulsion, or suspension. Tablets for oral use may include the active ingredient mixed with pharmaceutically acceptable excipients such as inert diluents, disintegrating agents, binding agents, lubricating agents, sweetening agents, flavoring agents, coloring agents and preservatives. Suitable inert fillers include sodium and calcium carbonate, sodium and calcium phosphate, lactose, starch, sugar, glucose, methyl cellulose, magnesium stearate, mannitol, sorbitol, and the like; typical liquid oral excipients include ethanol, glycerol, water and the like. Starch, polyvinyl-pyrrolidone, sodium starch glycolate, microcrystalline cellulose, and alginic acid are suitable disintegrating agents. Binding agents may include starch and gelatin. The lubricating agent, if present, will generally be magnesium stearate, stearic acid or talc. If desired, the tablets may be coated with a material such as glyceryl monostearate or glyceryl distearate to delay absorption in the gastrointestinal tract, or may be coated with an enteric coating. Capsules for oral use include hard gelatin capsules in which the active ingredient is mixed with a solid, semi-solid, or liquid diluent, and soft gelatin capsules wherein the active ingredient is mixed with water, an oil such as peanut oil or olive oil, liquid paraffin, a mixture of mono and di-glycerides of short chain fatty acids, polyethylene glycol 400, or propylene glycol.

[0126] Liquids for oral administration may be suspensions, solutions, emulsions or syrups or may be presented as a dry product for reconstitution with water or other suitable vehicles before use. Compositions of such liquid may contain pharmaceutically-acceptable excipients such as suspending agents (for example, sorbitol, methyl cellulose, sodium alginate, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminium stearate gel and the like); non-aqueous vehicles, which include oils (for example, almond oil or fractionated coconut oil), propylene glycol, ethyl alcohol or water; preservatives (for example, methyl or propyl p-hydroxybenzoate or sorbic acid); wetting agents such as lecithin; and, if needed, flavoring or coloring agents.

[0127] The compounds of this invention may also be administered by non-oral routes. The compositions may be formulated for rectal administration as a suppository. For parenteral use, including intravenous, intramuscular, intraperitoneal, or subcutaneous routes, the compounds of the invention will generally be provided in sterile aqueous solutions or suspensions, buffered to an appropriate pH and isotonicity or in parenterally acceptable oil. Suitable aqueous vehicles include Ringer's solution and isotonic sodium chloride. Such forms will be presented in unit dose form such as ampules or disposable injection devices, in multi-dose forms such as vials from which the appropriate dose may be withdrawn, or in a solid form or pre-concentrate that can be used to prepare an injectable formulation. Another mode of administration of the compounds of the invention may utilize a patch formulation to affect transdermal delivery. The compounds of this invention may also be administered by inhalation, via the nasal or oral routes using a spray formulation consisting of the compound of the invention and a suitable carrier.

[0128] Methods are known in the art for determining effective doses for therapeutic (treatment) and prophylactic (preventative) purposes for the pharmaceutical compositions or the drug combinations of the present invention, whether or not formulated in the same composition. The specific dosage level required for any particular patient will depend on a number of factors, including severity of the condition being treated, the route of administration, and the weight of the patient. For therapeutic purposes, “effective dose” or “effective amount” refers to that amount of each active compound or pharmaceutical agent, alone or in combination, that elicits the biological or medicinal response in a tissue system, animal, or human that is being sought by a researcher, veterinarian, medical doctor, or other clinician, which includes alleviation of the symptoms of the disease or disorder being treated. For prophylactic purposes (i.e., preventing or inhibiting the onset or progression of a disorder), the term “effective dose” or “effective amount” refers to that amount of each active compound or pharmaceutical agent, alone or in combination, that inhibits in a subject the onset or progression of a disorder as being sought by a researcher, veterinarian, medical doctor, or other clinician, the delaying of which disorder is mediated, at least in part, by the modulation of the serotonin receptor. Methods of combination therapy include co-administration of a single formulation containing all active agents; essentially contemporaneous administration of more than one formulation; and administration of two or more active agents separately formulated.

[0129] It is anticipated that the daily dose (whether administered as a single dose or as divided doses) will be in the range 0.01 to 1000 mg per day, more usually from 1 to 500 mg per day, and most usually from 10 to 200 mg per day. Expressed as dosage per unit body weight, a typical dose will be expected to be between 0.0001 mg/kg and 15 mg/kg, especially between 0.01 mg/kg and 7 mg/kg, and most especially between 0.15 mg/kg and 2.5 mg/kg.

[0130] Preferably, oral doses range from about 0.05 to 200 mg/kg, daily, taken in 1 to 4 separate doses. Some compounds of the invention may be orally dosed in the range of about 0.05 to about 50 mg/kg daily, others may be dosed at 0.05 to about 20 mg/kg daily, while still others may be dosed at 0.1 to about 10 mg/kg daily. Infusion doses can range from about 1 to 1000 μg/kg/min of inhibitor, admixed with a pharmaceutical carrier over a period ranging from several minutes to several days. For topical administration compounds of the present invention may be mixed with a pharmaceutical carrier at a concentration of about 0.1% to about 10% of drug to vehicle.

EXAMPLES

[0131] In order to illustrate the invention, the following examples are included. These examples do not limit the invention. They are only meant to suggest a method of practicing the invention. Those skilled in the art may find other methods of practicing the invention, which are obvious to them. However, those methods are deemed to be within the scope of this invention.

[0132] Preparative Reversed-Phase HPLC was performed as follows:

Method A. Instrument, Hewlett Packard Series 1100; Column, Agilent ZORBAX® Bonus RP, 5 μm, 4.6×250 mm; Flow rate, 1 mL/min; Detection, λ=220 & 254 nm; Gradient, 1 to 99% acetonitrile/water, 0.05% trifluoroacetic acid over 20 min.

Method B. Instrument, Hewlett Packard HPLC; Column, Agilent ZORBAX® Eclipse XDB-C8, 5 μm, 4.6×150 mm; Flow rate, 1 mL/min; Detection, λ=220 & 254 nm; Gradient, 1 to 99% acetonitrile/water, 0.05% trifluoroacetic acid over 8 min.

[0133] Mass spectra were obtained on an Agilent series 1100 MSD using electrospray ionization (ESI) in either positive or negative modes as indicated.

[0134] Thin-layer chromatography was performed using Merck silica gel 60 F₂₅₄2.5 cm×7.5 cm 250 μm or 5.0 cm×10.0 cm 250 μm pre-coated silica gel plates. Preparative thin-layer chromatography was performed using EM Science silica gel 60 F₂₅₄20 cm×20 cm 0.5 mm pre-coated plates with a 20 cm×4 cm concentrating zone.

[0135] NMR spectra were obtained on either a Bruker model DPX400 (400 MHz), DPX500 (500 MHz), or DPX600 (600 MHz) spectrometer. The format of the ¹H NMR data below is: chemical shift in ppm down field of the tetramethylsilane reference (multiplicity, coupling constant J in Hz, integration).

[0136]

Example 1

2-tert-Butyl-4-(4-fluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

[0137] Step A. 2-tert-Butyl-4-(4-fluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine hydrochloride. To a tert-BuOH (17 mL) solution of 4-oxo-piperidine-1,3-dicarboxylic acid-1-tert-butyl ester-3-ethyl ester (2.18 g, 8.05 mmol), and 2,2-dimethyl-propionamidine hydrochloride (1.0 g, 7.3 mmol) was added Et₃N (3.0 mL, 22.0 mmol). The reaction solution was heated at reflux for 48 h, cooled to rt, and concentrated. The resulting solid was dissolved in CH₂Cl₂and washed with water. The aqueous layer was extracted with CH₂Cl₂. The combined organic layers were dried and concentrated to give a yellow solid that was triturated with Et₂O to give 1.74 g (70%) of the title compound as a white solid. MS (ESI): exact mass calcd. for C₁₆H₂₅N₃O₃, 307.19; m/z found, 308.4 [M+H]⁺. ¹H NMR (CDCl₃): 4.35 (s, 2H), 3.68-3.67 (m, 2H), 2.74-2.65 (m, 2H), 1.49 (s, 9H), 1.37 (s, 9H).
Step B. 2-tert-Butyl-4-trifluoromethanesulfonyloxy-7,8-dihydro-5H-pyrido[4,3-d]pyrimidine-6-carboxylic acid tert-butyl ester. To a 0° C. solution of the product from Step A (1.0 g, 3.25 mmol) in CH₂Cl₂(16 mL) was added Et₃N (0.53 mL, 3.80 mmol) and trifluoromethanesulfonic anhydride (0.64 mL, 3.8 mmol) dropwise over 10 min. After 2 h at 0° C., the mixture was diluted with CH₂Cl₂and washed with water. The aqueous layer was extracted with CH₂Cl₂. The combined organic layers were dried and concentrated. The resulting residue was purified via SiO₂chromatography (10-30% EtOAc/hexanes) to give 1.28 g (91%) of the title compound. MS (ESI): exact mass calcd. for C₁₇H₂₄F₃N₃O₃S, 439.14; m/z found, 440.3 [M+H]⁺. ¹H NMR (CDCl₃): 4.56 (s, 2H), 3.77 (t, J=5.7, 2H), 2.99-2.95 (m, 2H), 1.50 (s, 9H), 1.36 (s, 9H).
Step C. 2-tert-Butyl-4-(4-fluoro-phenyl)-7,8-dihydro-5H-pyrido[4,3-d]pyrimidine-6-carboxylic acid tert-butyl ester. To the product from Step B (0.17 g, 0.39 mmol) was added 4-fluorophenylboronic acid (0.082 g, 0.586 mmol), K₃PO₄(0.124 g, 0.584 mmol), Pd(Cl)₂dppf.CH₂Cl₂(0.018 g, 0.022 mmol) and dppf (0.008 g, 0.014 mmol). The mixture was evacuated with N₂, dioxane (4 mL) was added and the mixture was heated at reflux for 2 h. After cooling to room temperature (rt), the mixture was diluted with Et₂O, filtered through a small SiO₂plug, and the filtrate was concentrated. The resulting residue was purified via SiO₂chromatography (5-30% EtOAc/hexanes) to give 0.134 g (89%) of the title compound. MS (ESI): exact mass calcd. for C₂₂H₂₈FN₃O₂, 385.22; m/z found, 386.4 [M+H]⁺. ¹H NMR (CDCl₃): 7.60 (dd, J=5.4, 8.8, 2H), 7.17-7.14 (m, 2H), 4.59 (s, 2H), 3.76 (t, J=6.1, 2H), 3.09 (t, J=6.1, 2H), 1.44 (s, 9H), 1.41 (s, 9H).
Step D. 2-tert-Butyl-4-(4-fluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine hydrochloride. To an EtOAc solution of the product from Step D (0.130 g, 0.337 mmol) was added 4 M HCl in dioxane. After stirring for 18 h the volatiles were removed and the solid partitioned between water and EtOAc. The aqueous layer was made basic with 1 N NaOH and extracted with EtOAc (2×). The combined organic layers were dried with MgSO₄, filtered and concentrated. The resulting residue was purified via SiO₂chromatography (1-7% 2 M NH₃in MeOH/CH₂Cl₂) to give 0.079 g (82%) of the title compound. The corresponding HCl salt was obtained upon treatment of the free base in Et₂O with 1 M HCl in Et₂O. MS (ESI): exact mass calcd. for C₁₇H₂₀FN₃, 285.16; m/z found, 286.4 [M+H]⁺. ¹H NMR (DMSO-d₆): 9.74 (s, 2H), 7.71 (dd, J=5.5, 8.6, 2H), 7.42 (d, J=8.8, 2H), 4.31 (m, 2H), 3.49-3.48 (m, 2H), 3.16 (t, J=6.2, 2H), 1.38 (s, 9H).

[0138]

Example 2

2-Benzyl-4-(4-fluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

[0139] Step A. 2-Benzyl-4-trifluoromethanesulfonyloxy-7,8-dihydro-5H-pyrido[4,3-d]pyrimidine-6-carboxylic acid tert-butyl ester. To a solution of 2-benzyl-4-hydroxy-7,8-dihydro-5H-pyrido[4,3-d]pyrimidine-6-carboxylic acid tert-butyl ester (2.0 g, 5.9 mmol; prepared from 2-phenyl-acetamidine hydrochloride as described in Example 1, Step A) in THF (15 mL) was added KOtBu (0.408 g, 3.6 mmol). After 15 min, the mixture was treated with N-phenyl-bis(trifluoromethanesulfonimide) (1.18 g, 3.3 mmol) and the mixture was stirred for 18 h. The mixture was diluted with water and extracted with EtOAc (2×). The combined organic layers were dried and concentrated. The resulting residue was purified via SiO₂chromatography (10-40% EtOAc/hexanes) to give 1.15 g (81%) of the title compound which was contaminated with byproducts from N-phenyl-bis(trifluoromethanesulfonimide).
Step B. 2-Benzyl-4-(4-fluoro-phenyl)-7,8-dihydro-5H-pyrido[4,3-d]pyrimidine-6-carboxylic acid tert-butyl ester. The title compound was prepared as described in Example 1, Step C. MS (ESI): exact mass calcd. for C₂₅H₂₆FN₃O₂, 419.20; m/z found, 420.5 [M+H]⁺. ¹H NMR (CDCl₃): 7.53 (dd, J=5.3, 8.7, 2H), 7.43-7.41 (m, 2H), 7.31-7.28 (m, 2H), 7.23-7.14 (m, 3H), 4.55 (s, 2H), 4.27 (s, 2H), 3.75 (t, J=6.1, 2H), 3.00 (t, J=6.0, 2H), 1.43 (s, 9H).
Step C. 2-Benzyl-4-(4-fluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine. A solution of the product from Step B (0.131 g, 0.312 mmol) in CH₂Cl₂was treated with TFA. After stirring for 4 h, the mixture was concentrated and partitioned between saturated (satd.) aq. NaHCO₃and CH₂Cl₂(2×). The combined organic layers were dried and concentrated. The resulting residue was purified via SiO₂chromatography (1-7% 2 M NH₃in MeOH/CH₂Cl₂) to give 0.084 g (84%) of the title compound. MS (ESI): exact mass calcd. for C₂₀H₁₈FN₃, 319.15; m/z found, 320.4 [M+H]⁺. ¹H NMR (CDCl₃): 7.51 (dd, J=5.4, 8.8, 2H), 7.41 (d, J=7.4, 2H), 7.31-7.27 (m, 2H), 7.22-7.19 (m, 1H), 7.15 (dd, J=8.7, 2H), 4.27 (s, 2H), 3.95 (s, 2H), 3.24 (t, J=6.1, 2H), 2.97 (t, J=6.1, 2H).
Unless otherwise specified, the compounds in Examples 3-57 were prepared using methods similar to those described in Examples 1 and 2, utilizing the appropriate β-ketoesters, amidine hydrochlorides, and arylboronic acids.

[0140]

Example 3

2-sec-Butyl-4-(4-fluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine hydrochloride

[0141] MS (ESI): exact mass calcd. for C₁₇H₂₀FN₃, 285.16; m/z found, 286.4 [M+H]⁺. ¹H NMR (DMSO-d₆): 9.72 (s, 2H), 7.69 (dd, J=5.5, 8.8, 2H), 7.42 (dd, J=8.8, 2H), 4.33-4.27 (m, 2H), 3.52-3.44 (m, 2H), 3.16 (t, J=6.4, 2H), 2.96-2.88 (m, 1H), 1.88-1.77 (m, 1H), 1.66-1.56 (m, 1H), 1.26 (d, J=6.9, 3H), 0.83 (t, J=7.4, 3H).

[0142]

Example 4

2-sec-Butyl-4-p-tolyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine hydrochloride

[0143] MS (ESI): exact mass calcd. for C₂₁H₂₁N₃, 281.19; m/z found, 282.5 [M+H]⁺. ¹H NMR (DMSO-d₆): 9.69 (s, 2H), 7.52 (d, J=8.1, 2H), 7.38 (d, J=7.4?, 2H), 4.33-4.26 (m, 2H), 3.52-3.54 (m, 2H), 3.15 (t, J=6.3, 2H), 2.96-2.87 (m, 1H), 2.92 (m, 1H), 2.40 (s, 3H), 1.88-1.77 (m, 1H), 1.67-1.55 (m, 1H), 1.26 (d, J=6.9, 3H), 0.83 (t, J=7.4, 3H).

[0144]

Example 5

2-Cyclobutyl-4-(4-fluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine hydrochloride

[0145] MS (ESI): exact mass calcd. for C₁₇H₁₈FN₃, 283.15; m/z found, 284.3 [M+H]⁺. ¹H NMR (DMSO-d₆): 9.72 (m, 2H), 7.70 (dd, J=5.5, 8.8, 2H), 7.44-7.40 (m, 2H), 4.32-4.26 (m, 2H), 3.79-3.73 (m, 1H), 3.50-3.45 (m, 2H), 3.16 (t, J=6.4, 2H), 2.42-2.27 (m, 4H), 2.08-1.99 (m, 1H), 1.91-1.83 (m, 1H).

[0146]

Example 6

2-Cyclobutyl-4-p-tolyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

[0147]

Example 7

2-Cyclopropyl-4-(4-fluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

[0148] MS (ESI): exact mass calcd. for C₁₆H₁₆FN₃, 269.13; m/z found, 270.3 [M+H]⁺. ¹H NMR (DMSO-d₆): 9.81 (m, 2H), 7.67 (dd, J=5.4, 8.6, 2H), 7.40 (dd, J=8.8, 2H), 4.26-4.22 (m, 2H), 3.48-3.42 (m, 2H), 3.11 (t, J=6.3, 2H), 2.24-2.19 (m, 1H), 1.08-1.01 (m, 4H).

[0149]

Example 8

2-Benzyl-4-p-tolyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

[0150] MS (ESI): exact mass calcd. for C₂₁H₂₁N₃, 315.17; m/z found, 316.4 [M+H]⁺. ¹H NMR (CDCl₃): 7.43-7.41 (m, 4H), 7.30-7.25 (m, 4H), 7.21-7.18 (m, 1H), 4.27 (s, 2H), 3.97 (s, 2H), 3.23 (t, J=6.1, 2H), 2.96 (t, J=6.1, 2H), 2.40 (s, 3H).

[0151]

Example 9

2-Benzyl-4-(4-trifluoromethyl-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

[0152]

Example 10

2-Benzyl-4-(3,4-difluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

[0153]

Example 11

2-Benzyl-4-phenyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

[0154]

Example 12

2-Benzyl-4-(3-fluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

[0155]

Example 13

2-(4-Fluoro-benzyl)-4-(4-fluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

[0156] MS (ESI): exact mass calcd. for C₂₀H₁₇F₂N₃, 337.14; m/z found, 338.4 [M+H]⁺. ¹H NMR (CDCl₃): 7.53-7.49 (m, 2H), 7.38-7.35 (m, 2H), 7.18-7.13 (m, 2H), 6.99-6.95 (m, 2H), 4.23 (s, 2H), 3.96 (s, 2H), 3.25 (t, J=6.1, 2H), 2.97 (t, J=6.1, 2H).

[0157]

Example 14

2-(4-Fluoro-benzyl)-4-(4-fluoro-phenyl)-6-methyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

[0158]

Example 15

4-[2-(4-Fluoro-benzyl)-6-methyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yl]-benzonitrile

[0159]

Example 16

4-[2-(4-Fluoro-benzyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yl]-benzonitrile

[0160]

Example 17

2-Cyclopentyl-4-(4-fluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

[0161] MS (ESI): exact mass calcd. for C₁₈H₂₀FN₃, 297.16; m/z found, 298.4 [M+H]⁺. ¹H NMR (CDCl₃): 7.55 (dd, J=5.4, 8.8, 2H), 7.15 (t, J=8.8, 2H), 3.97 (s, 2H), 3.36-3.28 (m, 1H), 3.26 (t, J=6.1, 2H), 2.97 (t, J=6.1, 2H), 2.12-1.64 (m, 8H).

[0162]

Example 18

2-Cyclopentyl-4-p-tolyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

[0163] MS (ESI): exact mass calcd. for C₁₉H₂₃N₃, 293.19; m/z found, 294.5 [M+H]⁺. ¹H NMR (CDCl₃): 7.55 (dd, J=5.4, 8.8, 2H), 7.15 (t, J=8.8, 2H), 3.97 (s, 2H), 3.36-3.27 (m, 1H), 3.26 (t, J=6.1, 2H), 2.97 (t, J=6.1, 2H), 2.12-1.64 (m, 8H).

[0164]

Example 19

2-Cyclopentyl-4-(4-methoxy-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

[0165]

Example 20

4-(2-Cyclopentyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yl)-benzonitrile

[0166]

Example 21

4-(4-Fluoro-phenyl)-2-isopropyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine hydrochloride

[0167] MS (ESI): exact mass calcd. for C₁₆H₁₈FN₃, 271.15; m/z found, 272.4 [M+H]⁺. ¹H NMR (MeOH-d₄): 7.75-7.70 (m, 2H), 7.37-7.31 (m, 2H), 4.47 (s, 2H), 3.72-3.68 (m, 2H), 3.37-3.32 (m, 2H), 3.30-3.22 (m, 1H), 1.39 (d, J=6.9, 6H).

[0168]

Example 22

4-(4-Fluoro-phenyl)-2-isopropyl-6-methyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

[0169]

Example 23

4-(3,4-Dichloro-phenyl)-2-isopropyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine hydrochloride

[0170] MS (ESI): exact mass calcd. for C₁₆H₁₇Cl₂N₃, 321.08; m/z found, 322.3 [M+H]⁺. ¹H NMR (MeOH-d₄): 7.86-7.84 (m, 1H), 7.77-7.74 (m, 1H), 7.60-7.57 (m, 1H), 4.47 (s, 2H), 3.71-3.67 (m, 2H), 3.35-3.32 (m, 2H), 3.29-3.21 (m, 1H), 1.38 (d, J=6.9, 6H).

[0171]

Example 24

4-(3,4-Difluoro-phenyl)-2-isopropyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine hydrochloride

[0172] MS (ESI): exact mass calcd. for C₁₆H₁₇F₂N₃, 289.14; m/z found, 290.4 [M+H]⁺. ¹H NMR (MeOH-d₄): 7.67-7.62 (m, 1H), 7.54-7.47 (m, 2H), 4.48 (s, 2H), 3.71-3.67 (m, 2H), 3.35-3.32 (m, 2H), 3.29-3.21 (m, 1H), 1.38 (d, J=6.9, 6H).

[0173]

Example 25

4-(3-Fluoro-phenyl)-2-isopropyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

[0174]

Example 26

4-(2-Fluoro-phenyl)-2-isopropyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

[0175]

Example 27

4-(2,4-Difluoro-phenyl)-2-isopropyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

[0176]

Example 28

2-Isopropyl-4-p-tolyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

[0177]

Example 29

4-(4-Chloro-phenyl)-2-isopropyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

[0178]

Example 30

2-Isopropyl-4-(4-methoxy-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

[0179]

Example 31

2-Isopropyl-4-phenyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

[0180]

Example 32

2-Isopropyl-4-(4-trifluoromethyl-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

[0181]

Example 33

2-Isopropyl-4-(2-phenoxy-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

[0182]

Example 34

2-Isobutyl-4-thiophen-3-yl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

[0183] MS (ESI): exact mass calcd. for C₁₅H₁₉N₃S, 273.13; m/z found, 274.1 [M+H]⁺. ¹H NMR (CDCl₃): 7.67 (dd, J=1.3, 2.9, 1H), 7.52 (dd, J=1.3, 5.0, 1H), 7.40 (dd, J=2.9, 5.0, 1H), 4.11 (s, 2H), 3.2 (t, J=6.1, 2H), 2.96 (t, J=6.1, 2H), 2.80 (d, J=7.3, 2H), 2.35-2.25 (m, 1H), 0.98 (d, J=6.7, 6H).

[0184]

Example 35

2-Isobutyl-4-thiophen-2-yl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

[0185] MS (ESI): exact mass calcd. for C₁₅H₁₉N₃S, 273.13; m/z found, 274.1 [M+H]⁺. ¹H NMR (CDCl₃): 7.52 (dd, J=1.0, 5.1, 1H), 7.48 (dd, J=1.0, 3.8, 1H), 7.16 (dd, J=3.8, 5.1, 1H), 4.22, (s, 2H), 3.27 (t, J=6.0, 2H), 2.96 (t, J=6.0, 2H), 2.78 (d, J=7.3, 2H), 2.36-2.26 (m, 1H), 0.99 (d, J=6.7, 6H).

