SA05260355B1 - ARYL PYRIMIDINE DERIVATIVES AND THEIR USES - Google Patents

Abstract

Abstract : The present invention relates to aryl pyrimidine derivatives, and pharmacologically acceptable salts and N-oxides thereof, which exhibit beneficial pharmacological properties, warranting their use as selective 5HT2B-antagonists. The antagonist 5-HT2B is a compound of formula: (I) where: R1 is hydroxyalkyl, lower alkoxy, alkyl, hydrogen, lower, alkenyl, cycloalkyl lower alkyl, cycloalkyl NR6R7'fluoroalkyl -halo, thioalkoxy -, - ,-CO2R8 O(CH2) ) nR9, or a lower alkyl optionally substituted with a hydroxy, halo, alkoxy, or aryl; in which: n is 1, 2, or 3; R7 and R6 are hydrogen or lower alkyl; R8 is hydrogen or lower alkyl; and R9 is hydroxy, lower alkyl, hydrogen, lower alkenyl, hydroxy lower alkyl, or lower alkoxy; R2 is halo, lower alkoxy, lower alkyl, hydrogen, or lower fluoroalkyl; R3 is an optionally substituted aryl other than pyridyl; thienyl; or to furanyl; R4 is hydrogen; lower alkyl; amido, amino, acyl, alkenyl, cycloalkyl; aryl, -CH2)mNR10R11), or a lower alkyl optionally substituted with a single-substituted amino, double-substituted amino, hydroxy carboxy; in which: R10 and R11 are hydrogen or lower alkyl; and r5 is hydrogen or lower alkyl; Provided that: (1) when R3 is naphthyl; indol-1-yl, or dihydroindol-l-yl, R4' R2, R5, 2,3- each is hydrogen, R1 is not methyl; (2) when R3 is phenyl or naphthyl, R1 is not NR6r7-; (3) when R3 is phenyl, R2 is not lower alkoxy, and R1 and R2 are not halo; (4) when R3 is phenyl and R1 is H, R2 is not methyl; (5) When R3 is 1,2,3,4-tetrahydroquinolinyl-, R4 and R5 are hydrogen; Or salt or N-oxide acceptable medicinally thereof.

Description

v Aryl Pyrimidine and its uses Arylpyrimidine derivatives Full description Background of the invention This application is a partial application of Application No. 17180191, which was filed in the Kingdom of Saudi Arabia, corresponding to 1317/: 9// 01 AD. E 1 EVAL Y/Y Saudi Arabia with an acceptable date N-oxides 5 and with caryl pyrimidine derivatives salts with Mall derivatives. The invention relates pharmacologically to terminations that exhibit beneficial pharmacological properties; including their use as selective SHT,p-0 antagonists. The neurotransmitter has some mixed and complex pharmacological characteristics; Serotonin has been identified and since then has become a major topic of research. EA is referred to as its discovery year and acts on the sporadic (5-111) receptors “(5-HT) 5-hydroxytryptamine serotonin subfamily of receptor 88010010 that have been identified and thoroughly described in central and peripheral VE. Currently there are Ye families 5-111 and 1117-E 5-HT, family Jala .5-1117 families », 5-111 to V M5-1112. These families share ordinal similarity, and it has been shown that there is divergence in characteristics and associations over a wide range. The nomenclature and subdivision of the 5-111 receptor was newly revised; See:

Martin and Humphrey, Neuropharm., 1994, 33, 261-273 and Hoyer et al., Pharm.

Rev., 1994, 46, 157-203. Vo, where serotonin or an S-HTp-like receptor was initially identified as a 5-HT,p receptor was identified in isolated mouse gastric cavities; See:

Clineschmidt et al. (1985), J. Pharmacol. Exp. Ther., 235, 696-708; Cohen and

Wittenauer, (1987), J. Cardiovasc. Pharmacol., 10, 176-181. The receiver is characterized by H5-1112; widely distributed in the human brain; That it is like the Ye family, see: 5-1112

Pazos et al. (1984), Eur. J. Pharmacol. 106, 539-546, then I consider it to belong to the future family 1117-5; See:

Pritchett et al. (1988), EMBO 1.7, 4135-4140, 777 p.

Because of the symmetry in the pharmacological interactions between the 5-1112 5,5-Htop receptors, many of the therapeutic targets that targeted the 1117-5 receptor antagonists are also the same targets for the receptor and 5-1117 antagonists. At present, evidence strongly supports the therapeutic role of receptor antagonists 5-1128 in the treatment of anxiety (Jie generalized anxiety disorder, fear disorder, and obsessive-compulsive disorder 0); alcoholism and drug addiction; Depression; migraines; sleep disturbances; Eating disorders (such as anorexia nervosa) and persistent painful erections. In addition, current evidence strongly supports a therapeutic role for selective f-1117-5 receptor antagonists that confer distinct therapeutic advantages combined in efficacy. Fast onset of action and no side effects. These agents are expected to be useful in treating high blood pressure. Gastrointestinal Disorders (Sie) 00 symptom of upset stomach; overactive lower esophageal sphincter (lower esophageal sphincter disturbances); renarrowing of the lil arteries of asthma and obstructive airway disease; Sia (benign prostatic hyperplasia). Many of the aryl substituted pyrimidine compounds are listed in the chemical literature and patents. For example: Budesinsky et al., Collection Czechoslav.

Chem.

Commun., 26, 2865-2870 (1961), Yo reported 2-amino-6-methyl-4-(naphth-1-yl)-pyrimidine as a useful intermediate in the preparation of antibacterial compounds. Pyrimidine derivatives are described in: Mariella et al., J.

Org.

Chem., 25, 647-648 (1960); Zagulyaeva et al., Izv.

Sib.

Otd. Akad.

Nauk SSSR, Ser.

Khim.

Nauk, 4, 27-31 (1990); Essawy et al., Egypt.

J. |Chem., 37(4), 423-31(1994); Y. US Patent Nos. (£0ETYEA 11773 for Scratch ¢©+1YA0Y (£TT0L YY) by Stringfellow et al.; US Patent No. 49789716 (0) Mizuchi et al.; US Patent No. 07772565 Hargreaves and others; and EP 830 459 0 (EP) assigned to the Wellcome Foundation Yo. Disclosure of these and other documents referenced throughout this specification and incorporated herein by reference. General Description of the Invention p.777

° The invention relates to a method for treating a mammalian organism with a pathological condition that is mitigated by treatment with an antagonist:] and 5117 by administering to a mammalian organism in need of treatment a therapeutically effective amount of a compound of the formula

Rr?

R! N 1 2 hd RS rR? where: “cycloalkyl hydroxyalkyl subsampled alkoxy “alkyl <hydrogen s— a R' ° phenyl “fluoroalkyl <halo <lower thioalkoxy calkenyl “cycloalkyl lower alkyl optionally substituted with lower alkyl or -O(CHp) aR' for -NRR optionally substituted taryl or <halo alkoxy <hydroxy in which: oF or 1 7 is Ye 'lower alkyl hydrogen of which separately is JSR74R® and slower alkyl hydrogen see R® or dower alkenyl «hydroxy lower alkyl <hydroxy lower alkyl hydrogen sa R' - ¢lower alkoxy slower fluoroalkyl 4 <halo lower alkoxy «lower alkyl »hydrogen Her R? Yo optionally substituted; aryl is R3 «aryl <amido «amino «acyl «alkenyl »cycloalkyl lower alkyl <hydrogen is R* amino «amino optionally substituted with lower alkyl or «- SO,R'? -C(NH)NR''R!! “amido dower alkoxy “aryl” carboxy hydroxy substituted by thymsa amino monosulfonamido i.e. <hydroxyalkoxy ctetrahydrofuran-2-yl “alkoxycarbonyl | 0 in which: slower alkyl hydrogen “core and alkyl hydrogen each separately is” and flower alkyl ag is “lower alkyl ol hydrogen bitter” R’

0, salt, or N-oxide that are medically acceptable. Detailed description of the invention Definitions as used herein: “alkyl” ° means a saturated hydrocarbon chain that is branched or unbranched containing 1 to VY carbon atoms such as n-octyl n- hexyl tert-butyl “propyl” ethyl “methyl” n-dodecyl etc. "alkenyl" refers to a monovalent unsaturated hydrocarbon moiety having a 1 to Y carbon atom. This term is also represented by the moieties “pent-3-enyl” prop-2-enyl “vinyl Jie coct-2-enyl < hex-5-enyl 00 etc. “cycloalkyl” means a monovalent saturated carbocyclic moiety containing an unsaturation having from three to eight carbon atoms; For example, “cyclobutyl “2-methylcyclopropyl” cyclopropyl .cyclooctyl “cycloheptyl “cyclohexyl” cyclopentyl “3-ethylcyclobutyl” “lower alkyl” means a saturated hydrocarbon chain branched or unbranched containing CY le ve to + carbon atoms” e.g. methyl lat “n-hexyl” butyl tert-butyl “isopropyl” propyl etc; Unless specified otherwise. "lower alkenyl" refers to a monovalent unsaturated hydrocarbon moiety having from one to six carbon atoms. This term Lay is represented by the moieties “prop-2-enyl “vinyl Je < hex-5-enyl 5 “pent-3-enyl etc. “cycloalkyl lower alkyl” Y. As specified here means the cycloalkyl as specified above is bound to the lower alkyl moiety as specified above for example » «cyclopropylethyl »cyclopropylmethyl ‎«cyclopentylmethyl ~~ <cyclobutylethyl «cyclobutylmethyl »cyclopropylpropyl cyclooctylmethyl cycloheptylmethyl cyclohexylmethyl etc. "phenyl lower alkyl" means phenyl bonded to a lower alkyl moiety as defined by def eg vo <phenylpropy! “phenethyl” phenylmethyl (benzyl) etc.

No “fluoroalkyl” means an alkyl as specified above substituted by 1 to © fluorine atoms at any position; eg <1,1,1-trifluoro-n-propyl “pentafluoroethyl trifluoromethyl <1 -fluorooctane «1,2-difluoro-3-methylpentane «1-fluoro-n-butyl etc. “lower fluoroalkyl” means lower alkyl as specified above substituted by 1 to o oe atoms Fluorine at any position; Jp lo Example; “pentafluoroethyl “trifluoromethyl ¢1,2-difluoro-3-methylpentane “1-fluoro-n-butyl” 1,1,1-100010-0- 01 etc. "acyl" denotes the group “-C(O)-R' where R' is the lower alkyl as defined here. "lower alkoxy" means the group -O-R' where R' is the Jawer alkyl as specified here. Similarly; "lower thioalkoxy" denotes the group ~S-R' "hydroxyalkyl" 0" means the alkyl group as specified above substituted by YoY) hydroxy groups eg “2-hydroxyethyl “1-hydroxyethyl <hydroxymethyl “2-hydroxyisopropyl” 1-hydroxyisopropyl “1,2-dihydroxyethyl ¢1,3-dihydroxybutyl” 1 -hydroxybutyl <1 2-dihydroxyisopropyl etc. in a similar way; then “hydroxy lower alkyl” means a lower alkyl group as specified above replaced by 1 – 00 7 or ? hydroxy groups “halo” denotes “bromo “chloro” fluoro or 00 unless otherwise specified that. "amino monosubstituted" means dus -NHR moiety where R is optionally substituent lower alkyl lower alkyl as Hana specifies for example; 1 cetylamine chopsticks, etc. double-substituted amino’ 21828 of which 18 “JSR” is selected separately from lower alkyl | 0 or optionally inferred lower alkyl as specified by Hana on the example dow .diethylamino “dimethylamino “alkoxycarbonyl” means the -C(O)OR® moiety where R® is the lower alkyl aryl as specified by Hana e.g. phenoxycarbonyl sl methoxycarbonyl “amido” means RY Cus -C(O)NRIR® moiety and 85 each separately being chydrogen door alkyl 0 or aryl as specified here. “sulfonamido” means moiety 11890785 where RY and 25 each separately are hydrogen or lower alkyl as specified by cla for example .methanesulfonamido

A

2-hydroxyethoxy as specified here substituted with the group Jower alkoxy meaning "hydroxyalkoxy". Optional and that this description includes cases in which the event or adverb chang does not occur but the aryl' substituent is not necessarily an optional 'or phenyl' substituent 'Jia' and cases in which it does not occur. For example 0 may be or may not be substituted with a substituent chosen from the aryl group or optionally phenyl" means that < halo 5 (lower fluoroalkyl «nitro <hydroxy »lower alkoxy dower alkyl formed from the unsubstituted aryl s phenyl isomer All unsubstituted aryls are phenyl and include a lower or ternary alkyl substituent. Likewise, a potential LAD that is a monosubstituted may or may not be substituted with a chosen lower alkyl substituent. Optionally by “means that > 0 hydroxy di-substituted amino “amino” group consisting of “tetrahydrofuran-2-yl “alkoxycarbonyl” acting as alkoxy “aryl” carboxy and their isomeric forms. csulfonamido or ¢hydroxyalkoxy as used herein means a monocyclic aromatic ring system of at least one sa al gring member of which It has VE of 9 to bicyclic or tricyclic ring and 16160070168 has one or two atoms of ccarbocycles in nature and includes aromatic but aryl groups. Examples of Lsulfurs coxygen “nitrogen” groups are selected from the hetero “anthracene” acenaphthene “naphthalene thiophene” phenyl hypochlorite <ndole ¢1,2,3,4-tetrahydroquinoline “isoquinoline” quinoline “phenanthrene 0 2,3,4,5-tetrahydro-1H-benzo[bJazepine <1H-benzo] blazepine ¢2,3-dihydroindole <3,4-dihydro-2H-benzo[1,4]oxazine «2H-benzo[1,4]oxazine «6,7,8,9-tetrahydro-5-oxa-9- benzocycloheptane “1H,3H-benzo[del]isochromene” includes aryl structures, the term “JS” etc. In particular (2,3-dihydro-1,4-benzodioxane of the formula: Yo Free

and their derivatives; <naphth-2-yl 5 naphth-1-yl Sls

ON x 1

NF

and derivatives thereof; cacenaphthen-6-yl 5 acenaphthen-5-yl «Mie

N

]

NF

etc; and their derivatives, cquinolin-8-yl “quinolin-4-yl” quinolin-2-yl Se©ee, etc.; and their derivatives; cisoquinolin-8-yl «isoquinolin-4-yl < isoquinolin-1-yl methyl N NY { SF and their derivatives; ¢1,2,3,4-tetrahydroquinolin-5-yl < 1,2,3,4-tetrahydroquinolin-1-yl (methyl N NY )

I

A 0 1 «3,4-dihydro-2H-benzo[1,4]oxazin-5-yl «3,4-dihydro-2H-benzo[1,4]oxazin-1-yl «Sis and Mbt. A;

N

NY

{:

SZ

«1H-indol-4-yl «indol-1-yl Sia dy lial double bond J Say where dashed line and their derivatives; «2,3-dihydroindol-1-yl 00

N

NY

{

ZF

and its derivatives; “2,3,4,5-tetrahydro-1H-benzo[b]azepine, for example, 777 p.

1

N

FY

“AN D 0 «7,8-dihydro-6H-5-0xa-9-aza-benzocyclohepten-9-yl «Mia and their derivatives; ¢7,8-dihydro-6H-5-0xa-9-aza-benzocyclohepten -4-yl

Co Ag & its derivatives <benzo-1,4-dioxane Example © “inert solvent or 'inert organic solvent' The term 'inert organic solvent' means that the solvent is inert The conditions for the reaction described and associated with it [include; On “dimethylformamide “tetrahydrofuran acetonitrile” toluene standardized example “(CHCl) or dichloromethane (or methylene chloride “(CHCIl3) chloroform “ethanol” methanol “methylethyl ketone acetone ethyl acetate” diethyl ether 0 etc.]. Unless otherwise specified, “pyridine” dioxane stert-butanol “isopropanol” propanol These solvents used in the reactions of the present invention are inert solvents. “Pharmacologically acceptable acid addition salt” refers to these salts that retain the properties and biological activity of the bases free and also to these non-biological or on the other hand undesirable <hydrobromic acid »hydrochloric acid formed with non-organic acids such as cacetic acid etc.; and organic acids such as «phosphoric acid «nitric acid» sulfuric acid «malonic acid malic acid «oxalic acid »pyruvic acid »glycolic acid «propionic acid »benzoic acid «citric acid »tartaric acid »fumaric acid «meleic acid »succinic acid cethanesulfonic acid »methanesulfonic acid »mandelic acid »cinnamic acid etc. »salicylic acid p-toluenesulfonic acid ~~ v. The constant formed at one of the amino oxide atoms refers to an “N-oxide”. Pyrimidine nitrogen as used herein denotes any treatment of disease in an organism. specifically human; It includes: 777 p

11 A (1) preventing the disease from occurring in a person who may be at higher risk for the disease but not yet diagnosed; (7) inhibiting the disease, meaning stopping its progression; or (V) mitigating the disease, meaning causing the disease to recede. The term “therapeutically effective amount Ladle” refers to an amount of a Formula 1 compound © that is sufficient for effective treatment as defined above; when administered by GIS to a breast in need of treatment. The effective amount Ladle varies depending on the subject's condition and the disease condition being treated pad The disease state which as alleviable by treatment with as used herein means that 0 covers all Pathological conditions generally known in this art because it is useful to treat them with compounds met with affinity for 51112 receptors in general and pathological conditions for which it is useful to treat with special compounds [lie] gals Formula 1 compounds. Thus, pathological conditions include, but are not limited to, anxiety disorder (eg; anxiety disorder generalized anxiety”; panic disorder and obsessive-compulsive disorder); alcoholism and drug addiction (AY) depression; Migraines; hypertension; Disorders ve gastrointestinal tract De) presentation of an upset stomach; overactive lower esophageal sphincter (lower esophageal sphincter disturbances); re-narrowing of the heart's arteries; asthma and obstructive airway disease; prostatic hyperplasia (lie) benign prostatic hyperplasia); Sleep disorders; Eating disorders (Jia anorexia nervosa) and persistent painful penile erection. 7 Compounds of formula J shown [ola] will be named using the numbering system shown: un R! ad N. os A ? r3 A compound of formula 1 where RY is R* (R? isopropyl major they sa Rj hydrogen “1-naphthyl” is called: 2-amino -6-isopropyl-4-(naphth-1-yl)-pyrimidine.VY'Y

VY

and 1783 is <hydrogen Hm R',R* (R? tert-butyl sa R! be Cun 1 The compound of the formula is called: <S-acenaphthen 4-(acenaphthen-5-yl) -2-amino-6-tert-butylpyrimidine.The 1583 is a hydrogen rang them R* (R? cisopropyl s R' The compound of formula 1 where it is called: ¢«1H-indol-4-yl E0 2-amino-4-(1H-indol-4-yl)-6-isopropylpyrimidine. “methyl sa R' < hydrogen and they are “methyl sa R! The compound of formula 1 where it is is called: 1,23 4-tetrahydroquinolin-1-yl is 4-(3,4-dihydro-2H-quinolin-1-yl)-2-(methylamino)-6-methylpyrimidine. —a R? -chloro-4-(4-methoxyphenyl)-5-methylpyrimidine-1-N-oxide Preferred embodiments Within the family of compounds of the present invention, one preferred section includes compounds of Formula 1 which are preferred include de gana compounds in which 187 and 85 are both p70:0 Within this section the vo is optionally substituted in particular where 18.3 is aryl is the RY lower alkyl of which 18 is the N-oxides s «<indol -4-yl see «5-acenaphthen facultatively substituted with 1-naphthyl Currently, preferred compounds include: 2-amino-4-(2-methylnaphth-1-yl)-6-methylpyrimidine; 2-amino-4-(4-fluoronaphth-1-yl)-6-isopropylpyrimidine; Yo 2-amino-4-(4-fluoronaphth-1-yl)-6-isopropylpyrimidine-1-N-oxide; 2-amino-4-(4-fluoronaphth- 1-y1)-6-(2-methylpropyl)-pyrimidine; 2-amino-6-(tert-butyl)-4-(4-fluoronaphth-1-yl)-pyrimidine; 2-amino-4-(1H-indol-4-yl)-6-methylpyrimidine; 2-amino-4-(4-fluoronaphth-1-y1)-6-(1-fluoro-1-methylethyl)pyrimidine; Yo 2-amino-4-(4-fluoronaphth-1-yl)-6-(1-hydroxy-1-methylethyl)pyrimidine; 4-(acenaphthene-5-yl)-2-amino-6-isopropylpyrimidine; and

Vy'y

L-4-(acenaphthene-5-yl)-2-amino-6-tert-butylpyrimidine. Preparation Methods for Formula I Compounds A method for preparing formula 1 compounds from intermediate compounds of formula (4); whose preparation oe is shown in reaction program 1 below. Reaction program 1 NH 0 0 O Aa + HN A NRIRS R? 0 0 RS Nag a D" R R? 2 OH M RY 1 1 yb N d" R N R? 7 a 5 ( Cua being R is R' 5 lower alkyl and 22 are as specified in the general description of the invention; and 85 and 1857 are Jawer alkyl sf hydrogen 1 preparation of compounds of formula ) a { The starter ketoester of formula (1) may be obtained commercially as Jil of Aldrich Chemical Co., Ins. Or it may be prepared according to methods well known in the art. Compounds of guanidine or guanidine are commercially available substituted from the formula (?)” or it may be prepared according to methods well known in Art. 777 p

AR

With an addition of derivatives (1) of formula ketoester to prepare compounds of formula (?); treat at recondensation temperature of cethanol of formula (?) in a protonated solvent; preferably guanidine 1 hour. Isolate the product of formula (7) derivative 16 preferably steamed for about 7-heli; Preparation of compounds of the corresponding formula 4-chloro from formula (?) to 2-amino-4-hydroxypyrimidine (Fide) The “chlorinating agent of formula (£) is converted by the reaction of the compound of formula (7); with a chlorinating agent preferably in the presence of a solvent The reaction is carried out at a temperature of 0 10800005 oxychloride preferably hours; It is preferable to recrystallize before the reaction <2-amino-4-chloropyrimidine derivative “(4) additive. To compound Bal (4) of 2-amino-4,6-dichloro compound may transform (Alay in the manner of the corresponding 4,6-dichloro of formula (4) by reaction of the corresponding compound 6-alkoxy-4-chloro or potassium hydroxide in the presence of a base; Preferably an alcohol of formula (£) with 1 001 the reaction takes place at a temperature of about *10°C to a potassium tert-butoxide derivative of) hours. Isolate product of formula 10 min to * Mg asa WA ie by conventional means; It is purified by chromatographic analysis. 6-alkoxy-4-chloropyrimidine

I prepare_compounds of formula Below is one way to convert a formula compound (;) to a formula 1 compound in the reaction program Ye

Y

777 p

11 1 interaction program rR?

