MXPA98007759A - Pyridines and pyrimidines fused with arilam - Google Patents

Abstract

Antagonists of the corticortropin releasing factor (CRF) of the formula (I) or formula (II), and its use in the treatment of anxiety, depression and other psychiatric and neurological disorders

Description

PYRIDINES AND PYRIMIDINES FUSED WITH ARILAMINO FIELD OF THE INVENTION This invention relates to new compounds and pharmaceutical compositions, and to methods for using same in the treatment of psychiatric disorders and neurological diseases including major depression, anxiety-related disorders, tension or traumatic disorders, supranuclear impotence and eating disorders.

BACKGROUND OF THE INVENTION The corticotropin release factor (referred to herein as CRF), a 41 amino acid peptide, is the main physiological regulator of peptide secretion derived from proopiomelanocortin (POMC) of the anterior pituitary gland [J. Rivier et al., Proc. Nat. Acad. Sci. (USA) 80: 4851 (1983) /. Vale et al., Science 213: 1394 (1981)]. In addition to its endocrine role in the pituitary gland, the immunohistochemical localization of CRF has shown that the hormone has a wide distribution REF .: 28377 extrahypothalamic in the central nervous system and produces a broad spectrum of electrophysiological and behavioral, autonomic effects, consistent with a role of neurotransmitter or neuromodulator in the brain [W. Vale et al., Rec. Prog. Horm. Res. 39: 245 (1983); G.F. Koob, Persp. Behav. Med. 2:39 (1985); E.B. De Souza et al., J. Neurosci. 5: 3189 (1985)]. There is also evidence that CRF plays a significant role in the integration of the response of the immune system to physiological, psychological, and immunological tensors [J. E. Blalock, Physiological Riviews 69: 1 (1989); J.E. Morley, Life Sci. 41: 527 (1987)]. Clinical data provide evidence that CRF has a role in psychiatric disorders and neurological diseases that include depression, anxiety-related disorders, and eating disorders A role for CRF has also been postulated in the etiology and pathophysiology of the disease of Alzheimer's, Parkinson's disease, Huntington's disease, progressive supranuclear impotence and amyotrophic lateral sclerosis since they are related to the dysfunction of CRF neurons in the central nervous system [for review see EB De Souza, Hosp. Practice 23:59 ( 1988).] In affective disorder, or major depression, the concentration of CRF increases significantly in the spinal, cerebral fluid (CSF) of the drug-free individuals [C.B.

Nemeroff et al., Science 226: 1342 (1984); C.M. Banki et al., Am. J. Psychiatry 144: 873 (1987); R.D. France et al., Biol. Psychiatry 28:86 (1988); M. Arato et al., Biól Psychiatry 28:86 (1988); M. Arato et al., Biol Psychiatry 25: 355 (1989)]. In addition, the density of CRF receptors is significantly decreased in the frontal cortex of suicide victims, consistent with hypersecretion of CRF [C.B. Nemeroff and collaborators, Arch. Gen. Psychiatry 45: 577 (198'8)]. In addition, there is a mitigated response of adrenocorticotropin (ACTH) to CRF (administered i.v.) observed in depressed patients) [P.W. Gold et al., Am. J. Psychiatry 141: 619 (1984); F. Holsboer et al., Psychoneuroendocrinilogy 9: 147 (1984); P.V. Gold and collaborators New Egn. J. Med. 314: 1129 (1986)]. Preclinical studies in rats and non-human primates provide additional support for the hypothesis with hypersecretion of CRF may be comprised of the symptoms seen in human depression. [R.M. Sapolsky, Arch. Gen. Psychiatry 46: 1047 (1989)]. There is preliminary evidence that tricyclic antidepressants can alter CRF levels and thus modulate the numbers of CRF receptors in the brain [Grigoriadis et al., Neuropsychopharmacology 2: 53 (1989)]. There has also been a postulated role for him CRF in the etiology of disorders related to anxiety. CRF produces anxiogenic effects in animals and interactions between benzodiazepine / non-benzodiazepine anxiolytics and CRF has been demonstrated in a variety of behavioral anxiety models [D.R. Britton et al., Life Sci. 31: 363 (1982)]; C.W. Berridge "and AJ Dunn Regul, Peptides 16:83 (1986).] Preliminary studies using the CRF a-helical putative CRF receptor antagonist (9-41) in a variety of behavioral paradigms demonstrate that the antagonist produces effects" as anxiolytics "which are qualitatively similar to benzodiazepines [CW Berridge and AJ Dunn Horm. Behav. 21: 393 (1987), Brain Research Reviews 15:71 (1990)]. Receptor binding, endocrine and neurochemical studies have demonstrated interactions between CRF and benzodiazepine anxiolytics that provide additional evidence for CRF involvement in these disorders Chlordiazepoxide attenuates the "anxiolytic" effects of CRF in both the conflict test [KT Britton et al., Psychopharmacology 86: 170 (1985 ), KT Britton et al., Psychopharmacology 94: 306 (1988)] and in the acoustic jump test [NR Swerdlow et al., Psychopharmacology 88: 147 (1986)] in rats. The benzodiazepine receptor (Rol5-1788), who was without behavioral activity alone in the operant conflict test, reversed the effects of CRF in a dose-dependent manner while the inverse benzodiazepine agonist (FG7142) improved the actions of the "CRF [KT Britton et al., Psychopharmacology 94: 306 (1988)]. The mechanisms and sites of action through which anxiolytics and antidepressants• normal produce their therapeutic effects and remain elucidated. However, there has been the hypothesis, that they are included in the suppression of hypersecretion of CRF these disorders are observed. Of particular interest is that preliminary studies examining the effects of the CRF receptor antagonist (a-helical CRF9-41) on a variety of behavioral paradigms have shown that the CRF antagonist produces "as anxiolytic" effects qualitatively similar to benzodiazepines [for review see G.F. Koob and K.T. Britton, in: Corticotropin-Releasing Factor: Basic and Clinical Studies- of a Neuropeptide, E.B. De Souza and C.B. Nemeroff eds., CRC Press p221 (1990) ] . The DuPont Merck PCT application No.