[0186]

Example 36

2-Isobutyl-4-pyridin-4-yl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

[0187] MS (ESI): exact mass calcd. for C₁₆H₂₀N₄, 268.17; m/z found, 269.2 [M+H]⁺. ¹H NMR (CDCl₃): 8.75-8.74 (m, 2H), 7.44-7.43 (m, 2H), 3.97 (s, 2H), 3.28 (t, J=6.0, 2H), 3.01 (t, J=6.0, 2H), 2.83 (d, J=7.3, 2H), 2.34-2.23 (m, 1H), 0.98 (d, J=6.7, 6H).

[0188]

Example 37

4-(4-Fluoro-phenyl)-2-isobutyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

[0189]

Example 38

2-Isobutyl-4-p-tolyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

[0190]

Example 39

4-(4-Fluoro-3-methyl-phenyl)-2-isobutyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

[0191]

Example 40

4-(2-Isobutyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yl)-benzonitrile

[0192]

Example 41

2-Isobutyl-4-(4-methoxy-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

[0193]

Example 42

2-sec-Butyl-4-(2-fluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine hydrochloride

[0194] MS (ESI): exact mass calcd. for C₁₇H₂₀FN₃, 285.16; m/z found, 286.4 [M+H]⁺. ¹H NMR (DMSO-d₆): 9.62 (s, 2H), 7.66-7.61 (m, 1H), 7.51-7.39 (m, 3H), 4.08-4.06 (m, 2H), 3.55-3.47 (m, 2H), 3.17 (dd, J=6.3, 2H), 2.93 (tq, J=6.9, 7.4, 1H), 1.86-1.75 (m, 1H), 1.66-1.55 (m, 1H), 1.25 (d, J=6.9, 3H), 0.82 (t, J=7.4, 3H).

[0195]

Example 43

2-sec-Butyl-4-(3-fluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

[0196]

Example 44

2-sec-Butyl-4-(4-methoxy-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

[0197]

Example 45

2-sec-Butyl-4-(4-trifluoromethoxy-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

[0198] The following Examples 46-57 were prepared as described in Examples 1 and 2, substituting 5-oxo-azepane-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester (J. Het. Chem. 1992, 29(4), 779-786) for 4-oxo-piperidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester.

[0199]

Example 46

2-Cyclopentyl-4-(4-fluoro-phenyl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine

[0200] MS (ESI): exact mass calcd. for C₁₉H₂₂FN₃, 311.18; m/z found, 312.4 [M+H]⁺. ¹H NMR (CDCl₃): 7.46 (dd, J=5.4, 8.6, 2H), 7.14 (dd, J=8.7, 2H), 3.32-3.26 (m, 1H), 3.18-3.16 (m, 2H), 3.07-3.05 (m, 2H), 2.96-2.92 (m, 4H), 2.12-2.06 (m, 2H), 1.99-1.91 (m, 2H), 1.87-1.80 (m, 2H), 1.72-1.64 (m, 2H).

[0201]

Example 47

2-Cyclopentyl-4-p-tolyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine

[0202] MS (ESI): exact mass calcd. for C₂₀H₂₅N₃, 307.2; m/z found, 308.4 [M+H]⁺. ¹H NMR (CDCl₃): 7.37 (d, J=8.1, 2H), 7.26 (m, 2H), 3.32-3.26 (m, 1H), 3.17-3.15 (m, 2H), 3.07-3.05 (m, 2H), 2.94 (m, 4H), 2.41 (s, 3H), 2.11-2.05 (m, 2H), 2.0-1.93 (m, 2H), 1.86-1.79 (m, 2H), 1.71-1.62 (m, 2H).

[0203]

Example 48

2-Cyclopentyl-4-(4-methoxy-phenyl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine

[0204] MS (ESI): exact mass calcd. for C₂₀H₂₅N₃O, 323.2; m/z found, 324.5 [M+H]⁺. ¹H NMR (CDCl₃): 7.44 (d, J=8.9, 2H), 6.98 (d, J=8.9, 2H), 3.86 (s, 3H), 3.35-3.26 (m, 1H), 3.17-3.15 (m, 2H), 3.07-3.05 (m, 2H), 2.12-2.05 (m, 2H), 2.00-1.92 (m, 2H), 1.87-1.80 (m, 2H), 1.71-1.64 (m, 2H).

[0205]

Example 49

4-(2-Cyclopentyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl)-benzonitrile

[0206]

Example 50

4-(4-Fluoro-phenyl)-2-isopropyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine hydrochloride

[0207] MS (ESI): exact mass calcd. for C₁₇H₂₀FN₃, 285.16; m/z found, 286.2 [M+H]⁺. ¹H NMR (MeOH-d₄): 7.76-7.71 (m, 2H), 7.41-7.36 (m, 2H), 3.69-3.65 (m, 2H), 3.63-3.59 (m, 2H), 3.49-3.45 (m, 2H), 3.42-3.34 (m, 3H), 1.45 (d, J=6.9, 6H).

[0208]

Example 51

4-(4-Chloro-phenyl)-2-methyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine

[0209]

Example 52

2-Methyl-4-phenyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine

[0210]

Example 53

4-(3-Chloro-phenyl)-2-methyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine

[0211]

Example 54

2-Benzyl-4-(4-fluoro-phenyl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine

[0212] MS (ESI): exact mass calcd. for C₂₁H₂₀FN₃, 333.16; m/z found, 334.4 [M+H]⁺. ¹H NMR (CDCl₃): 7.44-7.42 (m, 4H), 7.31-7.28 (m, 2H), 7.23-7.20 (m, 1H), 7.16-7.13 (m, 2H), 4.25 (s, 2H), 3.18-3.16 (m, 2H), 3.06-3.03 (m, 2H), 2.94-2.90 (m, 4H).

[0213]

Example 55

2-Benzyl-4-p-tolyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine

[0214] MS (ESI): exact mass calcd. for C₂₂H₂₃N₃, 329.19; m/z found, 330.5 [M+H]⁺. ¹H NMR (CDCl₃): 7.45-7.43 (m, 2H), 7.35-7.33 (m, 2H), 7.30-7.25 (m, 4H), 7.22-7.19 (m, 1H), 4.25 (s, 2H), 3.17-3.15 (m, 2H), 3.05-3.03 (m, 2H), 2.41 (s, 3H).

[0215]

Example 56

2-Benzyl-4-(4-trifluoromethyl-phenyl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine

[0216] MS (ESI): exact mass calcd. for C₂₂H₂₀F₃N₃, 383.16; m/z found, 384.4 [M+H]⁺. ¹H NMR (CDCl₃): 7.72 (d, J=8.1, 2H), 7.55 (d, J=8.0, 2H), 7.43 (d, J=7.5, 2H), 7.31-7.28 (m, 2H), 7.23-7.20 (m, 1H), 4.26 (s, 2H), 3.20-3.18 (m, 2H), 3.06-3.04 (m, 2H), 2.95-2.93 (m, 2H), 2.90-2.88 (m, 2H).

[0217]

Example 57

2-(4-Fluoro-benzyl)-4-(4-fluoro-phenyl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine

[0218] MS (ESI): exact mass calcd. for C₂₁H₁₉F₂N₃, 351.15; m/z found, 352.4 [M+H]⁺. ¹H NMR (CDCl₃): 7.44-7.41 (m, 2H), 7.40-7.36 (m, 2H), 7.18-7.12 (m, 2H), 7.01-6.95 (m, 2H), 4.21 (s, 2H), 3.19-3.17 (m, 2H), 3.07-3.04 (m, 2H), 2.96-2.92 (m, 4H).

[0219]

Example 58

2-Cyclopentyl-4-(4-fluoro-phenyl)-7-methyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine

[0220] To a solution of 2-cyclopentyl-4-(4-fluoro-phenyl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine (0.035 g, 0.112 mmol) in MeOH (1 mL) was added formaldehyde (37% in water; 0.10 mL) and NaBH(OAc)₃(0.032 g, 0.151 mmol). After the reaction was judged complete, the mixture was diluted with 1 N NaOH and extracted with CH₂Cl₂(3×). The combined organic layers were dried and concentrated. The resulting residue was purified via SiO₂chromatography (1-7% 2 M NH₃in MeOH/CH₂Cl₂) to give 0.031 g (87%) of the title compound. MS (ESI): exact mass calcd. for C₂₀H₂₄FN₃, 325.20; m/z found, 326.4 [M+H]⁺. ¹H NMR (CDCl₃): 7.47 (dd, J=5.4, 8.8, 2H), 7.15 (t, J=8.7, 2H), 3.38-3.30 (m, 1H), 3.20 (dd, J=4.1, 6.3, 2H), 2.97 (dd, J=4.2, 5.9, 2H), 2.71-2.70 (m, 2H), 2.60 (m, 2H), 2.41 (s, 3H), 2.12-2.05 (m, 2H), 1.99-1.91 (m, 2H), 1.87-1.79 (m, 2H), 1.73-1.63 (m, 2H).
The following compounds in Examples 59-62 were prepared using methods similar to those described in Example 58, starting with the corresponding unmethylated azepines from the preceding examples.

[0221]

Example 59

2-Cyclopentyl-7-methyl-4-p-tolyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine

[0222] MS (ESI): exact mass calcd. for C₂₁H₂₇N₃, 321.22; m/z found, 322.5 [M+H]⁺. ¹H NMR (CDCl₃): 7.39-7.37 (m, 2H), 7.27-7.25 (m, 2H), 3.35-3.26 (m, 1H), 3.20-3.18 (m, 2H), 3.0-2.97 (m, 2H), 2.7-2.68 (m, 2H), 2.59 (m, 2H), 2.41 (s, 3H), 2.40 (s, 3H), 2.12-2.04 (m, 2H), 2.0-1.91 (m, 2H), 1.88-1.79 (m, 2H), 1.72-1.61 (m, 2H).

[0223]

Example 60

2-Cyclopentyl-4-(4-methoxy-phenyl)-7-methyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine

[0224] MS (ESI): exact mass calcd. for C₂₁H₂₇N₃O, 337.22; m/z found, 338.5 [M+H]⁺. ¹H NMR (CDCl₃): 7.44 (d, J=8.8, 2H), 6.98 (d, J=8.8, 2H), 3.86 (s, 3H), 3.34-3.26 (m, 1H), 3.19 (dd, J=4.2, 6.2, 2H), 3.01 (dd, J=4.3, 5.5, 2H), 2.71-2.69 (m, 2H), 2.61 (m, 2H), 2.41 (s, 3H), 2.12-2.05 (m, 2H), 2.0-1.91 (m, 2H), 1.87-1.79 (m, 2H), 1.71-1.63 (m, 2H).

[0225]

Example 61

2-Benzyl-7-methyl-4-p-tolyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine

[0226] MS (ESI): exact mass calcd. for C₂₃H₂₅N₃, 343.2; m/z found, 344.5 [M+H]⁺. ¹H NMR (CDCl₃): 7.43 (d, J=7.3, 2H), 7.35 (d, J=8.0, 2H), 7.30-7.25 (m, 4H), 7.21-7.19 (m, 1H), 4.26 (s, 2H), 3.18-3.16 (m, 2H), 2.97-2.95 (m, 2H), 2.66-2.65 (m, 2H), 2.56 (m, 2H), 2.41 (s, 3H), 2.38 (s, 3H).

[0227]

Example 62

2-(4-Fluoro-benzyl)-4-(4-fluoro-phenyl)-7-methyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine

[0228] MS (ESI): exact mass calcd. for C₂₂H₂₁F₂N₃, 365.17; m/z found, 366.4 [M+H]⁺. ¹H NMR (CDCl₃): 7.46-7.42 (m, 2H), 7.39-7.36 (m, 2H), 7.18-7.13 (m, 2H), 7.0-6.95 (m, 2H), 4.22 (s, 2H), 3.20-3.17 (m, 2H), 2.96-2.93 (m, 2H), 2.67-2.65 (m, 2H), 2.58-2.55 (m, 2H), 2.39 (s, 3H).

[0229]

Example 63

2-(4-Fluoro-benzyl)-4-(4-fluoro-phenyl)-7-methyl-9-methylene-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine

[0230] To a solution of 2-(4-fluoro-benzyl)-4-(4-fluoro-phenyl)-5,6,8,9-tetrahydro-pyrimido[4,5-d]azepine-7-carboxylic acid tert-butyl ester in formic acid was added paraformaldehyde (10 equiv.). The mixture was heated at 80° C. for 6 h. The mixture was diluted with water and basified to pH ˜10 with 1 M NaOH. The mixture was extracted with CH₂Cl₂, dried and concentrated. Chromatography on SiO₂(0-5% 2 M NH₃in MeOH/CH₂Cl₂) afforded the desired compound. 2-(4-Fluoro-benzyl)-4-(4-fluoro-phenyl)-7-methyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine was also obtained. MS (ESI): exact mass calcd. for C₂₃H₂₁F₂N₃, 377.17; m/z found, 378.4 [M+H]⁺. ¹H NMR (CDCl₃): 7.50-7.46 (m, 2H), 7.42-7.37 (m, 2H), 7.17-7.12 (m, 2H), 6.99-6.94 (m, 4H), 6.03-6.01 (m, 1H), 5.47-5.46 (m, 1H), 4.25 (s, 2H), 3.51 (s, 2H), 2.87-2.83 (m, 2H), 2.76-2.72 (m, 2H), 2.41 (s, 3H).

[0231]

Example 64

2-Benzyl-4-(4-fluoro-phenyl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-c]azepine hydrochloride

[0232] Step A. 3-Oxo-azepane-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester and 4-oxo-azepane-1,3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester. To a 0° C. solution of 3-oxo-piperidine-1-carboxylic acid tert-butyl ester (11.3 g, 56.7 mmol) in Et₂O (170 mL) was added BF₃.Et₂O (7.2 mL, 56.7 mmol) and ethyl diazoacetate (7.2 mL, 68.0 mmol) dropwise over 30 min. After an additional 1 h, satd. aq. NaHCO₃was added and the solution was stirred for 1 h, then was extracted with Et₂O (2×). The combined organic layers were washed with brine, dried and concentrated. The resulting residue was purified via SiO₂chromatography (10-30% EtOAc/hexanes) to give 5.48 g (34%) of 3-oxo-azepane-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester. In addition, 5.25 g (32%) of the more polar 4-oxo-azepane-1,3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester was isolated.
Step B. 2-Benzyl-4-(4-fluoro-phenyl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-c]azepine. The title compound was prepared from 3-oxo-azepane-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester according to the methods described in Example 1. MS (ESI): exact mass calcd. for C₂₁H₂₀FN₃, 333.16; m/z found, 334.4 [M+H]⁺. ¹H NMR (DMSO-d₆): 9.81 (m, 2H), 7.55 (dd, J=5.5, 8.7, 2H), 7.40-7.35 (m, 4H), 7.31-7.27 (m, 2H), 7.22-7.19 (m, 1H), 4.46-4.43 (m, 2H), 4.21 (s, 2H), 3.43-3.33 (m, 2H), 3.00-2.93 (m, 2H), 1.98-1.88 (m, 2H).
The following compounds in Examples 65-68 were prepared using methods similar to those described in Example 64.

[0233]

Example 65

4-(4-Fluoro-phenyl)-2-isopropyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-c]azepine hydrochloride

[0234] MS (ESI): exact mass calcd. for C₁₇H₂₀FN₃, 285.16; m/z found, 286.4 [M+H]⁺. ¹H NMR (DMSO-d₆): 9.77 (s, 2H), 7.57 (dd, J=5.5, 8.7, 2H), 7.40-7.37 (m, 2H), 4.49-4.44 (m, 2H), 3.43-3.36 (m, 2H), 3.19-3.10 (m, 1H), 2.99-2.97 (m, 2H), 1.99-1.92 (m, 2H), 1.30 (d, J=6.9, 6H).

[0235]

Example 66

2-Isopropyl-4-p-tolyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-c]azepine hydrochloride

[0236] MS (ESI): exact mass calcd. for C₁₈H₂₃N₃, 281.19; m/z found, 282.4 [M+H]⁺. ¹H NMR (DMSO-d₆): 9.80 (s, 2H), 7.41 (d, J=8.0, 2H), 7.35 (d, J=8.0, 2H), 4.46 (m, 2H), 3.50-3.36 (m, 2H), 3.18-3.10 (m, 1H), 3.90-2.98 (m, 2H), 2.8 (s, 3H), 1.98-1.90 (m, 2H), 1.29 (d, J=6.9, 6H).

[0237]

Example 67

2-Isopropyl-4-(4-methoxy-phenyl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-c]azepine

[0238]

Example 68

2-Isopropyl-4-phenyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-c]azepine

[0239]

Example 69

2-Benzyl-4-(4-fluoro-phenyl)-6,7,8,9-tetrahydro-5H-1,3,6-triaza-benzocycloheptene hydrochloride

[0240] The title compound was synthesized as described in Example 64 using 4-oxo-azepane-1,3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester. MS (ESI): exact mass calcd. for C₂₁H₂₀FN₃, 333.16; m/z found, 334.4 [M+H]⁺. ¹H NMR (DMSO-d₆): 9.59 (s, 2H), 7.66 (dd, J=5.5, 8.8, 2H), 7.42-7.27 (m, 6H), 7.22-7.19 (m, 1H), 4.29-4.26 (m, 2H), 4.21 (s, 2H), 3.42-0.36 (m, 2H), 3.22-3.20 (m, 2H), 2.01-1.95 (m, 2H).

[0241]

Example 70

2,7-Dibenzyl-4-(4-fluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidine hydrochloride

[0242] The title compound was synthesized as described in Example 1, Steps A-C, using 1-benzyl-3-oxo-piperidine-4-carboxylic acid ethyl ester hydrochloride. Purification was performed using SiO₂chromatography (2 M NH₃in MeOH/CH₂Cl₂). MS (ESI): exact mass calcd. for C₂₇H₂₄FN₃, 409.2; m/z found, 410.5 [M+H]⁺. ¹H NMR (MeOH-d₄): 7.74-7.70 (m, 2H), 7.66-7.63 (m, 2H), 7.56-7.53 (m, 3H), 7.36-7.18 (m, 7H), 4.59 (s, 2H), 4.49 (br s, 2H), 4.29 (s, 2H).
The compounds in Examples 71-75 were prepared using methods similar to those described in Example 70.

[0243]

Example 71

2,7-Dibenzyl-4-p-tolyl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidine

[0244]

Example 72

2,7-Dibenzyl-4-phenyl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidine

[0245]

Example 73

2,7-Dibenzyl-4-(4-methoxy-phenyl)-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidine

[0246]

Example 74

7-Benzyl-4-(4-fluoro-phenyl)-2-isopropyl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidine

[0247]

Example 75

7-Benzyl-2-isopropyl-4-phenyl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidine

[0248]

Example 76

2-Benzyl-4-(4-fluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidine hydrochloride

[0249] To a solution of 2,7-dibenzyl-4-(4-fluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidine hydrochloride in EtOH was added 10% Pd/C (1 equiv) followed by 1,4-cyclohexadiene (5 equiv). The mixture was heated at 85° C. for 5 h, filtered and concentrated. The residue was dissolved in CH₂Cl₂and treated with Dowex 550A resin. After 1 h, the resin was removed by filtration and the filtrate was concentrated. Chromatography on SiO₂(2 M NH₃in MeOH/CH₂Cl₂) afforded the title compound. MS (ESI): exact mass calcd. for C₂₀H₁₈FN₃, 319.15; m/z found, 320.4 [M+H]⁺. ¹H NMR (MeOH-d₄): 7.70-7.67 (m, 2H), 7.36-7.35 (m, 2H), 7.31-7.25 (m, 4H), 7.20-7.17 (m, 1H), 4.42 (s, 2H), 4.26 (s, 2H), 3.48 (t, J=6.1, 2H), 3.09 (t, J=6.1, 2H).
The compounds in Examples 77-81 were prepared using methods similar to those described in Example 76.

[0250]

Example 77

2-Benzyl-4-p-tolyl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidine hydrochloride

[0251] MS (ESI): exact mass calcd. for C₂₁H₂₁N₃, 315.17; m/z found, 316.4 [M+H]⁺. ¹H NMR (MeOH-d₄): 7.55-7.54 (m, 2H), 7.44-7.36 (m, 4H), 7.29-7.26 (m, 2H), 7.22-7.19 (m, 1H), 4.46 (s, 2H), 4.29 (s, 2H), 3.48 (t, J=6.1, 2H), 3.12 (t, J=6.1, 2H), 2.44 (s, 3H).

[0252]

Example 78

2-Benzyl-4-phenyl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidine

[0253]

Example 79

2-Benzyl-4-(4-methoxy-phenyl)-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidine

[0254]

Example 80

4-(4-Fluoro-phenyl)-2-isopropyl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidine hydrochloride

[0255] MS (ESI): exact mass calcd. for C₁₆H₁₈FN₃, 271.15; m/z found, 272.4 [M+H]⁺. ¹H NMR (MeOH-d₄): 7.74-7.72 (m, 2H), 7.33-7.30 (m, 2H), 4.48 (s, 2H), 3.51 (t, J=6.0, 2H), 3.26-3.20 (m, 1H), 3.12 (t, J=6.0, 2H), 1.37 (d, J=7.2, 6H).

[0256]

Example 81

2-Isopropyl-4-phenyl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidine

The compounds in Examples 82-85 were prepared using methods similar to those described in Example 58.

[0257]

Example 82

2-Benzyl-4-(4-fluoro-phenyl)-7-methyl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidine hydrochloride

[0258] MS (ESI): exact mass calcd. for C₂₁H₂₀FN₃, 333.16; m/z found, 334.4 [M+H]⁺. ¹H NMR (MeOH-d₄): 7.70-7.68 (m, 2H), 7.36-7.17 (m, 7H), 4.70-4.60 (m, 1H), 4.45-4.35 (m, 1H), 4.25 (s, 2H), 3.76 (brs, 1H), 3.11-3.01 (m, 4H).

[0259]

Example 83

2-Benzyl-4-(4-fluoro-phenyl)-7-isopropyl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidine

[0260]

Example 84

4-(4-Fluoro-phenyl)-2-isopropyl-7-methyl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidine hydrochloride

[0261] MS (ESI): exact mass calcd. for C₁₇H₂₀FN₃, 285.16; m/z found, 286.3 [M+H]⁺. ¹H NMR (MeOH-d₄): 7.74-7.71 (m, 2H), 7.32-7.29 (m, 2H), 4.72-4.62 (m, 1H), 4.49-4.37 (m, 1H), 3.79 (brs, 1H), 3.43-3.32 (m, 2H), 3.25-3.19 (m, 1H), 3.13 (s, 3H), 3.09-2.99 (m, 1H), 1.35 (d, J=6.6, 6H).

[0262]

Example 85

2-Isopropyl-7-methyl-4-phenyl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidine

[0263]

Example 86

7-Benzyl-2-isopropyl-4-(5-methyl-thiophen-3-yl)-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidine hydrochloride

Step A. 4-(7-Benzyl-2-isopropyl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidin-4-yl)-thiophene-2-carbaldehyde. The title compound was prepared as described in Example 1, Steps A-C.

[0264] Step B. 7-Benzyl-2-isopropyl-4-(5-methyl-thiophen-3-yl)-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidine. To a solution of the product of Step A (0.230 g) in ethylene glycol was added hydrazine hydrate (0.1 mL). The mixture was heated at 200° C. for 1 h, then KOH (0.150 g) was added and the heating continued for 6 h. The mixture was allowed to cool then was diluted with water and extracted with Et₂O. The combined organic extracts were dried and concentrated to 0.210 g of pale yellow solid. Chromatography on SiO₂(EtOAc/hexanes) afforded 0.146 g of the title compound. MS (ESI): exact mass calcd. for C₂₂H₂₅N₃S, 363.18; found m/z 364.4 [M+H]⁺. ¹H NMR (MeOH-d₄): 7.85-7.84 (m, 1H), 7.65-7.63 (m, 2H), 7.56-7.55 (m, 3H), 7.37-7.36 (m, 1H), 4.60 (br s, 2H), 4.44 (brs, 2H), 3.46-3.32 (m, 2H), 3.22-3.17 (m, 1H), 2.55 (s, 3H), 1.34 (d, J=7.2, 6H).

[0265]

Example 87

7-Benzyl-2-isopropyl-4-thiophen-3-yl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidine hydrochloride

The title compound was prepared according to the methods described in Example 86.