R Nr Nags + RP°B(OH); Ht, ZN

R?

Ci (£®)

Rrr! }

R N ~ #5 Ra R? 2 rR} f or hydrogen are R®5 and 83 are as specified in the general description of the invention; And 1 RP RY where is: Jawer alkyl

I Preparation of compounds of formula ° A 2-amino-4-chloropyrimidine derivative of formula (£) reacts with a boronic acid derivative of formula (0) in a solvent Se ¢ preferably a mixture of cethanol with water 5 » dimethoxyethane containing a palladium catalyst preferably (palladium tetrakistriphenylphosphine) and an inorganic base preferably sodium carbonate. The reaction should be carried out at a vapor recondensation temperature of the solvent Ve preferably about 0/0 “residence for about Yeo hr preferably about 4 hr. The Formula 1 product is isolated by a satellite (dani) preferably purified by recrystallization. Alternative preparation of Formula I compounds An alternative method for converting a Formula 1 compound (£) to a Formula 1 compound in the reaction program Y is shown below

Jelly program? Wht233)0 a R3¥Br 00( 00 R¢ t NE 8 5 b R CY to—J rR? A" cl 3 0 z Cua be R hr dower alkyl sf t s t s t they as specified in the general description of the invention; r s r > h s Jawer alkyl sf hydrogen © Preparation of compounds of formula (V) React bromoaryl derivative of formula (1) With a strong base, eg dower alkyl lithium preferably n-butyl lithium, the reaction is carried out in an ether solvent (eg dioxane “dimethoxyethane” diethyl ether Ar Ja 4 “tetrahydrofuran” (tetrahydrofuran) at Heat from about - 90 to dare preferably about 0 dso (0 dso) for about veo minutes; after that add about 1 equivalent of ctrialkoxyborane preferably ctrimethoxyborane and leave the mixture to warm to room temperature. Formula (V) ¢ cdimethoxyborane is removed from the solvent and used in the following reaction without further purification Preparation of compounds of formula I vo A 2-amino-4-chloropyrimidine derivative of formula (;) reacts with a compound boron of formula (V) obtained above in an inert solvent; preferably an aromatic solvent; most preferably toluene containing a catalyst “palladium” preferably palladium tetrakistriphenylphosphine and an aqueous inorganic base; Preferably [sodium carbonate] water. The reaction preferably takes place at the solvent vapor re-condensation temperature; Preferably about 80*-40" simmered; for about 10 minutes to 10 hours; preferably about 1 hour. The product of Formula 1 is isolated and purified by conventional means; preferably purified by chromatography. : 777p

VY bicyclic ring system 13 is a bicyclic ring system Cun 1 Preparation of formula compounds as junction point N containing in which 183 is oT An alternative method is available to convert the formula compound (;) to the formula compound Binding to the nucleus of ALES 17 containing a bicyclic ring system: the following represents R? Namely; “pyrimidine ° ™.”

CC

Optionally replace the rings as (NH©; 5) or “CHp is YY or 1 yellow; san in which is 4 . is specified above. This method in reaction program 4 is illustrated below. Interaction program:

H

N

7 + (8) — (CHa,

Y y button RrR¢ NN R J NG ~gs x oN

I

™ y y (CH), 77 0 and 8 are as 18 R* lac NH R 8 OCH, or 7 AH 1 yellow gan in which it is specified above in the general description of the invention ..

I Preparation of compounds of formula in (A) of formula (€) with a compound of formula 2-amino-4-chloropyrimidine reacting as a derivative as a solvent. It is preferable that the reaction be carried out at the degree of sulfuric acid preferably (sf A mixture of water and acid ve

Ya

hours; Preferably about 2 hours. 10 minutes to 700 °C, about 100 °C; For a period of about, the product of formula 1 is isolated by conventional means, preferably purified by recrystallization. by an alternative method; Compounds of formula (4) and (4) react together in a polar solvent; preferred

Gf 0-070 The reaction is preferably carried out at a temperature of about 0.0110©0 7110056 h. Isolate Formula 1 product by conventional means; YE h; Preferably about 11-77 for a period of about © and preferably purified by chromatography. acyl derivatives of I preparation of compounds of formula of formula (91); As it is acyl aryl starting from derivatives T, compounds of formula co described below can also be prepared in the reaction program © reaction program Ve

Ae. A sold

SQ)A)

AA

Rr? aM) ri 8 0 8 y L (1) + HN NRR® are xX 00 R? 1

R3 dower alkyl of hydrogen of which separately JS R' 5 RY dower alkyl is R wherein they are as specified in the general description of the invention. RPS RZ GRY (1) Preparation of compounds of the formula article from dis of formula (9) commercially on an acyl aryl derivative may be obtained yo or it may be prepared according to methods well known in the art; on <Aldrich Chemical Co., Inc. p. 777

Spell “Jha” Friedel-Crafts interaction in general; An aryl derivative of formula 1311 reacts with an acylating agent, preferably anhydride 206028, in the presence of Lewis acid, for example, aluminum chloride. The reaction takes place at a temperature of about -0°C to 10°C. “Celsius; preferably 0C for about ½ minutes to”? hours; Preferably Ye is a minute. 0 isolates the product of formula (9)»; acyl aryl is derived by conventional means; It is preferably purified by chromatography. Preparation of compounds of formula (11) The aryl derivative 1p of formula (1) reacts with a large increase of :6808 of formula (01) in the presence of a strong base; preferably sodium hydride preferably at a temperature From 0 about 80" enameled; until the compound of formula (1) is consumed, the dione of formula (11) is isolated by conventional means; preferably purified by chromatography. Preparation of compounds of formula I React dione of formula (11) with a compound of formula oY) preferably in the absence of a solvent. The reaction is carried out at a temperature of about 100©-800”C; preferably at about Augie) on for a period of about 1-01 ve hours; preferably about © hours The product of formula 1 is isolated by means of pals and preferably purified by chromatography Alternative preparation of compounds of formula T where 18 is the hydrogen of the compound of formula (8) An alternative method for the preparation of compounds of formula 1 where R is shown below ' is the hydrogen of an acyl aryl derivative of formula (1) in reaction program 6.

Y. 1 Interaction Program

JR? ©

Rr + (CHN N{(CHz), blow 0 A N(CHj)2 rR? 09

Rr: a m PN 2 ow (YY + Hy NRR> ym SN 2 0) R i

RrR3, 82 and 23 are as specified lower alkyl or hydrogen wherein 14 and 18 each separately are in the general description of the invention. (17) Preparation of compounds of formula © tert-butoxybis(dimethylamino)methane of formula ) 3) with an acyl aryl derivative reacts preferably at ethanol in a protonated solvent; preferably (Bredereck Jule's reagent) about two days. for a period of about 0 °C by conventional means; preferably used in the following reaction without purification (VF) isolate the formula compound further. 1 0 Preparation of the formula compounds with the compound of formula (1); Preferably in the absence of a solvent Conduct (VT) of formula enone reacts “returning for 0 a ton” preferably at about ae of about 5a) reacting at a temperature by conventional means; Preferably T hours Product of formula VE isolates about 5-74 hours; preferably approx. Purified by recrystallization.ve 777 p.

An alternative method for the preparation of formula 1 compounds from thio derivatives An alternative method for the preparation of formula 1 compounds from thio intermediates of formula (V1) is shown below in reaction program 7. Reaction program for NH 0 0 ALK R2 M (Y&) SCH; R! "SS SCH, D L (YT (7 A "0 ane OH Cl (Ye) OH . where R is an alkyl action and killed two patches as specified in the general description of the invention. Preparation of the compounds of formula (12) The starter ketoester of formula (1) may be obtained commercially on Ji dia of Aldrich Chemical Co., Inc. or it may be prepared according to methods well known in the art. Compounds of formula (€1) or may be prepared according to methods well known in the art. The ketoester of formula (1) reacts with about ? molecular equivalent of the isothiourea derivative of formula (?01) in an aqueous solution containing An excess of an inorganic base preferably carbonate 8001070. The reaction is carried out at a temperature of about Asie to 0C; preferably at about 7"C; for a period of about 10 to 100 hours; preferably 1 h.1 The product of formula (10) isolates the “4-hydroxy-2-methylthiopyrimidine” derivative by conventional means and preferably reacts in the next step without additional purification. Preparation of the compounds of formula (11) transforms the 4-hydroxy-2 derivative -methylthiopyrimidine of formula (V0) to the corresponding 4-chloro compound of formula (V1) under conditions similar to those described above for p777

YY

; Derivative (1) Isolate the product of formula 1. Prepare the compounds of formula (¢) in the reaction program by conventional means. <4-chloro-2-methylthiopyrimidine

I Preparation of Formula 1 Compounds Below is a method for converting a compound of formula 1 into a compound of formula 1 in a program

A ee interaction program interaction m

R! NS SCH; . 1 step | 1 ae

N

Rr? 7

Cl

OY

R! ~SCH;

Y 5 shod

LZ N Sel

Rr? rR? ov) sẖ 'l SO, CH, step ?

N ...B Rr? 2

Rr?

OA)

Rr

R~N~ie

A

R? 7

Rr? 1 They are as specified in the general description of the invention. RPGR? RY where lower alkyl is R' where is (VY) Preparation of compounds of formula 1: Step 777 p vy a capacitive derivative (V1) of formula 4-chloro-2- methylthiopyrimidine reacts a compound of formula (7); and by following the procedures of dimethoxyborane of formula (*) or boronic acid 2-methylthiopyrimidine derivative (VV) respectively; The product of formula oF is isolated from reaction programs ¥ or purified by conventional means. dower alkyl is R' Cus aryl is substituted with lower alkyl where any 1 is (VY) substituted: preparation of formula compounds 1 step © hydroxy i.e. where © is (VY) of the formula 2-methylthiopyrimidine ! A product where (VY) of the formula 2-methylthiopyrimidine Gide may transform to the above product To the dower alkyl of the formula lower alkyl reacting a hydroxy aryl derivative substituted by a lower alkyl is R! in an anhydrous ether solvent; dithium diisopropylamide with an increment of 3228 np; Preferably (VV) 0 to 10*residence; Agito is preferred at a temperature of about tetrahydrofuran preferably eg A min. An increase of To factor is added for about cd Vom at about to ambient temperature. Bad and the reaction mixture is left cbenzaldehyde or benzyl bromide or aryl substituted by lower alkyl is R' Cum (VV) The formula product is then isolated and purified by conventional means; Preferably by chromatography. Hydroxy ve (VA) compounds of formula iY are prepared step by step with about 4-7 molecular equivalents (VY) of formula 2-methylthiopyrimidine reacting as a strong derivative. oxidizing agent Grammy Prefer about? gram molecular equivalent; From an oxidizing agent, the reaction is carried out in an inert solvent »meta-chloroperbenzoic acid is preferred for example. Producer 11 hours; preferably about Vo about ©?”Celsius; for about one hour to conventional means. “2-methanesulfonylpyrimidine Formula (81); derivative

Formula I CS jo Prepare iV step protoamine with an excess of (VA) from formula 2-methanesulfonylpyrimidine react as derivative or undiluted. The reaction is carried out in cethanol or a secondary in a suitable polar solvent; For example, at a temperature ranging from about 10 °C to a sonication bath of 777 °C.

Ye 1] for about 1 hour to £0 an hour. formula product isolates ute uterine; Preferably 1 and purified by conventional means. 1 Various preparations of formula 4 compounds: Demonstrate various methods for formula 1 compounds in reaction program 1 reaction program o

R r R?

H N ) Cl N D N° TNs B > 8 R 82 _ 3p Rr? i I hydroxy ss R' is Cua chloro Hr R! where it is

R* R® R* B oh bo

N° Ng 77 kg SRS m

N N r R? rR?

I I chloro is R' mo 1157 where R! where it is

R* R* d

N

Cl NS NG os SN ~ RS —

N N

R? 2 R? 2 rR} 3 g 1 I ye chloro R! where hydrogen is R! Where is and 83 and 83 are as specified by dower alkyl or hydrogen is sas where 14 and 15 each are on in the general description of the invention. chloro where is 1 hr T Preparation of compounds of formula 777 p. ,

Yo

I of compounds of formula chloro is RY Compounds of formula 1 where 7 is 01 can be synthesized in a similar manner as shown in the hydroxy reaction program where 18 is above. Compounds can be synthesized Formula 1 where 18 is 001070 of Aly compounds in a way by reacting 4,6-dichloropyrimidine (ie; chloro derivatives of formula £) where 18 is © 7 in a similar way as shown in the program Reaction ?or dichloro derivative 118787 is R! Preparation of formula 1 compounds where it is primary or secondary of formula amine with chloro The compound of formula 1 where 1 is !1 is reacted in a solvent dower alkyl is R' 5 lower alkyl § hydrogen s R® is Cus (R°R'NH Preferably the reaction is carried out at a temperature of "high-boiling polar ethylene glycol" preferably 0 Preferably about two days. A compound of formula al © is isolated hr to 11 about 100'C; for a period of about 11887 is by conventional means. RY where is 1 hydrogen in R' where T is Preparation of compounds of formula In the presence of hydrogen with chloro is RY Cun 1 catalytically reduces the formula compound The carbon reaction takes place on a palladium support preferably platinum i.e. palladium ise extended in the presence of a strong base ; Preferably cethanol of methanol in a protonated solvent preferably -*01 aqueous. Preferably the reaction should be carried out at a temperature of about sodium hydroxide atmospheric pressure until complete 1 preferably of about room temperature; at about the pressure of Ag iE by means of hydrogen reduction” for about one hour. Compound formula 1 isolates where 18 is conventional. vy. thioalkoxy Preparation of formula 1 compounds where 18 is is In the thioalkoxy reaction program below shows the preparation of formula 1 compounds where 18 is

Ne 777 p

Reaction program 01 SCH; 0 0 Jo 2 — AA R? 3 sc; + R2 YH 5 I CH3S 27 No N hand NS 1 lrb 0 HN 3 where 87 and 87 each on sas is hydrogen or lower alkyl And 82 and 1282 are as specified in the general description of the invention. Preparation of compounds of formula (03) The acyl aryl derivative of formula (9) which may be commercially available, from Aldrich Chemical Co. In a non-protic solvent, for example, benzene diethyl ether ctoluene diethyl ether is preferred in the presence of a strong base; preferably potassium tert-butoxide at 0 °C of about AA YY leaves a mixture Bad reaction to room temperature; then re-cooled to about 10”©-0”C; Laie added dropwise 1 moeq of methyl iodide mixture kept at about 109©-80 Residual; preferably around room temperature; for about YE—0 hr; preferably about VT hr. A bismethylsulfanyl compound of formula (V9) is isolated by Aad subsatellites and preferably purified by crystallization. Preparation of the formula compound 1 where I have a thioalkoxy acid The compound of formula (19) reacts with the compound of formula (7) in the presence of a strong base; preferably sodium hydride in a non-protic polar solvent; preferably dimethylformamide. The reaction is carried out at room temperature for about 1 hour; then at about 100©-8500"C; preferably at about 150"C; for about 1-01 hours; Preferably about © hours. The product of formula 1© is isolated by conventional means; It is preferably purified by chromatography. 777 p

Wrap the preparation of ya cup of formula 1 Cun R! is an alkoxy or hydroxyalkoxy The compound of formula (19) reacts with the compound of formula (7) with the corresponding alcohol in a non-protic polar solvent; preferably dimethylformamide in the presence of a strong base; preferably -sodium hydride the reaction was carried out at room temperature for about 1 hour; then at about 06-00 0 preferably at about dito for about 1 to 01 hours hours; preferably about #0 hours. The formula T product is isolated by conventional means; preferably purified by chromatography. Preparation of N-oXides from Formula 1 compounds Preparation of N-oXides from Formula T compounds is shown below In reaction program AY reaction program 11 R* -O R¢ R! 0 1 , 1 N R SZ hd ~ RS Zz hd ~ RS + SS N N NY 2” NY 2 3p R? I Ia R* } ! AN 1 > 82 Rr? Ib 0 where R* 3 5 R! Preparation of N-oxide of Formula I The compound of Formula 1 reacts with an oxidizing agent, preferably an-chloroperbenzoic acid in an inert solvent, preferably chloroform or dichloride 710(6,6). Yee temperature from about 0 a developmental preferably about 130 “pal cloaca about 1 minutes to 2 hours preferably about Fe minutes. The N-oxide is isolated from the compound of formula T by conventional means. The position of -N oxidation of N-oxidation varies depending on the steric inhibition of the group le .R' pathway JB where 11 is 631 The occurrence of 7<- N-oxidation is limited to the position | 77

Ya

3-N-oxide (Formula 18). however; As group 8 increases in size, we see an increase in the amounts of 1. Most of the oxidation is directed towards the ctert-butyl position, which is RY, where the Jal pathway is Je (Tb) (formula 1-N-oxides). The N-oxides can separate for oxidation whereby a mixture of WF is obtained by chromatography; or by selective crystallization from a suitable solvent, eg 3-N-oxides ether [ethanol] from a mixture of N-oxides from alkenyl sf hydroxyalkyl preparation of formula 1 compounds where 18 Hr of alkenyl i.e. hydroxyalkyl s R' is Cua 1 The preparation of formula compounds is shown below

AY of Formula 1 in Reaction Program N-oxides 101 Reaction Program 1

Co4

To

R mk Nps

XT:

R 1 8 R Nw M and/or 0 8 R I

R Na Mes rR? ©:

JX M]? of the formula alkenyl or hydroxyalkyl sa R's Ib Ia of the formula alkyl is RY wherein they are as specified in the general description of the invention. RPS RY GRP R754 [ of the formula N-oxides of I preparation of compounds of formula is God with an increase of R' from formula 1 where the N-oxide reacts yo in an inert solvent; Preferably trifluoroacetic anhydride Preferably “carboxylic anhydride” The reaction takes place at a temperature from about © to 10 ºC; Preferably methylene chloride an hour. After the development of the reaction with the base £A h; preferably 10 to 10 approximately sad dy giao approximately 777 p.m.