US94 / 11050 discloses corticotropin releasing factor antagonist compounds of the formula: and its use to treat psychiatric disorders and neurological diseases. Included in the description are pyridines and fused pyrimidines of the formula: where: V is CRia or N; Z is CR or N; A is CR or N; and D is CR28 or N. WO 95/33750 of Pfizer discloses corticotropin releasing factor antagonist compounds useful in the treatment of CNS disorders and stress. The description includes the compounds of the formulas: where A is CR7 or N; B is -NR1R2; R1 is substituted or unsubstituted alkyl; R 2 is substituted or unsubstituted alkyl, aryl or heteroaryl; R3 is methyl, halo, cyano, methoxy, etc .; R is H, substituted or unsubstituted alkyl, halo, amino, nitro, etc .; R5 is aryl or substituted or unsubstituted heteroaryl; R6 is H or substituted or unsubstituted alkyl; R7 is H, methyl, halo, cyano, etc .; R16 and R17 taken together form an oxo group (= 0); and G is = 0, = S, = NH, = NCH3, hydrogen, methyl, methoxy, etc. WO 95/33750 of Pfizer also discloses intermediates of the formula: where A can be N, D can be OH, R4 can be nitro, R19 is methyl or ethyl, Z can be NH or N (CH3), and R5 is substituted phenyl or substituted pyridyl, each substituted with 2 or 3 selected substituents from alkyl of 1 to 4 carbon atoms, chlorine and bromine. WO 95/34563 to Pfizer discloses corticotropin releasing factor antagonist compounds, which include compounds of the formula: where A, B and the R groups have definitions similar to those in WO 95/33750. WO 95/33727 to Pfizer discloses corticotropin releasing factor antagonist compounds of the formula: wherein A is CH2 and Z may be a portion of heteroaryl. U.S. Patent No. 4,076,711 to Ganguly et al. Describes triazolo [4,5-d] pyrimidines of the formula: where halo is I, Br, or Cl, Ph is phenyl and Me is methyl. The utility for the compounds is not described. Settimo et al., II Drug, Ed. Se, 35 (4), 308-323 (1980) describes 8-azaadenines (triazolo [4,5-d] pyrimidines) of the formula: where R1 is H or benzyl and R2 is p-methylphenyl. Biagi et al., II Drug, 49 (3), 183-186 (1994), describes N (6) -substituted 2-n-butyl-9-benzyl-8-azaadenines of the formula: where R2 can be alkyl, phenyl or benzyl. The article states that the compounds have affinity for adenosine receptors. Thompson et al., J. Med. Chem., 1991, 34, 2877-2882, describes N6, 9-disubstituted adenines of the formula: where Ph is phenyl or (when C-2 is unsubstituted) 2-fluorophenyl. The article states that the compounds have selective affinity for the Ai-adenosine receptor. Kelley et al. J. Med. Che. 1990, 31, 606-612, describes the compound: where R6 is NHC6H5 and R9 is CH2CSH5, and reports that the compound was inactive when tested for anticonvulsant activity. The article reports that several 6- (alkylamino) -9-benzyl-9H-purine analogs of the above compound exhibited anticonvulsant activity. Kelley et al., J. Med. Chem. 1990, 33, 1360-1363, describes 6-anilino-9-benzyl-2-chloro-9H-purines by the formula: where B-z is benzyl or (when R is H) p-methylbenzyl and R 4 is H or alkyl, slcoxy, halo, cyano, nitro, etc. The tests of the compounds for antirrinoviral activity are reported.

Kelley et al., J. Heteroeyelie Chem., 28, 1099 (1991), describes 6-its thiou-9- (3-formamidobenzyl) -9H-purines of the formula: where R1 is NH2 or NHCHO. The compound where R1 is NHCHO was tested for benzodiazepine receptor binding and was inactive, and several analogues were active. Khairy et al., J. Heteroeyelie Chem., 22, 853 (1985), describes the synthesis of certain 9-aryl-9H-purin-6-amines of the formula: where the R groups are H, methyl, ethyl, isopropyl, chlorine or fluorine.