[0266] MS (ESI): exact mass calcd. for C₂₁H₂₃N₃S, 349.16; m/z found, 350.4 [M+H]⁺. ¹H NMR (MeOH-d₄): 8.29-8.28 (m, 1H), 7.72-7.69 (m, 4H), 7.56-7.55 (m, 3H), 4.65 (s, 2H), 4.59 (br s, 2H), 3.89 (br s, 1H), 3.57-3.32 (m, 4H), 1.40 (d, J=6.6, 6H).

[0267]

Example 88

2-Isopropyl-4-(5-methyl-thiophen-3-yl)-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidine hydrochloride

[0268] A solution of 7-benzyl-2-isopropyl-4-(5-methyl-thiophen-3-yl)-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidine hydrochloride (0.133 g) in 1,2-dichloroethane (7 mL) was treated with 1-chloroethylchloroformate (0.105 mL). The mixture was heated at 95° C. for 16 h, concentrated, dissolved in MeOH, and heated at 50° C. for an additional 2 h. The mixture was concentrated and chromatographed on SiO₂(2 M NH₃in MeOH/CH₂Cl₂). MS (ESI): exact mass calcd. for C₁₅H₁₉N₃S, 273.13; m/z found, 274.3 [M+H]⁺. ¹H NMR (MeOH-d₄): 7.81-7.80 (m, 1H), 7.36-7.35 (m, 1H), 4.42 (s, 2H), 3.55 (t, J=6.0, 2H), 3.25 (t, J=6.0, 2H), 3.19 (m, 1H), 2.55 (s, 3H), 1.35 (d, J=7.2, 6H).

[0269]

Example 89

2-Isopropyl-4-thiophen-3-yl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidine hydrochloride

The title compound was prepared according to the methods described in Example 88.

[0270] MS (ESI): exact mass calcd. for C₁₄H₁₇N₃S, 259.11; m/z found, 260.3 [M+H]⁺. ¹H NMR (MeOH-d₄): 8.16-8.15 (m, 1H), 7.70-7.65 (m, 2H), 4.49 (s, 2H), 3.57 (t, J=6.0, 2H), 3.31-3.23 (m, 3H), 1.39 (d, J=7.2, 6H).

The following Examples 90-91 were prepared using methods similar to those described in Example 58.

[0271]

Example 90

2-Isopropyl-7-methyl-4-(5-methyl-thiophen-3-yl)-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidine hydrochloride

[0272] MS (ESI): exact mass calcd. for C₁₆H₂₁N₃S, 287.15; m/z found, 288.3 [M+H]⁺. ¹H NMR (MeOH-d₄): 7.79 (s, 1H), 7.36 (s, 1H), 4.65-4.54 (m, 1H), 4.45-4.35 (m, 1H), 3.83 (br s, 1H), 3.41 (brs, 1H), 3.27 (brs, 1H), 3.20-3.13 (m, 4H), 2.55 (s, 3H), 1.34 (d, J=7.2, 6H).

[0273]

Example 91

2-Isopropyl-7-methyl-4-thiophen-3-yl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidine hydrochloride

[0274] MS (ESI): exact mass calcd. for C₁₅H₁₉N₃S, 273.13; m/z found, 274.3 [M+H]⁺. ¹H NMR (MeOH-d₄): 8.27 (t, J=1.8, 1H), 7.71 (d, J=1.8, 2H), 4.82-4.71 (m, 1H), 4.63-4.49 (m, 1H), 3.95-3.81 (m, 1H), 3.57-3.41 (m, 1H), 3.34-3.32 (m, 1H), 3.16 (s, 3H), 1.41 (d, J=6.6, 6H).

[0275] The following compounds in Examples 92-99 were prepared using the methods similar to those described for Example 70 utilizing 1-benzyl-5-methyl-4-oxo-piperidine-3-carboxylic acid ethyl ester in place of 1-benzyl-3-oxo-piperidine-4-carboxylic acid ethyl ester hydrochloride.

[0276]

Example 92

6-Benzyl-4-(4-fluoro-phenyl)-2-isopropyl-8-methyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

[0277]

Example 93

6-Benzyl-4-(3-chloro-4-fluoro-phenyl)-2-isopropyl-8-methyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

[0278]

Example 94

6-Benzyl-2-isopropyl-8-methyl-4-p-tolyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

[0279]

Example 95

6-Benzyl-2-isopropyl-8-methyl-4-phenyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

[0280]

Example 96

6-Benzyl-2-isopropyl-8-methyl-4-(4-trifluoromethyl-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

[0281]

Example 97

6-Benzyl-4-(4-chloro-phenyl)-2-isopropyl-8-methyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

[0282]

Example 98

6-Benzyl-2-isopropyl-8-methyl-4-thiophen-3-yl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

[0283]

Example 99

6-Benzyl-4-(4′-chloro-biphenyl-4-yl)-2-isopropyl-8-methyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

The following compounds in Examples 100-105 were prepared using methods similar to those described in Example 76.

[0284]

Example 100

4-(4-Fluoro-phenyl)-2-isopropyl-8-methyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine hydrochloride

[0285] MS (ESI): exact mass calcd. for C₁₇H₂₀FN₃, 285.16; m/z found, 286.4 [M+H]⁺. ¹H NMR (MeOH-d₄): 7.69-7.66 (m, 2H), 7.34-7.30 (m, 2H), 4.56-4.53 (m, 1H), 4.32-4.29 (m, 1H), 3.81-3.78 (m, 1H), 3.45-3.38 (m, 1H), 3.36-3.30 (m, 1H), 3.26-3.24 (m, 1H), 1.55 (d, J=7.2, 3H), 1.37 (d, J=6.6, 6H).

[0286]

Example 101

4-(3-Chloro-4-fluoro-phenyl)-2-isopropyl-8-methyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine hydrochloride

[0287] MS (ESI): exact mass calcd. for C_1-7H₁₉ClFN₃, 319.13; m/z found, 320.3 [M+H]⁺. ¹H NMR (MeOH-d₄): 7.79-7.77 (m, 1H), 7.60-7.58 (m, 1H), 7.46-7.44 (m, 1H), 4.56-4.54 (m, 1H), 4.32-4.29 (m, 1H), 3.80-3.77 (m, 1H), 3.40-3.32 (m, 2H), 3.26-3.20 (m, 1H), 1.54 (d, J=7.2, 3H), 1.36 (d, J=7.2, 6H).

[0288]

Example 102

2-Isopropyl-8-methyl-4-p-tolyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine hydrochloride

[0289] MS (ESI): exact mass calcd. for C₁₈H₂₃N₃, 281.19; m/z found, 282.4 [M+H]⁺. ¹H NMR (MeOH-d4): 7.57-7.56 (m, 2H), 7.45-7.44 (m, 2H), 4.59-4.56 (m, 1H), 4.35-4.33 (m, 1H), 3.83-3.80 (m, 1H), 3.52-3.49 (m, 1H), 3.40-3.30 (m, 2H), 2.46 (s, 3H), 1.58 (d, J=7.2, 3H), 1.41 (d, J=6.6, 6H).

[0290]

Example 103

2-Isopropyl-8-methyl-4-phenyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

[0291]

Example 104

2-Isopropyl-8-methyl-4-(4-trifluoromethyl-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

[0292]

Example 105

2-Isopropyl-8-methyl-4-thiophen-3-yl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

[0293]

Example 106

4-(4-Fluoro-phenyl)-2-isopropyl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidine hydrochloride

[0294] Step A. 6-Benzyl-2-isopropyl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-ol. To a solution of 1-benzyl-4-oxo-pyrrolidine-3-carboxylic acid ethyl ester hydrochloride (U.S. Pat. No. 3,312,716; 0.568 g, 2.30 mmol) in tert-BuOH was added isobutyramidine hydrochloride (0.282 g, 2.30 mmol) and KOtBu (0.516 g, 4.6 mmol). After heating for 6 h at 100° C., the reaction was cooled to rt, concentrated, diluted with water and washed with Et₂O. The organic layer discarded. The aqueous layer was adjusted to pH 7 and extracted with Et₂O. The organic layers were then dried and concentrated to give 0.145 g (23%) of the title compound of yellow solid that was used without further purification.
Steps B and C. The title compound was prepared according to the methods described in Example 1, Steps B and C. MS (ESI): exact mass calcd. for C₂₂H₂₂FN₃, 347.18; m/z found, 348.3 [M+H]⁺. ¹H NMR (MeOH-d₄): 7.99-7.96 (m, 2H), 7.61-7.60 (m, 2H), 7.53-7.51 (m, 3H), 7.34-7.32 (m, 2H), 5.09 (br s, 2H), 4.71 (br s, 4H), 3.31-3.25 (m, 1H), 1.38 (d, J=7.2, 6H).

[0295]

Example 107

4-(4-Fluoro-phenyl)-2-isopropyl-7-pyrrolidin-1-yl-5,6,7,8-tetrahydro-quinazoline

[0296] Step A. 4-Ethoxy-2-oxo-cyclohex-3-enecarboxylic acid ethyl ester. To a −78° C. solution of LDA (192 mmol) in THF (200 mL) was added 3-ethoxy-cyclohex-2-enone (23 mL) dropwise. After stirring for 1 h at −78° C., ethyl cyanoformate (16 mL) was added. The mixture was stirred at −78° C. for 4 h and then was warmed to rt and stirred for 1 h. The mixture was concentrated, diluted with aq. NH₄Cl (300 mL), and poured into water. The resulting solids were collected by suction filtration and washed with hexanes followed by water, then was dried and concentrated to provide 17.1 g of a brown solid. TLC (SiO₂, 33% EtOAc/hexanes): R_f=0.43.
Step B. 7-Oxo-1,4-dioxa-spiro[4.5]decane-8-carboxylic acid ethyl ester. To a solution of the product of Step A (25.4 g resulting from iterative reactions) in toluene (500 mL) was added ethylene glycol (8.5 mL) and p-TsOH (1.9 g). The mixture was heated at reflux for 4 h in a flask fitted with a Dean-Stark trap. The mixture was then cooled and concentrated. Chromatography on SiO₂(0 to 15% EtOAc/hexanes) afforded 7.76 g of the desired compound. TLC (SiO₂, 25% EtOAc/hexanes): R_f=0.42.
Step C. 2-Isopropyl-7-(2-[1,3]dioxolane)-5,6,7,8-tetrahydro-quinazolin-4-ol. The title compound was prepared according to the method described in Example 1, Step A. MS (ESI): exact mass calcd. for C₁₃H₁₈N₂O₃, 250.13; m/z found, 251.3 [M+H]⁺.
Step D. Trifluoro-methanesulfonic acid 2-isopropyl-7-(2-[1,3]Dioxolane)-5,6,7,8-tetrahydro-quinazolin-4-yl ester. The title compound was prepared according to the method described in Example 1, Step B. TLC (SiO₂, 25% EtOAc/hexanes): R_f=0.46. MS (ESI): exact mass calcd. for C₁₄H₁₇F₃N₂O₅S, 382.08; m/z found, 383.2 [M+H]⁺.
Step E. 4-(4-Fluoro-phenyl)-2-isopropyl-7-(2-[1,3]dioxolane)-5,6,7,8-tetrahydro-quinazoline. The title compound was prepared according to the method described in Example 1, Step C. TLC (SiO₂, 25% EtOAc/hexanes): R_f=0.40. MS (ESI): exact mass calcd. for C₁₉H₂₁FN₂O₂, 328.16; m/z found, 329.3 [M+H]⁺.
Step F. 4-(4-Fluoro-phenyl)-2-isopropyl-5,8-dihydro-6H-quinazolin-7-one. To a solution of the product of Step E (1.15 g) in THF (70 mL) was added 1 M HCl (6 mL). The mixture was heated at 60° C. for 10 h, cooled to rt, and poured into 350 mL of water. The aqueous mixture was basified to pH ˜9 with 1 M NaOH, and was extracted with CH₂Cl₂. The organic layer was dried and concentrated to afford 0.98 g of the desired compound, which was used in the next step without purification. MS (ESI): exact mass calcd. for C₁₇H₁₇FN₂O, 284.13; m/z found, 285.3 [M+H]⁺.
Step G. 4-(4-Fluoro-phenyl)-2-isopropyl-7-pyrrolidin-1-yl-5,6,7,8-tetrahydro-quinazoline. To a solution of the product of Step F (0.128 g) in MeOH (4 mL) was added of bromocresol green (0.003 g), pyrrolidine (0.06 mL), and NaBH₃CN (0.20 g). To this mixture was added 1 M HCl in MeOH until a persistent color change to yellow was observed. After 30 min, the mixture was quenched with 1 M NaOH and poured into water (50 mL). The mixture was extracted with CH₂Cl₂, dried and concentrated. Chromatography on SiO₂(0 to 5% 2 M NH₃in MeOH/CH₂Cl₂) afforded 0.015 g of the desired compound. MS (ESI): exact mass calcd. for C₂₁H₂₆FN₃, 339.21; m/z found, 340.4 [M+H]⁺. ¹H NMR (CDCl₃): 7.59-7.54 (m, 2H), 7.18-7.13 (m, 2H), 3.76-3.68 (m, 1H), 3.50-3.44 (m, 1H), 3.41-3.35 (m, 1H), 3.28-3.14 (m, 2H), 3.0-2.93 (m, 1H), 2.88-2.70 (m, 4H), 2.36-2.23 (m, 3H), 2.19-2.09 (m, 1H), 1.98-1.87 (m, 2H).

[0297]

Example 108

[4-(4-Fluoro-phenyl)-2-isopropyl-5,6,7,8-tetrahydro-quinazolin-7-yl]-methyl-amine hydrochloride

The title compound was prepared according to the method described for Example 107.

[0298] MS (ESI): exact mass calcd. for C₁₈H₂₂FN₃, 299.18; m/z found, 300.4 [M+H]⁺. ¹H NMR (MeOH-d₄): 7.80-7.72 (m, 2H), 7.37-7.30 (m, 2H), 3.81-3.71 (m, 1H), 3.65-3.56 (m, 1H), 3.35-3.26 (m, 1H), 3.22-3.14 (m, 1H), 3.11-3.00 (m, 1H), 2.99-2.91 (m, 1H), 2.85 (s, 3H), 2.42-2.33 (m, 1H), 1.92-1.82 (m, 1H), 1.43-1.38 (m, 6H).

[0299]

Example 109

[4-(4-Fluoro-phenyl)-2-isopropyl-5,6,7,8-tetrahydro-quinazolin-6-yl]-methyl-amine hydrochloride

[0300] The title compound was prepared according to the methods described for Example 107, using 1,4-dioxa-spiro[4.5]decan-8-one. MS (ESI): exact mass calcd. for C₁₈H₂₂FN₃, 299.18; m/z found, 300.4 [M+H]⁺. ¹H NMR (MeOH-d₄): 7.87-7.82 (m, 2H), 7.40-7.35 (m, 2H), 3.59-3.52 (m, 1H), 3.41-3.24 (m, 4H), 3.20-3.13 (m, 1H), 2.76 (s, 3H), 2.54-2.47 (m, 1H), 2.21-2.11 (m, 1H), 1.45 (d, J=6.9, 3H), 1.44 (d, J=6.9, 3H).

[0301]

Example 110

4-(4-Fluoro-phenyl)-2-isopropyl-5,6,7,8-tetrahydro-quinazolin-7-ol

[0302] To a solution of 4-(4-fluoro-phenyl)-2-isopropyl-5,8-dihydro-6H-quinazolin-7-one (0.126 g) in EtOH (3 mL) was added NaBH₄(0.053 g). After 16 h, the mixture was treated with 1 M NaOH (5 mL) and water (10 mL). The mixture was stirred for 30 min then extracted with CH₂Cl₂. The organic layer was dried and concentrated. Chromatography on SiO₂(10 to 35% EtOAc/hexanes) afforded 0.98 g of the title compound. TLC (SiO₂, 50% EtOAc/hexanes): R_f=0.18. MS (ESI): exact mass calcd. for C₁₇H₁₉FN₂O, 286.15; m/z found, 287.3 [M+H]⁺.

[0303]

Example 111

4-(4-Fluoro-phenyl)-2-isopropyl-5,6,7,8-tetrahydro-quinazoline

[0304] The title compound was obtained as a minor product from the hydrogenation of of 4-(4-fluoro-phenyl)-2-isopropyl-5,8-dihydro-6H-quinazolin-7-one with 10% Pd/C in the presence of pyrrolidine. MS (ESI): exact mass calcd. for C₁₇H₁₉FN₂, 270.15; m/z found, 271.3 [M+H]⁺. ¹H NMR (CDCl₃): 7.59-7.55 (m, 2H), 7.16-7.12 (m, 2H), 3.21-3.13 (m, 1H), 2.95-2.91 (m, 2H), 2.71-2.67 (m, 2H), 1.95-1.89 (m, 2H), 1.77-1.72 (m, 2H), 1.35 (d, J=6.9, 6H).

[0305]

Example 112

(2-Benzyl-6-p-tolyl-pyrimidin-4-ylmethyl)-dimethyl-amine

[0306] Step A. 2-Benzyl-4-(tetrahydro-pyran-2-yloxymethyl)-6-p-tolyl-pyrimidine. To a solution of Pd(PPh₃)₂Cl₂(0.285 g, 0.41 mmol) and CuI in THF (50 mL) (0.148 g, 0.777 mmol) was added Et₃N (1.5 mL, 11.0 mmol), p-toluoyl chloride (1.3 mL, 10.0 mmol) and tetrahydro-2-(2-propynyloxy)-2H-pyran (1.4 mL, 10.0 mmol). After stirring for 2.5 h, a solution of 2-phenylacetamidine hydrochloride (2.0 g, 11.7 mmol) in THF/MeOH (1:1, 10 mL) was added followed by additional MeOH (5 mL) and Na₂CO₃(3.2 g, 30.0 mmol). The reaction mixture was heated at reflux for 15 h, cooled to rt, diluted with Et₂O and filtered through a small pad of diatomaceous earth. The filtrate was concentrated and purified via SiO₂chromatography (10-45% EtOAc/hexanes) to give 2.0 g (53%) of the title compound. ¹H NMR (CDCl₃): 8.02-8.00 (m, 2H), 7.68 (s, 1H), 7.46-7.44 (m, 2H), 7.30-7.27 (m, 4H), 7.21-7.19 (m, 1H), 4.87 (d, J=14.7, 1H), 4.77 (t, J=3.5, 1H), 4.62 (d, J=15.1, 1H), 4.31 (s, 2H), 3.91-3.86 (m, 1H), 3.57-3.52 (m, 1H), 2.41 (s, 3H), 1.96-1.87 (m, 1H), 1.84-1.72 (m, 2H), 1.66-1.55 (m, 3H).
Step B. (2-Benzyl-6-p-tolyl-pyrimidin-4-yl)-methanol. To a solution of the product from Step A (2.0 g, 5.3 g) in MeOH (30 mL) was added p-TsOH.H₂O. After 18 h, the reaction was diluted with satd. aq. NaHCO₃and extracted with EtOAc (2×). The combined organic layers were dried and concentrated to give the 1.53 g (99%) of the title compound. MS (ESI): exact mass calcd. for C₁₉H₁₈N₂O, 290.14; m/z found, 291.4 [M+H]⁺. ¹H NMR (CDCl₃): 8.00-7.98 (m, 2H), 7.45-7.43 (m, 3H), 7.32-7.28 (m, 4H), 7.23-7.20 (m, 1H), 4.74 (d, J=4.8, 2H), 4.33 (s, 2H), 3.62 (t, J=5.1, 1H), 2.42 (s, 3H).
Step C. (2-Benzyl-6-p-tolyl-pyrimidin-4-ylmethyl)-dimethyl-amine. To a solution of the product from Step B (0.102 g, 0.35 mmol) in CH₂Cl₂(2 mL) was added the Dess-Martin periodinane (0.228, 0.53 mmol). After 30 min, the mixture was diluted satd. aq. NaHCO₃and extracted with CH₂Cl₂(2×). The combined organic layers were dried, concentrated, and filtered through a small plug of SiO₂(25% EtOAc in hexanes). The filtrate was concentrated to give 2-benzyl-6-p-tolyl-pyrimidine-4-carbaldehyde (0.55 g, 54%). To a solution of this aldehyde in CH₂Cl₂(3 mL) was added dimethylamine (2 M in THF; 0.15 mL, 0.30 mmol) and NaBH(OAc)₃(0.058 mg, 0.27 mmol). After 15 h, the reaction was diluted with CH₂Cl₂and washed with 1 N NaOH. The aqueous layer was extracted with CH₂Cl₂(1×). The combined organic layers were dried and concentrated. The resulting residue was purified via SiO₂chromatography (1-7% 2 M NH₃in MeOH/CH₂Cl₂) to give 0.050 g (79%) of the title compound. MS (ESI): exact mass calcd. for C₂₁H₂₃N₃, 317.19; m/z found, 318.4 [M+H]⁺. ¹H NMR (CDCl₃): 8.02 (d, J=8.2, 2H), 7.66 (s, 1H), 7.22 (d, J=7.5, 2H), 7.31-7.26 (m, 4H), 7.22-7.18 (m, 1H), 4.33 (s, 2H), 3.58 (s, 2H), 2.41 (s, 3H), 2.32 (s, 6H).
The compounds in Examples 113-114 were prepared using methods similar to those described in Example 112, with the appropriate substituent changes.

[0307]

Example 113

2-Benzyl-4-(4-methyl-piperazin-1-ylmethyl)-6-p-tolyl-pyrimidine

[0308] MS (ESI): exact mass calcd. for C₂₄H₂₈N₄, 372.23; m/z found, 373.5 [M+H]⁺. ¹H NMR (CDCl₃): 8.02-7.99 (m, 2H), 7.66 (s, 1H), 7.46-7.44 (m, 2H), 7.31-7.27 (m, 4H), 7.22-7.18 (m, 1H), 4.32 (s, 2H), 3.66 (s, 2H), 2.58-2.50 (m, 8H), 2.42 (s, 3H), 2.32 (s, 3H).

[0309]

Example 114

[6-(4-Fluoro-phenyl)-2-isopropyl-pyrimidin-4-ylmethyl]-methyl-amine

[0310] Prop-2-ynyl-carbamic acid tert-butyl ester was converted to [6-(4-fluoro-phenyl)-2-isopropyl-pyrimidin-4-ylmethyl]-methyl-carbamic acid tert-butyl ester using methods described in Example 112, Step A. This ester was deprotected according to the methods described in Example 1, Step D, to provide the title compound. MS (ESI): exact mass calcd. for C₁₅H₁₈FN₃, 259.15; m/z found, 260.3 [M+H]⁺. ¹H NMR (DMSO-d₆): 9.45 (s, 2H); 8.31-8.28 (m, 2H), 8.10 (s, 1H), 7.45-7.41 (m, 2H), 4.35 (t, J=6.0, 2H), 3.26-3.18 (m, 1H), 2.69 (t, J=5.4, 3H), 1.37 (d, J=6.9, 6H).

[0311]

Example 115

2-(2-Benzyl-6-p-tolyl-pyrimidin-4-yl)-ethylamine

[0312] Step A and B. 2-(2-Benzyl-6-p-tolyl-pyrimidin-4-yl)-ethanol. The title compound was prepared from 2-(3-butynyloxy)tetrahydro-2H-pyran using the methods described in Example 112, Steps A and B. MS (ESI): exact mass calcd. for C₂₀H₂₀N₂O, 304.16; m/z found, 305.4 [M+H]⁺. ¹H NMR (CDCl₃): 7.98 (d, J=8.2, 2H), 7.42-7.42 (m, 2H), 7.34-7.29 (m, 4H), 7.25-7.22 (m, 1H), 4.31 (s, 2H), 3.98 (t, J=5.3, 2H), 2.97 (t, J=5.3, 2H), 2.42 (s, 3H).
Step C. 4-(2-Azido-ethyl)-2-benzyl-6-p-tolyl-pyrimidine. To a 0° C. solution of the product of Step B (0.150 g, 0.493 mmol) in THF (2.5 mL) was added MsCl (0.042 mL, 0.54 mmol) followed by Et₃N (0.76 mL, 0.54 mmol). After 1 h, EtOAc was added and the mixture washed with brine, dried and concentrated to give methanesulfonic acid 2-(2-benzyl-6-p-tolyl-pyrimidin-4-yl)-ethyl ester (0.185 g). To a solution of this mesylate (0.120 g, 0.32 mmol) in DMF (1 mL) was added sodium azide (0.105 g, 1.6 mmol). The flask was heated at 40° C. for 10 h, then was cooled to rt, diluted with water, and extracted with EtOAc (3×). The combined organic layers were dried and concentrated. The resulting residue was purified via SiO₂chromatography (5-15% EtOAc/hexanes) to give 0.080 g (76%) of the title compound. MS (ESI): exact mass calcd. for C₂₀H₁₉N₅, 329.16 m/z found, 330.4 [M+H]⁺. ¹H NMR (CDCl₃): 7.98 (d, J=8.2, 2H), 7.46-7.43 (m, 2H), 7.38 (s, 1H), 7.32-7.28 (m, 4H), 7.23-7.19 (m, 2H), 4.31 (s, 2H), 3.76 (t, J=6.8, 2H), 3.02 (t, J=6.8, 2H), 2.42 (s, 3H).
Step D. To a solution of the product of Step C (0.066 g, 0.2 mmol) in THF (2 mL) was added PPh₃(0.059 g, 2.2 mmol). After 18 h, water was added (0.10 mL) and the mixture was stirred for 48 h. The mixture was diluted with water and extracted with CH₂Cl₂(2×). The combined organic layers were dried and concentrated. The resulting residue was purified via SiO₂chromatography (5-15% EtOAc/hexanes) to give 0.060 g (99%) of the title compound. MS (ESI): exact mass calcd. for C₂₀H₂₁N₃, 303.17; m/z found, 304.4 [M+H]⁺. ¹H NMR (CDCl₃): 7.98-7.96 (m, 2H), 7.45-7.44 (m, 2H), 7.36 (s, 1H), 7.32-7.28 (m, 4H), 7.23-7.19 (m, 1H), 4.31 (s, 2H), 3.13 (t, J=6.5, 2H), 2.91 (t, J=6.5, 2H), 2.42 (s, 3H).