Yq

Aqua; Such as ammonium hydroxide in the alcohol or csodium hydroxide isolates the product »mixture

A compound of formula 1 where R' is 6-alkenyl s 6-hydroxyalkyl purified by conventional means;

Preferably by chromatography.

Convert compounds of formula 1 to other compounds of formula I

° Formula 1 vehicles may transform where the RPGR? GRY are as specified in the general description of the invention; 5 Rs RY are hydrogen to other compounds of formula T by substituting one or both of the

Hydrogen atoms of R* and A8 with other groups:

(a) for example; A compound of formula T where 87 and 1853 are hydrogen reacts with a cacylating agent optionally a cacetic anhydride in the presence of a catalyst

.4-dimethylaminopyridine Jie ye The reaction mixture was conducted at a temperature ranging from ia © to 100 °C for a period of about hours. The diacyl product is isolated by conventional means; dissolved in a protonated solvent; e.g. 0060:8001 and treated with an inorganic base such as sodium bicarbonate for about 1 hour to YE 1 hour. The monoacyl cal product isolates the compound of formula 1 Cus the RY is R*5acyl is chydrogen and purified by traditional yo means.

(b) lo for example; The compound of Formula 1, where 8 R*5 is hydrogen, reacts with a tertiary amine, preferably ctriethyl amine, and a sulfonylating agent, preferably methanesulfonyl chloride. The reaction takes place in an inert organic solvent, Jie. dichloromethane at a temperature of about 0°C for a period of about ½ minutes to ?

I Compound of formula lll bis-methanesulfonyl min. The product of 1 hour is isolated; Y is preferred. It is purified by conventional means. -SOR™ are RPS RY where it is

(c) for example; A compound of formula 1 where R* is -SOR? and 8 is hydrogen may be prepared from the bis-sulfonyl product previously described above in section (b). The reaction is carried out under basic conditions; preferably in the presence of hydroxide 8001107107; in an organic solvent

0 min to 0 at approx room temperature for approx protonated Yo methanol Jie resulting; Formula 1 compound where mono-sulfonyl h; Preferably one hour. Product is isolated and purified by conventional means. hydrogen is 502812- and 17 is RY be

Ye

(9) For example (JO) a compound of formula 1 where R and 1857 are hydrogen reacts with an isocyanate derivative preferably phenyl isocyanate in an organic solvent (Jala preferably “benzene”) at a temperature of vapor condensation s.d. about 01 to dela 10 preferably 8 hr. The resulting reaction product isolates the compound of formula 1 where 18 is aR'amido

° 000+ and purified by conventional means. ALTERNATIVE CONVERSION OF FORMULA 1 COMPOUNDS TO OTHER COMPOUNDS OF FORMULA 1 A compound of Formula 1 may be transformed where R25 RY are as specified in the general description of the invention;

1 to other compounds of formula hydrogen and 8 are RY chalo substituted with an aryl substituent of R?

By replacing halo with other groups:

Je ) 0 eg; a compound of formula 1 in which 183 is an aryl substituted with a molar substituent R' 4 R* are chydrogen reacts with the alkali metal azide preferably sodium azide in a polar solvent Unprotonated preferably N-methyl pyrrolidinone The reaction mixture is brought to a temperature of about 001 to 100*H; preferably about Bie) under an inert atmosphere for a period of about 0 to dela 70 preferably about 11 hours. Isolate the reaction product. compound

Formula 1 Cun 187 is an aryl substituted with a camino substituent and purified by conventional means.

(b) for example; A compound of Formula 1 in which 183 is an aryl substituted with a tweezer substituent and 18 Rs is a chydrogen reacts with an excess of the alkali metal thioalkyloxide; preferably sodium thiomethoxide in a non-protic polar solvent; preferably dimethyl sulfoxide. The reaction mixture is conducted at about room temperature for about 10 to 10 minutes.

7 hours; preferably about; hours. Isolate the reaction product. Compound of Formula 1 wherein 183 is an aryl substituted with a dower thioalkyl substituent and purified by conventional means.

Substitute conversion of Formula 1 compounds into other Formula 1 compounds

The compounds of Formula 1 wherein R75 is 87 GRP GR may transform are as specified in the general description of the invention; R%, is hydrogen to other compounds of formula 1 by replacing the hydrogen of R? with

Other groups:

For example; A compound of formula 1 Cua be 2+ is <hydrogen reacts with <halogen preferably cbromine in the presence of a GB catalyst preferably iron powder; in an inert organic solvent eg

carbon tetrachloride The reaction takes place at about room temperature for about 10 minutes to 10 hours; Preferably about one hour. The Jeli product isolates the Formula 1 compound where R? is halo and is purified by conventional means. Alternative conversion of compounds of formula T to various compounds of formula I may transform compounds of formula 1 where RRP RY are as defined in the general description of the invention R* is a lower alkyl substituted by an amino dc sane or “carboxy and 1283 is hydrogen to other compounds of formula T by converting RY to other groups: (f) for example (Jad) compound of formula 1 is dissolved where 83 is lower alkyl Substituted by R® 5 amino is hydrogen in an inert organic solvent as diethyl ether 01 and reacts with a sulfonic agent; preferably .methanesulfonyl chloride. The reaction is carried out at about room temperature for 10 minutes to 10 hours; Preferably one hour. Isolate the sulfonylurea reaction product; Formula 1 compound where RY is Jats “lower alkyl by sulfonamido and RY is chydrogen and purified by conventional means. (9) eg JU A compound of formula 1 where R* is lower alkyl substituted Vo by R® carboxylic acid ester is 13700860 is dissolved in a protonated solvent solution containing primary or secondary amine Preferably ethanolic methyl amine solution Treated with ultrasonics for about Te minutes to 10 hours Preferably “ hours Camido reaction product isolates compound of formula 1 Cun the RY is the lower alkyl substituted By camido and purified by conventional means Ye Isolation and purification of compounds The isolation and purification of the compounds and intermediates described herein can occur if desired by any suitable separation or purification procedure ie JL filtration extraction crystallization column chromatography analysis Thin layer chromatography; Thick layer chromatography; Preliminary high or low pressure liquid chromatography or a combination of these procedures. Specific descriptions of appropriate separation and purification procedures can be obtained from preparations and examples. Other than that there are other separation and isolation procedures that we can use. Salts of formula compounds 1 add

YY

Compounds of the formula [] become basic; It may therefore be converted to the salt of the corresponding acid addition. The conversion is effected by treatment with at least standard amounts of the appropriate acid; such as “phosphoric acid “nitric acid” sulfuric acid < hydrobromic acid < hydrochloric acid “pyruvic acid” glycolic acid “propionic acid acetic acid” etc.; And organic acids such as fumaric acid maleic acid succinic acid malic acid oxalic acid © mandelic acid cinnamic acid benzoic acid citric acid tartaric 480 salicylic acid p-toluenesulfonic acid <ethanesulfonic acid “methanesulfonic acid cethyl acetate” diethyl ether etc. Typically the free base is dissolved in an inert organic solvent eg etc.; The acid is added in a similar solvent. The degree of cmethanol or ethanol “chloroform” maintains temperature at zero * temperature -. **residency. The resulting salt precipitates spontaneously or we may get it out of solution 0 with a little polar solvent. The acid addition salts of formula 1 compounds may convert to the corresponding free bases by treatment with “sodium or potassium hydroxide” at least a standard amount of the appropriate base say Etc. <ammonia «sodium bicarbonate »potassium carbonate Preferred processes Yo According to the following last steps: T Briefly prepare compounds of formula A process for preparing compounds of formula 1 includes: A complex reaction of formula: (1) 4 E:

R Naor I~ os 56 for N 0 or hydrogen are as specified in the general description of the invention and 83 and 15 are RPS 18 where 'lower alkyl | 0 is as specified in R® be Cua (R'B(OH), “sl ¢ (°) of the formula boronic acid with a derivative of the general description of the invention. Formula 1 compounds include: (7) The reaction of the formula compound: F vy

R*! M R Nr ~gs ls

Rr? 7 a or hydrogen being R75 and 1852 being as specified in the general description of the invention; and 85 RY where flower alkyl where 183 is as determined in (RPB(OCH3), i.e. oY) of the formula boron with the compound of the general description of the invention.0 by an alternative method; The process for preparing formula 1 compounds includes: (7) A compound reaction of the formula:

R*m R and ~ RS ls

R? 2 al or hydrogen and 1857 are R* and 18 are as specified in the general description of the invention; R' where is ©107?; alkyl 0 0 (A) with the compound of the formula ™ [ ) _ (CH)a

Y~ 0 are as specified in the general description of the invention. ny Y where is by an alternative method; a process for preparing compounds of formula 1 involves: (€) the reaction of a compound of formula: Vo 0 0 of the R!

Rr? and 83 are as specified in the general description of the invention; (RZ GRY where 777 p ve are as specified by Rss Ry (formula (7)); where is NH,CENHNRR® with the compound of the formula In the general description of the invention. Alternatively, a process for the preparation of compounds of formula 1 comprises: (©) reaction of the compound of formula: 0 8 A N(CH):

R? o and 83 are as specified in the general description of the invention; RY where they are as specified by Rss Ry (formula (7)); where NH,C(NH)NR'R® with the compound of the formula is in the general description of the invention. By an alternative method; The process for preparing compounds of formula 1 includes: (1): reaction of compound of formula Ye 0 SCH;

R? AA SCH; 12 where 183 is as specified in the general description of the invention; as specified in Ry (formula (7)); where NHC(NH)NRR® with compound of formula is the general description of the invention. For the preparation of compounds of formula 1 include: lee van (Aly) by the method of (V) vo :chloro hr R' Reaction of a compound of formula 1 where 14 l a N he ~ 5c R? 2

R3 or hydrogen is Ry RY as specified in the general description of the invention; RP R? It should be with: alkyl tinter

YY

Yo sa RY where T is to give a compound of formula reducing agent dele (a) or ¢hydrogen and 87 are as specified in R® primary or secondary of formula 110878 where is amine (b) .-118987 is RY the general description of the invention; To give the compound of formula 1 where it is, a process for the preparation of the compounds of formula 1 includes: Allay by (A) the reaction of the compound of formula: 8 O, SO,CH; "15

I N

Rr? secondary of formula amine and 183 are as specified in the general description of the invention; with RZ 18 where they are as specified in the general description of the invention; To give a compound RP RY wherein 1187 is formula 1 wherein 187 and 85 are as specified in the general description of the invention. : alkenyl or carboxylic anhydride with an alkyl e R! From the formula 1 compound where it is N-oxide Jeli

J to give the formula compound by an alternative method; a process for the preparation of formula 1 compounds includes: (01) Ve of an N-oxide stacy oxidizing agent with an oxidizing agent I reaction of the compound of formula [; or; 1. the reaction of the compound of formula 1 with A strong acid to give a pharmaceutically acceptable salt of the formula compound Usage and administration: general use 0 Selectivity 5-Htop affinity can be proven The compounds of this invention are receptor antagonists: for receptors and 5-1112 by using a binding test in the laboratory By using a combination of the following, YY 5111-[11] appears, as shown in the example of Jie 5-1112 receptors with a radioactive substance attached (for details, 5-HToc 5 5-HToa receptor selectivity 5-1117 on antagonistic exploration of the v1 receptor below.) These antagonists were characterized in the longitudinal muscle of the gastrocnemius muscle (YT see example below). YE (for further details see example accordingly; the The compounds of this invention are useful in the treatment of diseases that can be improved by blocking the M5-1112 receptors.Because of the similarity in the pharmacology of the interactions between ligands, most of the therapeutic purposes that targeted the 5-HToc 5 5-1118M receptor antagonists Numerous dials for antireceptors and 5-1112. As Lay Is Same As Purpose 5-1110 Clinical Notes The therapeutic role of receptor antagonists 5-1112 in preventing migraine is recommended; It is believed that stimulation of 5-117 into plasma is an etiological factor in migraine headaches. In addition to this, non-selective receptor antagonists and 5-1117 trigger migraine attacks in non-selective have the effect of preventing the onset of S-HT,p in people most susceptible to it; And anticonvulsants 0 See: Headache attacks

Kalkman, Life Sciences, 1994, 54, 641-644. Experimental evidence indicates that compounds of the present invention are useful in the treatment of pain; Including acute and chronic pain, pain due to nerves, pain due to inflammation and cancer.” Especially pain, a major role in regulating the transmission of (serotonin) 5-111 below). YY plays the inflammatory role. (See, for example, ve nociceptive information at various levels of the peripheral and central nervous systems. See:

Richardson, B.P., "Serotonin and Pain", Ann. N.Y. Acad. Sci., 1990, 600, 511-520. In addition, neural systems are involved, which 117-5 affects; Not only in regulating the entry of a nociceptor at the spinal and supraspinal level; But in interfering with the action of the nociceptor due to other analgesics, which include opioids. 111-5 is a mediator of peripheral pain receptor sensing that may © It arises due to pain associated with inflammation. The 5-1117 receptor is very sensitive to activation by 5-111 and specific inhibition by selective 5-1772 antagonists may provide a new avenue for analgesic therapy. There is empirical evidence supporting a therapeutic role for 5-1117 receptor antagonists in the treatment of hypertension. . in high blood pressure; One of the most abundant increases in vascular response is observed. Two lines of evidence suggest that this results from a shift in blood serotonin receptor-induced vasoconstriction from predominantly P1117-5 to predominantly P1112-5. First, the contractions induced by 80010010 in separate blood vessels of animals with hypertensive 777p

blood becomes resistant to inhibition by selective M5-1117 receptor antagonists; However, it remains sensitive to non-selective 5-Htop receptor antagonists. Second, an increase in 5-Htop receptor mRNA occurs in vessels of 0-hypertensive animals.” See: Watts et al., J.

Pharmacol.

Exp.

Ther. 1996, 277, 1103-13 and Watts et al., Hypertension 1995, 26, 1056-1059. | ° This hypertension-induced shift in the receptor subtype group that induces apoptotic responses to 5-111 suggests that selective inhibition of the vasoconstrictor 5-1177 receptors may have therapeutic benefit in the treatment of hypertension. There is clinical and experimental evidence supporting a therapeutic role for 5-Htop receptor antagonists in the treatment of 0 disorders of the gastrointestinal tract; specifically irritable bowel disease (IBS) although the pathology of IBS is still unclear; There is a well-established postulated role for serotonin cell interference. Meals with a high serotonin content can exacerbate symptoms in some patients; See Lessorf, Scand.

J.

Gastroenterology 1985, 109, 117-121, 0 While in preliminary clinical studies; It has been shown that serotonin directly sensitizes splanchnic sensory neurons, leading to an increased pain response similar to that observed in BS (see Christian et al., J.

Applied Physiol. 1989, 67, 584-591 and Sanger et al., Neurogastroenterology and Motility 1996, 8, 319-331. The possibility is that 5-Htop receptors play a critical role in the effects of sensitization to serotonin. Many lines of evidence suggest it. These 1112-5 receptors are present in the human intestine; See: Borman et al., Brit.

J.

Pharmacol. 1995, 114, 1525-1527 and Borman et al., Ann. of the New York Academy. of Sciences 1997, 812, 222-223. Second, activation of 5-Htop receptors can lead to the production of cnitric oxide, an agent capable of sensitizing sensory nerve fibers; Look:

Ya

Glusa et al., Naunyn-Schmied. Arch. Pharmacol. 1993, 347, 471-477 and Glusa et al., Brit. J. Pharmacol. 1996, 119, 330-334. Clinically Effective in 5-Htop III Poor Selective Drugs Showing High Affinity for the receptor and Associated Disorders; See: IBS Reducing Associated Pain

Symon et al., Arch. Disease in Childhood 1995, 72, 48-50 and Tanum et al., Scand. °

J. Gastroenterol. 1996, 31, 318-325. 5-Htop selectively will attenuate both gastric pain. Together, these findings suggest that an antipyretic

IBS and associated intestinal motility abnormalities Clinical and experimental evidence supports a therapeutic role for 1170-5 receptor antagonists in the treatment of restlessness. Angioplasty and lateral compass grafting are associated with narrow return, which limits the effectiveness of these procedures. The formation of a platelet-rich thrombus is the predominant cause of acute embolism while 8©010; Among other platelet-derived pathogens; It is believed to contribute to delayed return of distress; See:

Barradase et al., Clinica Chim. Acta 1994, 230, 157-167. This delayed restenosis involves division of vascular smooth muscle. There are two lines of active serotonin activity evidence indicating a role for the 1112-5 receptor in this process. These are shown to induce mitogenicity in culture smooth muscle and vascular endothelial cells through activation of 0-receptor 1117-5; See:

Pakala et al., Circulation 1994, 90, 1919-1926. Second, this mitotic activity appears to be mediated through activation of a second messenger pathway. See: mitogen-activated protein (MAPK) activator kinase comprising tyrosine kinase.

Lee et al., Am. J. Physiol. 1997, 272 (1 pt 1), 223-230 and Kelleher et al., Am. J.

Physiol. 1995, 268(6 pt 1), 1.894-901. Coupled with a high affinity for MAPK, it is associated with 5-Htop receptors for this subtype of receptor; suggests that selective 1177-5 receptor antagonists and serotonin Ye antagonists may provide protection against re-narrowing of autologous or angioplasty blood vessels after angioplasty. v4 There is clinical and experimental evidence supporting a therapeutic role for 1117-5 receptor antagonists in the treatment of asthma and MS. Airway obstruction. Abnormal division of airway smooth muscle, along with hyperactivity of smooth muscle in response to constrictive stimuli including 56010010; It plays an important role in the pathogenesis of human airway disease such as asthma and bronchial rheumatoid dysplasia.” See:

James et al., Am. Review of Respiratory Disease 1989, 139, 242-246 and Margraf et al., Am. Review of Respiratory Disease 1991, 143, 391-400. It is present in the 5-Htop serotonin receptor as well as other popular smooth muscle receptor subtypes; See:

Choi et al., Febs Letters 1996, 391, 45-51. x was shown to stimulate filament formation of smooth muscle in airway smooth muscle; See:

Lee et al., Am. J. Physiol. 1994, 266, 146-52. Free circulation in the blood is associated with a large degree of clinical severity of serotonin because elevated concentrations of serotonin play an important role in pulmonary function in symptomatic asthmatic patients, the pathophysiology of acute attacks; See: 1

Lechin et al., Ann. Allergy, Asthma, Immunol. 1996, 77, 245-253. These data suggest that a selective agonist of 1112-5 receptors in airway smooth muscle may contain serotonin that may be useful in preventing constriction of the airways due to elevated levels of circulating blood and preventing the division of airway smooth muscle that contributes to prolonged pathology. : for this disease. addy. In the treatment of 5-Htop hyperplasia there is empirical evidence to support the therapeutic role of PSAs. Urinary tract obstruction can occur as a result of hyperplasticity of the prostate and excessive prostatic contraction of the urethra. This, in turn, leads to lower urine flow rates and an increase in urinary urgency and frequency of urination. The F-1112-5 receptor is present in the human prostate; See:

Kursar et al., Mol. Pharmacol. 1994, 46, 227-234 Yo and that the receptor that has the pharmacological contributions of this receptor subtype causes contraction See: call 777 p.

Killam et al., Eur.

J.

Pharmacol. 1995, 273, 7-14. Some drugs effective in the treatment of benign prostatic hyperplasia (BPH) stop contractions caused by 5-7 of the prostate. See Noble et al., Brit.

J.

Pharmacol. 1997, 120, 231-238.0 The 5-HTpp receptors cause hyperplasia of smooth and accretive muscle.” See: J.

Biol.

Chem. Launay et al. 1996, 271, 3141-3147 and that serotonin induces mitosis in the prostate see Cockett et al., Urology 1993, 43, 512-519, therefore a selective 1178-5 receptor antagonist can be used. Not only in suppressing excessive prostatic contraction ys but also in preventing the increase in hyperplasia of the tissue. Clinical evidence and trials support a therapeutic role for 1112-5 receptor antagonists in the treatment of anxiety. The receptor modulator 5-1117 Laie (mCPP) 1-(3-chlorophenyl)piperazine s—a taken in human volunteers causes concern; See: Charney et al. (1987), Psychopharmacology, 92, 14-24. 0 MCPP also produces worrisome effects in mice; Social interference (SI) and heightened X-maze paradigms can block these effects with non-selective SHTocna receptor antagonists but not with 5-HT2A (ABE) receptor antagonists See Kennett et al. (1989), Eur.