BRIEF DESCRIPTION OF THE INVENTION This invention is a class of novel compounds which are CRF receptor antagonists and which can be represented by formula I or formula II: II or a pharmaceutically acceptable salt or prodrug form thereof, wherein: X is N or CR1; And it is N or CR2; Z is NR3, O, or S (O) n; G is O or S; Ar is phenyl, naphthyl, pyridyl, pyrimidinyl, triazinyl, furanyl, quinolinyl, isoquinolinyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuranyl, benzothienyl, benzthiazolyl, isoxazolyl, or pyrazolyl, each optionally substituted with 1 to 5 groups R5, R1 is independently at each occurrence H, alkyl of 1 to 4 carbon atoms, alkenyl of 2 to 4 carbon atoms, alkynyl of 2 to 4 carbon atoms, halo, CN, haloalkyl of 1 to 4 carbon atoms, -NR9R10, NR9COR10, -OR11, SH or -S (0) nR12; R2 is H, alkyl of 1 to 4 carbon atoms, cycloalkyl of 1 to 6 carbon atoms, halo, CN, -NR6R7, NR9COR10, haloalkyl of 1 to 4 carbon atoms, -OR7, SH or -S (0) nR12; R3 is H, alkyl d 1 to 10 carbon atoms, alkenyl of 2 to 10 carbon atoms, alkynyl of 2 to 10 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, or cycloalkylalkyl of 4 to 12 carbon atoms, each optionally substituted with 1 to 3 substituents independently selected in each occurrence from alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, halo, haloalkyl of 1 to 4 carbon atoms, cyano, -OR7, SH, S (O) nR13, -COR7, -C02R7, -OC (0) R13, -NR8COR7, N (COR7) 2, -NR8CONR6R7, - NR8CO = R13, -NR6COR7, CONR6R7, aryl, heteroaryl and heterocyclyl, where 'the aryl, heteroaryl or heterocyclyl is Optionally substituted with 1 to 3 substituents independently selected at each occurrence from alkyl of 1 to 6 carbon atoms, cycloalkyl of 1 to 3 carbon atoms, halo, haloalkyl of 1 to 4 carbon atoms, cyano, -OR7, SH, -S (O) nR13, -COR7, -C02R7, OC (0) R13, -NR8COR7, -N (COR) 2, -NR8CONR6R7, NRBC02R, -NR 6bpR1 ', and -CONR .6 ° -Rn7d is H, alkyl of 1 to 4 carbon atoms, allyl or Propargyl, wherein alkyl of 1 to 4 carbon atoms, allyl propargyl is optionally substituted with cycloalkyl of 3 to 6 carbon atoms and where alkyl of 1 to 4 carbon atoms is optionally substituted with -OR7, S (0) nR12 or -co2R7; R5 is independently in each occurrence alkyl of 1 to 10 carbon atoms, alkenyl of 2 to 10 carbon atoms, alkynyl of 2 to 10 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, cycloalkylalkyl of 4 to 12 carbon atoms , - N02, halo, -CN, haloalkyl of 1 to 4 carbon atoms, and -NR6R7, NR8COR7, NR8C02R7, -COR7 -OR7, - CONR6R7, -C0 (N0R9) R7, C02R7, or -S (0) nR7 , wherein alkyl of 1 to 10 carbon atoms, alkenyl of 2 to 10 carbon atoms, alkynyl of 2 to 10 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, and cycloalkylalkyl of 4 to 12 carbon atoms are optionally substituted with 1 to 3 substituents independently selected in each occurrence from alkyl of 1 to 4 carbon atoms, -N02. Jalo, -CN, -NR6R7, NR6R7, NR8COR7, NR8C02R7, -COR7 -OR7. -CONR6R7, C02R7, -CO (NOR9) R7, or -S (0) nR7; R6 and R7 are independently selected at each occurrence of H, alkyl of 1 to 4 carbon atoms, haloalkyl of 1 to 4 carbon atoms, alkoxyalkyl of 2 to 8 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, cycloalkylalkyl of 4 to 12 carbon atoms, aryl, aryl (C? -C alkyl) -; heteroaryl or heteroaryl (C? -C alkyl) -; NR6R7 is pyridine, pyrrolidine, piperazine, N-methylpiperazine, morpholine or thiomorpholine; R8 is independently at each occurrence H or alkyl of 1 to 4 carbon atoms; R9 and R10 are independently in each occurrence selected from H, alkyl of 1 to 4 carbon atoms, or cycloclakyl of 3 to 6 carbon atoms; R11 is H, alkyl of 1 to 4 carbon atoms, haloalkyl of 1 to 4 carbon atoms, or cycloalkyl of 3 to 6 carbon atoms; R 12 is alkyl of haloalkyl carbon atoms of 1 to 4 carbon atoms; R 13 is alkyl of 1 to 4 carbon atoms, haloalkyl of 1 to 4 carbon atoms, alkoxyalkyl of 2 to 8 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, cycloalkylalkyl of 4 to 12 carbon atoms, aryl, aryl (C? -C4 alkyl) -, heteroaryl or heteroaryl (C? -C4 alkyl) -; aryl is phenyl or naphthyl, each optionally substituted with 1 to 3 substituents independently selected in each occurrence from alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, halo, haloalkyl of 1 to 4 carbon atoms, carbon, cyano, -OR7, SH, -S (0) nR13, -COR7, -C02R7, C0 (0) R13, -NR8COR7, -N (COR7) 2, -NR8CONR6R7, NR8C02R13, -NR6R7, and -CONR6R7; heteroaryl is pyridyl, pyrimidinyl, triazinyl, furanyl, quinolinyl, isoquinolinyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuranyl, benzothienyl, benzthiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, or indazolyl, each optionally substituted with 1 or 3 substituents independently selected in each "occurrence of alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, halo, haloalkyl of 1 to 4 carbon atoms, cyano, -OR7, SH, -S (0) nR13, -COR7 , -C02R7, 0C (0) R13, -NR8C0R7, -N (COR7) 2, -NR8CONR6R7, NR8C02R13, -NRSR7, and -C0NRsR7; heterocyclyl is saturated or "partially saturated" heteroaryl, optionally substituted with 1 or 3 substituents independently selected in each occurrence from alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, halo, haloalkyl of 1 to 4 atoms carbon, cyano, -OR7, SH, -S (0) nR13, -COR7, -C02R7, -OC (0) R13, -NR8COR7, -N (COR7) 2 / -NR8CONR6R7, NR8C02R13, NR6R7, -CONR6R7; n is independently in each occurrence 0, 1 or 2; with the proviso that R in formula I is not H: (a) when X is N, Y is N, Z is NR3, R1 is H, R3 is H or benzyl, and Ar is p-methylphenyl; (b) when X ^ is N, Y is -N, Z is NR3, R1 is butyl, R3 is benzyl, and Ar is phenyl; (c) when X is N, Y is CH, Z is NR3, R3 is methyl, R1 is H and Ar is phenyl or 2-fluorophenyl; (d) when X is N, Y is CH, Z is NR3, R3 is methyl, R1 is Cl and Ar is phenyl; (e) when X is N, Y is CH, Z is NR3, R1 is Cl, R3 is benzyl, and Ar is phenyl or substituted phenyl; (f) when X is N, Y is CH, Z is NR3, R3 is p-methylbenzyl, and Ar is., phenyl; (g) when X is N, Y is CR2, Z is NR3, R2 is CH3, R3 is H, and Ar is phenyl or phenyl substituted with methyl, ethyl, isopropyl, fluoro or chloro; (h) when X is N, Y is N, Z is NR3, R3 is cyclopropylmethyl, R1 is H, and Ar is 2-bromo-4-isopropylphenyl, or (i) when X is N, Y is N, Z is s, R1 ES h, and Ar is 2-bromo-4-isopropylphenyl. Preferred compounds of this invention are compounds of formula I and formula II and pharmaceutically acceptable salts and prodrug forms thereof, independently or concurrently: X is N or CR1; And it is N or CR2; Z is NR3, O, or S (O) n; * G is O or S; Ar is phenyl or pyridyl, each optionally substituted with 1 to 3 groups R5, R1 is independently at each occurrence H, alkyl of 1 to 4 carbon atoms, halo, CN, haloalkyl of 1 to 4 carbon atoms, -NR9R10, - OR11, or -S (O) nR12; R is H, alkyl of 1 to 4 carbon atoms, cycloalkyl of 1 to 6 carbon atoms, halo, CN, -NR6R7, NR9COR10, haloalkyl of 1 to 4 carbon atoms, -OR7, or -S (0) nR12; R3 is H, alkyl of 1 to 10 carbon atoms, alkenyl of 2 to 10 carbon atoms, alkynyl of 2 to 10 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, or cycloalkylalkyl of 4 to 12 carbon atoms, each optionally substituted with 1 to 3 substituents independently selected at each occurrence from alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, halo, haloalkyl of 1 to 4 carbon atoms, cyano, -OR7, -S (0) nR13 / - C02R7, -NR8C0R7, -NR8C0NR6R7, -NR8C02R13, -NR6C0R7, aryl and heteroaryl, where the aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected at each occurrence from alkyl of 1 to 4 carbon atoms, halo, cyano, -OR7, -S (0) nR7, C02R7, -NR8COR7, -NR8CONR6R7, -NR8C02R7. and -NR6R7; R 4 is H, alkyl of 1 to 4 carbon atoms, allyl or propructile; R5 is independently in each occurrence alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, cycloalkylalkyl of 4 to 8 carbon atoms , -N02, halo, -CN, haloalkyl of 1 to 4 carbon atoms, -NR6R7, COR7, -OR7, -CONR6R7, -CO (NOR9) R7, C02R7, or -S (0) nR7, wherein alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, and cycloalkylalkyl of 4 to 12 carbon atoms are optionally substituted with 1 to 3 substituents independently selected at each occurrence from alkyl of 1 to 4 carbon atoms, -N02. halo, -CN, -NR6R7, COR7-OR7. -CONR6R7, C02R7, -CO (NOR9) R7, or -S (0) nR7; R6 and R7 are independently at each occurrence H, alkyl of 1 to 4 carbon atoms, haloalkyl of 1 to 4 carbon atoms, alkoxyalkyl of 2 to 8 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, cycloalkylalkyl of 4 to 12 carbon atoms, aryl, aryl (C? -C alkyl) -; heteroaryl or heteroaryl (C? -C4alkyl) -; or NRSR7 is piperidine, pyrrolidine, piperazine, N-methylpiperazine, morpholine or thiomorpholine; R8 is independently at each occurrence H or alkyl of 1 to 4 carbon atoms; R9 and R10 are independently in each occurrence selected from H, alkyl of 1 to 4 carbon atoms, or cycloalkyl of 3 to 6 carbon atoms; R 11 is H, alkyl of 1 to 4 carbon atoms, haloalkyl of 1 to 4 carbon atoms, or cycloalkyl of 3 to 6 carbon atoms; R 12 is alkyl of haloalkyl carbon atoms of 1 to 4 carbon atoms; R 13 is alkyl of 1 to 4 carbon atoms, haloalkyl of 1 to 4 carbon atoms, alkoxyalkyl of 2 to 8 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, cycloalkylalkyl of 4 to 12 carbon atoms, aryl, aryl (C? -C4 alkyl) -, heteroaryl or heteroaryl (C? -C4 alkyl) -; aryl is phenyl or naphthyl, optionally substituted with 1 to 3 substituents independently selected in each occurrence from alkyl of 1 to 4 carbon atoms, halo, cyano, -OR7, -S (0) nR12, -C02R8, -NR8COR7, -NR8CONRsR7, NR8C02R12 and -NRSR7; heteroaryl is pyridyl, pyrimidinyl, triazinyl, furanyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, or indazolyl, each optionally substituted with 1 or 3 ^ substituents independently selected in each occurrence from of alkyl of 1 to 4 carbon atoms, halo, cyano, -OR7, -S (0) nR12, -C02R8, -NR8COR7, -NR8CONRsR7, NR8C02R12, and -NR6R7; n is independently in each occurrence 0, 1 or 2; Of the preferred compounds, the preferred ones are those of the formula I wherein Z and NR3 and the pharmaceutically acceptable salts and prodrug forms thereof. Included in this invention is the method for treating affective disorder, anxiety depression, irritable bowel syndrome, post-traumatic stress disorder, supranuclear impotence, immunosuppression, Alzheimer's disease, gastrointestinal disease, anorexia nervosa or other eating disorders, drug alcohol / drug addiction symptoms, inflammatory disorders or fertility problems in a mammal which comprises administering to the mammal a therapeutically effective amount of a compound of formula I or II. Also included in this invention are pharmaceutical compositions comprising pharmaceutically acceptable carrier and a therapeutically effective amount of any of the compounds described above.