[0313]

Example 116

[2-(4-Fluoro-benzyl)-4-p-tolyl-pyrimidin-5-ylmethyl]-dimethyl-amine

[0314] Step A. 2-(4-Fluoro-benzyl)-4-p-tolyl-pyrimidine-5-carboxylic acid ethyl ester. To solution of 3-dimethylamino-2-(4-methyl-benzoyl)-acrylic acid ethyl ester (Tetrahedron, 2002, 58, 8581-8589; 0.567 g, 2.15 mmol) in EtOH (10 mL) was added 2-(4-fluoro-phenyl)-acetamidine hydrochloride (0.405 g, 2.15 mmol) and Et₃N (0.90 mL, 6.5 mmol). The mixture was heated at reflux for 18 h, and then was diluted with water and extracted with EtOAc (2×). The combined organic layers were dried and concentrated. The resulting residue was purified via SiO₂chromatography (5-20% EtOAc/hexanes) to give 0.560 g (74%) of the title compound. MS (ESI): exact mass calcd. for C₂₁H₁₉FN₂O₂, 350.14; m/z found, 351.4 [M+H]⁺. ¹H NMR (CDCl₃): 8.97 (s, 1H), 7.51 (d, J=8.2, 2H), 7.38-7.35 (m, 2H), 7.27-7.26 (m, 2H), 7.01-6.97 (m, 2H), 4.32 (s, 2H), 4.23 (q, J=7.1, 2H), 2.42 (s, 3H), 1.16 (t, J=7.1, 3H).
Step B. [2-(4-Fluoro-benzyl)-4-p-tolyl-pyrimidin-5-yl]-methanol. To a 0° C. solution of the product from Step A (0.606 g, 1.73 mmol) in THF (8 mL) was added DIBAL-H (1.5 M in toluene; 2.5 mL, 3.8 mmol). The mixture was allowed to warm to rt, and was stirred for 18 h. The mixture was diluted with 20% aq. sodium potassium tartrate and extracted with EtOAc (2×). The combined organic layers were dried and concentrated. The resulting residue was purified via SiO₂chromatography (40-60% EtOAc/hexanes) to give 0.330 g (62%) of the title compound. MS (ESI): exact mass calcd. for C₁₉H₁₇FN₂O, 308.13; m/z found, 309.4 [M+H]⁺. ¹H NMR (CDCl₃): 8.77 (s, 1H), 7.58 (d, J=8.0, 2H), 7.38-7.35 (m, 2H), 7.29 (d, J=7.9, 2H), 6.99-6.96 (m, 2H), 4.70 (s, 2H), 4.29 (s, 2H), 2.42 (s, 3H).
Step C. The title compound was prepared using the methods described in Example 112, Step C. MS (ESI): exact mass calcd. for C₂₁H₂₂FN₃, 335.18; m/z found, 336.4 [M+H]⁺. ¹H NMR (CDCl₃): 8.67 (s, 1H), 7.69 (d, J=8.1, 2H), 7.40-7.36 (m, 2H), 7.29 (d, J=7.9, 2H), 7.01-6.96 (m, 2H), 4.29 (s, 2H), 3.36 (s, 2H), 2.42 (s, 3H), 2.22 (s, 6H).

[0315]

Example 117

4-(4-Fluoro-phenyl)-2-phenyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

[0316] The title compound was prepared as described in the preceding examples. MS (ESI): exact mass calcd. for C₁₉H₁₆FN₃, 305.35; m/z found, 306.4 [M+H]⁺. ¹H NMR (CDCl₃): 8.48-8.46 (m, 2H), 7.66 (dd, J=5.4, 8.7, 2H), 7.49-7.45 (m, 3H), 7.21-7.17, (m, J=8.7, 2H), 4.06 (s, 2H), 3.31 (t, J=6.1, 2H), 3.08 (t, J=6.1, 2H).
The following Examples 118-163 may be prepared according to the methods described in the preceding examples.

[0317]

Example 118

2-(3,3-Difluoro-cyclopentyl)-4-(4-fluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

[0318]

Example 119

4-(4-Fluoro-phenyl)-2-(tetrahydro-furan-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

[0319]

Example 120

4-(4-Fluoro-phenyl)-2-(2-piperidin-1-yl-ethyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

[0320]

Example 121

2-(1-Fluoro-1-methyl-ethyl)-4-(4-fluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

[0321]

Example 122

3-(4-Fluoro-phenyl)-5-isopropyl-4,6,12-triaza-tricyclo[7.2.1.02,7]dodeca-2,4,6-triene

[0322]

Example 123

7-(4-Fluoro-phenyl)-5-isopropyl-4,6,13-triaza-tricyclo[8.2.1.03,8]trideca-3,5,7-triene

[0323]

Example 124

4-(4-Fluoro-phenyl)-2-(tetrahydro-pyran-4-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

[0324]

Example 125

4-(4-Fluoro-phenyl)-2-(tetrahydro-pyran-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

[0325]

Example 126

4-(4-Fluoro-phenyl)-2-(2-methoxy-ethyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

[0326]

Example 127

2-[4-(4-Fluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-2-yl]-propan-2-ol

[0327]

Example 128

4-(4-Fluoro-phenyl)-2-(1-methyl-1-phenyl-ethyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

[0328]

Example 129

2-Cyclopent-3-enyl-4-(4-fluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

[0329]

Example 130

3-[4-(4-Fluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-2-yl]-cyclohexanol

[0330]

Example 131

4-(4-Fluoro-phenyl)-2-piperidin-4-yl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

[0331]

Example 132

4-(4-Fluoro-phenyl)-2-(1-methyl-piperidin-4-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

[0332]

Example 133

[4-(4-Fluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-2-yl]-phenyl-methanol

[0333]

Example 134

4-(4-Fluoro-phenyl)-2-(fluoro-phenyl-methyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

[0334]

Example 135

2-(Difluoro-phenyl-methyl)-4-(4-fluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

[0335]

Example 136

4-(4-Fluoro-phenyl)-2-phenyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

[0336]

Example 137

4-(4-Fluoro-phenyl)-2-(3-fluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

[0337]

Example 138

4-(4-Fluoro-phenyl)-2-(4-methoxy-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

[0338]

Example 139

4-(4-Fluoro-phenyl)-2-o-tolyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

[0339]

Example 140

3-[4-(4-Fluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-2-yl]-benzonitrile

[0340]

Example 141

4-(4-Fluoro-phenyl)-2-(2,2,2-trifluoro-1-trifluoromethyl-ethyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

[0341]

Example 142

4-(4-Fluoro-phenyl)-2-(1-methyl-cyclopropyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

[0342]

Example 143

2-[4-(4-Fluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-2-yl]-2-methyl-propionic acid

[0343]

Example 144

2-[4-(4-Fluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-2-yl]-propionic acid

[0344]

Example 145

2-(4-Fluoro-cyclohexyl)-4-(4-fluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

[0345]

Example 146

2-(4,4-Difluoro-cyclohexyl)-4-(4-fluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

[0346]

Example 147

4-(4-Fluoro-phenyl)-2-phenethyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

[0347]

Example 148

4-Furan-2-yl-2-isopropyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

[0348]

Example 149

2-Isopropyl-4-(5-methyl-furan-2-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

[0349]

Example 150

4-Furan-3-yl-2-isopropyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

[0350]

Example 151

4-(5-Fluoro-pyridin-2-yl)-2-isopropyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

[0351]

Example 152

2-Isopropyl-4-oxazol-2-yl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

[0352]

Example 153

4-(4,5-Dimethyl-oxazol-2-yl)-2-isopropyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

[0353]

Example 154

2-Isopropyl-4-thiazol-2-yl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

[0354]

Example 155

2-Isopropyl-4-(3H-[1,2,3]triazol-4-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

[0355]

Example 156

2-Isopropyl-4-(2H-pyrazol-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

[0356]

Example 157

2-Isopropyl-4-(1H-pyrazol-4-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

[0357]

Example 158

4-(4-Fluoro-phenyl)-2,6-diisopropyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

[0358]

Example 159

6-Ethyl-4-(4-fluoro-phenyl)-2-isopropyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

[0359]

Example 160

6-Cyclopropyl-4-(4-fluoro-phenyl)-2-isopropyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

[0360]

Example 161

6-Cyclobutyl-4-(4-fluoro-phenyl)-2-isopropyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

[0361]

Example 162

6-Cyclopentyl-4-(4-fluoro-phenyl)-2-isopropyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

[0362]

Example 163

6-Butyl-4-(4-fluoro-phenyl)-2-isopropyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

Example 164

Alternative preparation of 4-(4-fluoro-phenyl)-2-isopropyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

[0363] Step A. 1-(3,4,5,6,3′,6′-Hexahydro-2H,2′H-[1,4′]bipyridinyl-1′-yl)-ethanone. A flask equipped with a Dean-Stark trap and a reflux condenser was charged with 1-acetyl-piperdin-4-one (100 g, 0.71 mol) and toluene (1 L). Piperidine (63.4 g, 0.75 mol) and p-toluenesulfonic acid monohydrate (0.27 g, 1.4 mmol, 0.2 mol %) were added, and the resulting solution was heated at reflux for 8 h. The mixture was cooled to rt and concentrated to give a crude product which was used directly in the next reaction.
Step B. 1-[5′-(4-Fluoro-benzoyl)-3,4,5,6,3′,6′-hexahydro-2H,2′H-[1,4′]bipyridinyl-1′-yl]-ethanone. A solution of crude 1-(3,4,5,6,3′,6′-hexahydro-2H,2′H-[1,4′]bipyridinyl-1′-yl)-ethanone in CH₂Cl₂(1.5 L) was treated with Et₃N (108 mL, 0.78 mol) and then cooled to 0° C. A solution of 4-fluorobenzoyl chloride (107 g, 0.68 mol) in CH₂Cl₂(150 mL) was added over 1 h. The reaction mixture was stirred at rt for 2 h, then was concentrated to give a crude material which was directly used on next reaction. HPLC: R_T=7.52 min. MS (ESI): exact mass calcd. for C₁₉H₂₃FN₂O₂, 330.17; m/z found, 331.0 [M+H]⁺.
Step C. 1-[4-(4-Fluoro-phenyl)-2-isopropyl-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl]-ethanone. A solution of crude 1-[5′-(4-fluoro-benzoyl)-3,4,5,6,3′,6′-hexahydro-2H,2′H-[1,4′]bipyridinyl-1′-yl]-ethanone in t-amyl alcohol (1.5 L) was treated with Et₃N (108 mL, 0.78 mol) and 2-methyl propanimidamide hydrochloride (82.6 g, 0.67 mol). The reaction mixture was heated at reflux for 16 h and then was cooled to rt. The mixture was concentrated, and the residue was diluted with water (2 L) and extracted with EtOAc (2×). The combined organic layers were dried (MgSO₄) and concentrated to afford the crude title compound, which was used in next reaction without further purification. HPLC: R_T=8.11 min. MS (ESI): exact mass calcd. for C₁₈H₂₀FN₃O, 313.16; m/z found, 314.0 [M+H]⁺. ¹H NMR (CDCl₃; mixture of rotamers): 7.60-7.50 (m, 2H), 7.24-7.12 (m, 2H), 4.71 (s, 1.4H), 4.56 (s, 0.6H), 3.93 (t, J=6.2, 0.6H), 3.80 (t, J=6.2, 1.4H), 3.18 (sept, J=6.8, 1H), 3.07 (t, J=6.2, 1.4H), 3.02 (t, J=6.2, 0.6H), 2.15 (s, 2.1H), 2.00 (s, 0.9H), 1.34 (d, J=6.8, 6H).
Step D. A mixture of crude 1-[4-(4-fluoro-phenyl)-2-isopropyl-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl]-ethanone in 10% aq. HCl (800 mL) was heated at reflux for 2 h and then cooled to rt. The aqueous solution was washed with EtOAc (400 mL) and then was basified with NaOH pellets (˜120 g) to pH>12. The basic solution was extracted with CH₂Cl₂(2×500 mL). The combined organic layers were washed with 1 N NaOH (400 mL), dried (MgSO₄), and concentrated to give the crude product (100 g), which was used in the next reaction without further purification. HPLC: RT=6.89 min. MS (ESI): exact mass calcd. for C₁₆H₁₈FN₃, 271.15; m/z found, 271.9 [M+H]⁺.

Example 165

4-(4-Fluoro-phenyl)-2-isopropyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine, citrate salt

[0364] A solution of crude 4-(4-fluoro-phenyl)-2-isopropyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine (Example 164) in EtOH (1 L) was treated with citric acid (71 g, 0.37 mol). The solution was warmed to 50° C. to form a homogeneous solution, then was cooled to rt and stirred for 16 h. The mixture was diluted with Et₂O (750 mL) and was stirred for 1 h. The precipitated white solid was collected by filtration and washed with cold EtOH (ca. 100 mL). The white solid was dried in a vacuum oven at 55° C. to give an off-white solid (157.3 g, 50% overall yield). HPLC: RT=6.86 min. MS (ESI): exact mass calcd. for C₁₆H₁₈FN₃, 271.15; m/z found, 271.9 [M+H]⁺. ¹H NMR (D₂O): 7.49-7.43 (m, 2H), 7.27-7.19 (m, 2H), 4.28 (s, 2H), 3.60 (t, J=6.5, 2H), 3.20 (t, J=6.5, 2H), 3.11 (sept, J=6.9, 1H), 2.77 (d, J=15.4, 2H), 2.65 (d, J=15.4, 2H), 1.23 (d, J=6.9, 6H). ¹³C NMR (D₂O): 176.59, 172.69, 171.99, 162.59 (d, J_C-F=11.6), 160.67, 159.41, 129.42, 128.53 (d, J_C-F=8.8), 115.91, 113.89 (d, J_C-F=22.4), 71.78, 41,61, 40.10, 38.77, 34.78, 25.33, 18.64.
The compounds in Examples 166-167 were prepared using methods analogous to those described in the preceding examples.

[0365]

Example 166

{2-[2-tert-Butyl-6-(4-fluoro-phenyl)-pyrimidin-4-yl]-ethyl}-methyl-amine

[0366] MS (ESI): exact mass calcd. for C₁₇H₂₂FN₃, 287.18; m/z found, 288.7 [M+H]⁺.

[0367]

Example 167

{2-[2-tert-Butyl-6-(4-fluoro-phenyl)-pyrimidin-4-yl]-ethyl}-dimethyl-amine

[0368] MS (ESI): exact mass calcd. for C₁₈H₂₄FN₃, 301.20; m/z found, 302.7 [M+H]⁺.

Assay Methods

In Vitro Pharmacology

[0369] Stock drug solutions (10 mM) were prepared in DMSO (the final assay concentration of DMSO not exceeding 0.4%). Drug dilutions were prepared in assay buffer.

[0370] Sigmoidal inhibition curves were generated and fitted by nonlinear regression analysis (GraphPad Prism). K_ivalues were calculated according to the Cheng and Prussoff equation (Biochem. Pharmacol. 1973, 22, 3099-3108), IC₅₀/(1+[S]/K_d), where the following values were used: 5-HT₇([S]=1 nM; K_d=0.42); 5-HT_2A([S]=1 nM; K_d=0.4 nM); 5-HT_2B([S]=4 nM; K_d=3.5 nM); 5-HT_2C([S]=3 nM; K_d=3 nM); 5-HT₆([S]=1.7 nM; K_d=1.7 nM).

[0371] Data obtained for compounds tested in Assays 1-4 are presented in Table 1 below.

1. Affinity for 5-HT₇Receptor Binding Sites

[0372] The affinity of the compounds described in this invention for the 5-HT₇receptor binding site was evaluated by single competition radioligand binding assay. The assay was performed on membranes prepared from HEK-293 cells that had been subjected to stable transfection with the rat 5-HT_7areceptor (GB: NM022938). Cells were scraped from the culture plates, suspended in Tris-HCl 50 mM pH 7.5 and collected through centrifugation (1000 rpm for 5 min). The cell pellets were homogenized (Polytron, 15 s, setting 5) in 50 mM Tris-HCl (pH 7.5), 5 mM EDTA. Following centrifugation (15,000 rpm for 25 min), membranes (135 μg protein/mL) were resuspended in the same buffer and incubated for 60 min at RT with 1 nM [³H]5-CT in the presence of increasing concentration of test compounds. Nonspecific binding was defined in the presence of 10 μM 5-HT. Incubation was stopped by rapid filtration using the cell harvester (Packard). Radioactivity was counted in a TopCount-NXT (Packard). Experiments were conducted in triplicate.

2. Affinity for 5-HT_2AReceptor Binding Sites

[0373] The affinity of the compounds for the rat 5-HT_2Areceptor was evaluated by competitive radioligand binding assay using [³H]ketanserine as the radioligand. The assay was performed on membranes from rat cortex (Schotte, A. et al. Psychopharmacology 1996, 124, 57-73). Brain tissue (rat cortex) was homogenized in 20 volumes per wet weight tissue of Tris-HCl buffer (50 mM, pH 7.4). The total membrane fraction was collected by centrifugation and washed by subsequent centrifugation runs (25 min at 25,000 g at 4° C.). Membranes were re-suspended in Tris-HCl buffer (50 mM, pH 7.4) containing 1 nM [³H]ketanserin. Non-specific binding was estimated in the presence of 10 μM risperidone. The incubation was terminated by rapid filtration over Whatman GF/B filters pre-soaked in 0.1% polyethylenimine, and one washing step with 1 mL ice-cold Tris-HCl buffer, pH 7.4.

3. Affinity for 5HT₂Receptor Binding Sites

[0374] Receptor binding was performed using the human recombinant 5-HT_2A(GB: X57830), 5-HT_2B(GB: Z36748) and 5-HT_2C(GB: M81778) receptors. The affinity of the compounds for the 3 different human 5-HT₂receptor subtypes was evaluated by competitive radioligand binding assays using [³H]ketanserin (h5-HT_2A) or [³H]mesulergine (h5-HT_2Band h5-HT_2C). The assays were performed on membranes prepared from NIH3T3 stably transfected with h5-HT_2Aor CHO stably transfected with h5-HT_2Band h5-HT_2C.

4. Affinity for 5-HT₆Receptor Binding Sites

[0375] Receptor binding was performed using the human recombinant 5-HT₆(GB: BC0794995) receptor. The affinity of the compounds for the human 5-HT₆receptor was evelauated by competitive radioligand binding assays using [³H]LSD. The assays were preformed on membranes prepared from HEK-293 stably transfected with h5-HT₆. Non-specific binding was estimated in the presence of 1 μM clozapine.

[0376]

TABLE 1

Binding Affinities (nM)
Ex.	K_i5-HT₇	K_i5-HT_2A	K_i5-HT_2B	K_i5-HT_2C	K_i5-HT₆

1	540	4	70	90	NT
2	>10000	20	5000	510	NT
3	>10000	11	2250	1020	>10000
4	>10000	20	250	200	NT
5	>10000	13	350	250	NT
6	>10000	50	200	300	NT
7	>10000	25	900	900	NT
8	1000	20	1000	320	200
9	5000	1350	>10000	7500	NT
10	>10000	200	>10000	5000	NT
11	>10000	100	>10000	2000	NT
12	>10000	300	>10000	5000	NT
13	>10000	12.5	2200	1000	NT
14	>10000	30	4000	4000	NT
15	>10000	1000	>10000	>10000	NT
16	>10000	2000	>10000	>10000	NT
17	>10000	4	250	70	NT
18	525	10	80	60	330
19	>10000	100	140	200	NT
20	>10000	700	1200	>10000	NT
21	>10000	25	1185	1170	>10000
22	>10000	32	500	1300	NT
23	>10000	500	>10000	>10000	NT
24	>10000	240	>10000	>10000	NT
25	>10000	300	>10000	>10000	NT
26	>10000	300	>10000	>10000	NT
27	>10000	60	>10000	>10000	NT
28	>10000	100	400	3000	NT
29	>10000	240	1600	2000	>10000
30	>10000	800	1000	2500	NT
31	>10000	70	2000	>10000	NT
32	>10000	2000	>10000	>10000	NT
33	>10000	>10000	>10000	>10000	NT
34	>10000	150	400	1000	NT
35	500	70	400	2000	NT
36	>10000	>10000	>10000	>10000	NT
37	>10000	40	400	1000	NT
38	>10000	40	50	800	NT
39	>10000	150	>10000	>10000	NT
40	>10000	500	>10000	>10000	NT
41	>10000	2000	5000	5000	NT
42	>10000	120	>10000	>10000	NT
43	>10000	200	>10000	>10000	NT
44	>10000	400	500	1000	NT
45	>10000	>10000	>10000	>10000	NT
46	120	14	30	200	100
47	30	2.5	1	22	12
48	40	20	3	100	24
49	300	50	25	400	200
50	240	3.7	20	80	260
51	>10000	470	140	9000	NT
52	>10000	725	1150	9000	NT
53	>10000	1000	>10000	>10000	NT
54	5000	0.55	30	20	30
55	35	0.42	2.5	16	8.5
56	180	0.80	22	38	30
57	550	0.70	40	50	80
58	>10000	2	40	30	100
59	100	1.5	7.8	29	20
60	400	6	10	60	60
61	250	1.9	15	35	20
62	5275	0.75	21	21	27
63	>10000	1.5	52	46	60
64	>10000	10	1300	70	1300
65	>10000	20	300	570	>10000
66	300	8	30	145	NT
67	5400	56	80	495	NT
68	>10000	80	660	7100	NT
69	>10000	140	>10000	650	7100
70	>10000	117	>10000	3733	250
71	>10000	1027	4333	3583	300
72	>10000	130	>10000	>10000	NT
73	>10000	140	>10000	>10000	NT
74	>10000	47	1900	>10000	NT
75	5000	70	3000	>10000	NT
76	150	9	315	75	300
77	22	15	200	130	400
78	400	25	900	380	NT
79	300	115	435	900	NT
80	>10000	11	158	940	2800
81	>10000	25	450	6000	NT
82	>10000	2	500	20	230
83	>10000	30	1000	300	230
84	>10000	14	400	5000	NT
85	>10000	82	1150	>10000	NT
86	9000	100	4100	>10000	NT
87	>10000	600	2000	>10000	NT
88	550	13	60	185	NT
89	>10000	25	40	1400	NT
90	2300	17	130	1000	NT
91	>10000	75	200	9000	NT
92	>10000	300	>10000	>10000	NT
93	>10000	>10000	>10000	>10000	NT
94	>10000	>10000	>10000	>10000	NT
95	>10000	2000	>10000	>10000	NT
96	>10000	>10000	>10000	>10000	NT
97	>10000	>10000	>10000	>10000	NT
98	>10000	>10000	>10000	>10000	NT
99	>10000	>10000	>10000	>10000	NT
100	>10000	14	900	300	NT
101	>10000	400	>10000	>10000	NT
102	>10000	20	150	230	370
103	>10000	40	1000	1000	NT
104	>10000	700	500	3000	NT
105	>10000	40	100	400	NT
106	>10000	90	6300	>10000	NT
107	>10000	12	275	500	4000
108	>10000	18	42	1000	NT
109	>10000	400	>10000	>10000	>10000
110	>10000	220	1200	4000	NT
111	>10000	300	3500	>10000	NT
112	>10000	130	>10000	>10000	NT
113	>10000	650	>10000	>10000	NT
114	>10000	35	300	1000	NT
115	5000	1000	5000	>10000	NT
116	>10000	2000	>10000	>10000	NT
117	>10000	50	1000	4000	NT
166	NT	11	18	170	NT
167	450	7	14	200	NT

NT = not tested

5. In Vitro Functional Assay for 5-HT₂Receptor (Intracellular Calcium)

[0377] In vitro functional properties of these compounds on the different 5-HT₂receptor substypes were determined using fluorometric imaging plate reader (FLIPR) based calcium assay as previously described (Porter, R. H. et al. Br. J. Pharmacol. 1999, 128, 13-20; Jerman, J. C. et al. Eur. J. Pharmacol. 2001, 414, 23-30). The 5-HT₂receptors are linked to the Gq family of G proteins and to subsequent activation of phospholipase C, induction of phosphoinositide metabolism and to an increase in intracelular calcium concentration. The same cell lines as described in the previous section (receptor binding) were used for the FLIPR experiments. Data obtained for compounds tested are presented in Table 2.