J.

Pharmacol., 164, 445-454 and Kennett (1993) supra. The selective M5-1717 receptor does not share this property. These therapeutic purposes for 1117-5 receptor antagonists are equivalent to those for 1117-5 receptor antagonists. Furthermore it; When mMCPP is given to patients with anxiety disorder or patients with obsessive-compulsive disorder, it increases the rate of fear and/or anxiety; See: Charney et al. (1987), supra., and Zohar et al. (1987), Arch.

Gen.

Psychiat., 44, 946-0.951 | 777 p

so; Current evidence supports the application of selective 11170-5 receptor antagonists for the treatment of generalized anxiety disorder, fear disorder, and obsessive-compulsive disorder. These therapeutic purposes for the 1117-5 receptor antagonists are equivalent to those for the 1117-5 receptor antagonists. The effect of removing anxiety can be determined empirically by the two-chamber exploratory model Goodwins oe recognized by Crawley (dll, for example. See: Kilfoil et al. (1989), Neuropharmacology, 28(9), 901-905. In summary, the method of measuring the extent of the compound's effects on normal anxiety in mice is a new bright field (for more details see example vo below). -117 mCPP: Alcohol craving in heavy drinkers See: Benkelfat et al. (1991), Arch.

Gen.

Psychiat., 48, 383. On old (pail), the nonselective 5-HTona receptor antagonist ritanserin reduces alcohol preference in rats. See Meert et al., (1991), Drug Development Res. 24, 235. -249, Yo, while the selective 5-HToa receptor antagonist ketanserin had no effect on alcohol preference; see: Kennett et al., (1992), J.

Psychopharmacol., Abstr. ritanserin also reduces preference for cocaine intake with fentanyl s in mouse models of addiction (see Meert et al. (1991), Drug Development Res. 25, 39-53 and Meert et al., (1991), Y. Durg Development Res. 25, 55-66. Clinical studies show that ritanserin reduces alcohol intake in pia gall (alcoholics) see Monti et al. (1991), The Lancet. 337, 60 Yo and useful for patients who are withdrawn from other narcotic drugs; See: et al. (1989), Psychopharmacology, 98, 495-499. 580201 ty Therefore; Current evidence supports the application of selective 1112-5 receptor antagonists for the treatment of alcoholics and other narcotic drugs. These therapeutic effects of LA receptor antagonists are equivalent to those of W5-111 receptor antagonists. 5-1117 The curative effect of the compounds through drug withdrawal could be experimentally determined by testing the mouse for anxiety due to the accepted test; For example, see: 0

Carboni et al. (1988), Eur. J. Pharmacol, 151, 159-160. This method uses the heuristic model described above to measure the extent to which it improves

Cady is addictive and then the compound is Bale with drug withdrawal symptoms that occur after chronic treatment with the use of, below). 0 Depression For example, non-selective monon 5-1117 receptor antagonists show effective clinical effects in (EY) Murphy (1978), Brit. J. Pharmacol., 5, 815,855 (Klieser et al.) 1988),

Pharmacopsychiat., 21, 391-393; and Camara (1991), Biol. Psychiat., 29, 201A. The results of the experiments recommend that the mechanism of action of the traditional anti-depressant drugs show (dd Jes Sle vo see: (serontinergic) effective therapeutic effect through appropriate changes to the system

Anderson (1983), Life Sci, 32, 1791-1801. 5-HTc/<sadl mCPP reduces monoamine odixase eg; Chronic treatment with inhibitors that mediate functional responses in various paradigms. Similar effects are shown by selective 5-111-5 reuptake inhibitors. These findings suggest that therapies that induce increased rates of extraneuronal 0 desensitize the function of the 1172-5 receptor which in turn causes or contributes to the above activation. These therapeutic purposes for receptor antagonists are equivalent to antidepressants; see Kennett (1197) and 111-5-5 receptor antagonists. Volunteer decreases total sleep time Lexie mCPP receptor modulator 5-1117 is vo See: casi and rapid eye movement during (SWS) sleep; slow sleep wave BUS for sleep; Lawlor et al. ( 1991), Biol. Psychiat., 29, 281-286. 777 p.

In contrast, the nonselective 5-HTacna receptor antagonist ritanserin increases SWS, reduces delayed sleep onset and improves sleep quality in healthy volunteers (see Idzikowski et al. (1986), Brain Res., 378, 164-168). Declerck et al. (1987), Curr.

Therap.

Res., 41, and Adam et al. (1989), Psychopharmacology, 99, 219-221. ° ;427-432 therefore; The antistimulatory effects of 1112-5 receptors and 1112-5 receptor antagonists. Selective 1120-5 receptor antagonists are of significant therapeutic value in the treatment of sleep disorders; See Kennett (1447) above. These therapeutic purposes for 1177-5 receptor antagonists are equivalent to those for S5-Htop receptor antagonists. 8 Clinical evidence supports a therapeutic role for 1177-5 receptor antagonists in eating disorders. Non-selective M111202 receptor antagonists found. They increase appetite and increase weight.So there is some clinical evidence supporting the application of selective 1120-5 receptor antagonists for the treatment of anorexia nervosa.The pharmacological purposes of 1777-5 receptor antagonists are equal to those of 5-18 receptor antagonists.Vo Experimental evidence supports the therapeutic role of receptor antagonists 1117-5 In the treatment of persistent painful erection of the penis see: Kennett, Curr.

Open.

Invest.

Drugs 1993, 2, 317-362. mCPP causes rat penis erections. This effect is inhibited by non-selective 5-HTacna receptor antagonists but not by selective 5-HToa antagonists; See Hoyer, Peripheral actions of 5-HT 1989, Fozard J. (ed), Oxford University Press, Y. Oxford, 72-99. These pharmacological purposes for 1119-5 receptor antagonists are equivalent to those for 5-11 receptor antagonists. . General Administration Yo by applying the compounds of this invention to the treatment of the above conditions administer the active compounds and salts described herein by the accepted routes of administration; These include oral, injectable, and other general routes of administration. Any medically acceptable method may be used. Solid and semisolid forms include te suppositories; cereals; capsules; liquid powder; suspension opal BY) and liquid e.g. etc.; preferably in an appropriate dose by giving it in a single dose at a typical dose; or extended-release dosage forms of the compounds for extended use at a previously estimated rate. Compositions typically include a drug carrier or excipient and an active compound of [Formula] or pharmacologically acceptable salts thereof; addition; Medical factors can include; pharmacological agents; carrier materials; extra materials; etc. 0 The amount given depends of course on the person being treated; the severity of the disease; The method of use and the rule of injection or in other general ways varies dll the attending physician. However, the effective dose in kg is 71 mg/kg per day. For an average human being weighing 11-01 mg/kg/day (preferably Teme) from 1-700 mg/day; Preferably 1-1500, the usual quantity in the art of treating these diseases; without unnecessary experiments alll ve can and based on personal knowledge and data of this application; Determination of a therapeutically effective amount of a formulation compound for a specific disease. 1 For solid formulations; Conventional non-toxic solid carriers include; For example, “cellulose 0116l derivatives of <lactose”mannitol, cyclic grades of “Jill”talc “sodium saccharin”magnesium stearate “starch”sodium crosscarmellose eo etc. The active compound as previously defined amagnesium carbonate ¢sucrose “glucose “polyalkylene glycol, for example, dau, may be in the form of suppositories, by using, etc.; Salt solution 060086 aqueous 0 Optional Pharmaceutical 0 in the carrier such as eg water 0 etc. to make a solution or suspension If desired, the given drug formulations may contain glycerol cethanol containing small amounts of Auxiliaries such as wetting or emulsifying agents; sorbitan monolaurate sodium acetate (example “Jaw on x) pH” etc. “triethanolamine oleate” sorbitan monolaurate “triethanolamine sodium acetate” The composition or formulation contains which we give anyway; On the amount of active compounds in effective quantities vo : To relieve the symptoms of the person we are treating.

YY'Y

The dosage forms or formulations containing the active constituent fraction (Formula 1 compounds or their salts) range from 1.75 to 795 by balancing out the non-toxic carrier that may be prepared. for oral administration; An acceptable non-toxic pharmaceutical formulation can be made by introducing any of the natural additives (Jie, for example, pharmaceutical grades of dactose “mannitol” “cellulose ©” derivatives “magnesium stearate (starch” sodium crosscarmellose “cellulose” “carbonate” magnesium “sucrose” glucose “talcum” sodium saccharin etc. Both formulations take the form of liquids; suspension; cal BY) pills; powder capsules; extended-release formulations; etc. These compounds contain 71-795 constituent parts (DADS). More 7-55 Most Preferred E-// ve Parenteral drug administration is characterized by subcutaneous, intramuscular or intravenous injection Injections can be prepared by conventional methods either as a liquid solution or as a suspension; suitable solid forms can be as a solution or as a suspension in a liquid prior to Injection, or as an emulsion Suitable adjuvants eg water, natural salt, cethanol, glycerol, dextrose, etc. In addition, if desired, the given drug formulations may contain non-toxic auxiliaries Jie wetting agent or emulsifying agents ve pH regulators etc. e.g. sorbitan monolaurate sodium acetate triethanolamine sodium acetate triethanolamine oleate etc. The latest innovation is to give injections by implanting a slow-release or extended-release device so that a constant rate can be obtained. See example US Patent No. 9,719,746. The percentage of active compound in an injectable formulation depends entirely on its selective nature as well as the activity of the compound 0 and the individual's need. However the ratio of the active constituent part is 750.1 to 701 in the solution used; And it is high if the formula is solid and diluted to a higher percentage. A formulation containing 0.7-77 of the active agent in solution is preferred. By applying the compounds of the invention to treat diseases or ocular disorders that are associated with a high intraocular hin, it can be administered by any pharmacologically acceptable method that provides sufficient satisfactory concentration for Yo to give us the desired response. This includes administering it to the eye by drop, inserting a release or implant, and also administering it normally as previously described. 777 p

Drops and solutions administered directly into the eye are sterile aqueous solutions containing 70.1 to 701 preferably 70.5 to 77 of the active part with an appropriate buffer; Stabilizer and preservative. The SH concentration of the solute is Jia. If possible; The resulting solution is isotonic with the lacrimal fluid (although this is not at all important) and has a stoichiometric pH between 7-8. Typical preservatives © benzalkonium s “chlorobutanol” thimerosal “phenyl mercuric acetate lead) chloride Typical regulator and salts based on eg borate “citrate” or cphosphate Suitable stabilizers include glycerine and 80 001780:0216 . Aqueous solutions are simply formulated by dissolving a solute in an appropriate amount of water - with the pH set at about 8-7:8/; Makes the volume, Sel, justified with the added water.” And sterilization of the preparation using 0 methods known in this art. The resulting composition dose rate is of course dependent on the droplet concentration; The person's circumstances and how much the person is responding to treatment. however; Typical ophthalmic compositions may be administered at a rate of 7-01 drops per day in each eye of a solution of its active substance, Jo. The compositions of the present invention can be formulated for administration in any conventional manner in analogy to the topical ve formulations; suitable for use in mammals. These formulations may be introduced for use in a variety of conventional ways with the help of any of the wide variety of drug carriers or carriers. For topical use, this drug-accepted, non-toxic formulation takes a liquid semi-solid form; or solid Jie jelly; creams; lotion. clan suspended ointments; powder or something like that. (JS) The active ingredient can be formulated into a gel using “propylene carbonate “propylene glycol ¢ethanol cglycerol diisopropyl adipate “polyethylene glycols 00 water; etc. with a suitable gelling agent such as Klucels “Carbomers etc. If desired; Lad the formulation to contain small amounts of non-toxic auxiliaries such as preservatives; antioxidants; pH-regulating agents; surface-active agents, etc. The actual methods of preparing the dosage forms are either known or will be apparent to those skilled in the work; as an example see: Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pa., Yo 16th Edition, 1980.

The drug combination should preferably be administered in a single unit dose for continued treatment or in a single unit dose as desired when symptomatic relief is particularly needed. Representative Pharmaceutical Formulations Containing a Formula 1 Compound (Described in YAR) Examples > The following formulations and examples illustrate the invention and are intended to neutralize its scope. Preparation 1 Preparation of compounds of formula (3) i) Preparation of (¥) Cua carne 2 Hr tert-butyl R 2 p is hydrogen Mix 07 ) methyl 4,4-dimethyl-3- oxopentanoate g) § guanidine carbonate 01 (0 g) in Ae 6018001 milliliters; The solution vapor is re-condensed for 16 hours. The reaction mixture is concentrated to ill 00 by removing the solvent under reduced pressure”; lle 10 water is added. The remaining mixture was acidified to pH© with cacetic acid to provide a white precipitate. the precipitate is collected by filtration; wash with water; and dried in a vacuum oven to give 2-amino-4-hydroxy-6-tert-butylpyrimidine (1,¥ 1 g)-Ahi fusion—OYAS GL ACYAA 0 (hydrolysis). (b) preparation of (©) where RY < hydrogen sa R* is different in a similar way; by replacing methyl 4,4-dimethyl-3-oxopentanoate in place of: ethyl 3-oxopentanoate; ethyl 4-methyl-3-oxopentanoate; p ethyl 3-cyclobutyl-3-oxopropionate; ethyl 3-cyclopentyl ethyl 4-methyl-3-oxohexanoate ethyl 2-methyl-3-oxobutanoate ethyl 3-oxo-4-phenylpentanoate ethyl 3-cyclopropyl-3-oxopropionate Yo ethyl 2-fluoro-3-oxobutanoate; ethyl 2-aminocarbonylacetate; VY'Y

£A ethyl 4,4,4-trifluoro-3-oxobutanoate; and ethyl 3-phenyl-3-oxopropionate; And each of them works with the same tethyl ester instead of methyl ester (in some synthesis it uses efficiency): By following the preparation procedure 1a above. The following compounds of formula (©) were prepared: ° 2-amino-6-ethyl-4-hydroxypyrimidine; : 2-amino-4-hydroxy-6-isopropylpyrimidine,

Cu ACY 51-778 Melting point 2-amino-6-cyclobutyl-4-hydroxypyrimidine, (dh iCYoi—Yor Melting point ddan. 2-amino-6-cyclopentyl-4-hydroxypyrimidine, Melting point 51-779 ALY (Hydrolysis); 2-amino-6-(but-2-yl1)-4-hydroxypyrimidine, melting point 40 Gu ARYA 2-amino-5,6-dimethyl-4-hydroxypyrimidine; vo 2-amino-6-benzyl-4-hydroxypyrimidine; 2-amino-6-cyclopropyl-4-hydroxypyrimidine; 2-amino-5-fluoro-4-hydroxy-6-methylpyrimidine; 2,6- diamino-4-hydroxypyrimidine; 2-amino-4-hydroxy-6-trifluoromethylpyrimidine; and Y. 2-amino-4-hydroxy-6-phenylpyrimidine. ,4-dimethyl-3-oxopentanoate optionally in place of other compounds of Formula (I); and by optionally substituting guanidine carbonate with other compounds of Formula oY) and following the procedures for Preparation IY above; Preparation of other compounds of formula (7) Yo Preparation of Y Preparation of compounds of formula (£) (a) Preparation of (£) Cua being hydrogen sa R?, tert-butyl sa R! 777 p.

£9 (AY) 2-amino-4-hydroxy-6-tert-butylpyrimidine g) was dissolved in lille 0 phosphorus oxychloride and the vapor was re-condensed for 2 hours. The excess of phosphorus oxychloride was removed by aspiration and the residue was dissolved in 100 milliliters captured. The solution was adjusted to pH A with ammonium hydroxide cooled concentrate lll and the solvent removed under reduced pressure. The residue was filtered to give a white solid; which recrystallized from -ethanol water to give 2-amino-4-chloro-6-tert-butylpyrimidine (17, g) Melting point Gu SAA A=AYLY | (b) in a similar manner; by substituting 2-amino-4-hydroxy-6-tert-butylpyrimidine in place of other compounds of formula ( ) and following the procedures for preparation IY above”. The following compounds of formula (£) were prepared: 2-amino-4-chloro-6-ethylpyrimidine; 2-amino-4-chloro-6-isopropylpyrimidine, melting point 4 41°40 4 2-amino- 4-chloro-6-cyclopropylmethylpyrimidine, vo melting point 0, Ym 50 2-amino-4-chloro-6-cyclobutylpyrimidine, : melting point 195-987"C; 2-amino-6- (but-2-yl)-4-chloropyrimidine; melting point 5001001 $43 2-amino-4-chloro-6-cyclopentylpyrimidine, Y. -amino-4-chloro-5,6-dimethylpyrimidine; 2-amino-6-benzyl-4-chloropyrimidine; 2-amino-4-chloro-6-cyclopropylpyrimidine; 2-amino-4-chloro -5-fluoro-6-methylpyrimidine; Yo 2,6-diamino-4-chloropyrimidine; 2-amino-4-chloro-6-trifluoromethylpyrimidine; and 777p

2-amino-4-chloro-6-phenylpyrimidine (c) in a similar manner; By substituting 2-amino-4-hydroxy-6-tert-butylpyrimidine in place of other compounds of formula oY) and following the preparation procedure del IY, other compounds of formula () are prepared as follows. ° lotion? preparation of compounds of formula (3) (a) preparation (9) wherein R' is in 4,7-difluoronaphth-1-yl Rn in hydrogen dissolved NE ( 1,6-difluoronaphthalene g; 1 mmol) in 1,2-dichloroethane (© milliliters) and cooled to 0°C. aa +, Y1£) aluminum trichloride ? mtsa 0 g) is added as a solid to the solution 1 “allll + acetic anhydride (mM) is slowly added over 100 minutes to the solution while the temperature is maintained at 0°C. The reaction was poured onto an ice-cooled aqueous 701 hydrochloric acid and extracted with methylene chloride 0177 (mL). The organic layer was dried over sodium sulfate, concentrated and purified by column chromatography to give 1-(4,7-difluoronaphth-1-yl)-ethanone as oil (1159 ax d (LA z (b)) in a similar manner. By substituting 1,6-difluoronaphthalene in place of other compounds of formula 3 and following the preparation procedures? where R' bitter R?; methyl is hydrogen Add S-methylisothiourea (77.77 g; 001 mmol) to a solution of sodium carbonate (11.9 g 001 mmol) in water (04 mL) and stir at room temperature until complete dissolution of the S-methylisothiourea. Add ethyl acetoacetate (5100 g; 0 mmol) to the mixture all at once. After stirring for 10 hours at ve room temperature; The reaction neutralized with acetic acid to precipitate a white solid. solid matter gathering; washed with cols and vacuum dried to give (4,Y'A) 4-hydroxy-6-methyl-2-(methylthio)pyrimidine g 797/5); Melting point 71-7178 7 ?C. | 777

01 different RY hydrogen is R? wherein (V2) (b) prepare or ethyl-4-methyl-3-oxopentanoate replaces ethyl acetoacetate in a similar manner; By replacing and following preparation procedures 16 above. Prepare, »60971-4,4-01006171-3-0*:00©018006 the following: (V0) compounds of formula 4-hydroxy-6-isopropyl-2-(methylthio)pyrimidine; and ° 6-tert-butyl-4-hydroxy-2-(methylthio)pyrimidine; different 8! hydrogen s» R? (c) Preparation of (10) where by following (1) the place of other compounds of formula ethyl acetoacetate in a similar way; by substituting: (11) other compounds of formula dled 16 prepared. Procedures of the preparation © Preparation Vv. (01) Preparation of compounds of formula hydrogen and 23 is methyl Hr R' where (11) (a) preparation of two molecules 29 “a= 4,Y+) 4 -hydroxy-6-methyl-2-(methylthio)pyrimidine is combined in milliliters) and the vapor is re-contained for a period of ? hours. (1+) phosphorous oxychloride 5 g). The reaction mixture is cooled to room temperature and poured onto crushed ice. The mixture was extracted 1 sodium bicarbonate and the organic layer was washed with the resulting aqueous tethyl acetate with and vacuum dried to give saturated aqueous magnesium sulfate and then water; dried over melting point 7?*©- (LAs g AYV) 4-chloro-6-methyl-2-(methylthio)pyrimidine