This invention also includes intermediates using the preparation of CRF antagonist compounds and processes for making these intermediates, as described in the following description and claims. The CRF antagonist compounds provided by this invention (and the specially labeled compounds of this invention) are also useful as standards and reagents in determining the ability of a potential pharmaceutical product to bind to the CRF receptor.

DETAILED DESCRIPTION OF THE INVENTION Many compounds of this invention have one or more asymmetric centers or planes. Unless otherwise indicated, se. they include all chiral forms (enantiomeric and diastereomeric), and racemic in the present invention. Many geometric isomers of olefins, C = N double bonds, and the like may also be present in the compounds and all of these stable isomers are contemplated in the present invention. The compounds can be isolated in optically active or racemic forms. It is well known in the art to prepare optically active forms, such as by resolution of racemic forms or by synthesis from optically active starting materials. All chiral (diastereomeric enantiomeric) and racemic forms and all isomeric, geometric forms of A structure is proposed, unless the specific stereochemistry or the isomer form is specifically indicated. The term "alkyl" includes straight chain as branched alkyl having the specified number of carbon atoms. "Alkenyl includes straight and branched hydrocarbon chains and one or more carbon, unsaturated carbon bonds which may occur at any stable point along the chain, such as ethenyl, propenyl, and the like." Alkynyl includes chains of configuration hydrocarbon and either straight or branched and one or more triple carbon-carbon bonds, which may occur at any stable point along the chain, such as ethynyl, propynyl and the like. "Haloalkyl" is proposed to include both branched chain and branched alkyl having the specified number of carbon atoms, substituted with one or more halogens; "alkoxy" represents an alkyl group of the indicated number of carbon atoms attached through an oxygen bridge; "cycloalkyl" is proposed to include saturated ring groups, including mono-, bi- or polycyclic ring systems, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and so forth. "Halo" or "halogen" include fluoro, chloro, bromo and iodo. The term "substituted", as used herein, means that one or more hydrogens in the designated atom is replaced with a selection from the indicated group, provided that the normal valence of the designated atom is not exceeded, and that the substitution results in a stable compound. When a substituent is keto (ie, 2 = 0), then 2 hydrogens on the atom are replaced. s Combinations of substituents and / or variables are permissible only if these combinations result in stable compounds. By "stable compound" or "stable structure" is meant a compound is sufficiently strong to survive isolation to a useful degree of purity from a reaction mixture, and formulation in an effective therapeutic agent.