[0378]

TABLE 2

	pK_b	pK_b	pK_b
Ex.	5-HT_2A	5-HT_2B	5-HT_2C


13	7.1	5	NT
17	8.1	5.4	NT
18	7.6	6.7	NT
21	7.5	5	5
50	8.3	8.3	NT
57	8.2	6.9	NT
62	8.8	7.3	NT
63	7.8	6.3	NT
64	7.1	5	NT
69	6	5	NT
76	7	5	NT
78	7.1	5	NT
82	8.1	5.4	NT
100	7	5	NT

NT = not tested

Claims

What is claimed is:

1. A compound that is 4-(4-fluoro-phenyl)-2-isopropyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine or a pharmaceutically acceptable salt thereof.

2. A compound of claim 1 isotopically-labelled to be detectable by PET or SPECT.

3. The compound of claim 1 wherein said pharmaceutically acceptable salt is selected from the group consisting of hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactiobionate, and laurylsulfonate.

4. The compound of claim 3 wherein said pharmaceutically acceptable salt is hydrochloride.

5. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound that is 4-(4-fluoro-phenyl)-2-isopropyl-5,6,7,8-tetrahydro-pyrido [4,3-d]pyrimidine or a pharmaceutically acceptable salt thereof.

6. The composition of claim 5 wherein said pharmaceutically acceptable salt is selected from the group consisting of hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactiobionate, and laurylsulfonate.

7. The composition of claim 6 wherein said pharmaceutically acceptable salt is hydrochloride.

8. The compound of claim 3 wherein said pharmaceutically acceptable salt is citrate.

9. The composition of claim 6 wherein said pharmaceutically acceptable salt is citrate.

10. A compound which is a citric acid salt of 4-(4-fluoro-phenyl)-2-isopropyl-5,6,7,8-tetrahydro-pyrido [4,3-d]pyrimidine.

11. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound that is a citric acid salt of 4-(4-fluoro-phenyl)-2-isopropyl-5,6,7,8-tetrahydro-pyrido [4,3-d]pyrimidine.

Patent Citations (68)

Patent	Date	Inventor	Cited By
US3312716(A)	1967-04-01	Biel et al.	Applicant
US3969355(A)	1976-07-01	Schwan	Applicant
US4007196(A)	1977-02-01	Christensen et al.	Applicant
US4136193(A)	1979-01-01	Bogeso et al.	Applicant
US4314081(A)	1982-02-01	Molloy et al.	Applicant
US4536518(A)	1985-08-01	Welch et al.	Applicant
US4576604(A)	1986-03-01	Guittard et al.	Applicant
US4673405(A)	1987-06-01	Guittard et al.	Applicant
US4857330(A)	1989-08-01	Stephens et al.	Applicant
US5137890(A)	1992-08-01	Sanfilippo et al.	Applicant
US5405848(A)	1995-04-01	Sanfilippo et al.	Applicant
US5997905(A)	1999-12-01	McTeigue et al.	Applicant
US6025367(A)	2000-02-01	Forbes et al.	Applicant
US6149943(A)	2000-11-01	McTeigue et al.	Applicant
US6355642(B1)	2002-03-01	Koyama et al.	Applicant
US6407112(B1)	2002-06-01	Koyama et al.	Applicant
US6414149(B1)	2002-07-01	Chu-Moyer et al.	Examiner
US2002/0183519(A1)	2002-12-01	Nar et al.	Applicant
US2003/0153728(A1)	2003-08-01	Kolb et al.	Applicant
US2004/0229874(A1)	2004-11-01	Bright et al.	Applicant
US2005/0119295(A1)	2005-06-01	Carruthers et al.	Applicant
US2005/0232986(A1)	2005-10-01	Brown et al.	Applicant
US2005/0288355(A1)	2005-12-01	Mork et al.	Applicant
US2006/0194837(A1)	2006-08-01	Carruthers et al.	Applicant
US2006/0287292(A1)	2006-12-01	Carruthers et al.	Applicant
US2006/0293316(A1)	2006-12-01	Apodaca et al.	Applicant
US2007/0260057(A1)	2007-11-01	Deng et al.	Applicant
US2008/0004258(A1)	2008-01-01	Keith et al.	Applicant
US2008/0045508(A1)	2008-02-01	Allison et al.	Applicant
US2008/0045509(A1)	2008-02-01	Allison et al.	Applicant
EP1264820(A1)	2002-12-01		Applicant
EP1211246(B1)	2004-02-01		Applicant
JP3148265(A)	1991-06-01		Applicant
JP3148265	1991-06-01		Examiner
WO95/29909(A1)	1995-11-01		Applicant
WO96/32944(A1)	1996-10-01		Applicant
WO97/29097(A1)	1997-08-01		Applicant
WO97/47601(A1)	1997-12-01		Applicant
WO97/48681(A1)	1997-12-01		Applicant
WO97/49695(A1)	1997-12-01		Applicant
WO98/31354(A3)	1998-07-01		Applicant
WO99/24022(A3)	1999-05-01		Applicant
WO/32173(A1)	2000-06-01		Applicant
WO/37082(A1)	2000-06-01		Applicant
WO/56712(A1)	2000-09-01		Applicant
WO/59510(A1)	2000-10-01		Applicant
WO/73299(A1)	2000-12-01		Applicant
WO1/29029(A1)	2001-04-01		Applicant
WO1/41766(A1)	2001-06-01		Applicant
WO1/57039(A1)	2001-08-01		Applicant
WO2/14314(A2)	2002-02-01		Applicant
WO2/062788(A1)	2002-08-01		Applicant
WO2/072558(A1)	2002-09-01		Applicant
WO2072558	2002-09-01		Examiner
WO3/035070(A1)	2003-05-01		Applicant
WO3/053330(A2)	2003-07-01		Applicant
WO3053330	2003-07-01		Examiner
WO2004/011467(A1)	2004-02-01		Applicant
WO2004011467	2004-02-01		Examiner
WO2004094419	2004-04-01		Examiner
WO2004/039786(A1)	2004-05-01		Applicant
WO2004039786	2004-05-01		Examiner
WO2004/094419(A1)	2004-11-01		Applicant
WO2005/005387(A1)	2005-01-01		Applicant
WO2005/030132(A2)	2005-04-01		Applicant
WO2005/056056(A3)	2005-06-01		Applicant
WO2006/016262(A1)	2006-02-01		Applicant
WO2008/013556(A1)	2008-01-01		Applicant

Non-Patent Literature (91)

Appell, et al., Bioorganic & Medicinal Chemistry (2002), 10(5), 1197-1206.Examiner
Herrera, et al., Magnetic Resonance in Chemistry (2002), 40(4), 293-299.Examiner
Garcia Martinez, et al., Tetrahedron (1998), 54(18), 4607-4614.Examiner
Kawamura, et al., Bioscience, Biotechnology, and Biochemistry (1992), 56(11), 1897-9.Examiner
Collier, et al., Science of Synthesis (2004), 19, 403-425.Examiner
Voitenko, et al., Phosphorus, Sulfur and Silicon and the Related Elements (2005), 180(1), 163-177.Examiner
Herrera, et al., Tetrahedron Letters (2003), 44(10), 2149-2151.Examiner
Herrera, et al., Tetrahedron (2002), 58(19), 3755-3764.Examiner
Lafferty, et al., Journal of Organic Chemistry (1967), 32(5), 1591-6.Examiner
Poyurovsky, et al., Euro. Neuropsychopharmacol. 13 (2003) 123-128.Examiner
Kim, et al., Molec. & Cellular Probes (2000) 14, 47-52.Examiner
Khawam, et al., Cleveland Clinic J. Med., vol. 73, # 4, Apr. 2006, 351-361.Examiner
Mendelson, J. Clin. Psychiatry 2005: 66, 469-476.Examiner
Silvestre, et al., Methods Find Exp Clin Pharmacol 2005, 27(5): 289.Examiner
Kast, Support Care Cancer (2001) 9:469-470.Examiner
Naranjo, et al., Addiction, vol. 90, # 7, pp. 893-905, Jul. 1995.Examiner
May, et al., J. Pharmacol. & Experim. Therap., Apr. 3, 2003.Examiner
PCT International Search Report for International Application No. PCT/US2006/029437 dated Dec. 14, 2006.Applicant
Appell, M. et al. An analysis of the binding of cocaine analogues to the monamine transporters using tensor decomposition 3-D QSAR. Bioorg. Med. Chem. 2002, 10(5), 1197-1206.Applicant
Berge, S.M. et al. Pharmaceutical Salts. J. Pharm. Sci., 1977, 66:1-19.Applicant
Bonhaus, D.W. et al. RS-127443: A selective, high affinity, orally bioavailable 5-HT 2B receptor antagonist. Br. J. Pharmacol. 1999, 127(5), 1075-1082.Applicant
DeRuiter, J. et al. Investigation of the Synthesis and Analgesic Activity of 1-Substituted 4-(Propananilido)perhydroazepines. J. Het. Chem. 1992, 29(4), 779-786.Applicant
Dube, H. et al. Synthesis of chiral alpha-aminoalkylpyrimidines using an enantioselective three-component reaction. Synthesis 2004, 12, 2015-2025.Applicant
Herrera, A. et al. 1H and 13C NMR spectral assignments of 2,4-diaryl-substituted cycloalkyl[d]pyrimidines. Magn. Reson. Chem. 2002, 40(4), 293-299.Applicant
Herrera, A. et al. On the mechanism of reaction between ketones and nitriles. Unexpected results from benzyl nitriles. Tetrahedron 2002, 58(19), 3755-3764.Applicant
Hoyer, D. et al. Molecular, Pharmacological and functional diversity of 5-HT receptors. Pharmacol. Biochem. Behav. 2002, 71, 533-554.Applicant
Jerman, J.C. et al. Pharmacological characterisation of human 5-HT2 receptor subtypes. Eur. J. Pharmacol. 2001, 414, 23-30.Applicant
Kawamura, S. et al. Fused heterocycles, furo[3,2-d]pyrimidines and dihydrocyclopenta[d]pyrimidines, as potential new herbicides. Biosci. Biotechnol. Biochem. 1992, 56(11), 1897-1899.Applicant
Porter, R.H. et al. Functional characterization of agonists at recombinant human 5-HT2A, 5-HT2B and 5-HT2C receptors in CHO-K1 cells. Br. J. Pharmacol. 1999, 128, 13-20.Applicant
Roth, B.L. et al. The Multiplicity of Serotonin Receptors: Uselessly Diverse Molecules or an Embarrassment of Riches? Neuroscientist 2000, 6(4), 252-262.Applicant
Sanfilippo et al. Novel tetrahydropyrido[4,3-d]pyrimidines as gastric antilesion agents. Eur. J. Med. Chem. 1992, 27(7), 655-661.Applicant
Schotte, A. et al. Risperidone compared with new and reference antipsychotic drugs: in vitro and in vivo receptor binding. Psychopharmacology 1996, 124, 57-73.Applicant
Stolle, W.A.W. et al. Intramolecular Diels-Alder reactions of pyrimidines: Synthesis of tricyclic annelated pyridines. Tetrahedron 1989, 45(20), 6511-6518.Applicant
Voitenko, Z.V. et al. Conversions of 2-(2-oxocycloehxylcarbonyl)benzoic acid derivatives to pyrazolo[5,1-a]isoindole and pyrimidine rings. Phosphorus, Sulfur Silicon Relat. Elem. 2005, 180(1), 163-177.Applicant
U.S. Appl. No. 60/938,790, filed May 18, 2007, Keith.Applicant
U.S. Appl. No. 11/939,881, filed Nov. 14, 2007, Keith et al.Applicant
Bard et al. Cloning of a Novel Human Serotonin Receptor (5-HT7) Positively Linked to Adenylate Cyclase. J. Biol. Chem. 1993, 268(31), 23422-23426.Applicant
Bonaventure et al. Radioligand Binding Analysis of Knockout Mice Reveals 5-Hydroxytryptamine7 Receptor Distribution and Uncovers 8-Hydroxy-2-(2-di-N-propylamino)tetralin Interaction with α2 Adrenergic Receptors. Neuroscience 2004, 124, 901-911.Applicant
Bonnet, U. Moclobemide: Evolution, Pharmacokinetic, and Pharmacodynamic Properties. CNS Drug Rev. 2002, 8(3), 283-308.Applicant
Bymaster et al. Fluoxetine, but not other selective serotonin reuptake inhibitors, increases norepinephrine and dopamine extracellular levels in prefrontal cortex. Psychopharmacology (Berlin) 2002, 160(4), 353-361.Applicant
Chen et al. P-Glycoprotein Limits the Brain Penetration of Nonsedating but Not Sedating H1-Antagonists. Drug Metab. Dispos. 2003, 31(3), 312-318.Applicant
Collier et al. Applications of Nitriles as Reagents for Organic Synthesis with the Loss of the Nitrile Functionality (including Cycloaddition Reactions). Science of Synthesis 2004, 19, 403-425.Applicant
Eglen et al. The 5-HT7 Receptor: Orphan Found. Trends Pharmacol. Sci. 1997, 18, 104-107.Applicant
Frazer, A. Serotonergic and Noradrenergic Reuptake Inhibitors: Prediction of Clinical Effects from In Vitro Potencies. J. Clin. Psychiatry 2001, 62 Suppl. 12, 16-23.Applicant
Garcia Martinez et al. About the Timing of Wagner-Meerwein and Nametkin Rearrangements, 6,2-Hydride Shift, Proton Elimination and Cation Trapping in 2-Norbornyl Carbocations. Tetrahedron 1998, 54(18), 4607-4614.Applicant
Glass et al. Midbrain Raphe Modulation of Nonphotic Circadian Clock Resetting and 5-HT Release in the Mammalian Suprachiasmatic Nucleus. J. Neurosci. 2003, 23(20), 7451-7460.Applicant
Glennon et al. Higher-End Serotonin Receptors: 5-HT5, 5-HT6, and 5-HT7. J. Med. Chem. 2003, 46(14), 2795-2812.Applicant
Guscott et al. The hypothermic effect of 5-CT in mice is mediated through the 5-HT7 receptor. Neuropharmacology 2003, 44(8), 1031-1037.Applicant
Guscott et al. Genetic knockout and pharmacological blockade studies of the 5-HT7 receptor suggest therapeutic potential in depression. Neuropharmacology 2005, 48(4), 492-502.Applicant
Hagan et al. Characterization of SB-269970-A, a selective 5-HT7 receptor antagonist. Br. J. Pharmacol. 2000, 13093), 539-548.Applicant
Hansen et al. Pharmacological Management of Allergic Rhinitis in the Elderly. Drugs Aging 2005, 22(4), 289-296.Applicant
Harsing et al. A 5-HT7 Heteroreceptor-Mediated Inhibition of [3H]Serotonin Release in Raphe Nuclei Slices of the Rat: Evidence for a Serotonergic-Glutamatergic Interaction. Neurochem. Res. 2004, 29(8), 1487-1497.Applicant
Hedlund et al. 5-HT7 Receptor Inhibition and Inactivation Induce Antidepressantlike Behavior and Sleep Pattern. Biol. Psychiatry 2005, 58(10), 831-837.Applicant
Hedlund et al. No hypothermic response to serotonin in 5-HT7 receptor knockout mice. Proc. Natl. Acad. Sci. U.S.A. 2003, 100(3), 1375-1380.Applicant
Hedlund et al. Functional, molecular and pharmacological advances in 5-HT7 receptor research. Trends Pharmacol. Sci. 2004, 24(9), 481-486.Applicant
Herrera et al. One-pot synthesis of new heterocycles: 2,4-disubstituted 6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidines. Tetrahedron Lett. 2003, 44(10), 2149-2151.Applicant
Ishiguro et al. Influx and Efflux Transport of H1-Antagonist Epinastine Across the Blood-Brain Barrier. Drug Metab. Dispos. 2004, 32(5), 519-524.Applicant
Keating et al. The effect of a series of organic cations upon the plasmalemmal serotonin transporter, SERT. Life Sci. 2004, 76, 109-119.Applicant
Lafferty et al. The Preparation and Properties of Certain Pyridylpyrimidines and Bidiazines as Potential Chelating Agents for Iron(II). J. Org. Chem. 1967, 32(5), 1591-1596.Applicant
Lovenberg et al. A Novel Adenylyl Cyclase-Activating Serotonin Receptor (5-HT7) Implicated in the Regulation of Mammalian Circadian Rhythms. Neuron 1993, 11(3), 449-458.Applicant
Marek et al. Synergistic Action of 5-HT2A Antagonists and Selective Serotonin Reuptake Inhibitors in Neuropsychiatric Disorders. Neuropsychopharmacology 2003, 28, 402-412.Applicant
Meneses, A. Effects of the 5-HT7 receptor antagonists SB-269970 and DR 4004 in autoshaping Pavlovian/instrumental learning task. Behav. Brain Res. 2004, 155(2), 275-282.Applicant
Murphy et al. Experimental gene interaction studies with SERT mutant mice as models for human polygenic and epistatic traits and disorders. Genes, Brain & Behav. 2003, 2(6), 350-364.Applicant
Ni et al. 5-Hydroxytryptamine in the Cardiovascular System: Focus on the Serotonin Transporter (SERT). Clin. Exp. Pharmacol. Physiol. 2006, 33(7), 575-583.Applicant
Pouzet, B. SB-258741: A 5-HT7 Receptor Antagonist of Potential Clinical Interest. CNS Drug Rev. 2002, 8(1), 90-100.Applicant
Read et al. Evidence for the involvement of central 5-HT7 receptors in the micturition reflex in anaesthetized female rats. Br. J. Pharmacol. 2003, 140, 53-60.Applicant
Read et al. Effects of SB-269970, the 5-HT7 Receptor Antagonist, on Micturition. Presentation Abstract, International Union of Basic & Clinical Pharmacology, XIVth World Congress of Pharmacology, San Francisco, CA, Jul. 2002.Applicant
Roberts et al. GABAergic modulationof 5-HT7 receptor-mediated effects on 5-HT efflux in the guinea-pig dorsal raphe nucleus. Neuropharmacology 2004, 46(7), 935-941.Applicant
Simons et al. The Pharmacology and Use of H1-Receptor-Antagonist Drugs. N. Engl. J. Med. 1994, 330, 1663-1670.Applicant
Spinks et al. Serotonin Reuptake Inhibition: An Update on Current Research Strategies. Curr. Med. Chem. 2002, 9, 799-810.Applicant
Steru et al. The Automated Tail Suspension Test: A Computerized Device which Differentiates Psychotropic Drugs. Prog. Neuropsychopharmacol. & Biol. Psychiatry 1987, 11(6), 659-671.Applicant
Tagawa et al. Neuroimaging of histamine H1-receptor occupancy in human brain by positron emission tomography (PET): A comparative study of ebastine, a second-generation antihistamine, and (+)-chlorpheniramine, a classical antihistamine. Br. J. Clin. Pharmacol. 2001, 52(5), 501-509.Applicant
Tashiro et al. Brain histamine H1 receptor occupancy of orally administered antihistamines measured by positron emission tomography with 11 C-doxepin in a placebocontrolled crossover study design in healthy subjects: a comparison of olopatadine and ketotifen. Br. J. Clin. Pharmacol. 2006, 61(1), 16-26.Applicant
Tashioro et al. Central Effects of Fexofenadine and Cetirizine: Measurement of Psychomotor Performance, Subjective Sleepiness, and Brain Histamine H1-Receptor Occupancy Using 11 C-Doxepin Positron Emission Tomography. J. Clin. Pharmacol. 2004, 44(8), 890-900.Applicant
Thomas et al. SB-656104-A, a novel selective 5-HT7 receptor antagonist, modulates REM sleep in rats. Br. J. Pharmacol. 2003, 139(4), 705-714.Applicant
Thomas et al. 5-HT7 Receptors. Curr. Drug Targets CNS Neurol. Disord. 2004, 3(1), 81-90.Applicant
To et al. Characterization and distribution of putative 5-HT7 receptors in guinea-pig brain. Br. J. Pharmacol. 1995, 115(1), 107-116.Applicant
Tuladhar et al. 5-HT7 receptors mediate the inhibitory effect of 5-HT on peristalsis in the isolated guinea-pig ileum. Br. J. Pharmacol. 2003, 138(7), 1210-1214.Applicant
PCT International Search Report for PCT/US 06/40911 dated Sep. 27, 2007.Applicant
Martel et al. Recent advances on the importance of the serotonin transporter SERT in the rat intestine. Pharmacol. Res. 2006, 54, 73-76.Applicant
Menza, et al. Modafinil Augmentation of Antidepressant Treatment in Depression. J. Clin. Psychiatry 2000, 61, 378-381.Applicant
Ohtsuki, S. New Aspects of the Blood-Brain Barrier Transporters; Its Physiological Roles in the Central Nervous System. Biol. Pharm. Bull. 2004, 27(10), 1489-1496.Applicant
Olver et al. Third-Generation Antidepressants: Do They Offer Advantages Over the SSRIs? CNS Drugs 2001, 15, 941-954.Applicant
Thomas et al. [3H]-SB-269970 radiolabels 5-HT7 receptors in rodent, pig and primate brain tissues. Neuropharmacology 2002, 42(1), 74-81.Applicant
Vanhoenacker et al. 5-HT7 receptors: current knowledge and future prospects. Trends Pharmacol. Sci. 2000, 21, 70-77.Applicant
Van Wauwe et al. In Vivo Pharmacology of Astemizole, a New Type of H1-Antihistaminic Compound. Arch. Int. Pharmacodyn. 1981, 251, 39-51.Applicant
Varnas et al. Distribution of 5-HT7 receptors in the human brain: a preliminary autoradiographic study using [3H]SB-269970. Neurosci. Lett. 2004, 367(3), 313-316.Applicant
Welch et al. H1-Antihistamines and the central nervous system. In Histamine and H1-Antihistamines in Allergic Disease, 2nd ed.; F.E.R. Simons, Ed.; Marcel Dekker, Inc.: New York, 2002; Chapter 11.Applicant
Yanai et al. Histamine H1 receptor occupancy in human brains after single oral doses of histamine H1 antagonists measured by positron emission tomography. Br. J. Pharmacol. 1995, 116, 1649-1655.Applicant
Yanai et al. Mapping of Histamine H1 Receptors in the Human Brain Using [11C]Pyrilamine and Positron Emission Tomography. J. Neurochem. 1992, 59, 128-136.Applicant
Yoon et al. Rapid Screening of Blood-Brain Barrier Penetration of Drugs Using the Immobilized Artificial Membrane Phosphatidylcholine Column Chromatography. J. Biomol. Screen 2006, 11(1), 13-20.Applicant

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Description

RELATED APPLICATIONS

[0001] The present application claims the benefit under 35 U.S.C. §119(e) of provisional application Ser. No. 60/705,719, filed on Aug. 4, 2005, which is incorporated herein in its entirety.

FIELD OF THE INVENTION

BACKGROUND OF THE INVENTION

[0005] 4-Phenyltetrahydropyrido[4,3-d]pyrimidines with utility in the treatment of gastrointestinal diseases have been described in U.S. Pat. No. 5,137,890 (Sanfilippo et al.):

[0006]

[0008] Described herein is a series of pyrimidine compounds with the ability to modulate the activity of serotonin receptors.