Jig CTA replaces 4-hydroxy-6-methyl-2-(methylthio)pyrimidine (b) in a similar manner; By substituting |* other compounds of Formula 0) and following the procedures for Preparation 10 above; The following compounds are prepared: (V1) of formula 4-chloro-6-isopropyl-2-(methylthio)pyrimidine, at a pressure of 0.0 Torr; and Ay) YA=OV YY Boiling point 6-tert-butyl-4-chloro-2-(methylthio)pyrimidine, Yo "C. EAOET Melting point 777 p oY 4-hydroxy place -6-methyl-2-(methylthio)pyrimidine In a similar way, by replacing (=) other compounds def fo other compounds of formula (10) and by following the preparation procedures (V1) of formula “preparation” (OY) preparation of compounds of formula ° aR hydrogen is R? “isopropyl is R where (OY) preparation ( i ) 4-fluoro-1-naphthyl g) £., 4°) 1-bromo-4-fluoronaphthalene cooled to -08*C, a stirred solution of 7,8 n-butyllithium molars, stirred and added dropwise tetrahydrofuran 001 mL in trimethoxyborane min; then Add V+ mL). The mixture was stirred for 10 (g 0 1 hour; then left to warm to room temperature sad mL); the mixture was stirred with 1) benzene and the solvent removed under reduced pressure. The residue is added (;?,;g) 4-chloro-6-isopropyl-2-(methylthio)pyrimidine mL) V+ + (01) (sodium carbonates + sc) 00 ( tetrakis(triphenylphosphine)palladium( 0)) (about 980 to Jad Milliliters from ? grammolecular); Then heated with re-condensation. 1 hour. The mixture was filtered and the solvent was removed under reduced pressure. The feared substance is referred to 16 years) for a period of “attachment.” To give [ethyl acetate 7] by filtering with silica gel chromatography on; C) which AY) impurity 4-(4-fluoronaphth-1 -yl)-6-isopropyl-2-(methylthio)pyrimidine is used in the following reaction without further purification. In place of 4-chloro-6 -isopropyl-2-(methylthio)pyrimidine (b) in a similar manner; By replacing the del 6 compounds, other compounds of formula (61) are prepared; And by following the following preparation procedures: (17) Formula 4-(4-fluoronaphth-1-yl)-6-methyl-2-(methylthio)pyrimidine,

Melting point EY OY Eu 1” tetra; and 4-(4-fluoronaphth-1-yl)-6-methoxy-2-(methylthio)pyrimidine,” HNMR 8.19Q2H,m), Ye 7.65( 3H,m), 7.25(1H,dd,J=8,10Hz), 6.45(1H,s), 3.98(3H,s), 2.55(3H,s).oy in place of 4-chloro-6- isopropyl-2-(methylthio)pyrimidine (C) in a similar way; by replacing other del I compounds and following the preparation procedures (V1) with other compounds of formula (VY) of formula chydroxy i.e. phenyl Substituted with a lower alkyl is R' where is (VY) (d) Substitutional preparation for an alkyl where [L] is (VY) from compounds of formula © 4-(4-fluoronaphth-2 -yl)-6-methyl-2-(methylthio)pyrimidine Add an aged solution (mL) dropwise to a solution of (Y) tetrahydrofuran mM) in 1.77 oa 2000) cooled to (alle 01 ( tetrahydrofuran equivalent) in Y,Y) lithium diisopropylamide

YY) milliliters +, YoY) benzyl bromide per minute; Add 00 -< ا * Celsius. After stirring, bring the solution to room temperature and dilute with By milligrams) to the solution in one go. 0 ml); Pour into water (00 milliliters). the organic layer separates; dried over 04) ethyl acetate and concentrated by vacuum; The resulting oil was purified by column chromatography to give magnesium sulfate (7% oY g +, VEY ( 4-(4-fluoronaphth-1-yl)-2-methylthio-6-phenethylpyrimidine © 4-(4-fluoronaphth-2- yl)-6-methyl-2-(methylthio)pyrimidine (E) in a similar way, by substituting D1 and following preparation procedures alkyl is R' where (V1) is in place of other compounds of formula 1 The following: (VV) above.” Compounds of formula 4-(4-fluoronaphth-1 -y1)-6-(2-hydroxyphenethyl)-2-(methylthio)pyrimidine; and 4-(4-fluoronaphth-1) are prepared. -y1)-6-(3-hydroxypropyl)-2-(methylthio)pyrimidine .4-(4-fluoronaphth-2-y1)-6-methyl-2-(methylthio)pyrimidine in a similar way; by substituting (5)

R! above; Where aT is lily (V1) in place of other compounds of formula Ye. (17) Other compounds of formula dower alkyl (V1) are prepared. (VA) preparation of formula compounds is 7 And 13 is a free hydrogen hydrogen R?«isopropyl in R' where is (VA) (a) preparation of 4-fluoro-1-naphthyl vo (a= +,Y¢Y) 4-( 4-fluoronaphth-1-yl)-2-methylthio-6-phenethylpyrimidine dissolved at room temperature. add methylene chloride (mM) in 64 mm) in VAY g » “008 [+ —00) saturated anhydrous meta-chloroperoxybenzoic acid. The layer was washed with sodium bisulfite for an hour. The reaction mixture was washed off with 11 small batches. After the concentration of “saturated aqueous magnesium sulfate and water; Organic sodium bicarbonate was dried over organic matter with 4-(4-fluoronaphth-1-y1)-2-methanesulfonyl-6-phenethylpyrimidine to give “Cy S (LAY aa .,5407(0)” HNMR 8.07(1H,m). ), 7.85(1H,m), 7.47(2H,m), 7.32(1H,s), 7.13(7H,m), 3.29 (2H,m), 3.07(2H,m).4-(4-fluoronaphth) -1 -y1)-2-methylthio-6-phenethylpyrimidine (b) in a similar manner by substituting IY compounds in the preparation of a) and following (VY) in place of other compounds of the following formula: (VA) Formula 0 4-(4-fluoronaphth-1-yl)-6-(2-hydroxyphenethyl)-2-methanesulfonylpyrimidine, $i 59 0 ~OAAY Melting point 4-(4-fluoronaphth-1 -yl)-6-(3-hydroxypropyl)-2-methanesulfonylpyrimidine, "HNMR 8.21(2H,m), 7.69(1H,dd,J=5.3,8.2Hz), 7.68(1H,s), 7.61(2H, m), 7.24(1H, dd,J=8,10Hz), 3.76(2H,t,J=7.5Hz), 3.40(3H,s), 3.09(2H,t,J=7.5Hz), 2.11(2H ,m); ,10Hz), 7.15(1H,s), 4.20(3H,s), 3.39(3H,s); and 4-(4-fluoronaphth-1-yl)-6-isopropyl-2-methanesulfonylpyrimidine, melting point 997 ,1-995,1" occult. ov. 4-(4-fluoronaphth-1-yl)-2-methylthio-6-phenethylpyrimidine (c) in a similar manner; by replacing the aad compounds above”IV in place of other compounds of formula (71)); And by following the preparation procedure another (VA) of formula 1 eg 1 prepare the compound of formula Yo, 8 and 2 are cnaphth-1-yl 5 » Ry amethyl are R* sR" (a) prepare 1 where is hydrogen

VY'Y oo heated with vapor recondensation (approx. 0+0" to 0*"C) heterotropic stirred solution of 2-amino-4-chloro-5,6-dimethylpyrimidine (g) +,¥AY) 1-naphthyl boronic acid ethyl alcohol (g) +, oY) tetrakis(triphenylphosphine)palladium(0)) «(a +,¥+) +,A®) sodium carbonate 5 mL) A) 1,2- dimethoxyethane (mL); Water (£ milliliters)” A) h. The solution is then cooled to room temperature; Filtered and extracted with VE (g) for 0 ia) at 866 volts. The solvent was removed under reduced pressure and the solid of color g) recrystallized; Point (+,YY) 2-amino-5,6-dimethyl-4-(naphth-1-yl)-pyrimidine produced to give .iom"715,1-©717,5 fusion optionally place 2 -amino-4-chloro-5,6-dimethylpyrimidine (b) in a similar way; optionally substituting 1-naphthyl boronic acid for the compounds 1-naphthyl boronic acid and (o£) other compounds of Formula 0 and following the procedures of Example 1a above The following compounds of formula [] were prepared: o(0) other of the formula 2-amino-6-cyclopentyl-4-(naphth-1-yl)-pyrimidine, 4, 1 EY, 6-0). 8 Melting point 2-amino-6-(but-2-yl)-4-(naphth-1-yl)-pyrimidine, uA) YAO) HA Melting point vo 2-amino-6-(2- methylpropyl)-4-(naphth-1-yl)-pyrimidine hydrobromide, 354101 01,0-CV 897. Melting point 2-amino-6-(tert-butyl)-4-(naphth-1-yl)- pyrimidine,

SAC TY, Y-0VTY Melting point 2-amino-6-benzyl-4-(naphth-1-yl)-pyrimidine, Y. iy Ae SAY OV 47,9 Melting point 2-amino-6-cyclobutyl melting point 2-amino-6-cyclopropyl-4-(naphth-1-yl)-pyrimidine,

Gu CY AE=OVAY A Melting point vo 2-amino-4-(naphth-1-yl)-6-n-propylpyrimidine, $4550°YY 4 ,0-°114,0 Melting dads

2-amino-6-isopropyl-4-(naphth-1-yl)-pyrimidine,

Gu AC YTV YE Melting point 2-amino-5-fluoro-6-methyl-4-(naphth-1-yl)-pyrimidine, UTM#1 07-0155 Melting point 2-amino-6- ethyl-4-(naphth-1-yl)-pyrimidine hydrochloride, °

Gy feV 1 = 2V oY Melting point 2,6-diamino-4-(naphth-1-yl)-pyrimidine hydrochloride,

ASOT AS Melting Point 2-amino-6-trifluoromethyl-4-(naphth-1-yl)-pyrimidine, yum”1 04-0157 Melting Point 0 2-amino-4-(naphth-1- yl)-6-phenylpyrimidine hydrochloride, melting point 777©-#771C; 2-amino-4-(3-fluorophenyl)-6-methylpyrimidine,

GACY £1,600 60.7 Melting point 2-amino-4-(5-chlorothiophen-2-yl)-6-methylpyrimidine, vo

Cy ACVAY, FOV AT) Melting point 2-amino-4-(3-methoxyphenyl)-6-methylpyrimidine,

Gu AC T4,1-0V YO, A Melting point 2-amino-6-methyl-4-(3-n-triphenyl)-pyrimidine, (401 49,1-0V4A,0 Melting point Y. 2 -amino-4-(3-chloro-4-fluorophenyl)-6-methylpyrimidine, tA 421 10,0-°V 717,8 Melting point 2-amino-4-(3,5-dichlorophenyl)-6- methylpyrimidine,

Ci BVA, ACV AY Melting point 2-amino-6-methyl-4-(3-trifluoromethylphenyl)-pyrimidine, Yo

Cy AY YY, ACY YY Melting point 2-amino-6-methyl-4-(naphth-1-yl)-pyrimidine hydrochloride,

ov $y ACY YT Melting point 2-amino-4-(4-amino-5-chloro-2-methoxyphenyl)- 6-isopropylpyrimidine hydrochloride,

Gui) 40, TOV AY) Melting point 2-amino-6-(3-methylbutyl)-4-(naphth-1-yl)-pyrimidine hydrochloride, ° Melting point 51.5 1*--"01#C and 2-amino-4-(4-amino-5-chloro-2-methoxyphenyl)-6-methylpyrimidine, melting point AV AE=OVAY (=) in a similar way; by substituting 2-amino-4 -chloro-5,6-dimethylpyrimidine optionally replacing cA alse of formula (4;); and optionally substituting 1-naphthyl boronic acid for other compounds of formula (0) and following the procedures of example TY above. Other compounds are prepared of formula J Example? *s are hydrogen to a stirred solution of 1-bromo-4-fluoronaphthalene (©, + g) in 01 milliliter of tetrahydrofuran at -6/la C under nitrogen added dropwise 01 ( n-butyllithium mol; 0.97 milliliters). The solution was stirred for 0 (BBs) and then added dropwise (YY) trimethoxyborane, + milliliters). The lad solution was brought to room temperature and the solvent 0 was removed under reduced pressure to give a solid “dimethoxy-(4-fluoronaphth-1-yl)borane compound of formula (7). The solid was dissolved in ¾ milliliters of <benzene and 2-amino-4-chloro-6-n-propylpyrimidine (*,TAY) g) was added (001) tetrakis(triphenylphosphine)palladium (0 g) and Tle sodium carbonate is gram molecular. The anisotropic solution is heated with vapor re-condensation ve (approximately 0 to 455000 ºC) for 1 hour; then the solution is cooled to room temperature; diluted with ethyl acetate and filtered. The filter material is concentrated by vacuum and the residue is analyzed by gel chromatography. 811168; by elucidation with a mixture of “ethyl acetate/hexanes to give oA g) ; melting point +) +) 2-amino-4-(4-fluoronaphth-1 -yD)-6-n-propylpyrimidine

AAI TY, E01 TA optionally in place of other compounds 1-bromo-4-fluoronaphthalene (b) in a similar manner; Optionally substituting in place of the 2-amino-4-chloro-6-n-propylpyrimidine compounds of formula (1)(“and by substituting the above.” The following compounds of formula 1 are prepared: IY and following the example procedure (o£) Other of formula 0 2-amino-4-(4-chloronaphth-1-yl)-6-(2-methylpropyl)-pyrimidine hydrochloride, 0) 184,491 AY melting point. 2-amino-4-(4-fluoronaphth-1-yl)-6-(2-methylpropyl)-pyrimidine hydrochloride, $3521 17-9191, melting point 2-amino-4-(4-chloronaphth-1-yl) )-6-ethylpyrimidine, Ye

CACY EY, YC 47,7 Melting point 2-amino-4-(4-methylnaphth-1-yl)-6-isopropylpyrimidine, ual) 46-01 47,5 Melting point 2-amino-6-( tert-butyl)-4-(4-fluoronaphth-1-yl)-pyrimidine hydrochloride, tm'1 4-9197 Melting Point 1 2-amino-4-(4,5-dimethylnaphth-1-yl) Melting Point -6-methylpyrimidine, Cm#1 915-919 4 Melting Point 2-amino-4-(4,5-difluoronaphth-1-yl)-6-isopropylpyrimidine, Cm#17 ©1777 Melting Point ‎ 2-amino-4-(4-chloronaphth-1-y1)-6-isopropylpyrimidine hydrochloride, Y. (iO AC, TOV AT,Y Melting point 2-amino-6-cyclopropyl-4-(4-fluoronaphth) -1-yl)-pyrimidine, ©9915 .,7 Melting point 2-amino-6-cyclopropylmethyl-4-(4-fluoronaphth-1-yl)-pyrimidine hydrochloride,

GAC YA, ECV YA Melting point Yo 2-amino-6-cyclobutyl-4-(4-fluoronaphth-1-yl)-pyrimidine hydrochloride,

Gy AV VI = CV TA Melting point

Vy'y

04 2-amino-4-(4,5-difluoronaphth-1-yl)-6-methylpyrimidine, melting point 2-amino-4-(1H,3H-benzo[de]isochromen-6- yl)-6-methylpyrimidine, (4 PY VAY) Melting point 4-(acenaphthen-5-yl)-2-amino-6-isopropylpyrimidine, °C”1 18-0177 Melting point 2-amino- 6-methyl-4-(phenanthren-9-yl)-pyrimidine,

Gig) A), AO AF Melting point 2-amino-4-(4-methylnaphth-1-y1)-6-methylpyrimidine,

Gu AC VT, VY Melting point 0 2-amino-4-(4-fluoronaphth-1-yl)-6-isopropylpyrimidine hydrochloride, (iy fe) OAV 0 Melting point 2-amino-4-(4- fluoronaphth-1-yl)-6-isopropylpyrimidine maleate, UTM#1 597-0155 Melting Point 2-amino-6-ethyl-4-(2-methyl-4-fluoronaphth-1-yl)-pyrimidine, vo;iam” 07 7-0171 Melting point 4-(acenaphthen-5-yl)-2-amino-6-methylpyrimidine,

Gy ALYY FOY YY Melting point 2-amino-4-(isoquinolin-4-yl)-6-methylpyrimidine, Melting point 717,5-0717"C; Y. 2-amino-6-methyl-4- (quinolin-8-yl)-pyrimidine, (iy) 40,0-01 4 lb A Melting point 2-amino-4-(4-fluoronaphth-1-yl)-pyrimidine, (hy AY 6,1- 97 7,4 Melting point 2-amino-6-ethyl-4-(4-fluoronaphth-1-yl)-pyrimidine hydrochloride, Yo iy Ae) 49-2) AA Melting point 2-amino-4- (4-fluoronaphth-1-yl)-6-methylpyrimidine hydrochloride,

+6 Melting Point #77/8.1-977/.2C; 2-amino-4-(2-methylnaphth-1-yl)-6-methylpyrimidine hydrochloride, Melting Point 7195.4-9717.76" 2-amino-4-(4-fluoronaphth-1-y1)-6-(3,3,3-trifluoropropyl)-pyrimidine hydrochloride, °C”155-©1 57 Melting Point 2- amino-4-(5-fluoronaphth-1-yl)-6-isopropylpyrimidine, $4 CAAA Melting point 2-amino-4-(2-fluoronaphth-1-yl)-6-isopropylpyrimidine hydrochloride, 7"C; 016-0706 Melting Point 0 2-amino-4-(2-fluoronaphth-1-yl)-6-methoxypyrimidine hydrochloride, eA ACY PYAR Melting Point 2-amino-4-(4-fluoronaphth-1- yl)-6-methoxypyrimidine hydrochloride, $40 AYA Melting point 2-amino-4-(4-fluoronaphth-1-y1)-6-(2,2,2-trifluoroethoxy)-pyrimidine Vo hydrochloride, iy YS ACY lol)! Point 2-amino-6-tert-butyl-4-(2-fluoronaphth-1-yt)-pyrimidine hydrochloride, iothem””777-©9771 Melting point 2-amino-4-(2- fluoronaphth-1-yl)-6-methylpyrimidine, sans (yf) 000) £9 Melting point 2-amino-6-isopropyl-4-(2-methylnaphth-1-yl)-pyrimidine hydrochloride, $3401 14-9187 Melting Point 2-amino-4-(6-methylacenaphthen-5-yl)-6-methylpyrimidine, $43 61.21 4-901 9A Melting Point Yo 2-amino-6-cyclopropyl-4-(1H -indol-4-yl)-pyrimidine hydrochloride, $4 YA < melting point

>“ 2-amino-6-tert-butyl-4-(1H-indol-4-yl)-pyrimidine,

CA YPC VY Melting point 2-amino-4-(8-hydroxymethylnaphth-1-yl)-6-methylpyrimidine, melting point 107*©-817*C; 2-amino-4-(1H-indol- 7-y1)-6-isopropylpyrimidine, °

Oy ga) 46-01 EY Melting point 2-amino-6-cyclobutyl-4-(1H-indol-4-yl)-pyrimidine,

Gu ALYY TOY YO Melting point 4-(acenaphthen-5-yl)-2-amino-6-methoxypyrimidine hydrochloride, yum"70-©*7016 Melting point 0 4-(acenaphthen-5-yl)- 2-amino-6-cyclopropylpyrimidine, and 4A PY 11,007) melting point 4-(acenaphthen-5-yl)-2-amino-6-tert-butylpyrimidine hydrochloride, melting point 4 ,#7715,1- 9777C. other compounds of formula o£) and by following the procedures of Example IY above.” Other compounds of formula 1 are prepared. Example ? An alternative preparation of the compound of formula 1 “| () is prepared [1 wherein the l is methyl 82 is hydrogen is great hydrogen < 6-methoxy-3,4-dihydro-2H-quinolin-1-yl Heat a flask containing 6-methoxy-1,2,3 4-tetrahydroquinoline (1,77 (g) (1) (2-amino-4-chloro-6-methylpyrimidine) (g) sulfuric acid (+) g) and 100 milliliters of water on a steam bath for two hours. Then the solution is cooled to room temperature and treated with Ye with ammonium hydroxide up to mua) solution Lael (pH (AA) the resulting solid was collected by filtration; precipitated from cd saad) and recrystallized from ethyl alcohol of