The term "appropriate amino acid protecting group" means any group known in the art of organic synthesis for the protection of amine or carboxylic acid groups. These amine protecting groups include those listed in Greene and Wuts, "Protective Groups in Organic Synthesis" John Wiley & Sons, New York (1991), and "The Peptides: Analysis, Synthesis, Biology, Vol. 3, Academic Press, New York (1981), the description of which is incorporated herein by reference. known in the art can be used Examples of amine protecting groups include, but are not limited to, the following: 1) acyl types such as formyl, trifluoroacetyl, phthalyl, and p-toluenesulfonyl; 2) aromatic carbamate types such as benzyloxycarbonyl (Cbz) and substituted benzyloxycarbonyls, 1- (p-biphenyl) -1-methylethoxycarbonyl, and 9-fluorenylmethyloxycarbonyl (Fmoc); () Aliphatic carbamate types such as tert-butyloxycarbonyl (Boc), ethoxycarbonyl ^ diisopropylmethoxycarbonyl, and allyloxycarbonyl; 4) cyclic alkylcarbamate types such as cyclopentyloxycarbonyl and adamantyloxycarbonyl; 5) alkyl types such as triphenylmethyl and benzyl; 6) trialkylsilane such as tri-ethylsilane; and 7) thiol-containing types such as phenylthiocarbonyl and dithiasuccinoyl. The term "amino acid" as used herein means an organic compound that contains basic amino groups such as carboxyl acid groups Included within this term are natural amino acids, unusual modified amino acids, as well as amino acids known to be biologically present in the free form combined but usually do not occur in proteins. Included within this term are the modified and unusual amino acids, such as those described, for example, in Roberts Vellaccio (1983) The Peptides, 5: 342-429, teaching of which reference is thus incorporated. Modified or unusual amino acids that can be used to practice the invention include, but are not limited to, D-aminoacid hydroxylysine, 4-hydroxyproline, a protected NC amino acid, ornithine, 2,4-diam.inobutyr homoarginine, norleucine, acid N-methylaminobutyri naphthylalanine, phenylglycine, β-phenylproline, t leucine, 4-aminocyclohexylalanine, N-raet norleucine, 3,4-dehydroproline, N-dimethylaminoglycine, N-methylaminoglycine, aminopiperidine-4-carboxylic acid, 6-aminocaproic acid, acid trans-4- (aminomethyl) -cyclohexanecarboxylic acid, 2-, 3-, and 4- (aminomethyl-benzoic acid, 1-aminociclopentanecarboxylic acid, 1-aminociclopropanecarboxylic acid, and 2-benzyl-5-aminopentanoic acid. "amino acid" as used herein means that the portion of an amino acid (as defined herein) is present in a peptide). The term "peptide" as used herein means a compound consisting of one or more amino acids (as defined herein) that is linked via peptide linkage. The term "peptide" also includes compounds that include both peptide and non-peptide components, such as pseudopeptides or mimetic residues of peptides or other non-amino acid components. This compound containing peptide components as well as peptide is also preferred as a "peptide analog". The term "peptide bond or link" means a covalent amide bond formed by the loss of a water molecule between the carboxyl group of an amino acid and the one amino group of a second amino acid. The term "pharmaceutically acceptable salts" includes the acid or basic salts of the compounds of formulas (I) and (II). Examples of the pharmaceutically acceptable salts include, but are not limited to, salts of mineral or organic acids of basic residues such as amines, alkaline or organic salts of acidic residues such as carboxylic acids; and similar. The pharmaceutically acceptable salts of the compounds of the invention can be prepared by reacting the free acid or free base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of two; In general, non-aqueous media similar to ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remingtond Pharmaceutical Sciences, 17a. ed., Mack Publishing Company, Easton, PA, 1985, p. 1418, the description of which is incorporated herein by reference. "Prodrugs" are considered to be any covalently linked carrier that releases the active, parent drug of formula (I) or (II) in vivo when this prodrug is administered to a mammalian subject. The prodrugs of the compounds of the formula (I) and (II). they are prepared by modifying present functional groups of the compounds in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the compounds of origin. Prodrugs include compounds wherein the hydroxy, amine or sulfhydryl groups are attached to any group which, when administered to a human subject, are cleaved to form a free hydroxyl, amino or sulfhydryl group, respectively. Examples of the prodrug include, but are not limited to, acetate, formate and alcohol benzoate derivatives, and amine functional groups in the compounds of formulas (I) and (II); and similar. The term "therapeutically effective amount" of a compound of this invention means an amount effective to antagonize the abnormal level of CRF or fara to treat the symptoms of affective disorder, anxiety or depression in a host.

SYNTHESIS The bicyclic fused pyrimidines and pyridines of this invention can be prepared by one of the general schemes summarized below (schemes 1-9). The compounds of the formula (I), where d =? = N and Z = NR3, can be prepared as shown in Scheme 1.

Scheme 1 whereX »Y» N; 2? NR3 The 4,6-dihydroxypyrimidines (III) can be nitrated using fuming nitric acid * and then converted into the intermediates (IV) by the action of phosphorus oxychloride with the optional assistance of a catalyst such as dialkylanilines (see: Brown, DJ et al., J. Ch. Soc., 1954, 3832). The amino group of the pyrimidines of the formula (V) can be prepared from the corresponding nitro compounds (IV) by treatment with reducing agents such as, but not limited to, sodium, iron or zinc dithionate, or catalytic hydrogenation (see: Larock, RC Comprehensive Organic Transformations., VCH Publishers, New York, 1989, 411). The reaction with Ar-NH 2 can be used to provide the compounds of the formula (V). Conditions that can facilitate this transformation include the optional presence of protic or aprotic acids, or bases such as alkali metal anhydrides, tpalkylamines, or alkali metal carbonates, or alkali metal bis (trimethylsilyl) amides where the metal can be sodium , lithium or potassium. These reactions can be carried out pure, or in the optional presence of solvents such as but not limited to, cyclic ethers such as tetrahydrofuran, dialkylformamides, ethylene glycol, 2-ethoxyethanol, halocarbons, alkanitriles, or alkyl alcohols at room temperature or at a temperature elevated to the boiling point of the solvent used. The person skilled in the art of organic synthesis will readily understand the optimum combinations of these conversions to prepare a number of compounds of the formula (VI) The cyclization of the triazolopyrimidines of the formula (VII) can then be easily achieved by diazotization and cyclization of the diamine compounds of the formula (VI) with an alkali metal nitrite in the presence of acid in water with the organic cosolvent such halocarbons, or cyclic ether. Treatment of the compound of formula (VII) with primary amines can then provide intermediate compounds (VIII) using reaction conditions similar to those used for conversion of (V) to (VI). The triazole or rearranged pyrimidi of the formula (IX) can be obtained from the triazolopyrimidine of the formula (VII) by the treatment with the base such as but limited to, alkali metal hydrides, alkaline earth metal hydrides, alkali metal dialkyls in inert solvents such dialkylformamides, dialkylacetates at temperatures ranging from 0 ° to 200 ° C. Finally, the reaction with an appropriate R 4 L wherein L is an appropriate leaving group such as halo, methanesulfonate, toluenesulfonate, or triflate in the presence absence of bases such as but not limited to alkali metal hydrides, alkaline earth metal hydrides, alkali metal dialkylamines, in inert solvents such as dialkylformamides or dialkylacetamides at temperatures ranging from 0 to 200 ° C can be used to generate the compounds of the Formula (I): Alternatively, the compounds of the formula (I) wherein X = Y = N and Z = NR3, of this invention can be prepared ar as described in Scheme 2: Scheme 2 I where XmY.N. ZmNR3 Treatment of the formula (V) with primary amines can provide the pyrimidines (X) substituted with diamine. The conditions that facilitate this transformation are detailed previously for the conversion of (VII) to (VIII). Cyclization to triazolopyrimidines of the formula (XI) can then be easily achieved by following the conditions already described for the conversion of (VI) to (VII) in Scheme 1. The leaving group such as. but not limited to, halogen can then be displaced by the addition of Ar-NH 2 to provide the compounds of the formula (IX) by using the conditions described for the conversion of (V) to (VI). The compounds of the formula (IX) can be converted to (I) in the same manner as summarized in Scheme 1. The compounds of the formula (VI) can also be prepared by another approach (Scheme 3) which comprises the addition of AR-NH2 to (IV) to give the compounds of the formula (XII).