SUMMARY OF THE INVENTION

[0009] The invention features a compound of Formulae (I) or (II):

[0010]

wherein

[0011] m is 1, 2, or 3;
[0012] n is 1, 2, or 3;
[0013] where when m and n are both present, m+n is greater than or equal to 2, and is less than or equal to 4;
[0014] R^aand R^bare independently —H, —C_1-7alkyl, or —C_3-7cycloalkyl, or R^aand R^btaken together with the nitrogen of attachment form piperidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, or piperazinyl, where each R^aand R^bis optionally and independently substituted with —C_1-4alkyl;
[0015] q is 0 or 1;
[0016] A is >NR¹, >CHNR^cR^d, >CHOH or —CH₂— wherein
- [0017] R¹is selected from the group consisting of —H, —C_1-7alkyl, —C_3-7cycloalkyl, and benzyl, where each alkyl, cycloalkyl, or benzyl is optionally mono-, di-, or tri-substituted with R^e;
  - [0018] R^eis selected from the group consisting of —C_1-4alkyl, —C_2-4alkenyl, —C_2-4alkynyl, —C_3-6cycloalkyl, halo, —CF₃, —OH, —OC_1-4alkyl, —OCF₃, —N(R^f)R^g(wherein R^fand R^gare independently —H or —C_1-4alkyl, or R^fand R^gtaken together with the nitrogen of attachment form piperidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, or piperazinyl), —C(O)N(R^f)R^g, —N(R^h)C(O)R^h, —N(R^h)SO₂C_1-7alkyl (wherein R^his —H or —C_1-4alkyl, or two R^hin the same substituent taken together with the amide of attachment form an otherwise aliphatic 4- to 6-membered ring), —S(O)_0-2—C_1-4alkyl, —SO₂N(R^f)R^g, —SCF₃, —C(O)C_1-4alkyl, —CN, —COOH, and —COOC_1-4alkyl;
- [0019] R^cand R^dare independently selected from the group consisting of —H, —C_1-7alkyl, —C_3-7alkenyl, —C_3-7alkynyl, —C_3-7cycloalkyl, —C_1-7alkylC_3-7cycloalkyl, and —C_3-7cycloalkylC_1-7alkyl, or R^cand R^dtaken together with the nitrogen of attachment form piperidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, or piperazinyl, where each R^cand R^dis optionally and independently substituted with R^e;
[0020] R³is —C_1-4alkyl, —C_1-4alkenyl, or benzyl, each optionally substituted with —C_1-3alkyl, —OH, or halo, or two R³substituents taken together form C_2-5alkylene optionally substituted with —C_1-3alkyl, —OH, or halo;
[0021] r is 0 or is an integer less than or equal to m+n+1;
[0022] Ar is an aryl or heteroaryl ring selected from the group consisting of:
- [0023] a) phenyl, optionally mono-, di-, or tri-substituted with Rⁱor di-substituted on adjacent carbons with —OC_1-4alkyleneO—, —(CH₂)_2-3NH—, —(CH₂)_1-2NH(CH₂)—, —(CH₂)_2-3N(C_1-4alkyl)—, or —(CH₂)_1-2N(C_1-4alkyl)(CH₂)—;
  - [0024] Rⁱis selected from the group consisting of —C_1-7alkyl, —C_2-7alkenyl, —C_2-7alkynyl, —C_3-7cycloalkyl, halo, —CF₃, —OH, —OC_1-7alkyl, —OCF₃, —OC_3-7alkenyl, —OC_3-7alkynyl, —N(R^j)R^k(wherein R^jand R^kare independently —H or —C_1-4alkyl), —C(O)N(R^j)R^k, —N(R^j)C(O)R^k, —N(R^j)SO₂C_1-6alkyl, —S(O)_0-2—C_1-6alkyl, —SO₂N(R^j)R^k, —SCF₃, —C(O)C_1-6alkyl, —NO₂, —CN, —COOH, and —COOC_1-7alkyl;
- [0025] b) a monocyclic aromatic hydrocarbon group having five ring atoms, having a carbon atom which is the point of attachment, having one carbon atom replaced by >O, >S, >NH, or >N(C_1-4alkyl), having up to two additional carbon atoms optionally replaced by —N═, optionally mono- or di-substituted with Rⁱ;
- [0026] c) a monocyclic aromatic hydrocarbon group having six ring atoms, having a carbon atom which is the point of attachment, having one or two carbon atoms replaced by —N═, optionally mono- or di-substituted with Rⁱ; and
- [0027] d) phenyl or pyridyl, substituted with a substituent selected from the group consisting of phenyl, phenoxy, pyridyl, thiophenyl, oxazolyl, and tetrazolyl, where the resultant substituted moiety is optionally further mono-, di-, or tri-substituted with Rⁱ;
[0028] ALK is a branched or unbranched C_1-7alkylene, C_2-7alkenylene, C_2-7alkynylene, C_3-7cycloalkylene, or C_3-7cycloalkenylene, optionally mono-, di-, or tri-substituted with R^m;
- [0029] R^mis selected from the group consisting of halo, —CF₃, —OH, —OC_1-7alkyl, —OC_3-7cycloalkyl, —OCF₃, —N(R^p)R^s(wherein R^pand R^sare independently —H or —C_1-7alkyl), —C(O)N(R^p)R^s, —N(R^t)C(O)R^t, —N(R^t)SO₂C_1-6alkyl (wherein R^tis —H or —C_1-7alkyl), —S(O)_0-2—C_1-6alkyl, —SO₂N(R^p)R^s, —SCF₃, —CN, —NO₂, —C(O)C_1-7alkyl, —COOH, and —COOC_1-7alkyl;
[0030] CYC is —H or is a ring system selected from the group consisting of:
- [0031] i) phenyl, optionally mono-, di-, or tri-substituted with R^uor di-substituted on adjacent carbons with —OC_1-4alkyleneO—, —(CH₂)_2-3NH—, —(CH₂)_1-2NH(CH₂)—, —(CH₂)_2-3N(C_1-4alkyl)-, or —(CH₂)_1-2N(C_1-4alkyl)(CH₂)—;
  - [0032] R^uis selected from the group consisting of —C_1-7alkyl, —C_3-7cycloalkyl, phenyl, benzyl, halo, —CF₃, —OH, —OC_1-7alkyl, —OC_3-7cycloalkyl, —Ophenyl, —Obenzyl, —OCF₃, —N(R^v)R^w(wherein R^vand R^ware independently —H or —C_1-7alkyl, or R^vand R^wtaken together with the nitrogen of attachment form piperidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, or piperazinyl, where each R^vand R^wis optionally and independently substituted with —OH or —C_1-7alkyl), —C(O)N(R^v)R^w, —N(R^x)C(O)R^x, —N(R^x)SO₂C_1-6alkyl (wherein R^xis —H or —C_1-7alkyl, or two R^xin the same substituent taken together with the amide of attachment form an otherwise aliphatic 4- to 6-membered ring), —N—(SO₂C_1-6alkyl)₂, —S(O)_0-2—C_1-6alkyl, —SO₂N(R^v)R^w, —SCF₃, —C(O)C_1-6alkyl, —NO₂, —CN, —COOH, and —COOC_1-7alkyl;
- [0033] ii) a monocyclic aromatic hydrocarbon group having five ring atoms, having a carbon atom which is the point of attachment, having one carbon atom replaced by >O, >S, >NH, or >N(C_1-4alkyl), having up to one additional carbon atoms optionally replaced by —N═, optionally mono- or di-substituted with R^u;
- [0034] iii) a monocyclic aromatic hydrocarbon group having six ring atoms, having a carbon atom which is the point of attachment, having one or two carbon atoms replaced by —N═, optionally mono- or di-substituted with R^u; and
- [0035] iv) a non-aromatic heterocyclic ring having 4 to 8 members, said ring having 0, 1, or 2 non-adjacent heteroatom members selected from the group consisting of O, S, —N═, >NH, and >N(C_1-4alkyl), having 0, 1, or 2 double bonds, having 0, 1, or 2 carbon members which is a carbonyl, optionally having one carbon member which forms a bridge, having 0 to 5 substituents R^u, and where when q is 0, said ring has a carbon atom which is the point of attachment;
[0036] and enantiomers, diastereomers, hydrates, solvates, and pharmaceutically acceptable salts, esters and amides thereof;
[0037] with the proviso that in Formula (I):
- [0038] (a) when ALK is methylene, ethylene, propylene, or isopropylene, CYC is —H, Ar is phenyl or mono-substituted phenyl, m is 2, n is 1, and A is >NR¹, then R¹is not —C_1-4alkyl or benzyl;
- [0039] (b) when q is 0, CYC is phenyl, Ar is phenyl or 3-chlorophenyl, m is 2, and n is 1, then A is not unsubstituted —CH₂—; and
- [0040] (c) when q is 0, CYC is 2-pyridyl, Ar is 2-pyridyl, m is 2, and n is 1, then A is not unsubstituted —CH₂—.

[0042] The present invention provides methods of treating or preventing diseases and conditions mediated by the serotonin receptors, particularly, 5-HT₇and/or 5-HT₂receptor subtypes.

[0045] Additional features and advantages of the invention will become apparent from the detailed description and examples below, and the appended claims.

DETAILED DESCRIPTION

[0047] Preferably, m is 1 and n is 1.

[0048] Preferably, m is 1 and n is 2.

[0049] Preferably, m is 2 and n is 1.

[0050] Preferably, m is 2 and n is 2.

[0051] Preferably, m is 1 and n is 3.

[0052] Preferably, m is 3 and n is 1.

[0053] Preferably, in Formula (II), n is 1.

[0054] Preferably, in Formula (II), n is 2.

[0055] Preferably, q is 1.

[0057] More preferably, —N(R^a)R^bis amino, methylamino, dimethylamino, or N-methylpiperazinyl.

[0058] Preferably, A is >NR¹.

[0060] More preferably, R¹, optionally R^esubstituted, is selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, and benzyl.

[0061] Even more preferably, R¹is hydrogen or methyl.

[0063] More preferably, R³is methyl.

[0064] Preferably, r is 0, 1, or 2.

[0065] Preferably Ar, optionally substituted, is selected from the group consisting of:

[0068] c) pyridinyl, pyridinyl-N-oxide, pyrazinyl, pyrimidinyl, pyridazinyl, and

[0069] d) biphenyl, and 4-tetrazolylphenyl.

[0070] More preferably, Ar, optionally substituted, is selected from the group consisting of phenyl, pyridyl, thiophen-2-yl, and thiophen-3-yl.

[0074] Preferably CYC, optionally substituted, is hydrogen or is a ring system selected from the group consisting of:

- [0076] ii) furanyl, oxazolyl, isoxazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, thiophenyl, thiazolyl, isothiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl,
- [0077] iii) pyridinyl, pyridinyl-N-oxide, pyrazinyl, pyrimidinyl, pyridazinyl, and
- [0078] iv) pyrrolinyl, pyrrolidinyl, pyrazolinyl, piperidinyl, homopiperidinyl, azepanyl, tetrahydrofuranyl, tetrahydropyranyl, piperazinyl, morpholinyl, thiomorpholinyl, and piperidinonyl.

[0082] In one embodiment of Formula (I), CYC-(ALK)_q- is —C_3-8cycloalkyl.

[0084] Compounds of Formulae (I) and (II) comprise compounds that satisfy any one of the combinations of definitions given herein and equivalents thereof.

[0085] It is understood that the symbol “>” when used herein immediately prior to an atom means that the atom immediately following this symbol is divalent.

[0088] Preferred compounds, which are pyrimidines, are selected from the group consisting of:

[0089]


Ex.	Chemical Name


1	2-tert-Butyl-4-(4-fluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;
2	2-Benzyl-4-(4-fluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;
3	2-sec-Butyl-4-(4-fluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine hydrochloride;
4	2-sec-Butyl-4-p-totyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine hydrochloride;
5	2-Cyclobutyl-4-(4-fluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine hydrochloride;
6	2-Cyclobutyl-4-p-tolyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;
7	2-Cyclopropyl-4-(4-fluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;
8	2-Benzyl-4-p-tolyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;
9	2-Benzyl-4-(4-trifluoromethyl-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;
10	2-Benzyl-4-(3,4-difluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;
11	2-Benzyl-4-phenyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;
12	2-Benzyl-4-(3-fluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;
13	2-(4-Fluoro-benzyl)-4-(4-fluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;
14	2-(4-Fluoro-benzyl)-4-(4-fluoro-phenyl)-6-methyl-5,6,7,8-tetrahydro-
	pyrido[4,3-d]pyrimidine;
15	4-[2-(4-Fluoro-benzyl)-6-methyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-
	yl]-benzonitrile;
16	4-[2-(4-Fluoro-benzyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yl]-benzonitrile;
17	2-Cyclopentyl-4-(4-fluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;
18	2-Cyclopentyl-4-p-tolyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;
19	2-Cyclopentyl-4-(4-methoxy-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;
20	4-(2-Cyclopentyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yl)-benzonitrile;
21	4-(4-Fluoro-phenyl)-2-isopropyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine hydrochloride;
22	4-(4-Fluoro-phenyl)-2-isopropyl-6-methyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;
23	4-(3,4-Dichloro-phenyl)-2-isopropyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine
	hydrochloride;
24	4-(3,4-Difluoro-phenyl)-2-isopropyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine
	hydrochloride;
25	4-(3-Fluoro-phenyl)-2-isopropyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;
26	4-(2-Fluoro-phenyl)-2-isopropyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;
27	4-(2,4-Difluoro-phenyl)-2-isopropyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;
28	2-Isopropyl-4-p-tolyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;
29	4-(4-Chloro-phenyl)-2-isopropyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;
30	2-Isopropyl-4-(4-methoxy-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;
31	2-Isopropyl-4-phenyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;
32	2-Isopropyl-4-(4-trifluoromethyl-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;
33	2-Isopropyl-4-(2-phenoxy-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;
34	2-Isobutyl-4-thiophen-3-yl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;
35	2-Isobutyl-4-thiophen-2-yl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;
36	2-Isobutyl-4-pyridin-4-yl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;
37	4-(4-Fluoro-phenyl)-2-isobutyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;
38	2-Isobutyl-4-p-tolyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;
39	4-(4-Fluoro-3-methyl-phenyl)-2-isobutyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;
40	4-(2-Isobutyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yl)-benzonitrile;
41	2-Isobutyl-4-(4-methoxy-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;
42	2-sec-Butyl-4-(2-fluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine hydrochloride;
43	2-sec-Butyl-4-(3-fluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;
44	2-sec-Butyl-4-(4-methoxy-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;
45	2-sec-Butyl-4-(4-trifluoromethoxy-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;
46	2-Cyclopentyl-4-(4-fluoro-phenyl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine;
47	2-Cyclopentyl-4-p-tolyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine;
48	2-Cyclopentyl-4-(4-methoxy-phenyl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine;
49	4-(2-Cyclopentyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl)-benzonitrile;
50	4-(4-Fluoro-phenyl)-2-isopropyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine
	hydrochloride;
51	4-(4-Chloro-phenyl)-2-methyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine;
52	2-Methyl-4-phenyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine;
53	4-(3-Chloro-phenyl)-2-methyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine;
54	2-Benzyl-4-(4-fluoro-phenyl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine;
55	2-Benzyl-4-p-tolyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine;
56	2-Benzyl-4-(4-trifluoromethyl-phenyl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine;
57	2-(4-Fluoro-benzyl)-4-(4-fluoro-phenyl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine;
58	2-Cyclopentyl-4-(4-fluoro-phenyl)-7-methyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine;
59	2-Cyclopentyl-7-methyl-4-p-tolyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine;
60	2-Cyclopentyl-4-(4-methoxy-phenyl)-7-methyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]
	azepine;
61	2-Benzyl-7-methyl-4-p-tolyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine;
62	2-(4-Fluoro-benzyl)-4-(4-fluoro-phenyl)-7-methyl-6,7,8,9-tetrahydro-5H-
	pyrimido[4,5-d]azepine;
63	2-(4-Fluoro-benzyl)-4-(4-fluoro-phenyl)-7-methyl-9-methylene-6,7,8,9-tetrahydro-
	5H-pyrimido[4,5-d]azepine;
64	2-Benzyl-4-(4-fluoro-phenyl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-c]azepine
	hydrochloride;
65	4-(4-Fluoro-phenyl)-2-isopropyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-c]azepine
	hydrochloride;
66	2-Isopropyl-4-p-tolyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-c]azepine hydrochloride;
67	2-Isopropyl-4-(4-methoxy-phenyl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-c]azepine;
68	2-Isopropyl-4-phenyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-c]azepine;
69	2-Benzyl-4-(4-fluoro-phenyl)-6,7,8,9-tetrahydro-5H-1,3,6-triaza-
	benzocycloheptene hydrochloride;
70	2,7-Dibenzyl-4-(4-fluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidine hydrochloride;
71	2,7-Dibenzyl-4-p-tolyl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidine;
72	2,7-Dibenzyl-4-phenyl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidine;
73	2,7-Dibenzyl-4-(4-methoxy-phenyl)-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidine;
74	7-Benzyl-4-(4-fluoro-phenyl)-2-isopropyl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidine;
75	7-Benzyl-2-isopropyl-4-phenyl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidine;
76	2-Benzyl-4-(4-fluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidine
	hydrochloride;
77	2-Benzyl-4-p-tolyl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidine hydrochloride;
78	2-Benzyl-4-phenyl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidine;
79	2-Benzyl-4-(4-methoxy-phenyl)-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidine;
80	4-(4-Fluoro-phenyl)-2-isopropyl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidine
	hydrochloride;
81	2-Isopropyl-4-phenyl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidine;
82	2-Benzyl-4-(4-fluoro-phenyl)-7-methyl-5,6,7,8-tetrahydro-pyrido[3,4-
	d]pyrimidine hydrochloride;
83	2-Benzyl-4-(4-fluoro-phenyl)-7-isopropyl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidine;
84	4-(4-Fluoro-phenyl)-2-isopropyl-7-methyl-5,6,7,8-tetrahydro-pyrido[3,4-
	d]pyrimidine hydrochloride;
85	2-Isopropyl-7-methyl-4-phenyl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidine;
86	7-Benzyl-2-isopropyl-4-(5-methyl-thiophen-3-yl)-5,6,7,8-tetrahydro-
	pyrido[3,4-d]pyrimidine hydrochloride;
87	7-Benzyl-2-isopropyl-4-thiophen-3-yl-5,6,7,8-tetrahydro-pyrido[3,4-
	d]pyrimidine hydrochloride;
88	2-Isopropyl-4-(5-methyl-thiophen-3-yl)-5,6,7,8-tetrahydro-pyrido[3,4-
	d]pyrimidine hydrochloride;
89	2-Isopropyl-4-thiophen-3-yl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidine
	hydrochloride;
90	2-Isopropyl-7-methyl-4-(5-methyl-thiophen-3-yl)-5,6,7,8-tetrahydro-
	pyrido[3,4-d]pyrimidine hydrochloride;
91	2-Isopropyl-7-methyl-4-thiophen-3-yl-5,6,7,8-tetrahydro-pyrido[3,4-
	d]pyrimidine hydrochloride;
92	6-Benzyl-4-(4-fluoro-phenyl)-2-isopropyl-8-methyl-5,6,7,8-tetrahydro-pyrido[4,3-d]
	pyrimidine;
93	6-Benzyl-4-(3-chloro-4-fluoro-phenyl)-2-isopropyl-8-methyl-5,6,7,8-tetrahydro-pyrido
	[4,3-d]pyrimidine;
94	6-Benzyl-2-isopropyl-8-methyl-4-p-tolyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;
95	6-Benzyl-2-isopropyl-8-methyl-4-phenyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;
96	6-Benzyl-2-isopropyl-8-methyl-4-(4-trifluoromethyl-phenyl)-5,6,7,8-
	tetrahydro-pyrido[4,3-d]pyrimidine;
97	6-Benzyl-4-(4-chloro-phenyl)-2-isopropyl-8-methyl-5,6,7,8-tetrahydro-pyrido[4,3-d]
	pyrimidine;
98	6-Benzyl-2-isopropyl-8-methyl-4-thiophen-3-yl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;
99	6-Benzyl-4-(4′-chloro-biphenyl-4-yl)-2-isopropyl-8-methyl-5,6,7,8-tetrahydro-
	pyrido[4,3-d]pyrimidine;
100	4-(4-Fluoro-phenyl)-2-isopropyl-8-methyl-5,6,7,8-tetrahydro-pyrido[4,3-
	d]pyrimidine hydrochloride;
101	4-(3-Chloro-4-fluoro-phenyl)-2-isopropyl-8-methyl-5,6,7,8-tetrahydro-pyrido[4,3-d]
	pyrimidine hydrochloride;
102	2-Isopropyl-8-methyl-4-p-tolyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine
	hydrochloride;
103	2-Isopropyl-8-methyl-4-phenyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;
104	2-Isopropyl-8-methyl-4-(4-trifluoromethyl-phenyl)-5,6,7,8-tetrahydro-
	pyrido[4,3-d]pyrimidine;
105	2-Isopropyl-8-methyl-4-thiophen-3-yl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;
106	4-(4-Fluoro-phenyl)-2-isopropyl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidine
	hydrochloride;
107	4-(4-Fluoro-phenyl)-2-isopropyl-7-pyrrolidin-1-yl-5,6,7,8-tetrahydro-quinazoline;
108	[4-(4-Fluoro-phenyl)-2-isopropyl-5,6,7,8-tetrahydro-quinazolin-7-yl]-methyl-
	amine hydrochloride;
109	[4-(4-Fluoro-phenyl)-2-isopropyl-5,6,7,8-tetrahydro-quinazolin-6-yl]-methyl-
	amine hydrochloride;
110	4-(4-Fluoro-phenyl)-2-isopropyl-5,6,7,8-tetrahydro-quinazolin-7-ol;
111	4-(4-Fluoro-phenyl)-2-isopropyl-5,6,7,8-tetrahydro-quinazoline;
112	(2-Benzyl-6-p-tolyl-pyrimidin-4-ylmethyl)-dimethyl-amine;
113	2-Benzyl-4-(4-methyl-piperazin-1-ylmethyl)-6-p-tolyl-pyrimidine;
114	[6-(4-Fluoro-phenyl)-2-isopropyl-pyrimidin-4-ylmethyl]-methyl-amine;
115	2-(2-Benzyl-6-p-tolyl-pyrimidin-4-yl)-ethylamine;
116	[2-(4-Fluoro-benzyl)-4-p-tolyl-pyrimidin-5-ylmethyl]-dimethyl-amine;
117	4-(4-Fluoro-phenyl)-2-phenyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;
118	2-(3,3-Difluoro-cyclopentyl)-4-(4-fluoro-phenyl)-5,6,7,8-tetrahydro-
	pyrido[4,3-d]pyrimidine;
119	4-(4-Fluoro-phenyl)-2-(tetrahydro-furan-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;
120	4-(4-Fluoro-phenyl)-2-(2-piperidin-1-yl-ethyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;
121	2-(1-Fluoro-1-methyl-ethyl)-4-(4-fluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]
	pyrimidine;
122	3-(4-Fluoro-phenyl)-5-isopropyl-4,6,12-triaza-tricyclo[7.2.1.0^2,7]dodeca-
	2,4,6-triene;
123	7-(4-Fluoro-phenyl)-5-isopropyl-4,6,13-triaza-tricyclo[8.2.1.0^3,8]trideca-3,5,7-
	triene;
124	4-(4-Fluoro-phenyl)-2-(tetrahydro-pyran-4-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;
125	4-(4-Fluoro-phenyl)-2-(tetrahydro-pyran-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;
126	4-(4-Fluoro-phenyl)-2-(2-methoxy-ethyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;
127	2-[4-(4-Fluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-2-yl]-propan-2-ol;
128	4-(4-Fluoro-phenyl)-2-(1-methyl-1-phenyl-ethyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]
	pyrimidine;
129	2-Cyclopent-3-enyl-4-(4-fluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;
130	3-[4-(4-Fluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-2-yl]-cyclohexanol;
131	4-(4-Fluoro-phenyl)-2-piperidin-4-yl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;
132	4-(4-Fluoro-phenyl)-2-(1-methyl-piperidin-4-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;
133	[4-(4-Fluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-2-yl]-phenyl-methanol;
134	4-(4-Fluoro-phenyl)-2-(fluoro-phenyl-methyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;
135	2-(Difluoro-phenyl-methyl)-4-(4-fluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;
136	4-(4-Fluoro-phenyl)-2-phenyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;
137	4-(4-Fluoro-phenyl)-2-(3-fluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;
138	4-(4-Fluoro-phenyl)-2-(4-methoxy-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;
139	4-(4-Fluoro-phenyl)-2-o-tolyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;
140	3-[4-(4-Fluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-2-yl]-benzonitrile;
141	4-(4-Fluoro-phenyl)-2-(2,2,2-trifluoro-1-trifluoromethyl-ethyl)-5,6,7,8-tetrahydro-
	pyrido[4,3-d]pyrimidine;
142	4-(4-Fluoro-phenyl)-2-(1-methyl-cyclopropyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;
143	2-[4-(4-Fluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-2-yl]-2-methyl-propionic
	acid;
144	2-[4-(4-Fluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-2-yl]-propionic acid;
145	2-(4-Fluoro-cyclohexyl)-4-(4-fluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;
146	2-(4,4-Difluoro-cyclohexyl)-4-(4-fluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]
	pyrimidine;
147	4-(4-Fluoro-phenyl)-2-phenethyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;
148	4-Furan-2-yl-2-isopropyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;
149	2-Isopropyl-4-(5-methyl-furan-2-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;
150	4-Furan-3-yl-2-isopropyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;
151	4-(5-Fluoro-pyridin-2-yl)-2-isopropyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;
152	2-Isopropyl-4-oxazol-2-yl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;
153	4-(4,5-Dimethyl-oxazol-2-yl)-2-isopropyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;
154	2-Isopropyl-4-thiazol-2-yl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;
155	2-Isopropyl-4-(3H-[1,2,3]triazol-4-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;
156	2-Isopropyl-4-(2H-pyrazol-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;
157	2-Isopropyl-4-(1H-pyrazol-4-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;
158	4-(4-Fluoro-phenyl)-2,6-diisopropyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;
159	6-Ethyl-4-(4-fluoro-phenyl)-2-isopropyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;
160	6-Cyclopropyl-4-(4-fluoro-phenyl)-2-isopropyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;
161	6-Cyclobutyl-4-(4-fluoro-phenyl)-2-isopropyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;
162	6-Cyclopentyl-4-(4-fluoro-phenyl)-2-isopropyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;
163	6-Butyl-4-(4-fluoro-phenyl)-2-isopropyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;
165	4-(4-Fluoro-phenyl)-2-isopropyl-5,6,7,8-tetrahydro-pyrido[4,3]pyrimidine, citrate salt;
166	{2-[2-tert-Butyl-6-(4-fluoro-phenyl)-pyrimidin-4-yl]-ethyl}-methyl-amine; and
167	{2-[2-tert-Butyl-6-(4-fluoro-phenyl)-pyrimidin-4-yl]-ethyl}-dimethyl-amine.