“+ to give « 2-amino-4-(6-methoxy-3,4-dihydro-2H-quinolin-1-y1)-6-methylpyrimidine (+,4Y) g); melting point 1786.7©-75.40*C.(b) in a similar way; optionally substituting 6-methoxy-1,2,3,4-tetrahydroquinoline for other compounds of formula (4) and optionally substituting 2-amino-4-chloro-6-methylpyrimidine 0 for other compounds of formula (); By following the procedures of Example A above. The following formula 1 compounds are prepared: 2-amino-4-(6-fluoro-3,4-dihydro-2H-quinolin-1-yl)-6-methylpyrimidine, melting point 57 dg fly oV—oY 2-amino-6-chloro-4-(3,4-dihydro-2H-quinolin-1-yl)-pyrimidine hydrochloride, 0 melting point LAVAS (hydrolysis); 2-amino-4-(indol-1-yl)-6-methylpyrimidine hydrochloride, melting point 57 7*©-#7760m; 2,6-diamino-4-(3,4-dihydro-2H-quinolin-1-yl)-pyrimidine dihydrochloride, melting point 997-0147 Gig fe) 6-(3,4-dihydro-2H) -quinolin-1-y1)-9H-purin-2-ylamine, VO melting point 3,5 7©-4 + 7#; 2-amino-4-(2-methyl-3,4-dihydro-2H-quinolin-1-yl)-6-methylpyrimidine, Melting point Gu ALY £0) EY) 2-amino-4 -(6-methoxy-3,4-dihydro-2H-quinolin-1 -yl)-6-trifluoromethylpyrimidine, Y. Melting point Gy ACV VY,0-0V V0 2-amino-4-( 3,4-dihydro-2H-quinolin-1-yl)-6-ethylpyrimidine, | Melting point 41,4 )0 Go AREY, 2-amino-6-methyl-4-(6-methyl-3,4-dihydro-2H-quinolin-1-yl)-pyrimidine, melting point CARI), E01 2-amino-4-(3,4-dihydro-2H-quinolin-1-yl)-6-trifluoromethylpyrimidine, Yo Melting point Gy AV TEV NY 2-amino-4-( 6-fluoro-2-methyl-3,4-dihydro-2H-quinolin-1-y1)-6-methylpyrimidine,

Yutham #1 05,7915 4,5 Melting Point 2-amino-6-methyl-4-(2,3,4,5-tetrahydro-benzo[b]azepin-1-yl)-pyrimidine, $00 YAEL YAY, Melting Point 2-amino-4-(7,8-dihydro-6H-5-0xa-9-azabenzocyclohepten-9-yl)-6- methylpyrimidine, ° ye) AY —0V AG, A Point fusion 2-amino-4-(2,3-dihydro-benzo[1,4]oxazin-4-yl)-6-methylpyrimidine,

Gy AY YA, 0=CVYY,Y Melting point 2-amino-4-(2,3-dihydro-indol-1 -yl)-6-methylpyrimidine,

Cy ACY EA=OYEY,Y Melting point 0 2-amino-4-(2-methyl-2,3-dihydro-indol-1-yl)-6-methylpyrimidine,

CCV AY, ECVAY, Melting point 2-amino-4-(3,4-dihydro-2H-quinolin-1-yl)-6-methylpyrimidine hydrochloride, (I AOTTY, YOY ,0) Melting point 2-amino -4-(3,4-dihydro-1H-isoquinolin-2-yl)-6-methylpyrimidine, Yo

Gu ACYET, FOV 47,7, Melting Point 2-amino-4-(3,4-dihydro-2H-quinolin-1-yl)-6-isopropylpyrimidine hydrochloride, Melting Point 710,16*©-711,1 2-amino-4-(6-fluoro-3,4-dihydro-2H-quinolin-1-yl)-6-isopropylpyrimidine hydrochloride, Y. (4, il OV,0-°Y 00,0 Melting point 2-amino-4-(3,4-dihydro-2H-quinolin-1 _yl)-6-tert-butylpyrimidine hydrochloride, melting point 7717.76*©-7715"C. It is hydrogen. is R? “chloro preparation 1 wherein H is (—a) hydrogen Rt are R* 5 (3,4-dihydro-2H-quinolin-1-yl ~~ vo mmol) 01 aa 7 ( 1,2,3,4-tetrahydroquinoline dissolved lle 01 mmol) in 10 g;

¢ (DMF) N,N-dimethylformamide and the entire solution is heated to 96©-097" for a period of Yé hours. The DMF is removed by vacuum; the residue vapor is re-condensed with ethyl acetate to give ; g of material Solid; the solid was analyzed chromatography on gel 11168, eluting with “methylene chloride” to give 2-amino-6-chloro-4-(3,4-dihydro-2H-quinolin-1-yl)-pyrimidine° (+ £1 mg); Melting point (TY,0-01 TY) (52 0) 2-amino-6-chloro-4-(3,4-dihydro-2H-quinolin-1-yl)-pyrimidine hydrochloride, melting point 7911"C (decomposition). (D) In a similar way; optionally substituting 6-methoxy-1,2,3,4-tetrahydroquinoline in place of 0 other compounds of formula (48)" and by substituting . 2-amino-4-chloro-6-methylpyrimidine (optionally in place of other compounds of formula o£) and by following the procedures of example ?a or “je def” prepare other compounds of formula J eg £ substitute preparation for the compound of formula I ve (a) attend 1 where L is R® (N,N-diethylamino Hr chydrogen 13 is “3,4-dihydro-2H-quinolin-1-yl” hydrogen An excess of diethylamine is added to a solution of 2-amino-6-chloro-4-(1,2,3,4-tetrahydroquinolin-1-yl)-pyrimidine YO!) mg) in * milliliters of ethylene glycol The mixture was heated for two days at 100”C. The crude product was purified by chromatography to give Tov mg solid. Treatment of the solid with ethanol alcohol-hydrochloric acid yields: 2-amino-6-dicthylamino-4-(3,4-dihydro-2H-quinolin-1-yl)-pyrimidine hydrochloride, melting point 0691*©-701”C. vo (b) in a similar fashion; optionally substituting diethylamine in place of other amines of formula (HNR®R’ and substituting 2-amino-6-chloro-4-(1,2,3,4-tetrahydroquinolin-1-yl)-pyrimidine

Optionally +6 in place of other compounds of Formula 1 where RY is chloro and following the procedures for Example A above.” Other compounds of formula 1 are prepared where RY is ANRR Example * An alternative preparation of a compound of formula I 0 (a) preparation of ] where R' is cmethyl Th1 live <hydrogen t s—a 41 amputele R*s | Two hydrogen vapors of 4-acetylindole (+ ),+ body) are recondensed in ¾ milliliters of ethyl acetate (1,701 g sodium hydride; oil dispersant £70) are added in batches to the recondensed solution until Thin layer chromatography shows complete consumption of the starting material.The reaction mixture is quenched with water and acidified to pH ¥.The ethyl acetate layer of magnesium sulfate is dried and concentrated to give a crude product.The raw material is analyzed by chromatography on a dia ill silica gel with ethyl acetate/hexane to give (p>001 4( 1-(1H-indol-4-yl)-1,3-butanedione compound of formula (11); melting point 5-014 10”C. (b) 1-(1H-indol-4-yl)-1,3-butanedione (0 431 g) is mixed with guanidine carbonate ofan +, Ve) 0 and the mixture is heated to 1501 Simmer for ? hours. Additional guanidine carbonate (Vr) (50 + g) is added; the mixture continues to be heated for another two hours. The reaction mixture is warmed with cethyl acetate filtered out; the ethyl acetate layer is concentrated to give a solid (09). flash chromatography on silica gel and elutation with cethyl acetate/hexane yielded 2-amino-4-(1H-indol-4-yl1)-6-methylpyrimidine (4 07 g); melting point 47 07-0 ©*,7; (c) in a similar way; by substituting 4-acetylindole in place of 1-acetylnaphthalene in step #a above and by replacing guanidine carbonate with c:a-1 in step b” and by following the procedure of example fo and proceeding to Compound “2-amino-5-(6-methyl-4-naphth-1-yl)-pyrimidin-2-ylamino)-pentanoic acid Melting point 711-0774”C. ve (3) in a similar way; by substituting 4-acetylindole in place of 1-acenaphthelene in step A and following the procedures of J Ad #a and a bear preparing a compound

1 1 (2-amino-6-methyl-4-(naphth-1-yl)-pyrimidine hydrochloride) Melting point —°YY. Ay AOTVY (e) in a similar way; by substituting -1 ( 1H-indol-4-y1)-1,3-butanedione in place of 1-(3-chlorophenyl)-1,3-butanedione and following the procedures of the above example bear.’ Compound c2-amino-4-(3-) is prepared. chlorophenyl)-6-methylpyrimidine 0 Melting point AG ALYYY, YON YY JT and preparation 1 where the live reaction R? anethyl is hydrogen is “2,3-dihydro-1,4-benzodioxin-5-vl B and B are hydrogen. Dissolve 117 (1-(2,3-dihydro-1,4-benzodioxin-5-yl)-ethanone g) in 10 mL ethyl acetate and add YY) sodium hydride , + g; dispersant (Cy) 770). Reaction mixture heated 0 to 80°C throughout Jill quenching with water; It neutralizes with carbon dioxide to give an oily product of (a> 717/( 1-(2,3-dihydro-1,4-benzodioxin-5-yl)butan-1,3-dione +,TV) 1 -(2,3-dihydro-1,4-benzodioxin-5-yl)-butan-1,3-dione Jats, g); with YY) guanidine carbonate, + g); The mixture is heated to dali Ye for one hour. The dark product is raised in cmethylene chloride, filtered; and focus. The residue oe was analyzed chromatography on silica gel by eluting with chexane/ethyl acetate to give a solid (V1+, g); which were treated with ethanol-hydrochloric acid to give 2-amino-4-(2,3-dihydro-1,4-benzodioxin-5-yl)-6-methylpyrimidine hydrochloride (Yo), + g); Melting point 60 EYOY ?C. (g) Prepare 1 where R® 5 R' is R® hydrogen Hr 13-71 mmSg-1 R*, R 0 is hydrogen Dissolve (3-acetyl-1-methylindole) (+,AY+) in ?mL absolute ethanol Add tert-butoxybis(dimethylamino)methane (reagent (Bredereck's (130, » g) in ¥mL) ethanol to this solution at the vapor re-condensation temperature.The solution was re-evaporated for two days and the solvent was removed at room temperature by vacuum.The residue Yo was pulverized with ethyl acetate/hexane to give a solid (4 0.04 g). The solid was mixed with 797/010 (guanidine carbonate g) and the mixture was heated to Aa Ye for 14 h. The reaction mixture was dissolved in hot absolute ethyl alcohol; filtered; and recrystallized to give 777 p.

any crystalline solid; White color of 2-amino-4-(1-methylindol-3-yl)-pyrimidine (KH +, + g) 0 dallas solid crystallized with ethyl acetate-hydrochloric acid and recrystallized salt of ethanol give 2-amino-4-(1-methylindol-3-yl)-pyrimidine hydrochloride (100 4A) g); Melting point 4 0797©-771 “tw. YY aa 09 0( 1-(4,7-difluoronaphth-1-yl)-ethanone, + mmol) was dissolved in dry dioxane (1mL) and cooled to 0*C. Sodium was added. hydride (£0 ),+ 1 mmol g; dispersion 7710 by weight) and the reaction mixture was stirred for 1 hour at 0 °C. Add (1 mL ethyl isobutyrate; VY mM) In one batch and the solution is heated with re-condensation of the steam for 11 minutes.After cooling to the temperature of God al Jada the reaction is poured on aqueous hydrochloric acid 701 and extracted with methylene chloride.The organic layer is dried over sodium sulfate and purified by column chromatography to give +,VY +) 1-(4,7-difluoronaphth-1 -yl)-4-methylpentane-1,3-dione GVY#( .m(i)conjugate 1-(4,7-difluoronaphth-1-yl)-4-methylpentane-1,3-dione ) 64 g; 1.0 mmol) with Av) guanidine carbonate ) + g; 1. 5 mM) and heated to Vor C for 7 hours. The reaction was cooled to room temperature and purified directly by column chromatography to give oY) 2-amino-4-(4,7-difluoronaphth-1 -yl)-6-isopropylpyrimidine +,+ C4 77); Melting point ?10©-5100” resolving. by substituting 1-(4,7-difluoronaphth-1-yl)-ethanone for ¢1-(4,8-difluoronaphth-1-yl)-ethanone ¢1-(4,6-difluoronaphth-1-yl) -ethanone “1-(4-methoxynaphth-1-yl)-ethanone or -methyl-1H-indol-4-yl)-ethanone 1 in sha 5 dah” and optionally substituting ethyl isobutyrate In place of 4,4-dimethyl-3-oxopentanoate or “4,4-dimethyl-3-oxopentanoate” or “guanidine 5” ethyl-2-fluoroisobutyrate in place of the guanidine Ye salts substituted in step (hao) and following Example procedures 5h dao prepare the following compounds: 2-amino-4-(4,6-difluoronaphth-1-yl)-6-isopropylpyrimidine hydrochloride, melting point 6-0177 Cg ALY

TA

2-amino-4-(4,8-difluoronaphth-1-yl)-6-isopropylpyrimidine hydrochloride,

AY) A=OY YT Melting point 2-amino-4-(4-methoxynaphth-1-yl)-6-isopropylpyrimidine hydrochloride,

A041 AY-014T Melting point 2-amino-6-tert-butyl-4-(4-methoxynaphth-1-yl)-pyrimidine hydrochloride, °

G0 5PYY 0-18 Melting Point 2-amino-4-(1H-indol-4-yl)-6-isopropylpyrimidine hydrochloride,

Ga ALYY YON) melting point 2-amino-4-(1-methyl-1H-indol-4-yl)-6-isopropylpyrimidine,

Gua) FO YA Melting Point 0 2-amino-4-(4-fluoronaphth-1-yl)-6-(1-fluoro-1-methylethyl)-pyrimidine,

Cy AV FY ¥0,0 Melting point 2-amino-4-(4-fluoronaphth-1-y1)-6-(1-fluoro-1-methylethyl)-pyrimidine hydrochloride,

Cy SCY AY, ACVAT,T Melting point vo 4-(4-fluoronaphth-1-y1)-6-(1-fluoro-1-methylethyl)-2-methyl aminopyrimidine, ius) V0) 44 Melting point 2-amino-4-(4-methoxynaphth-1-yl)-6-methylpyrimidine hydrochloride, $550 £9.0-°V 47 Melting point 2-amino-6-ethyl-4-(4-methoxynaphth-1) -yl)-pyrimidine hydrochloride, 0 718.5-97" YA 0 Melting point 2-amino-4-(4,6-difluoronaphth-1-y1)-6-(1-fluoro-1) -methylethyl)-pyrimidine hydrochloride, AAC TY, FO YET Melting point 2-amino-4-(acenaphthen-5-y1)-6-(1-methyl-1-fluoroethyl)-pyrimidine, Yo

Ag ALIYY ECVV 0 Melting point 1 Example

Joa preparation of compound of formula 1 (f) preparation 1 where R' hr R? “chloro bitter hydrogen is 5 naphth-1-yl and is replaced by two hydrogens added 2-amino-6-hydroxy-4-(naphth-1-yl)-pyrimidine (+ +4 mg) ; to a solution of chlorosulfonic acid (0.0 0 milliliters) in *.7 milliliters oxychloride 0105010118 and the mixture was stirred at 15 * decontamination for 7 hours. pour mixture over ice; Neutralize with “potassium carbonate” and extract with ethyl acetate. The crude product (Vo) is purified by silica gel chromatography by filtering with <methylene chloride and treated with ethanol-hydrochloric acid to give (Y©) 2- amino-6-chloro-4-(naphth-1-yl)-pyrimidine hydrochloride mg); droplet 0 . fusion A AOYO OT EA (b) Prepare 1 where R®yR' is R*, naphth-1-yl s— R® hydrogen and 1285 is dissolved hydrogen (a— == VV+) 2-amino-6-chloro-4-(naphth-1-yl)-pyrimidine in 10 milliliters of methyl alcohol at ia "C. Palladium is added to the active carbon ve) 701 mg) and approximately 1 mL of ZX + sodium hydroxide to the solution” and the mixture was hydrogenated (pressure 1 atmosphere) s.h.als 33 to give 2-amino-4-(naphth). -1-yl)-pyrimidine solid (A+) mg) The dallas solid with ethyl alcohol/hydrochloric acid yields YO) 2-amino-4-(naphth-1-yl)-pyrimidine hydrochloride mg); yl-substances R' are hydrogen. YY (1-acetonaphthalene g) in Vo) carbon disulfide g) is added within 11 minutes to an 11-degree temperature Yo solution containing 1958 milliliters of 1 1 potassium tert-butoxide in 50060 milliliters ether left reaction mixture lad to room temperature; Re-cooled to 10©-71"C; then methyl iodide (©©g) is added dropwise over 0£ min. Up to

Bring the reaction mixture to room temperature for VT hr; filter and focus. The residue recrystallized from the methyl plant to give 3,3-(bis-methylsulfanyl)-(1-naphth-1-yl)-prop-2-en-1-one VY (g); Melting point 4-977 to 7*C. b Add 3,3-(bis-methylsulfanyl)-(1-naphthalen-1-yl)prop-2-en-1-one (1.748 g) 0 to 10 mL methanolic solution of sodium hydride ) 184 mg; Oil dispersant (I+ T+) guanidine carbonate s g). The reaction mixture vapor is re-condensed for > “lela, poured into cethyl acetate and washed with saturated bicarbonate 20; cele and brine. The organic layer was dried over potassium carbonate and concentrated to about ¾ milliliters to give a crystalline solid of 2-amino-6-methoxy-4-(naphth-1-yl)-pyrimidine Melting point 2104.1—800 *1C Treatment of the crystalline solid with ethyl alcohol /hydrochloric acid gives (Yo +) 2-amino-4-methoxy-6-(naphth-1-yl)-pyrimidine hydrochloride mg) Melting point 865-01840.” C. (c) in a similar manner; By substituting the methanolic solution in place of the corresponding alcohol “ethylene glycol” (ethyl alcohol “isopropyl alcohol”) and following the procedures of Example B above, the following vo compounds of formula 1 are prepared: 2-amino-6-(2-hydroxyethoxy)- 4-(naphth-1-yl)-pyrimidine hydrochloride, melting point 0-9194 7"C; 2-amino-6-isopropyloxy-4-(naphth-1-yl)-pyrimidine hydrochloride, melting point 10 ACTIV 540 2-amino-6-ethoxy-4-(naphth-1-yl)-pyrimidine hydrochloride, Y. Melting point 9% 40-01 ACY (3) Prepare 1 where R is ! -prop-2-en-1-one (1,17 pH) Yo to a mixture of +,VA) sodium hydride g; oil dispersant +41( guanidine carbonate )+£,+ g) in 01 milliliters (DMF) N,N-dimethylformamide at room temperature. After 1 hour, the mixture is heated to 15600"C for #© hours. The interaction is 777 p

Only extractive yields a crude product which (lad chromatography on silica gel by eluting ethyl acetate/hexane x—a) to give 2-amino-4-methylthio-6-(1-naphthyl)-pyrimidine VE) mg). Treatment of the free base with ethylalcohol-hydrochloric acid gives A+) 2-amino-6-methylthio-4-(naphth-1-yl)-pyrimidine hydrochloride mg)oo melting point dg aYoR-oYoo (decomposition). Example A An alternative preparation of a compound of formula 1 i ) ) Preparation of 1 Cua A is ag is R? dsopropyl hr hydrogen p is rR? aphth-1-yl is R® 4 ethyl in hydrogen Yee added 4-(4-fluoronaphth-1 -y1)-6-isopropyl-2-methanesulfonylpyrimidine )+ + \,+ g; 79 mmol) to a solution of 0,A «lille +, YY (mM ethylamine) in 1 (mL ethanol). The reaction vessel was placed in an acoustic wave bath for 1 night at a bath temperature of 46 *C. The ethanol is removed by vacuum to leave a viscous oil. The oil crystallizes from ethanol and water to give 6-isopropylpyrimidine-4-(4-fluoronaphth-1 -yl)-6-isopropylpyrimidine ve (£23) Melting point 7/7a-9-28a*C. ( b) in a similar manner; by substituting ethylamine in place of other amines of formula NHR*R® and optionally substituting 4-(4-fluoronaphth-1 -yl)-6-isopropyl-2-methanesulfonylpyrimidine in place of other compounds of Formula (VA) and following the procedures of Example IA above,” prepare the following compounds of Formula 1: 4-(4-fluoronaphth-1-yl)-2-hydrazino-6-isopropylpyrimidine hydrochloride, Ys Melting point £1 £001 1” morph; 4-(4-fluoronaphth-1-yl)-6-isopropyl-2-(2-methoxyethylamino) -pyrimidine, vo. Melting point 897.1/©-8/.7"C; 4-(4 -fluoronaphth-1-y1)-6-isopropyl-2-n-propylamino-pyrimidine, melting point, £099,909(