Scheme 3 The nitro group in (XXII) can be reduced to give the compounds of the formula (VI) under conditions similar to those described for the transformation of (IV) to (V) in Scheme 1. Alternatively, as shown in Scheme 3, in addition to Ar-NH2 to the compounds of the formula (IV), the pyrimidones (XIII) can be generated in situ. For example, the treatment of dichloropyrimidines of the formula (IV) with an equivalent of Ar-NH 2 in the presence of solvents such as (but not limited to) dialkylsulphoxides, dialkylformamides, and alkyl alcohols readily generate pyrimidones (XIII). The compounds of the formula (XIII) can be converted to (IV) by the action of phosphorus oxychloride with the optional assistance of a catalyst such as dialkylanilines with an inert solvent. The compounds of formula (VI) are made to structures of formula (I) as previously shown in Scheme 1. Scheme 4 summarizes another route for the fused triazolopyrimidine-like compounds of this invention.

Scheme 4 I where X > And «N; Z »NR3 The 4,6-dihydroxy-5-nitropyrimidines can be treated with the anhydrides, aryl sulphonic, aryl-sulfonyl chlorides, alkyl sulfonic anhydrides or alkyl sulfonyl chlorides in the presence or absence of bases such as metal hydrides. alkaline, alkaline earth metal hydrides, alkali metal dialkyl amides in inert solvent such as dialkylformamides, dialkylacetamides at temperatures ranging from 0 to 200 ° C to give intermediate compounds of the formula (XIV). The compounds of the formula (XIV) are treated with primary amines to give aminonitropyrimidines (XV). Treatment of (XV) 'with Ar-NH2 can provide compounds of the formula -XVI). The compounds of formula (XVI) can be reduced to amino derivatives (XVII) using the reagents described for the conversion of (IV) to (V) in Scheme 1. Intermediate (XVII) can be converted into the mixture of (VIII) and (IX) by diazotization and cyclization The compounds of the formula (VIII) can be converted to (IX) by the treatment with the base such as but not limited to, alkali metal hydrides, hydrides of alkaline earth metals, dialkyl amines of alkali metals in an inert solvent The compounds of the formula (IX) are elaborated to give (I) as outlined in the Scheme 1. The fused imidazolopyrimidines of the formula (I) wherein "X = N, Y = CR2 and Z = NR3, can be prepared from the compound (X) as shown in Scheme 5.

Scheme 5 ArNH2, alor XIX where XsN, Y «CRa, Z» NR3 Treatment of (X) with an acylating agent such as, but not limited to, alkyl anhydrides, haloalkenyl anhydrides, alkylamides, haloalkylamides, trialkylortoesters R2 (OR) 3 (where R is alkyl of 1 to 4 carbon atoms, guanidines , cyanogen bromide, R2COOH, urea or thiourea in the presence or absence of an acid (such as HOAc, HCl, H2S04) 'in the presence or absence of an organic cosolvent such as alkyl alcohols, cyclic ethers, or aromatic solvents at temperatures which vary from 0 to 200 ° C. The treatment of (XVIII) with Ar-NH2 can provide the compounds of the formula (XIX) Finally, the alkylation of the compound (XIX) can provide imidazolopyrimidine (I, where X = N, Y = CR2, Z = NR3) The 1, 2, 3-thiadiazolo [5, 4-d] pyrimidines of the formula (I) (wherein X = Y = N and Z = S), can be prepared as shown in Scheme 6.

Scheme 6 The compounds of the formula (VIII) with thiourea can react on heating in the presence of solvent such as but not limited to cyclic ethers such as tetrahydrofuran, dialkylformamides such as dimethylformamide, dialkyl acetamides, ethylene glycol, (2-ethoxyethanol, halocarbons such as methylene chloride, alkanenitriles such as acetonitrile, or alkyl alcohols such as methanol, ethanol to give the compound (XX) which is alkylated to give thiadiazolpyrimidine (I) (wherein X = Y = N and Z = S). The compounds of the formula (I) can be converted to sulfoxides as well as to sulfones under a variety of oxidation agents such as, but not limited to, NaI04, KMnÜ4, or m-chlorophenobenzoic acid.The synthesis method of the triazolopyridines of this invention is shown in Scheme 7.

XXII XXIII The hydroxy groups in (XXI) can be converted to chloro groups by the action of phosphorus oxychloride with the optional assistance of a catalyst such as dialkylaniline (see: Brown, DJ et al. J. Chem. Soc., 1954, 3832) for give the compounds of the formula (XXII). In addition to the primary amines the compound (XXII) can provide alkylaminonitropyridines (XXIII). The nitro group in (XXIII) can be reduced using the conditions employed for the transformation of (IV) to (V) to give (XXIV). The diazotization and cyclization of (XXIV) can provide chlorotriazolopyridine derivatives (XXV) as described for the conversion of (VI) to (VII) in Scheme 1. The chlorine group can then be displaced by the addition of Ar-NH2 to give the compounds of Ar-NH2 to give the compounds (XXVI) and then treat with R4L to give (I) • The imidazolopyridines of the present invention can be prepared from the compound (XXIV) as shown in Scheme 7 by following the conditions summarized for the conversion of (X) to (XVIII) in Scheme 5. The treatment of the compound (XXVII) with AR-NH2 using the conditions summarized in Scheme 1 can provide the compounds of the formula (I) wherein R = H) The alkylation with R4L can give imidazolopyridines of the formula I (where R4 is not equal to H). Alternatively, the triazolopyridines can be synthesized as shown in Scheme 8.