[0090] Preferably, the compound is 4-(4-fluoro-phenyl)-2-isopropyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine or a pharmaceutically acceptable salt thereof.

[0094]


Table of Acronyms
	Term	Acronym

	Tetrahydrofuran	THF
	N,N-Dimethylformamide	DMF
	N,N-Dimethylacetamide	DMA
	Dimethyl sulfoxide	DMSO
	tert-Butylcarbamoyl	Boc
	High-pressure liquid chromatography	HPLC
	Thin layer chromatography	TLC
	N,N-Diisopropylethylamine	DIEA
	1,2-Dichloroethane	DCE
	Ethylene glycol dimethyl ether	DME
	Acetyl	Ac
	Diisobutylaluminum hydride	DIBAL-H
	Ethyl acetate	EtOAc
	Trifluoroacetic acid	TFA
	Methanesulfonyl chloride	MsCl

[0095]

[0100]

[0102]

[0104]

[0106]

[0121] Said methods of treating and preventing comprise the step of administering to a mammal suffering therefrom an effective amount of at least one compound of the present invention.

EXAMPLES

[0132] Preparative Reversed-Phase HPLC was performed as follows:

[0133] Mass spectra were obtained on an Agilent series 1100 MSD using electrospray ionization (ESI) in either positive or negative modes as indicated.

[0136]

Example 1

2-tert-Butyl-4-(4-fluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

[0138]

Example 2

2-Benzyl-4-(4-fluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

[0140]

Example 3

2-sec-Butyl-4-(4-fluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine hydrochloride

[0142]

Example 4

2-sec-Butyl-4-p-tolyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine hydrochloride

[0144]

Example 5

2-Cyclobutyl-4-(4-fluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine hydrochloride

[0146]

Example 6

2-Cyclobutyl-4-p-tolyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

[0147]

Example 7

2-Cyclopropyl-4-(4-fluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

[0149]

Example 8

2-Benzyl-4-p-tolyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

[0151]

Example 9

2-Benzyl-4-(4-trifluoromethyl-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

[0152]

Example 10

2-Benzyl-4-(3,4-difluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

[0153]

Example 11

2-Benzyl-4-phenyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

[0154]

Example 12

2-Benzyl-4-(3-fluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

[0155]

Example 13

2-(4-Fluoro-benzyl)-4-(4-fluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

[0157]

Example 14

2-(4-Fluoro-benzyl)-4-(4-fluoro-phenyl)-6-methyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

[0158]

Example 15

4-[2-(4-Fluoro-benzyl)-6-methyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yl]-benzonitrile

[0159]

Example 16

4-[2-(4-Fluoro-benzyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yl]-benzonitrile

[0160]

Example 17

2-Cyclopentyl-4-(4-fluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

[0162]

Example 18

2-Cyclopentyl-4-p-tolyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

[0164]

Example 19

2-Cyclopentyl-4-(4-methoxy-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

[0165]

Example 20

4-(2-Cyclopentyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yl)-benzonitrile

[0166]

Example 21

4-(4-Fluoro-phenyl)-2-isopropyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine hydrochloride

[0168]

Example 22

4-(4-Fluoro-phenyl)-2-isopropyl-6-methyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

[0169]

Example 23

4-(3,4-Dichloro-phenyl)-2-isopropyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine hydrochloride

[0171]

Example 24

4-(3,4-Difluoro-phenyl)-2-isopropyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine hydrochloride

[0173]

Example 25

4-(3-Fluoro-phenyl)-2-isopropyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

[0174]

Example 26

4-(2-Fluoro-phenyl)-2-isopropyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

[0175]

Example 27

4-(2,4-Difluoro-phenyl)-2-isopropyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

[0176]

Example 28

2-Isopropyl-4-p-tolyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

[0177]

Example 29

4-(4-Chloro-phenyl)-2-isopropyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

[0178]

Example 30

2-Isopropyl-4-(4-methoxy-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

[0179]

Example 31

2-Isopropyl-4-phenyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

[0180]

Example 32

2-Isopropyl-4-(4-trifluoromethyl-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

[0181]

Example 33

2-Isopropyl-4-(2-phenoxy-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

[0182]

Example 34

2-Isobutyl-4-thiophen-3-yl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

[0184]

Example 35

2-Isobutyl-4-thiophen-2-yl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

[0186]

Example 36

2-Isobutyl-4-pyridin-4-yl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

[0188]

Example 37

4-(4-Fluoro-phenyl)-2-isobutyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

[0189]

Example 38

2-Isobutyl-4-p-tolyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

[0190]

Example 39

4-(4-Fluoro-3-methyl-phenyl)-2-isobutyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

[0191]

Example 40

4-(2-Isobutyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yl)-benzonitrile

[0192]

Example 41

2-Isobutyl-4-(4-methoxy-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

[0193]

Example 42

2-sec-Butyl-4-(2-fluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine hydrochloride

[0195]

Example 43

2-sec-Butyl-4-(3-fluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

[0196]

Example 44

2-sec-Butyl-4-(4-methoxy-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

[0197]

Example 45

2-sec-Butyl-4-(4-trifluoromethoxy-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

[0199]

Example 46

2-Cyclopentyl-4-(4-fluoro-phenyl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine

[0201]

Example 47

2-Cyclopentyl-4-p-tolyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine

[0203]

Example 48

2-Cyclopentyl-4-(4-methoxy-phenyl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine

[0205]

Example 49

4-(2-Cyclopentyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl)-benzonitrile

[0206]

Example 50

4-(4-Fluoro-phenyl)-2-isopropyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine hydrochloride

[0208]

Example 51

4-(4-Chloro-phenyl)-2-methyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine

[0209]

Example 52

2-Methyl-4-phenyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine

[0210]

Example 53

4-(3-Chloro-phenyl)-2-methyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine

[0211]

Example 54

2-Benzyl-4-(4-fluoro-phenyl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine

[0213]

Example 55

2-Benzyl-4-p-tolyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine

[0215]

Example 56

2-Benzyl-4-(4-trifluoromethyl-phenyl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine

[0217]

Example 57

2-(4-Fluoro-benzyl)-4-(4-fluoro-phenyl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine

[0219]

Example 58

2-Cyclopentyl-4-(4-fluoro-phenyl)-7-methyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine

[0221]

Example 59

2-Cyclopentyl-7-methyl-4-p-tolyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine

[0223]

Example 60

2-Cyclopentyl-4-(4-methoxy-phenyl)-7-methyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine

[0225]

Example 61

2-Benzyl-7-methyl-4-p-tolyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine

[0227]

Example 62

2-(4-Fluoro-benzyl)-4-(4-fluoro-phenyl)-7-methyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine

[0229]

Example 63

2-(4-Fluoro-benzyl)-4-(4-fluoro-phenyl)-7-methyl-9-methylene-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine

[0231]

Example 64

2-Benzyl-4-(4-fluoro-phenyl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-c]azepine hydrochloride

[0233]

Example 65

4-(4-Fluoro-phenyl)-2-isopropyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-c]azepine hydrochloride

[0235]

Example 66

2-Isopropyl-4-p-tolyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-c]azepine hydrochloride

[0237]

Example 67

2-Isopropyl-4-(4-methoxy-phenyl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-c]azepine

[0238]

Example 68

2-Isopropyl-4-phenyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-c]azepine

[0239]

Example 69

2-Benzyl-4-(4-fluoro-phenyl)-6,7,8,9-tetrahydro-5H-1,3,6-triaza-benzocycloheptene hydrochloride

[0241]

Example 70

2,7-Dibenzyl-4-(4-fluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidine hydrochloride

[0243]

Example 71

2,7-Dibenzyl-4-p-tolyl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidine

[0244]

Example 72

2,7-Dibenzyl-4-phenyl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidine

[0245]

Example 73

2,7-Dibenzyl-4-(4-methoxy-phenyl)-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidine

[0246]

Example 74

7-Benzyl-4-(4-fluoro-phenyl)-2-isopropyl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidine

[0247]

Example 75

7-Benzyl-2-isopropyl-4-phenyl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidine

[0248]

Example 76

2-Benzyl-4-(4-fluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidine hydrochloride

[0250]

Example 77

2-Benzyl-4-p-tolyl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidine hydrochloride

[0252]

Example 78

2-Benzyl-4-phenyl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidine

[0253]

Example 79

2-Benzyl-4-(4-methoxy-phenyl)-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidine

[0254]

Example 80

4-(4-Fluoro-phenyl)-2-isopropyl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidine hydrochloride

[0256]

Example 81

2-Isopropyl-4-phenyl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidine

The compounds in Examples 82-85 were prepared using methods similar to those described in Example 58.

[0257]

Example 82

2-Benzyl-4-(4-fluoro-phenyl)-7-methyl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidine hydrochloride

[0259]

Example 83

2-Benzyl-4-(4-fluoro-phenyl)-7-isopropyl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidine

[0260]

Example 84

4-(4-Fluoro-phenyl)-2-isopropyl-7-methyl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidine hydrochloride

[0262]

Example 85

2-Isopropyl-7-methyl-4-phenyl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidine

[0263]

Example 86

7-Benzyl-2-isopropyl-4-(5-methyl-thiophen-3-yl)-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidine hydrochloride

Step A. 4-(7-Benzyl-2-isopropyl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidin-4-yl)-thiophene-2-carbaldehyde. The title compound was prepared as described in Example 1, Steps A-C.

[0265]

Example 87

7-Benzyl-2-isopropyl-4-thiophen-3-yl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidine hydrochloride

The title compound was prepared according to the methods described in Example 86.

[0267]

Example 88

2-Isopropyl-4-(5-methyl-thiophen-3-yl)-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidine hydrochloride

[0269]

Example 89

2-Isopropyl-4-thiophen-3-yl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidine hydrochloride

The title compound was prepared according to the methods described in Example 88.

The following Examples 90-91 were prepared using methods similar to those described in Example 58.

[0271]

Example 90

2-Isopropyl-7-methyl-4-(5-methyl-thiophen-3-yl)-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidine hydrochloride

[0273]

Example 91

2-Isopropyl-7-methyl-4-thiophen-3-yl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidine hydrochloride

[0276]

Example 92

6-Benzyl-4-(4-fluoro-phenyl)-2-isopropyl-8-methyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

[0277]

Example 93

6-Benzyl-4-(3-chloro-4-fluoro-phenyl)-2-isopropyl-8-methyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

[0278]

Example 94

6-Benzyl-2-isopropyl-8-methyl-4-p-tolyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

[0279]

Example 95

6-Benzyl-2-isopropyl-8-methyl-4-phenyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

[0280]

Example 96

6-Benzyl-2-isopropyl-8-methyl-4-(4-trifluoromethyl-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

[0281]

Example 97

6-Benzyl-4-(4-chloro-phenyl)-2-isopropyl-8-methyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

[0282]

Example 98

6-Benzyl-2-isopropyl-8-methyl-4-thiophen-3-yl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

[0283]

Example 99

6-Benzyl-4-(4′-chloro-biphenyl-4-yl)-2-isopropyl-8-methyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

The following compounds in Examples 100-105 were prepared using methods similar to those described in Example 76.

[0284]

Example 100

4-(4-Fluoro-phenyl)-2-isopropyl-8-methyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine hydrochloride

[0286]

Example 101

4-(3-Chloro-4-fluoro-phenyl)-2-isopropyl-8-methyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine hydrochloride

[0288]

Example 102

2-Isopropyl-8-methyl-4-p-tolyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine hydrochloride

[0290]

Example 103

2-Isopropyl-8-methyl-4-phenyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

[0291]

Example 104

2-Isopropyl-8-methyl-4-(4-trifluoromethyl-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

[0292]

Example 105

2-Isopropyl-8-methyl-4-thiophen-3-yl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

[0293]

Example 106

4-(4-Fluoro-phenyl)-2-isopropyl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidine hydrochloride

[0295]

Example 107

4-(4-Fluoro-phenyl)-2-isopropyl-7-pyrrolidin-1-yl-5,6,7,8-tetrahydro-quinazoline

[0297]

Example 108

[4-(4-Fluoro-phenyl)-2-isopropyl-5,6,7,8-tetrahydro-quinazolin-7-yl]-methyl-amine hydrochloride

The title compound was prepared according to the method described for Example 107.

[0299]

Example 109

[4-(4-Fluoro-phenyl)-2-isopropyl-5,6,7,8-tetrahydro-quinazolin-6-yl]-methyl-amine hydrochloride

[0301]

Example 110

4-(4-Fluoro-phenyl)-2-isopropyl-5,6,7,8-tetrahydro-quinazolin-7-ol

[0303]

Example 111

4-(4-Fluoro-phenyl)-2-isopropyl-5,6,7,8-tetrahydro-quinazoline

[0305]

Example 112

(2-Benzyl-6-p-tolyl-pyrimidin-4-ylmethyl)-dimethyl-amine

[0307]

Example 113

2-Benzyl-4-(4-methyl-piperazin-1-ylmethyl)-6-p-tolyl-pyrimidine

[0309]

Example 114

[6-(4-Fluoro-phenyl)-2-isopropyl-pyrimidin-4-ylmethyl]-methyl-amine

[0311]

Example 115

2-(2-Benzyl-6-p-tolyl-pyrimidin-4-yl)-ethylamine

[0313]

Example 116

[2-(4-Fluoro-benzyl)-4-p-tolyl-pyrimidin-5-ylmethyl]-dimethyl-amine

[0315]

Example 117

4-(4-Fluoro-phenyl)-2-phenyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

[0317]

Example 118

2-(3,3-Difluoro-cyclopentyl)-4-(4-fluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

[0318]

Example 119

4-(4-Fluoro-phenyl)-2-(tetrahydro-furan-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

[0319]

Example 120

4-(4-Fluoro-phenyl)-2-(2-piperidin-1-yl-ethyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

[0320]

Example 121

2-(1-Fluoro-1-methyl-ethyl)-4-(4-fluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

[0321]

Example 122

3-(4-Fluoro-phenyl)-5-isopropyl-4,6,12-triaza-tricyclo[7.2.1.02,7]dodeca-2,4,6-triene

[0322]

Example 123

7-(4-Fluoro-phenyl)-5-isopropyl-4,6,13-triaza-tricyclo[8.2.1.03,8]trideca-3,5,7-triene

[0323]

Example 124

4-(4-Fluoro-phenyl)-2-(tetrahydro-pyran-4-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

[0324]

Example 125

4-(4-Fluoro-phenyl)-2-(tetrahydro-pyran-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

[0325]

Example 126

4-(4-Fluoro-phenyl)-2-(2-methoxy-ethyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

[0326]

Example 127

2-[4-(4-Fluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-2-yl]-propan-2-ol

[0327]

Example 128

4-(4-Fluoro-phenyl)-2-(1-methyl-1-phenyl-ethyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

[0328]

Example 129

2-Cyclopent-3-enyl-4-(4-fluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

[0329]

Example 130

3-[4-(4-Fluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-2-yl]-cyclohexanol

[0330]

Example 131

4-(4-Fluoro-phenyl)-2-piperidin-4-yl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

[0331]

Example 132

4-(4-Fluoro-phenyl)-2-(1-methyl-piperidin-4-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

[0332]

Example 133

[4-(4-Fluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-2-yl]-phenyl-methanol

[0333]

Example 134

4-(4-Fluoro-phenyl)-2-(fluoro-phenyl-methyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

[0334]

Example 135

2-(Difluoro-phenyl-methyl)-4-(4-fluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

[0335]

Example 136

4-(4-Fluoro-phenyl)-2-phenyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

[0336]

Example 137

4-(4-Fluoro-phenyl)-2-(3-fluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

[0337]

Example 138

4-(4-Fluoro-phenyl)-2-(4-methoxy-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

[0338]

Example 139

4-(4-Fluoro-phenyl)-2-o-tolyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

[0339]

Example 140

3-[4-(4-Fluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-2-yl]-benzonitrile

[0340]

Example 141

4-(4-Fluoro-phenyl)-2-(2,2,2-trifluoro-1-trifluoromethyl-ethyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

[0341]

Example 142

4-(4-Fluoro-phenyl)-2-(1-methyl-cyclopropyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

[0342]

Example 143

2-[4-(4-Fluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-2-yl]-2-methyl-propionic acid

[0343]

Example 144

2-[4-(4-Fluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-2-yl]-propionic acid

[0344]

Example 145

2-(4-Fluoro-cyclohexyl)-4-(4-fluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

[0345]

Example 146

2-(4,4-Difluoro-cyclohexyl)-4-(4-fluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

[0346]

Example 147

4-(4-Fluoro-phenyl)-2-phenethyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

[0347]

Example 148

4-Furan-2-yl-2-isopropyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

[0348]

Example 149

2-Isopropyl-4-(5-methyl-furan-2-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

[0349]

Example 150

4-Furan-3-yl-2-isopropyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

[0350]

Example 151

4-(5-Fluoro-pyridin-2-yl)-2-isopropyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

[0351]

Example 152

2-Isopropyl-4-oxazol-2-yl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

[0352]

Example 153

4-(4,5-Dimethyl-oxazol-2-yl)-2-isopropyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

[0353]

Example 154

2-Isopropyl-4-thiazol-2-yl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

[0354]

Example 155

2-Isopropyl-4-(3H-[1,2,3]triazol-4-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

[0355]

Example 156

2-Isopropyl-4-(2H-pyrazol-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

[0356]

Example 157

2-Isopropyl-4-(1H-pyrazol-4-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

[0357]

Example 158

4-(4-Fluoro-phenyl)-2,6-diisopropyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

[0358]

Example 159

6-Ethyl-4-(4-fluoro-phenyl)-2-isopropyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

[0359]

Example 160

6-Cyclopropyl-4-(4-fluoro-phenyl)-2-isopropyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

[0360]

Example 161

6-Cyclobutyl-4-(4-fluoro-phenyl)-2-isopropyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

[0361]

Example 162

6-Cyclopentyl-4-(4-fluoro-phenyl)-2-isopropyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

[0362]

Example 163

6-Butyl-4-(4-fluoro-phenyl)-2-isopropyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

Example 164

Alternative preparation of 4-(4-fluoro-phenyl)-2-isopropyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine

Example 165

4-(4-Fluoro-phenyl)-2-isopropyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine, citrate salt

[0365]

Example 166

{2-[2-tert-Butyl-6-(4-fluoro-phenyl)-pyrimidin-4-yl]-ethyl}-methyl-amine

[0366] MS (ESI): exact mass calcd. for C₁₇H₂₂FN₃, 287.18; m/z found, 288.7 [M+H]⁺.

[0367]

Example 167

{2-[2-tert-Butyl-6-(4-fluoro-phenyl)-pyrimidin-4-yl]-ethyl}-dimethyl-amine

[0368] MS (ESI): exact mass calcd. for C₁₈H₂₄FN₃, 301.20; m/z found, 302.7 [M+H]⁺.

Assay Methods

In Vitro Pharmacology

[0369] Stock drug solutions (10 mM) were prepared in DMSO (the final assay concentration of DMSO not exceeding 0.4%). Drug dilutions were prepared in assay buffer.

[0371] Data obtained for compounds tested in Assays 1-4 are presented in Table 1 below.