YY

2-allylamino-4-(4-fluoronaphth-1-yl)-6-isopropylpyrimidine, (hy 408 T, ECT, A) Melting point 4-(4-fluoronaphth-1-y1)-6-isopropyl-2- (piperidin-1-yl) -pyrimidine, $i AOVY OV Melting point 2-benzylamino-4-(4-fluoronaphth-1-yl)-6-isopropylpyrimidine, ° ty APY 4-977 Melting point 2- cyclopropylamino-4-(4-fluoronaphth-1 -yl)-6-isopropylpyrimidine, th 40) + AY v0) Melting point 2-(2-hydroxyethylamino)-4-(4-fluoronaphth-1-y1)-6 -isopropylpyrimidine hydrochloride, Ye 6h PVN —OV Melting point 4-(4-fluoronaphth-1-y1)-6-isopropyl-2-morpholinopyrimidine, (1 BPAY OA) Melting point 2-butylamino-4-(4- fluoronaphth-1-y1)-6 -isopropylpyrimidine, (ly OAA—OAY melting point eo 2-butylamino-4-(4-fluoronaphth-1-yl)-6-methylpyrimidine hydrochloride,

Cy ALITA TY Melting Point 2-dimethylamino-4-(4-fluoronaphth-1 -yl)-6-isopropylpyrimidine,

Sg AC 47-941 Melting Point 4-(4-fluoronaphth-1-yl) -6-isopropyl-2-methylaminopyrimidine, Y. ig) 1 VV 0 Melting Point 4-(4-fluoronaphth-1-yl) )-6-(2-hydroxy-2-phenethyl) -2-methylaminopyrimidine, (iCY TA, Y VFA) Melting point 4-(4-fluoronaphth-1-yl)- 6-phenethyl-2-methylaminopyrimidine hydrochloride,

Gy CITY, YO YY Melting Point Yo 4-(4-fluoronaphth-1-yl)-2-isopropylamino-6-methoxypyrimidine hydrochloride, YW#191.1-91 951.7 Melting Point

2-(dimethylaminoethyl)amino-4-(4-fluoronaphth-1-y1) -6-isopropylpyrimidine hydrochloride,

Gy ALYY, 0 Melting point 4-(4-fluoronaphth-1-y1)-6-isopropyl-2-(methylamino ethyl)amino-pyrimidine hydrochloride, °C#1 0-9107 Melting point 4- (4-fluoronaphth-1-y1)-6-(2-hydroxypropyl) -2-(methylamino)ethylamino-pyrimidine hydrochloride,

Ah GP Va —CY Yo Melting point 2-(2-hydroxyethyl)amino-4-(4-fluoronaphth-1 -yl)-6-methoxypyrimidine Ye hydrochloride, iothem” 111,1-9191,73 Melting point ‎ 6-tert-butyl-4-(4-fluoronaphth-1-yl)-2-methylamino-pyrimidine,

Gua Feo YALE Melting Point 2-benzylamino-6-tert-butyl-4-(4-fluoronaphth-1-yl)-pyrimidine, Yo $A 82) 0 LAY 56,7 Melting Point 6-tert-butyl -4-(4-fluoronaphth-1-yl)-2-isopropyl amino-pyrimidine hydrobromide, Melting point 4-(4-fluoronaphth-1-yl)-6 -isopropyl-2-(pyridin-4 -yl)methylamino-pyrimidine, 3541021 £4,001 49,1 Melting point 2-(2-amino)ethylamino-4-(4-fluoronaphth-1 -yl)-6-isopropyl fusion Aki Yo 4-(4-fluoronaphth-1 -yl)-6-isopropyl-2-(4-methoxyphenyl)methylamino-pyrimidine hydrochloride

Y¢ Melting Point 7-975>4-(4-fluoronaphth-1-yl)-2-(tetrahydro-2-furyl)methylamino-6-1 sopropyl-pyrimidine, Melting Point 77,8- 977.7"C; 4-(4-fluoronaphth-1-y1)-2-(2-hydroxyethyl)amino-6-isopropyl-pyrimidine maleate,

GUAR) £010), 8 M. Melting point 4-(4-fluoronaphth-1-y1)-2-(2-hydroxyethoxyethyl)amino-6-isopropyl-pyrimidine hydrobromide, $A ACV VTL Y=01 YOY point Fusion 2-(1,3-didhydroxyprop-2-yl)amino-4-(4-fluoronaphth-1-yl)-6-isopropyl-pyrimidine maleate, Ya;Yutham”077,1-917 5,73 Melting point 2-amino-4-(4-fluoronaphth-1-yl)-6-(2-methoxyethyl)pyrimidine maleate, 38%) 020 Melting point 2-amino-4-(4-fluoronaphth-1- yl)-6-phenethylpyrimidine maleate,

AAC) 45-91 65 Melting point 1 4-(4-fluoronaphth-1-y1)-2-(2-hydroxyethyl)amino-6-isopropylpyrimidine bromide, and yotham” 11,7-©11 0 F Melting point 2-(2-aminoethyl)amino-6-tert-butyl-4-(4-fluoronaphth-1-yl)-pyrimidine fumarate,

Au) TY, 0-0 TY melting point

Other NHRAR® amines optionally replace ethylamine in a similar manner; By substituting (=) + optionally a 4-(4-fluoronaphthl-yl)-6-isopropyl-2-methanesulfonylpyrimidine and by following the procedures of example 8a above, other compounds (VA) are prepared in place of other compounds of the formula ,

J of the formula is hydrogen is R? "isopropyl is R!" Alternative preparation of compound 1 in which (3) hydrogen s” is phenyl hr R* (naphth-1-yl +0). (4-fluoronaphth-1 -yl)-6-isopropyl-2-methanesulfonylpyrimidine yo Licover 9070 No solvent at higher temperatures Aged Melting point «4-(4-fluoronaphth-1-yl)-6- isopropyl-2-phenylaminopyrimidine Ard 1-9 R/"C. Example I of a compound of formula N-oxide preparation ° + aR' hydrogen is R? methyl fer R! of formula 1 wherein the N-oxide preparation (1) hydrogen is R' 3 R* 5 cnaphth-1-yl milliliters Yo g) in 57 A) 2-amino-6-methyl-4- (naphth-1-yl)-pyrimidine (.; g) is dissolved into .4 (m-chloroperbenzoic acid) at zero Celsius. The chloroform solution is added in batches within * minutes. After the completion of the addition.; the solution is warmed to ‎ 0

J+ aqueous sodium thiosulfate min. The solution was washed with 01 for 0 day sodium sulfate a gram molecular chloroform difference; and water. 1 layer of sodium hydroxide was dried to give diethyl ether/ethyl alcohol and concentrated; The solid residue recrystallized from melting point (aa +, + VY) 2-amino-6-methyl-4-(naphth-1-yl)-pyrimidine-1-N-oxide

A AOTYA,0-0V YAY ao place 2-amino-6-methyl-6-(naphth-1-yl)-pyrimidine (b) in a similar manner; by substituting the N-oxides and following the procedures of Example 4a above. Of other compounds are brought from the formula

H of formula 2-amino-4-(4-fluoronaphth-1-yl)-6-isopropylpyrimidine-3-N-oxide, yum” 084-91/878 Melting Point - © 2-amino- 6-tert-butyl-4-(4-fluoronaphth-1-yl)-pyrimidine-3-N-oxide, ge) 40, 4—0Y AAT Melting point 2-amino-4-(4-fluoronaphth-1 -yl)-6-isopropylpyrimidine-1-N-oxide hydrochloride, 7*C;VAY 17 Melting point 2,6-diamino-4-(naphth-1-yl)-pyrimidine-1-N-oxide , Yo (4, 5i0Y00,0-°Y0 8,1, melting point 2-amino-4-(4-fluoronaphth-1-yl)-6-isopropylpyrimidine-1-N-oxide,

Youtham #1 50-0157 Melting Point 2-amino-4-(4-fluoronaphth-1-yl)-6-isopropylpyrimidine-3-N-oxide, (a2 ACV AA) Melting Point 4-(4 -fluoronaphth-1-yl)-6-isopropylpyrimidine-2-methylamino-1 -N-oxide,

58 ACYAY, 0 AY Melting point 0 2-amino-4-(acenaphthen-5-yl)-6-isopropylpyrimidine-1-N-oxide,

Melting point As AE, YAY, (=) in a similar manner; by substituting 2-amino-6-methyl-4-(naphth-1-yl)-pyrimidine for other compounds of formula i and following the procedures of Example 18 above.” N-oxides prepare Jamal 0 compounds

E.g. 01 preparation of compound of formula 1 where R'hr is alkenyl § hydroxyalkyl (a) preparation of ] where R! is 1-hydroxy-1-methylethyl see dsopropenyl 182 is < hydrogen by passing anaphth-1-yl with two precipitants (hydrogen vo) added (YY) trifluoroacetic anhydride, + mL lle 1,900 mol) to a solution of A) 2-amino-4- (4-fluoronaphth-1 -yl)-6-isopropylpyrimidine-3-N-oxide ng; 284A, + milligrams) in methylene chloride (© milliliters) at room temperature. The mixture was stirred for 54 hours at room temperature and then poured into 1 N aqueous sodium hydroxide. the organic layer is removed; Concentrate by aspiration by thin layer chromatography primer 0 Administer a mixture of: 2-amino-4-(4-fluoronaphth-1-yl)-6-(1-hydroxy-1-methylethyl)-pyrimidine can +, 0 ET) | 779); Melting point 181*-840" aggie; and 2-amino-4-(4-fluoronaphth-1-yl)-6-isopropenylpyrimidine (000+c777); melting point 0-0178 Aggie) ve (b) In a similar way, by replacing 2-amino-4-(4-fluoronaphth-1-yl)-6-isopropylpyrimidine-3-N-oxide

Replace other N-oxides of formula 1 compounds by following cel a) example !01 above. Other compounds of formula 1 where .alkenyl hydroxyalkyl sa R' are prepared as 11 Conversion of compounds of formula 1 where RYH RZ RY are as specified in the general description of the invention; R',R*,° are hydrogens to other compounds of the dye RY J and/or 18 different (a) preparation of 1 wherein RY is in R® acetyl ether hydrogen dissolved 2-amino-4-(4-fluoronaphth-1 -yl)-6-isopropylpyrimidine (°, + g) in 10 ( acetic anhydride mL) and add (Yo)4-dimethylaminopyridine (+ g). The reaction mixture was stirred overnight at room temperature; then heated at 75*"C to 0+8"C for 0 total time; hours; It evaporates to dryness by vacuum. The residue was divided between ethyl acetate water and then dried over magnesium sulfate. The diacetyl compound was isolated as oil by evaporation and then dissolved in (10 milliliters) methanol. The solution was treated with a saturated sodium bicarbonate solution (? milliliters) and left to stir overnight. The resulting 01 derivative is evaporated to dryness by vacuum drying. The residue was raised in boiled ve hexane and decanted from an AL amount of insoluble residue and crystallized to yield 2-acetylamino-4-(4-fluoronaphth-1-yl)-6-isopropylpyrimidine Jaa point Aga) 17-1164 in a similar manner; May react: 2-amino-4-(4-fluoronaphth-1-yl)-6-isopropylpyrimidine-1-N-oxide 0 | with acetic anhydride to give a monoacetyl product directly of formula J 2-acetylamino-4-(4-fluoronaphth-1-yl)-6-isopropylpyrimidine-1-N-oxide," HNMR (200MHz) , J 1.39(d,6H), 2.51(s,3H), 3.81(m,1H), 7.21 7.27(m,2H), 7.62-7.68(m, 3H), 8.10-8.23(m, 1H) (b) Preparation of 1 where methanesulfonyl Lea RPG RY Yo dissolves ,7174( 2-amino-4-(4-fluoronaphth-1 -yl)-6- isopropylpyrimidine g) in (Yo) dichloromethane mL) and cooled to Af joa triethyl amine (0,+ mL) was added to the solution and (ull +,)Y) methanesulfonyl chloride was added dropwise

Ya

milliliters). After stirring the mixture for 10 minutes; Add successively (©) dichloromethane in (tl methanesulfonyl chlorides mL) +,Yo ) triethyl amine from the -al individual fresh product fraction. tle minute evaporates The process is repeated and the 11 milliliter test appears. After filtering with silica gel the reaction mixture to dryness and purified by ether-hexane chromatography. The colorless crystalline substance is recrystallized from acetate lads © «2-(bis-methanesulfonyl)amino-4-(4-fluoronaphth-1 -yl)-6-isopropylpyrimidine 3 sul

Ags) EE, YC 4.48 mg); The melting point (YO £) hydrogen and p-methanesulfonyl is R* Preparation 1 where (=) melts product: 2-(bismethanesulfonyl)amino-4-(4-fluoronaphth-1-yl)- 6-isopropylpyrimidine Ve milliliters) and treat at room temperature (©) methanol g) in Sel +, Y + £) for example in 01 milliliters). The reaction mixture was stirred at a temperature of 1,7 N (¥,0 sodium hydroxide) with a solution of ethyl acetate 5 N 1 hydrochloric acid in the room for one hour. The mixture was divided between, evaporated to dryness and recrystallized. magnesium sulfate The organic layer was dried over 2-(methanesulfonyl)amino-4-(4-fluoronaphth-1-yl)-6-isopropylpyrimidine ligqsover ve (uso Y VY as a crystalline material; melting point 7716,4-9717/ 16"C (before hydrolysis at hydrogen R' and phenylamido (D) preparation [1 where MH is mg] in YAA, Y) 2-amino-4-(4-fluoronaphth) (-1 -yl)-6-isopropylpyrimidine Dissolve reaction Jay 18 mg. Heat 11 4, phenyl isocyanate (ml) and add benzene with re-condensation for 8 hours and remove solvent by vacuum hydrolyzed oY to yield ethyl acetate/hexane with Lia ills silica gel residue chromatography on mg) 49.1( 1-[4-(4-fluoronaphth- 1-yD) -6-isopropyl-pyrimidin-2-yl]-3-phenylurea

AY YAOI Y Melting Point 11 Example “4-fluoronaphth-1-yl is 9 dsopropyl is R! An alternative conversion of formula 1 compounds where n is Yo . to other compounds of formula [1] or different 183 hydrogen substituents are 4-fluoronaphth-1-yl and is bromo (a) preparation 1 where th 1 is 777 p va (base 2 -amino-4-(4-fluoronaphth-1-yl)-6-isopropyl-pyrimidine To a solution of 01 mL) iron powder (0.007 g) (carbon tetrachloride g) is added in 1001 f; g) at room temperature. The reaction mixture was stirred at room temperature (+, VE) bromine in milliliters). The V+ (saturated; sodium bicarbonate) was separated for one hour; after that it was decanted in mL solution. \ + XY) methylene chloride layers and the aqueous layer was extracted three times with oo evaporated. United organic layers until dry. The residue was purified by layer chromatography to give hexane/ether and recrystallized from cethyl acetate/hexane by filtration with a thin (gael) gm point 77 (2-amino-5-bromo-4-) 4-fluoronaphth-1 -yl)-6-isopropyl-pyrimidine

AAA OY Fusion 4-thiomethylnaphth-1-yl is hydrogen oR? (b) Prepare 1 in which 0 g) in YM) 2-amino-4-(4-fluoronaphth-1-yl)-6-isopropyl-pyrimidine dissolves +,+Y +) sodium thiomethoxide milliliter) and add (10 (DMSO) dimethyl sulphoxide g). The reaction mixture was stirred at room temperature for two hours, then another equivalent of milliliter (001) was added and the reaction was stirred for another two hours. The mixture was poured into milliliters of thiomethoxide water. The extracts were dried (0.XY) hexanefethyl acetate and the product was extracted in Ne and evaporated to dryness. The reaction product was purified by resolving sodium sulfate inorganic conjugates over to give ethyl acetate/hexane by eluting with silica gel column chromatography over g (0.0 ¥ drop) 2-amino-4-(4-methylthionaphth). -1 -yl)-6-isopropylpyrimidine ug) £00 FA Fusion 4-aminonaphth-1-yl is rR} and hydrogen is R? (c) Preparation of 1 where Yo is g) in +,YAA) 2-amino-4-(4-fluoronaphth-1-yl)-6-isopropyl-pyrimidine dissolved g). The mixture was brought to +, (YAA) sodium azide mL) and (©) N-methyl pyrrolidinone was added h. After cooling, the reaction mixture was poured into VT sad at a temperature of 1000 *C under an inert atmosphere (mL). The layer was dried (Yo XY) ethyl acetate with water (04 mL) and the reaction product was extracted with and evaporated to dryness. The product was purified by column chromatography on organic sodium sulfate over Yo tert-butyl methyl ether and recrystallized from cethyl acetate/hexane by filtration with silica gel.

Ae (gm) point +0) 2-amino-4-(4-aminonaphth-1-yl)-6-isopropyl-pyrimidine to give AAC ATV AC fusion 2-amino-4-(4 -fluoronaphth-1-yl)-6-isopropyl-pyrimidine (d) in a similar manner; by substituting del preparation C11 or B11VY and following the procedures of example J with other compounds of formula

Jaspal other compounds of 1 0 eg p] is hydrogen but dsopropyl is the R! Substitute conversion of a compound of formula 1 where the different 13 oI to compounds of formula 2-aminoethyl is rR and “4-fluoronaphth-1-yl 2-(methanesulfonamido)ethyl sa RY (a) Preparation 1 wherein 2-(2-aminoethyl)amino-4-(4-fluoronaphth-1-yl)-6-isopropylpyrimidine to a solution of Ye methansulfonyl chloride is added dropwise to a solution of diethyl ether dissolved in (p > 0 f) The reaction is carried out at room temperature.; After an hour, ether (g) in +, 10) methylene chloride is reduced. The raw material is raised in one Jar wim, the solvent is removed under, the organic layer is dried, sodium carbonate, the free base is released by adding a solution, and the reaction product is isolated by evaporation; Purified by chromatography magnesium sulfate above 0 to give hexane [ethyl acetate with dia 3 (silica gel perpendicular to .2-(2-methanesulfonamidoethy!)amino-4-(4-fluoronaphth-1-yl) )-6-isopropylpyrimidine

C) A353) —°A0 g)melting point +, VA+) From the product hydrochloride salt (ZV, 6A N atv 11 tphal (b) is made in a similar way; by substituting: Ye 2- (2-aminoethyl)amino-4-(4-fluoronaphth-1-yl)-6-isopropylpyrimidine following «2-(2-aminoethyl)amino-6-tert-butyl-4-(4-fluoronaphth-1- yl)-pyrimidine (place above).

AAV TY Y= TY,4 Melting point (c) in a similar fashion; By replacing:

A) 2-(2-aminoethyl)amino-4-(4-fluoronaphth-1-y1)-6-i sopropylpyrimidine Optionally in place of methanesulfonyl chloride and by substituting oJ in place of other compounds of the formula Other compounds are prepared from coded IVY Other" and following the procedures of the examples sulfonyl chlorides

J Formula 06 Example: aR hydrogen Are they R'R? isopropyl is R! Substitute conversion of a formula 1 compound where

R* I to a compound of formula 2-propionic acid methyl ester is R*; “4-fluoronaphth-1-yl dissolves: 0 2- [6-isopropyl-4-(4-fluoronaphth- 1-yl)pyrimidin-2-ylamino]-propionic acid methyl Ve ester ethanol (777) and is exposed to waves Sonication in an ultrasonic bath methyl amine in solution for ? hours. The solution was evaporated to dryness and removed in 00608001. Sufficient water, 2 silica gel, columnar chromatography impurity reaction product, Lad, was added to cause crystallization. Water is purified to give: /methanol and recrystallized from methanol/methylene chloride by filtering with 1 2-[6-isopropyl-4-(4-fluoronaphth-1-yl)pyrimidin-2-ylamino] -N- methylpropionamide,

AAR) 47-91 41.1 Melting point (b) in a similar fashion; by replacing: 2-[6-isopropyl-4-(4-fluoronaphth-1-yl)pyrimidin-2-ylamino] -propionic acid methyl Ye ester in place of: 2-[6-isopropyl-4-acenaphthen-5 -yl)pyrimidin-2-ylamino]-propionic acid methyl ester, above. A compound is prepared: NE JA, following the procedures of ve 2-[6-isopropyl-4-acenaphthen-5-yl)pyrimidin-2-ylamino] -N-methyl-propionamide, melting point 1069-91707.