Scheme 8 The treatment of the compounds of the formula (XXI) with an aliphatic or aromatic amine in the appropriate organic solvent, but not limited to, alkyl alcohols such as methanol, ethanol, propanol, butanol, alkyl alkanoates such as ethyl acetate, alkanitriles such as acetonitrile, dialkylformamides such as DMF gives the corresponding ammonium salt, which in the treatment with POCI3 at temperatures from 25 to 120 ° C, gives the compounds of the formula (XXVIII). Treatment of the compounds of the formula (XVIII) with appropriate primary amine in an organic solvent such as but not limited to, alkyl alcohols such as methanol, ethanol, propanol, butanol, alkyl alkanoates such as alkyl acetate, alkanonitrile such as acetonitrile , dialkyl formamides such as DMF, dialkylsulfoxides at temperatures from 25-120 ° C to give (XXIX). This was converted to (XXII by treatment with P0C13 at temperatures from 120 ° C. Compounds of the formula (XIII) can be coupled with Ar-NH2 with or without the presence of solvent at temperatures from 25 to 200 ° C to give product (XXX) These could be converted intermediate compounds (XXXI) by reducing the nitro group under a variety of reducing conditions, such as those used for conversion from (IV) to (V) in Scheme 1. final cyclization was carried performed as described for the conversion of (VI) to (VII) in Scheme 1. The compounds of the general formula (II) can be prepared according to the procedures outlined in Scheme 9.

Scheme 9 (X) X (XXIV (XV) , (XXXV) base, R L, solvent R3N- ^ R- R1 k * l NR4 I Ar (XXXVI) Intermediates of the formula (X), (XV) or (XXIV) can be converted to the compounds of the formula (XXXIII) by treatment with an acylating agent in the presence or absence of a base in an inert solvent at temperatures of reaction ranging from -78 ° C to 200 ° C. Acylating agents include, but are not limited to, phosgene, thiophosphene, diphosgene, triphosgene, carbonyldiimidazole, thiocarbonyl-diimidazole, dialkylcarbonate (such as diethyl carbonate) or RaRbN (C = G) 0rc (where G = 0, S; Ra, Rb, and Rc is independently alkyl of 1 to 8 carbon atoms). Bases include, but are not limited to, alkali metal alkoxides, alkali metal hydrides, trialkylamines, pyridine, 4-di-ethylaminopyridine, alkali metal dialkyl amides, or alkali metal bis (trimethylsilyl) amides. Inert solvents include, but are not limited to, halocarbons, alkanenitriles, dialkylformamides, dialkylacetamides, dialkyl ethers, cyclic ethers such as tetrahydrofuran dioxane, or alkyl alcohols. The intermediate compounds of (XXXIII) can be converted compounds of the formula (XXXIV) (formula (II) where R4 = H) by the reaction with ArNH2, using the conditions described for the conversion of compound (V) to (VI) into Scheme 1. The compounds of the formula (XXXV) s can be prepared from the structure compounds (XXXIII) by the reaction with R13L (where it is a leaving group such as halide, alkanesulfonate or arylsulfonate) in the presence or absence from a base in an inert solvent. The bases and inert solvents may be the same as those listed above for the preparation of (XXXIII). The intermediates of the formula (XXXV) can be reacted with ArNH2 to give the compounds of the formula (XXXVI) (formula (II), where R4 = H) using the conditions described for the conversion of the compound (V) to ( VI) in Scheme 1. The compounds of the formula (XXXVI) can be converted to the compounds of (XXXVIII) (formula (II), where R4 is not equal to H) by the treatment with R4L (where L is a group salient such as halide, alkanesulfonate or arylsulfonate) in the presence or absence of a base in an inert solvent. The bases and inert solvents may be the same as those listed above for the preparation of (XXXIII). As illustrated in Scheme 10, the treatment of the compounds of the formula (XXI) with an aromatic- * or aliphatic amine in an appropriate organic solvent (such as, but not limited to, alkyl alcohols such as methanol, ethanol, propanol) , butanol, alkyl alkanoates such as alkyl acetate, alkanenitriles such as acetonitrile, dialkylformamides such as DMF) give the corresponding ammonium salt, which in the treatment with POCI3 the temperatures from 25 to 120 ° C, gives the compounds of the formula (XXVIII). The treatment of the compounds of the formula (XXVIII) with appropriate primary amines R3NH2 in an organic solvent (such as, but not limited to, alkyl alcohols such as methanol, ethanol, propanol, butanol, alkyl alkanoates such as ethyl acetate, alkanitriles such as acetonitrile, dialkylformamides such as DMF, dialkylsulfoxides) at temperatures from 25 to 120 ° C provide the compounds of the formula (XXIX). These can be converted to XXIII) by treatment with P0C13 at temperatures from 25 to 120 ° C. The compounds of the formula (XXIII) can be converted to the intermediates (XXIV) by the reduction of the nitro group under a variety of reduction conditions, such as those used for the conversion of (IV) to (V) in the Scheme 1. Diazotization and cyclization of (XXIV) can provide chlorothiazolopyridine (XXV) as described for the conversion of (VI) to (VII) in Scheme 1. The chloro group can then be displaced by the addition of Ar-NH2 in the presence of an acid such as, but not limited to, HCl, H2S0, AcOH, methanesulfonic acid, p-toluenesulfonic acid in inert solvents such as toluene, xylenes at temperatures ranging from 0 ° C to 200 ° C to give product I. The salts of I are prepared by combining the base free with the appropriate acid in an appropriate organic solvent.

Scheme 10 I Ac acid addition salt of I where X = CR1, Y «N, Z > NR3 Co or is shown in Scheme 11, reaction of a 4-amino-3-nitro-pyridone of the formula (XXIX) with a reducing agent, such as Na2S204 gives corresponding 4-amino-3-amino-pyridone of formula ( XXXVII). This transformation can be effected under a variety of reducing conditions, such as catalytic hydrogenation reaction with reducing metal (Fe, Sn, Zn), reaction with hydrides (NaBH4, LiAlH4) etc., which are known to those skilled in the art. ' The 4-am.ino-3 -am.in pyridone can be converted to the triazolopyridone formula (XXXVIII) by the treatment with alkali metal nitride, such as NaN02, under acidic conditions. The triazolopyridone results can be converted to the corresponding allo-triazolopyridi of the formula (XXXIX) (X = Cl, Br by treatment with a halogenation agent t such as P0C13, PBR3, POBR3) Alternatively, X can be an appropriate leaving group which The triazolopyridone treatment with tricyclic, thosacic or mesylic anhydride in the presence of a base is triazolopyridine can be coupled with arynes ArNH2 under acidic, basic thermal catalysis to the compounds of the formula I.