1. Affinity for 5-HT₇Receptor Binding Sites

2. Affinity for 5-HT_2AReceptor Binding Sites

3. Affinity for 5HT₂Receptor Binding Sites

4. Affinity for 5-HT₆Receptor Binding Sites

[0376]

TABLE 1

Binding Affinities (nM)
Ex.	K_i5-HT₇	K_i5-HT_2A	K_i5-HT_2B	K_i5-HT_2C	K_i5-HT₆

1	540	4	70	90	NT
2	>10000	20	5000	510	NT
3	>10000	11	2250	1020	>10000
4	>10000	20	250	200	NT
5	>10000	13	350	250	NT
6	>10000	50	200	300	NT
7	>10000	25	900	900	NT
8	1000	20	1000	320	200
9	5000	1350	>10000	7500	NT
10	>10000	200	>10000	5000	NT
11	>10000	100	>10000	2000	NT
12	>10000	300	>10000	5000	NT
13	>10000	12.5	2200	1000	NT
14	>10000	30	4000	4000	NT
15	>10000	1000	>10000	>10000	NT
16	>10000	2000	>10000	>10000	NT
17	>10000	4	250	70	NT
18	525	10	80	60	330
19	>10000	100	140	200	NT
20	>10000	700	1200	>10000	NT
21	>10000	25	1185	1170	>10000
22	>10000	32	500	1300	NT
23	>10000	500	>10000	>10000	NT
24	>10000	240	>10000	>10000	NT
25	>10000	300	>10000	>10000	NT
26	>10000	300	>10000	>10000	NT
27	>10000	60	>10000	>10000	NT
28	>10000	100	400	3000	NT
29	>10000	240	1600	2000	>10000
30	>10000	800	1000	2500	NT
31	>10000	70	2000	>10000	NT
32	>10000	2000	>10000	>10000	NT
33	>10000	>10000	>10000	>10000	NT
34	>10000	150	400	1000	NT
35	500	70	400	2000	NT
36	>10000	>10000	>10000	>10000	NT
37	>10000	40	400	1000	NT
38	>10000	40	50	800	NT
39	>10000	150	>10000	>10000	NT
40	>10000	500	>10000	>10000	NT
41	>10000	2000	5000	5000	NT
42	>10000	120	>10000	>10000	NT
43	>10000	200	>10000	>10000	NT
44	>10000	400	500	1000	NT
45	>10000	>10000	>10000	>10000	NT
46	120	14	30	200	100
47	30	2.5	1	22	12
48	40	20	3	100	24
49	300	50	25	400	200
50	240	3.7	20	80	260
51	>10000	470	140	9000	NT
52	>10000	725	1150	9000	NT
53	>10000	1000	>10000	>10000	NT
54	5000	0.55	30	20	30
55	35	0.42	2.5	16	8.5
56	180	0.80	22	38	30
57	550	0.70	40	50	80
58	>10000	2	40	30	100
59	100	1.5	7.8	29	20
60	400	6	10	60	60
61	250	1.9	15	35	20
62	5275	0.75	21	21	27
63	>10000	1.5	52	46	60
64	>10000	10	1300	70	1300
65	>10000	20	300	570	>10000
66	300	8	30	145	NT
67	5400	56	80	495	NT
68	>10000	80	660	7100	NT
69	>10000	140	>10000	650	7100
70	>10000	117	>10000	3733	250
71	>10000	1027	4333	3583	300
72	>10000	130	>10000	>10000	NT
73	>10000	140	>10000	>10000	NT
74	>10000	47	1900	>10000	NT
75	5000	70	3000	>10000	NT
76	150	9	315	75	300
77	22	15	200	130	400
78	400	25	900	380	NT
79	300	115	435	900	NT
80	>10000	11	158	940	2800
81	>10000	25	450	6000	NT
82	>10000	2	500	20	230
83	>10000	30	1000	300	230
84	>10000	14	400	5000	NT
85	>10000	82	1150	>10000	NT
86	9000	100	4100	>10000	NT
87	>10000	600	2000	>10000	NT
88	550	13	60	185	NT
89	>10000	25	40	1400	NT
90	2300	17	130	1000	NT
91	>10000	75	200	9000	NT
92	>10000	300	>10000	>10000	NT
93	>10000	>10000	>10000	>10000	NT
94	>10000	>10000	>10000	>10000	NT
95	>10000	2000	>10000	>10000	NT
96	>10000	>10000	>10000	>10000	NT
97	>10000	>10000	>10000	>10000	NT
98	>10000	>10000	>10000	>10000	NT
99	>10000	>10000	>10000	>10000	NT
100	>10000	14	900	300	NT
101	>10000	400	>10000	>10000	NT
102	>10000	20	150	230	370
103	>10000	40	1000	1000	NT
104	>10000	700	500	3000	NT
105	>10000	40	100	400	NT
106	>10000	90	6300	>10000	NT
107	>10000	12	275	500	4000
108	>10000	18	42	1000	NT
109	>10000	400	>10000	>10000	>10000
110	>10000	220	1200	4000	NT
111	>10000	300	3500	>10000	NT
112	>10000	130	>10000	>10000	NT
113	>10000	650	>10000	>10000	NT
114	>10000	35	300	1000	NT
115	5000	1000	5000	>10000	NT
116	>10000	2000	>10000	>10000	NT
117	>10000	50	1000	4000	NT
166	NT	11	18	170	NT
167	450	7	14	200	NT

NT = not tested

5. In Vitro Functional Assay for 5-HT₂Receptor (Intracellular Calcium)

[0378]

TABLE 2

	pK_b	pK_b	pK_b
Ex.	5-HT_2A	5-HT_2B	5-HT_2C


13	7.1	5	NT
17	8.1	5.4	NT
18	7.6	6.7	NT
21	7.5	5	5
50	8.3	8.3	NT
57	8.2	6.9	NT
62	8.8	7.3	NT
63	7.8	6.3	NT
64	7.1	5	NT
69	6	5	NT
76	7	5	NT
78	7.1	5	NT
82	8.1	5.4	NT
100	7	5	NT

NT = not tested

Claims

What is claimed is:

1. A compound that is 4-(4-fluoro-phenyl)-2-isopropyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine or a pharmaceutically acceptable salt thereof.

2. A compound of claim 1 isotopically-labelled to be detectable by PET or SPECT.

4. The compound of claim 3 wherein said pharmaceutically acceptable salt is hydrochloride.

7. The composition of claim 6 wherein said pharmaceutically acceptable salt is hydrochloride.

8. The compound of claim 3 wherein said pharmaceutically acceptable salt is citrate.

9. The composition of claim 6 wherein said pharmaceutically acceptable salt is citrate.

10. A compound which is a citric acid salt of 4-(4-fluoro-phenyl)-2-isopropyl-5,6,7,8-tetrahydro-pyrido [4,3-d]pyrimidine.

Patent Citations (68)

Patent	Date	Inventor	Cited By
US3312716(A)	1967-04-01	Biel et al.	Applicant
US3969355(A)	1976-07-01	Schwan	Applicant
US4007196(A)	1977-02-01	Christensen et al.	Applicant
US4136193(A)	1979-01-01	Bogeso et al.	Applicant
US4314081(A)	1982-02-01	Molloy et al.	Applicant
US4536518(A)	1985-08-01	Welch et al.	Applicant
US4576604(A)	1986-03-01	Guittard et al.	Applicant
US4673405(A)	1987-06-01	Guittard et al.	Applicant
US4857330(A)	1989-08-01	Stephens et al.	Applicant
US5137890(A)	1992-08-01	Sanfilippo et al.	Applicant
US5405848(A)	1995-04-01	Sanfilippo et al.	Applicant
US5997905(A)	1999-12-01	McTeigue et al.	Applicant
US6025367(A)	2000-02-01	Forbes et al.	Applicant
US6149943(A)	2000-11-01	McTeigue et al.	Applicant
US6355642(B1)	2002-03-01	Koyama et al.	Applicant
US6407112(B1)	2002-06-01	Koyama et al.	Applicant
US6414149(B1)	2002-07-01	Chu-Moyer et al.	Examiner
US2002/0183519(A1)	2002-12-01	Nar et al.	Applicant
US2003/0153728(A1)	2003-08-01	Kolb et al.	Applicant
US2004/0229874(A1)	2004-11-01	Bright et al.	Applicant
US2005/0119295(A1)	2005-06-01	Carruthers et al.	Applicant
US2005/0232986(A1)	2005-10-01	Brown et al.	Applicant
US2005/0288355(A1)	2005-12-01	Mork et al.	Applicant
US2006/0194837(A1)	2006-08-01	Carruthers et al.	Applicant
US2006/0287292(A1)	2006-12-01	Carruthers et al.	Applicant
US2006/0293316(A1)	2006-12-01	Apodaca et al.	Applicant
US2007/0260057(A1)	2007-11-01	Deng et al.	Applicant
US2008/0004258(A1)	2008-01-01	Keith et al.	Applicant
US2008/0045508(A1)	2008-02-01	Allison et al.	Applicant
US2008/0045509(A1)	2008-02-01	Allison et al.	Applicant
EP1264820(A1)	2002-12-01		Applicant
EP1211246(B1)	2004-02-01		Applicant
JP3148265(A)	1991-06-01		Applicant
JP3148265	1991-06-01		Examiner
WO95/29909(A1)	1995-11-01		Applicant
WO96/32944(A1)	1996-10-01		Applicant
WO97/29097(A1)	1997-08-01		Applicant
WO97/47601(A1)	1997-12-01		Applicant
WO97/48681(A1)	1997-12-01		Applicant
WO97/49695(A1)	1997-12-01		Applicant
WO98/31354(A3)	1998-07-01		Applicant
WO99/24022(A3)	1999-05-01		Applicant
WO/32173(A1)	2000-06-01		Applicant
WO/37082(A1)	2000-06-01		Applicant
WO/56712(A1)	2000-09-01		Applicant
WO/59510(A1)	2000-10-01		Applicant
WO/73299(A1)	2000-12-01		Applicant
WO1/29029(A1)	2001-04-01		Applicant
WO1/41766(A1)	2001-06-01		Applicant
WO1/57039(A1)	2001-08-01		Applicant
WO2/14314(A2)	2002-02-01		Applicant
WO2/062788(A1)	2002-08-01		Applicant
WO2/072558(A1)	2002-09-01		Applicant
WO2072558	2002-09-01		Examiner
WO3/035070(A1)	2003-05-01		Applicant
WO3/053330(A2)	2003-07-01		Applicant
WO3053330	2003-07-01		Examiner
WO2004/011467(A1)	2004-02-01		Applicant
WO2004011467	2004-02-01		Examiner
WO2004094419	2004-04-01		Examiner
WO2004/039786(A1)	2004-05-01		Applicant
WO2004039786	2004-05-01		Examiner
WO2004/094419(A1)	2004-11-01		Applicant
WO2005/005387(A1)	2005-01-01		Applicant
WO2005/030132(A2)	2005-04-01		Applicant
WO2005/056056(A3)	2005-06-01		Applicant
WO2006/016262(A1)	2006-02-01		Applicant
WO2008/013556(A1)	2008-01-01		Applicant

Non-Patent Literature (91)

Appell, et al., Bioorganic & Medicinal Chemistry (2002), 10(5), 1197-1206.Examiner

Herrera, et al., Magnetic Resonance in Chemistry (2002), 40(4), 293-299.Examiner

Garcia Martinez, et al., Tetrahedron (1998), 54(18), 4607-4614.Examiner

Kawamura, et al., Bioscience, Biotechnology, and Biochemistry (1992), 56(11), 1897-9.Examiner

Collier, et al., Science of Synthesis (2004), 19, 403-425.Examiner

Voitenko, et al., Phosphorus, Sulfur and Silicon and the Related Elements (2005), 180(1), 163-177.Examiner

Herrera, et al., Tetrahedron Letters (2003), 44(10), 2149-2151.Examiner

Herrera, et al., Tetrahedron (2002), 58(19), 3755-3764.Examiner

Lafferty, et al., Journal of Organic Chemistry (1967), 32(5), 1591-6.Examiner

Poyurovsky, et al., Euro. Neuropsychopharmacol. 13 (2003) 123-128.Examiner

Kim, et al., Molec. & Cellular Probes (2000) 14, 47-52.Examiner

Khawam, et al., Cleveland Clinic J. Med., vol. 73, # 4, Apr. 2006, 351-361.Examiner

Mendelson, J. Clin. Psychiatry 2005: 66, 469-476.Examiner

Silvestre, et al., Methods Find Exp Clin Pharmacol 2005, 27(5): 289.Examiner

Kast, Support Care Cancer (2001) 9:469-470.Examiner

Naranjo, et al., Addiction, vol. 90, # 7, pp. 893-905, Jul. 1995.Examiner

May, et al., J. Pharmacol. & Experim. Therap., Apr. 3, 2003.Examiner

PCT International Search Report for International Application No. PCT/US2006/029437 dated Dec. 14, 2006.Applicant

Appell, M. et al. An analysis of the binding of cocaine analogues to the monamine transporters using tensor decomposition 3-D QSAR. Bioorg. Med. Chem. 2002, 10(5), 1197-1206.Applicant

Berge, S.M. et al. Pharmaceutical Salts. J. Pharm. Sci., 1977, 66:1-19.Applicant

Bonhaus, D.W. et al. RS-127443: A selective, high affinity, orally bioavailable 5-HT 2B receptor antagonist. Br. J. Pharmacol. 1999, 127(5), 1075-1082.Applicant

DeRuiter, J. et al. Investigation of the Synthesis and Analgesic Activity of 1-Substituted 4-(Propananilido)perhydroazepines. J. Het. Chem. 1992, 29(4), 779-786.Applicant

Dube, H. et al. Synthesis of chiral alpha-aminoalkylpyrimidines using an enantioselective three-component reaction. Synthesis 2004, 12, 2015-2025.Applicant

Herrera, A. et al. 1H and 13C NMR spectral assignments of 2,4-diaryl-substituted cycloalkyl[d]pyrimidines. Magn. Reson. Chem. 2002, 40(4), 293-299.Applicant

Herrera, A. et al. On the mechanism of reaction between ketones and nitriles. Unexpected results from benzyl nitriles. Tetrahedron 2002, 58(19), 3755-3764.Applicant

Hoyer, D. et al. Molecular, Pharmacological and functional diversity of 5-HT receptors. Pharmacol. Biochem. Behav. 2002, 71, 533-554.Applicant

Jerman, J.C. et al. Pharmacological characterisation of human 5-HT2 receptor subtypes. Eur. J. Pharmacol. 2001, 414, 23-30.Applicant

Kawamura, S. et al. Fused heterocycles, furo[3,2-d]pyrimidines and dihydrocyclopenta[d]pyrimidines, as potential new herbicides. Biosci. Biotechnol. Biochem. 1992, 56(11), 1897-1899.Applicant

Porter, R.H. et al. Functional characterization of agonists at recombinant human 5-HT2A, 5-HT2B and 5-HT2C receptors in CHO-K1 cells. Br. J. Pharmacol. 1999, 128, 13-20.Applicant

Roth, B.L. et al. The Multiplicity of Serotonin Receptors: Uselessly Diverse Molecules or an Embarrassment of Riches? Neuroscientist 2000, 6(4), 252-262.Applicant

Sanfilippo et al. Novel tetrahydropyrido[4,3-d]pyrimidines as gastric antilesion agents. Eur. J. Med. Chem. 1992, 27(7), 655-661.Applicant

Schotte, A. et al. Risperidone compared with new and reference antipsychotic drugs: in vitro and in vivo receptor binding. Psychopharmacology 1996, 124, 57-73.Applicant

Stolle, W.A.W. et al. Intramolecular Diels-Alder reactions of pyrimidines: Synthesis of tricyclic annelated pyridines. Tetrahedron 1989, 45(20), 6511-6518.Applicant

Voitenko, Z.V. et al. Conversions of 2-(2-oxocycloehxylcarbonyl)benzoic acid derivatives to pyrazolo[5,1-a]isoindole and pyrimidine rings. Phosphorus, Sulfur Silicon Relat. Elem. 2005, 180(1), 163-177.Applicant

U.S. Appl. No. 60/938,790, filed May 18, 2007, Keith.Applicant

U.S. Appl. No. 11/939,881, filed Nov. 14, 2007, Keith et al.Applicant

Bard et al. Cloning of a Novel Human Serotonin Receptor (5-HT7) Positively Linked to Adenylate Cyclase. J. Biol. Chem. 1993, 268(31), 23422-23426.Applicant

Bonaventure et al. Radioligand Binding Analysis of Knockout Mice Reveals 5-Hydroxytryptamine7 Receptor Distribution and Uncovers 8-Hydroxy-2-(2-di-N-propylamino)tetralin Interaction with α2 Adrenergic Receptors. Neuroscience 2004, 124, 901-911.Applicant

Bonnet, U. Moclobemide: Evolution, Pharmacokinetic, and Pharmacodynamic Properties. CNS Drug Rev. 2002, 8(3), 283-308.Applicant

Bymaster et al. Fluoxetine, but not other selective serotonin reuptake inhibitors, increases norepinephrine and dopamine extracellular levels in prefrontal cortex. Psychopharmacology (Berlin) 2002, 160(4), 353-361.Applicant

Chen et al. P-Glycoprotein Limits the Brain Penetration of Nonsedating but Not Sedating H1-Antagonists. Drug Metab. Dispos. 2003, 31(3), 312-318.Applicant

Collier et al. Applications of Nitriles as Reagents for Organic Synthesis with the Loss of the Nitrile Functionality (including Cycloaddition Reactions). Science of Synthesis 2004, 19, 403-425.Applicant

Eglen et al. The 5-HT7 Receptor: Orphan Found. Trends Pharmacol. Sci. 1997, 18, 104-107.Applicant

Frazer, A. Serotonergic and Noradrenergic Reuptake Inhibitors: Prediction of Clinical Effects from In Vitro Potencies. J. Clin. Psychiatry 2001, 62 Suppl. 12, 16-23.Applicant

Garcia Martinez et al. About the Timing of Wagner-Meerwein and Nametkin Rearrangements, 6,2-Hydride Shift, Proton Elimination and Cation Trapping in 2-Norbornyl Carbocations. Tetrahedron 1998, 54(18), 4607-4614.Applicant

Glass et al. Midbrain Raphe Modulation of Nonphotic Circadian Clock Resetting and 5-HT Release in the Mammalian Suprachiasmatic Nucleus. J. Neurosci. 2003, 23(20), 7451-7460.Applicant

Glennon et al. Higher-End Serotonin Receptors: 5-HT5, 5-HT6, and 5-HT7. J. Med. Chem. 2003, 46(14), 2795-2812.Applicant

Guscott et al. The hypothermic effect of 5-CT in mice is mediated through the 5-HT7 receptor. Neuropharmacology 2003, 44(8), 1031-1037.Applicant

Guscott et al. Genetic knockout and pharmacological blockade studies of the 5-HT7 receptor suggest therapeutic potential in depression. Neuropharmacology 2005, 48(4), 492-502.Applicant

Hagan et al. Characterization of SB-269970-A, a selective 5-HT7 receptor antagonist. Br. J. Pharmacol. 2000, 13093), 539-548.Applicant

Hansen et al. Pharmacological Management of Allergic Rhinitis in the Elderly. Drugs Aging 2005, 22(4), 289-296.Applicant

Harsing et al. A 5-HT7 Heteroreceptor-Mediated Inhibition of [3H]Serotonin Release in Raphe Nuclei Slices of the Rat: Evidence for a Serotonergic-Glutamatergic Interaction. Neurochem. Res. 2004, 29(8), 1487-1497.Applicant

Hedlund et al. 5-HT7 Receptor Inhibition and Inactivation Induce Antidepressantlike Behavior and Sleep Pattern. Biol. Psychiatry 2005, 58(10), 831-837.Applicant

Hedlund et al. No hypothermic response to serotonin in 5-HT7 receptor knockout mice. Proc. Natl. Acad. Sci. U.S.A. 2003, 100(3), 1375-1380.Applicant

Hedlund et al. Functional, molecular and pharmacological advances in 5-HT7 receptor research. Trends Pharmacol. Sci. 2004, 24(9), 481-486.Applicant

Herrera et al. One-pot synthesis of new heterocycles: 2,4-disubstituted 6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidines. Tetrahedron Lett. 2003, 44(10), 2149-2151.Applicant

Ishiguro et al. Influx and Efflux Transport of H1-Antagonist Epinastine Across the Blood-Brain Barrier. Drug Metab. Dispos. 2004, 32(5), 519-524.Applicant

Keating et al. The effect of a series of organic cations upon the plasmalemmal serotonin transporter, SERT. Life Sci. 2004, 76, 109-119.Applicant

Lafferty et al. The Preparation and Properties of Certain Pyridylpyrimidines and Bidiazines as Potential Chelating Agents for Iron(II). J. Org. Chem. 1967, 32(5), 1591-1596.Applicant

Lovenberg et al. A Novel Adenylyl Cyclase-Activating Serotonin Receptor (5-HT7) Implicated in the Regulation of Mammalian Circadian Rhythms. Neuron 1993, 11(3), 449-458.Applicant

Marek et al. Synergistic Action of 5-HT2A Antagonists and Selective Serotonin Reuptake Inhibitors in Neuropsychiatric Disorders. Neuropsychopharmacology 2003, 28, 402-412.Applicant

Meneses, A. Effects of the 5-HT7 receptor antagonists SB-269970 and DR 4004 in autoshaping Pavlovian/instrumental learning task. Behav. Brain Res. 2004, 155(2), 275-282.Applicant

Murphy et al. Experimental gene interaction studies with SERT mutant mice as models for human polygenic and epistatic traits and disorders. Genes, Brain & Behav. 2003, 2(6), 350-364.Applicant

Ni et al. 5-Hydroxytryptamine in the Cardiovascular System: Focus on the Serotonin Transporter (SERT). Clin. Exp. Pharmacol. Physiol. 2006, 33(7), 575-583.Applicant

Pouzet, B. SB-258741: A 5-HT7 Receptor Antagonist of Potential Clinical Interest. CNS Drug Rev. 2002, 8(1), 90-100.Applicant

Read et al. Evidence for the involvement of central 5-HT7 receptors in the micturition reflex in anaesthetized female rats. Br. J. Pharmacol. 2003, 140, 53-60.Applicant

Read et al. Effects of SB-269970, the 5-HT7 Receptor Antagonist, on Micturition. Presentation Abstract, International Union of Basic & Clinical Pharmacology, XIVth World Congress of Pharmacology, San Francisco, CA, Jul. 2002.Applicant

Roberts et al. GABAergic modulationof 5-HT7 receptor-mediated effects on 5-HT efflux in the guinea-pig dorsal raphe nucleus. Neuropharmacology 2004, 46(7), 935-941.Applicant

Simons et al. The Pharmacology and Use of H1-Receptor-Antagonist Drugs. N. Engl. J. Med. 1994, 330, 1663-1670.Applicant

Spinks et al. Serotonin Reuptake Inhibition: An Update on Current Research Strategies. Curr. Med. Chem. 2002, 9, 799-810.Applicant

Steru et al. The Automated Tail Suspension Test: A Computerized Device which Differentiates Psychotropic Drugs. Prog. Neuropsychopharmacol. & Biol. Psychiatry 1987, 11(6), 659-671.Applicant

Tagawa et al. Neuroimaging of histamine H1-receptor occupancy in human brain by positron emission tomography (PET): A comparative study of ebastine, a second-generation antihistamine, and (+)-chlorpheniramine, a classical antihistamine. Br. J. Clin. Pharmacol. 2001, 52(5), 501-509.Applicant

Tashiro et al. Brain histamine H1 receptor occupancy of orally administered antihistamines measured by positron emission tomography with 11 C-doxepin in a placebocontrolled crossover study design in healthy subjects: a comparison of olopatadine and ketotifen. Br. J. Clin. Pharmacol. 2006, 61(1), 16-26.Applicant

Tashioro et al. Central Effects of Fexofenadine and Cetirizine: Measurement of Psychomotor Performance, Subjective Sleepiness, and Brain Histamine H1-Receptor Occupancy Using 11 C-Doxepin Positron Emission Tomography. J. Clin. Pharmacol. 2004, 44(8), 890-900.Applicant

Thomas et al. SB-656104-A, a novel selective 5-HT7 receptor antagonist, modulates REM sleep in rats. Br. J. Pharmacol. 2003, 139(4), 705-714.Applicant

Thomas et al. 5-HT7 Receptors. Curr. Drug Targets CNS Neurol. Disord. 2004, 3(1), 81-90.Applicant

To et al. Characterization and distribution of putative 5-HT7 receptors in guinea-pig brain. Br. J. Pharmacol. 1995, 115(1), 107-116.Applicant

Tuladhar et al. 5-HT7 receptors mediate the inhibitory effect of 5-HT on peristalsis in the isolated guinea-pig ileum. Br. J. Pharmacol. 2003, 138(7), 1210-1214.Applicant

PCT International Search Report for PCT/US 06/40911 dated Sep. 27, 2007.Applicant

Martel et al. Recent advances on the importance of the serotonin transporter SERT in the rat intestine. Pharmacol. Res. 2006, 54, 73-76.Applicant

Menza, et al. Modafinil Augmentation of Antidepressant Treatment in Depression. J. Clin. Psychiatry 2000, 61, 378-381.Applicant

Ohtsuki, S. New Aspects of the Blood-Brain Barrier Transporters; Its Physiological Roles in the Central Nervous System. Biol. Pharm. Bull. 2004, 27(10), 1489-1496.Applicant

Olver et al. Third-Generation Antidepressants: Do They Offer Advantages Over the SSRIs? CNS Drugs 2001, 15, 941-954.Applicant

Thomas et al. [3H]-SB-269970 radiolabels 5-HT7 receptors in rodent, pig and primate brain tissues. Neuropharmacology 2002, 42(1), 74-81.Applicant

Vanhoenacker et al. 5-HT7 receptors: current knowledge and future prospects. Trends Pharmacol. Sci. 2000, 21, 70-77.Applicant

Van Wauwe et al. In Vivo Pharmacology of Astemizole, a New Type of H1-Antihistaminic Compound. Arch. Int. Pharmacodyn. 1981, 251, 39-51.Applicant

Varnas et al. Distribution of 5-HT7 receptors in the human brain: a preliminary autoradiographic study using [3H]SB-269970. Neurosci. Lett. 2004, 367(3), 313-316.Applicant

Welch et al. H1-Antihistamines and the central nervous system. In Histamine and H1-Antihistamines in Allergic Disease, 2nd ed.; F.E.R. Simons, Ed.; Marcel Dekker, Inc.: New York, 2002; Chapter 11.Applicant

Yanai et al. Histamine H1 receptor occupancy in human brains after single oral doses of histamine H1 antagonists measured by positron emission tomography. Br. J. Pharmacol. 1995, 116, 1649-1655.Applicant

Yanai et al. Mapping of Histamine H1 Receptors in the Human Brain Using [11C]Pyrilamine and Positron Emission Tomography. J. Neurochem. 1992, 59, 128-136.Applicant

Yoon et al. Rapid Screening of Blood-Brain Barrier Penetration of Drugs Using the Immobilized Artificial Membrane Phosphatidylcholine Column Chromatography. J. Biomol. Screen 2006, 11(1), 13-20.Applicant