AY

(c) in a similar manner; By substituting: 2-[6-isopropyl-4-(4-fluoronaphth-1-yl)pyrimidin-2-ylamino]-propionic acid methyl ester or optionally amines in place of methyl amine and by substituting of in place of compounds other than Formula 1 above. Other compounds of Formula IVY are secondary preparations; and by following the procedures of examples © 1 Ji to other compounds of hydrogen and let them be RY an alternative conversion of the compounds of formula 1 where hydrogen and p is 2-propionic acid methyl ester R* of formula 1 where is To other compounds of hydrogen compounds of formula 1 wherein 18' and 18 are are may be converted by following the hydrogen form 2-propionic acid methyl ester is RY of formula 1 wherein 0 is the procedure described in :,

Alcaide, Benito et al., J. Org. Chem., 55, 3143-3147 (1990): 2-(6-isopropyl-4-(4-fluoronaphth-1-yl)-pyrimidin-2-ylamino)-propionic acid methyl ester maleate,

LALIT 4,5-9177,7 Melting Point Yo 2-(6-isopropyl-4-(4-fluoronaphth-1-yl)-pyrimidin-2-ylamino)-propionic acid, Ag Al VF V0, Melting point 2-(4-acenaphthen-5-yl-6-isopropyl-pyrimidin-2-ylamino)-propionic acid methyl ester, melting point ©,/97,7-9/87"home; v. 01 Example This example illustrates the preparation of a representative pharmaceutical formulation for oral administration containing an active compound of 2-amino-4-(4-fluoronaphth-1-yl)-6-isopropylpyrimidine. Formula for example Quantitative ingredients per tablet mg

You are an active compound

YEA Spray Dried Lactose

Y Magnesium stearate The above ingredients are mixed and inserted into a hard-walled gelatin capsule.

AY

This preparation according to the examples)—0 1 can be used Jie of Other compounds of the formula as the active compound in. Preparation of oral formulations from this example.‎ 101 Examples of Oral Administration 'Contain an Active Compound IT' This example illustrates the preparation of another representative pharmaceutical formulation. 2-amino-4-(4-fluoronaphth-1-yl) -6-isopropylpyrimidine «Je 1] of Formula © active compound F or cornstarch maize Lis \¢o Lactose ° Magnesium stearate —— The above ingredients are thoroughly mixed and pressed into individual grooved tablets. May be used 15-1 This ABU prepared according to Jiao Other compounds of the formula as the active compound in the preparation of preparations that can be administered orally from this example.

YA Example Example (J This example illustrates the preparation of a representative pharmaceutical formulation containing an active compound of formula Ye. .2-amino-4-(4-fluoronaphth-1-yl)-6-isopropylpyrimidine Prepared as a suspension for administration Orally, it has the following composition: —————————— Under Ingredient Quantity __ttbsssssssplbl_______ b______ aat tt!l sa 1 g Active Compound g © Fumaric acid aa ¥ Sodium chloride g Methyl paraben 1 g Yo,0 granulated sugar granulated sugar g VY,A0 (V+) sorbitol solution 1 g (Vanderbilt (Veegum K) 8 ml flavoring) mg © colorings of coloring materials 100 milliliters sufficient for distilled water mmssssssssssssssssssld..mssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssss There is no SSA such prepared according to Examples 1-15; other compounds of formula I<I can be used as the active compound in the preparation of oral formulations from this example. 10? Example \o Example ( J This example illustrates the preparation of a representative pharmaceutical formulation containing an active compound of the formula: 2-amino-4-(4-fluoronaphth-1-yl)-6-isopropylpyrimidine p777.

You are preparing an injectable formula whose pH is fixed at; It has the following formula: ee se — quantitative ingredient — active compound 0” g pH stabilizer solution sodium acetate (£,+ ¥ mM): (ste 1) HCI amount Water (sterile ¢ distilled) in sufficient quantity up to 0 milliliters Other compounds of this Formula 1 Jie prepared according to the examples herein may be used as the active compound in the preparation of the injectable formulations of this example. © This example illustrates the preparation of a representative do-a formulation for topical use containing an active compound of formula 2-amino-4-(4-fluoronaphth-1-y1)-6-isopropylpyrimidine «Je < I . Quantitative ingredients - Active Compound Yo—o X Span 60 Y : Tween 60 Mineral oil mineral oil ° Petrolatum B Ve Methyl paraben Propyl paraben 00 (butylated hydroxy anisole BHA ) 0 water sufficient quantity up to 100 milliliters t_a #ltssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssss. Maas add enough water at iT, stirring vigorously, to emulsify the ingredients; Then add enough water until You g. Other compounds of formula of such as this prepared according to examples (=0)¢ may be used as the active compound in the preparation of topical formulations from this example. Example YY This example illustrates the preparation of an analog pharmaceutical formulation Sad on an active compound of formula (J eg. 2-amino-4-(4-fluoronaphth-1-yl)-6-isopropylpyrimidine B) prepared The suppository has a total of V0 g and has the following formulation: nt: rces ssds sossomm...cm sso-rsosssr,.a [EIT Ingredients ee — Active Compound Ow mg Witepsol H-15* The rest is 77 p

blood triglycerides * of saturated vegetable fatty acids; Produced by: Riches-Nelson, Inc., New York, N.Y. Other compounds of formula [; Jie prepared according to examples (Vo) can be used as the active compound in the preparation of suppository formulations from this example. Example: YY receptor binding test 5-1112 Jil cloned The following description of the in-vitro binding test using 5-111 receptors cloned and labeled with a radioactive substance such as [PH]-SHT

The primary fibroblast cell NIH;T; J showing the cloned 5-HT,p receptor preserved in medium

Dulbecco's Modified Eagle 0 with 701 Fetal Calf Serum and 1050 7 µg/mL 8 in 02/78/15// .CO;, cells were harvested using ¥ mM EDTA in solution

Saline pH stabilizer (magnesium/calcium phosphate) free) and centrifuged (+64

specific gravity). Homogenize the cell pellet using ruptured Polytron P10 (© mode; © seconds) in a fixer

Homogeneous pH 000 (Tris) mM; NaEDTA © milligram)

1 This homogenizer is centrifuged at 19.0 rpm using a Sorvall/Dupont RC5C with a 5534 JB 1800-7” 01 (type” 11 minute rotor). Homogenize the pellet (mode ©sec) in

Homogeneous pH Stabilizer and Homogeneous Centrifuge (EAs meen) specific gravity; 01 minutes). Homogenize the pellet (© mode; © seconds) in resuspension pH buffer (Tris) 50

Jl gram molecular; 15 mM EDTA (EDTA) Centrifuged Homogenizer (2000?*-

EA Ye specific gravity; VO min). Homogenize the pellet (© setting) in a small volume of resuspension pH buffer to give approximately AY Yo cells/mL. The membranes are separated into sections

1 mL complete and stored at -<76*C.

The films were released at room temperature and diluted with test pH buffer “2H,0) calcium chloride £0 mM; (Tris 00 milligram; 7001

(ascorbic acid ve binding is specific to at least 7460 complete binding with NY ex),0 cells

for each test tube. The membranes are homogenized (© mode; 0 sec) and the homogenate is then added to a test tube

Contains 5111-[311] 01017 (Molecular) of test compound (10H1-;

M) and test pH stabilizer (add sufficient amount up to 00000 μl). The test mixture was incubated at 46* dehydrated for 2 hours, then zn on a polyethyleneimine 70.11 pre-treated glass fiber filter using Brandel Cell Harvester. The test tubes were rinsed with a cold test pH stabilizer and dried with air drawn over the filter for 10 seconds. . The radioactivity retained on the filters is determined by a liquid scintillation counter. For each tested compound the concentration yielding 0.729 in inhibition of binding (IC50) can be determined using an appropriate iterative (nie) technique. Following the procedure in Example 77, compounds of the invention are found to have an affinity for the WR5-117 receptor. Example YrVe 5-111 Receptor Binding Methods 5-HTyg 5-111 The following describes receptor binding methods in which the ligand has a high affinity for 5-1119 receptors and is blocked at Mo5-111 and M5-111 receptors to determine their selectivity. 5-1112 with [3H]ketanserin in the human neocortex; in Cos-7 cells expressing the human cloned m5-111 receptor and in NIH-3T3 cells expressing the mouse m5-117 receptor. Jal ve Competitive binding studies the binding concentration is about 1.1 nM For saturating binding studies the radioactive bond concentrations range from 0501 nm to ?nM The test is performed in 9 milliliters of test pH buffer containing 0 mL mM 1101-1118 mM calcium chloride and 1.1 7 of ascorbic acid (pH 7.4 die *C). ketanserin is unmarked. After 10 min incubation at ATT the membranes were harvested onto filters treated with 75001 polyethylenimine and associated radioactivity assayed. Learning of human 5-HT,p receptors in 008-7 cells; as previously described above except The radioactive bond is 311[5-111] and the test pH stabilizer contains 01 mM pargyline and + Lascorbic acid, for competitive binding studies the radioactive bond concentration ve is approximately 1.46 nM gram while in saturated binding studies the concentration of 5-117 [BH] ranges from 8 to nMg A. Non-specific binding is determined with 01 mM of 5-7. The incubation is 171 min at ? Centennial. 777 p

AY

in HT) showing Cos-7 receptor learning receptor 5-1172 in the choroid plexus; Human cells and V11111-373 show the receptor 171-5 of the mouse. The test is conducted as previously described for the receiver MO 5-111 except for the radioactive bond which is 06:p311[0069016]. The concentration of the radioactive bond is in a nanoparticle, while in the saturated binding studies it ranges from 1.7 in competitive studies to about 101 nanograms. Non-specific binding with 08 to 1.1 concentration is defined from 0 unclassified. Gram mesulergine from analysis of competing radioligand binding data using ; Measurements of a logarithmic equation and a curve set from (Say kd) Hil values and the regression range of ICs is iterative suitable for the techniques to obtain an amount of (Ki) The radioactive correlation studies used are then used to calculate the dissociation inhibition constant of the compounds of the invention that It was found to have an affinity for the VY receptor arising from it as in the example of Ye 5-HT,g

Ye As 5-HT,p receptor tissue-based functional test in (5-HT,p follows in vitro functional test to distinguish 5-117 receptors (presumably Led) describes the longitudinal muscle of the gastric cavity Rat: vo (Baxter et al., (1994), Brit. J. Pharmacol., 112, 323-331).

Sprague Dawley Longitudinal muscle segments can be obtained from the gastric cavity of rodents

Tyrode g in solution 1 male. The lining mucosa is removed and the slides are attached with static tension as follows (mM Tyrode’s) at 717”C. The composition of a solution (CO; 75/0 140) is oxygenated NaHCO; R; glucose 1; MgCl, ¢+, ¢ NaH,PO4 ¢Y,Y KCl (4 NaCl): 7 (08) CaCl, 11,9. Concentration-response curves are constructed for antigens of the 5-111 receptor under inactivation conditions. And quenching dindomethacin activities by? Micromolecular cyclooxygenase activities mM; and suppression of absorption mechanisms 11 pargyline by µg monoamine oxidase. Yo corticosterone s 01 µm cocaine by Ye

AA

The effects of the drugs are monitored with voltage transducers and recorded on a double chart recorder. The tissue response is measured as changes in isometric tension (g). The arithmetic mean of efficacy and maximal response are evaluated by standard frequency curve matching procedures.(ECs) Effects of antigens are determined by measuring shifts to the right of the antigen concentration-response curve after antibody equilibration for at least one hour. The concentration ratio is measured at half-maximal response levels, eo, and the affinities for a monoconcentrated antagonist are determined by the equation: With many concentrations, Schild regression analysis is used. (VS A [antagonist concentration]/(ratio = KB) of the antagonist when the compound exhibits competitive behavior. Compounds of the present invention were found to be antagonists of the YE receptor by following the procedure in an example when tested in this way. |0

Yo Ji Anxiolytic Behavior Test The following describes an in vivo method for determination of anxiolytic activity by measuring the effect of a drug on the normal anxiety of rats when exposed to a novel environment such as brightly lit. 2 rats per 10 g in groups of 70- 18 0581/61 Untrained GN Male yo kept in sound, temperature and humidity controlled chambers. Water and food are available upon request. Phthran is kept in 1 hour of darkness and 1 hour of light, respectively; And the light from + morning ends + evening. VY begins the cycle of all trials at least 7 days after arriving at its place. An automatic device to indicate changes in detection can be obtained from

Crawley and Goodwin, which is similar to the device from Ommi-Tech Electronics Columbus Ohio 0 and others. Previously mentioned. Briefly, the chamber is made of Kilfoil as described in (VAL) a glass box (1*717464?cm); It is divided into two compartments by a black glass partition. It contains poison where the mouse can pass through it easily. Room 5707 The partition dividing the two rooms on a dark (hy £1) hatch has transparent sides and a white floor. A fluorescent lamp is placed on top of the room

Digiscan Animal Activity Monitor System 2020720416 To give illumination only. Recording © inside the test room. of ull Exploratory Activity (Omni-Tech Electronics)

Before we start the study, we give the catharsis 60 minutes to acclimate to the laboratory environment. After receiving the mouse, we return it to Jala. Either the tested compound or Cus (1.0) medium is injected into the peritoneal membrane of Jala into its cage for 10 minutes after the treatment period. Then the mouse is placed in the middle of the lighted room and observed for a period of time. Minutes 0 We see a general release of stress with an increase in exploratory activity in the lighted area Increased 8 exploratory activity appears in an increase in latency (the time it takes for the mouse to move into the dark room when first placed in the middle of the lighted area) with an increase in activity back and forth An increase or absence of a change in motor activity (the number of intersecting interwoven lines) and a decrease in the time of staying in the dark section. It was found that the compounds of the current invention improve stress-relieving behavior.

YJ - The Withdrawal Anxiety Test follows an in vivo method to determine the improvement of symptoms that may be caused by withdrawal of addictive Led substances by measuring the effect of the drug on the anxiety of mice after chronic treatment with addictive substances, and then suddenly stopping treatment. Of ten in Cle gana untrained male Phthran 11617 (©70-7 g) are caged in vo each chamber regulated for sound, temperature and humidity. Water and food are available upon request. Ideas + keep an hour of light and an 11 hour dark cycle respectively; And light from 7 AM to VY in the evening cycle. All trials begin at least 7 days after reaching their location. (kil) Goodwin s Crawley Anxiety levels are assigned a two-part model for exploration from Anxiety removal appears as a general increase in exploratory activity in the illuminated region. The increase in exploratory activity (VE JBe Ye moving into the room ll) is reflected by an increase in the latency period (the time required to be dark when first placed in the center of the lighted area). The increase or absence of a change in locomotor activity (number of intersecting lines) An increase in the number of times it rises to the top and the time of its stay in the dark section decreases. A day with VE for a period of J. An increase in exploratory activity in the bright area can be induced by treating Yo kg; in the peritoneum / 010 mg (nicotine) weight/volume in drinking water); A) ethanol, mg/kg peritoneal membrane twice a day). Determine the removal of stress (V) cocaine twice a day) or,

AR

On FO) 7 and 1 day after starting the drug regimen. Abruptly stop treatment and show exploratory activity in the illuminated area after EAS YE GA 1 hour. The carrier media or test compounds are administered during the withdrawal phase by intraperitoneal injection. Responses to ia inhibition or reduction of stressful behavior that occurs after cessation of treatment with cocaine cethanol or .nicotine 0. Following the procedure in the example of YT, the compounds of the present invention show improvement in symptoms resulting from withdrawal of the administered addictive substances. Such as YY pain test v. The following describes a procedure in the all body to determine pain relief especially inflammatory pain; By measuring the effect of compound(s) of the present invention on rat response to an animal palm pressure test with -carrageenan, male Sprague Dawley rats were kept with free access to food and water for at least seven days prior to use. GEN was weighed and randomly allocated to treatment groups. Carrageenan Lambda (vegetable gelatin; Irish moss) Type 17 is prepared in normal saline. Indomethacin is used as a reference material. The carrier used is DMSO 10 Jo propylene glycol and 660 water 7. Dose the ophthran (ten per group) into the peritoneum ip. with a vector/saline solution 1 (mL/kg) Y) carrageenan/ jil milliliters/indomethacin “(paS) 1 mg/kg); or a compound ».of the present invention (0.7 mg/kg). Oj ll is slightly anesthetized with halothane and injected with carrageenan 71 in the left hind palm (on the plantar). The amount of force applied to the left hind paw of each rat was tested using an anesthesia meter three hours after carrageenan (fa). Following the example (VY), we obtained the average withdrawal pressure (in grams) for each of the treatment groups to determine the effect on hyperalgesia in the paw. carrageenan elicits a painful inflammatory response Yo in rats; as indicated by the lower mean withdrawal pressure compared to rats given vector/saline. Compounds of the present invention have been found to relieve pain symptoms associated with administration of

WS carrageenan is indicated by a significant increase in the mean withdrawal pressure compared to the mean withdrawal pressure for bulls given vector/saline solution. Although the present invention has been described with reference to its particular applications; Those skilled in the art must realize that many changes can be made and equivalents can be substituted without giving up the true substance and scope of the invention. In addition to ell many modifications can be made to suit a situation; material; important combination; Ales is a process step or steps with specific goals; The essence and scope of the present invention. All such modifications are intended to be within the scope of claims supplementing subject matter.

Claims (1)

ay protective agents for the treatment of a mammalian organism with a pathological condition that is relieved by treatment with an anti-Watazie 10 qt-1 1 ::] and includes giving a mammalian organism in need of treatment a therapeutically effective amount of a compound of formula Y F R Na Teh 0.) : UN R 1 ; 0 where: “cycloalkyl <hydroxyalkyl lower alkoxy” alkyl hydrogen gu rR! ° «-NR°R' «fluoroalkyl <halo lower thioalkoxy «alkenyl »cycloalkyl lower alkyl or halo alkoxy ¢hydroxy optionally substituted with lower alkyl or -O(CHp)R' -COR® 7 taryl A Which is in it: 9 is 1-7-or ??; and alkyl or hydrogen is R® VY or lower alkenyl “hydroxy lower alkyl chydroxy lower alkyl hydrogen is R’ VY ‘lower alkoxy 4 slower fluoroalkyl <halo lower alkoxy ower alkyl <hydrogen sa R? Yo ¢furanyl 4 “thienyl pyridyl optionally substituted other than aryl p is” 8 “amido “amino cacyl” alkenyl “cycloalkyl dower alkyl hydrogen in R* 7 amino mono Jaf” amino “amino optionally substituted with lower alkyl or aryl p “alkoxy carbonyl “amido lower alkoxy” aryl “carboxy <hydroxy substituent dibasic 04 ¢sulfonamido i.e. <hydroxyalkoxy ctetrahydrofuran-2-yl | 0:1076? alkyl That is, hydrogen Hr R' 71, provided that: YY 777 p. av R*r 2,3-dihydroindol-1-yl § «indol-1-yl naphthyl is 183 is Laie (V) YY ¢methyl not RY the hydrogen of which is JS R', 4 ¢NR°R” is not an R! the naphthyl or phenyl is 13 hr Laie (7) Yo Laie (9 7 is 13 is “phenyl so R? is not RZ5 R' 5 dower alkoxy is not ¢halo for 5) Laie is 13 is R's phenyl is 11 then 2 is Not smethyl Laie (5) YA be 13 is 4-tetrahydroquinolinyl 1,2,3< the 125.2 are ¢thydrogen Ya or salt or N-oxide pharmacologically acceptable thereof. 1*?- Method 0 of Clause (¢) where the pathological condition involves pain. 1 ?- method of Cus oF The pathological condition includes pain from an inflammatory Y source. 1;- The method of the protective element, oY, where the pathological condition includes pain from a nerve source, Y. 001 #- Method 0 of oF protection where the condition includes cancer pain. 1 +”- method of protection oY where the pathological condition involves acute pain. -V 01 method of claim F where Aad pathology involves chronic pain.