Scheme 11 xxxvm xxxix E JEMPLO 1 N- [2-bromo-4- (1-methylethyl) phenyl] -5-methyl-1-3-propy 1-3 H-1,2,3-triazolo [4,5-d] pyrimidin-7-amine Part A: 4,6-Dihydroxy-2-methylpyrimidine (60 g) was added in portions to fuming nitric acid (120 L) at 0 ° C while the reaction flask is cooled. After completion of the addition, the reaction was stirred an additional 1 hour at 0 ° C followed by 1 hour at room temperature, the reaction mixture was then poured onto ice (200 g) and the ice allowed to melt. A light pink solid was isolated by filtration and washed with cold water (100 mL). The solid was dried in a vacuum oven overnight to yield 4,6-dihydroxy-2-methyl-5-nitropyrimidine (72.5 g).

Part B: The product of Part A was added in the form of portions to phosphorus oxychloride (400 mL) under a nitrogen atmosphere followed by the dropwise addition of N, N-diethylaniline (80 L). The reaction mixture was refluxed for 2 1/2 hours with stirring, cooled to room temperature, poured onto ice (2.0 kg) and stirred for 1 hour. The aqueous layer was extracted with diethyl ether (4 x 500 mL) and the extracts were combined. The extracts were combined with brine (500 L), dried over anhydrous magnesium sulfate, dried and extracted to give 4,6-dichloro-2-methyl-5-nitropyrimidine as a yellow solid (68.8 g) having a unpleasant smell.

Part C: The product of Part B (42 g) was added to acetic acid (77 L) and methanol (350 mL). To this mixture was added iron powder (42 g) in portions, stirred for 2 hours at 60-65 ° C, cooled to room temperature, and filtered. The filtrate was extracted to a brown solid, which was extracted with ethyl acetate (2 x 500 mL), washed with IN NaOH (250 L), and brine (500 L). The organic layer was dried over anhydrous magnesium sulfate, filtered and extracted to yield 5-amino-4,6-dichloro-2-methylpyrimidine as a pale yellow solid (25.4 g).

Part D: The product of Part C (14.2 g) and 2-bromo-4-isopropylaniline (17.1 g) were dissolved in 2-ethoxyethanol (60 L) and refluxed at 135 ° C for 30 hours. The reaction mixture was cooled, the solvent was removed, the residue was extracted with dichloromethane, washed with water, dried over anhydrous magnesium sulfate. The extract was filtered, the solvent was removed and the residue was purified by flash column chromatography on a silica gel using methanol + CH2Ck2 (1: 100) to produce 5-amino-4- (2-bromo-4-isopropylphenyl) -amino-6-chloro-2-methylpyrimidine as a cream-colored solid (16.05 g).

Part E: The product of Part D (12.5 g) was dissolved in dichloromethane (125 L) and 50% aqueous acetic acid (125 mL). To this stirred mixture is 3 added sodium nitrite (2.55 g) in water (10 mL) dropwise at room temperature. After the completion of the addition, the reaction was stirred for an additional 15 minutes. The organic layer was separated, washed with water, dried with anhydrous magnesium sulfate, and extracted to a residue. The residue was purified by flash column chromatography (CH2C12) to give light brown oil. The oil was crystallized from hexane + pentane 1: 1 (15 mL) to produce 3- [2-bromo-4- (1-methylethyl) phenyl] -7-chloro-5-methyl-1-3H-1, 2, 3-triazolo [4,5-d] pyrimidine as a completely white solid (12.15 g).

Part F: The product of Part E (0.65 g) was dissolved in dichloromethane (20 mL) and then 1.0 g of 1-propylamine was added at room temperature. The reaction mixture was stirred at room temperature for 1 hour, washed with water, dried with anhydrous magnesium sulfate, and extracted to a white solid. The white solid was crystallized from 2-propanol (2 L) to give 3- [2-bromo-4- (1-methylethyl) phenyl] -t-methyl-N-propyl-3H-1,2, 3- triazole [4, 5-d] pyrimidin-7-amine as white needles (0.58 g; mp 156-157 ° C). The elementary analysis for C? 7H2j.BrN6: Theory C: 52.45, H: 5.45, N: 21.59. Found: C: 52.47, H: '5.33, N: 21.46.

Part G: Rearrangement of Product F: The product of Part F (0.40 g) was dissolved in dry DMF (10 L) and NaH (0.103 g, 60% in oil) was added at room temperature under a nitrogen atmosphere . The mixture was stirred at room temperature for 14 hours and partitioned between ethyl acetate (25 mL) and water (25 mL). The organic layer was washed with brine, dried and extracted in vacuo to a solid. The solid was recrystallized from 2-propanol (0.5 mL) to give the title compound as a white crystalline solid (0.35 g, mp 80-81 ° C). Elemental analysis for CnH2? BrN6: Theory C: 52.45, H: 5.45, N: 21.59. Found: C: 52.19, H: 5.37, N: 21.48.

EXAMPLE 2 N- [2-bromo-4- (1-methylethyl) phenyl] -N-ethyl-5-methyl-3-propyl-3-Hl, 2,3-triazpl [4, 5, -d] pyrimidin-7- amine The title compound of Example 1 (0.30 g) was dissolved in dry DMF (10 mL) and NaH (62 mg, 60% in oil) was added at room temperature under a nitrogen atmosphere. The reaction mixture was stirred for 5 minutes, then added in EtI (0.2 mL) and continued for a further 24 hours. The reaction mixture was partitioned between ethyl acetate (25 L) and water (25 L), the organic layer was washed with brine, dried, and extracted in vacuo to yield a pale yellow oil. The sample was purified by flash column chromatography MeOH + CH2C12 1: 100) to give the compound as a colorless oil (0.16 g). Elemental analysis for C? 9H25BrNs: Theory C: 54.68, H: 6.05 Found: C: 54.66, H.6.02.

EXAMPLE 3 N- [2-bromo-4- (1-methylethyl) phenyl] -3-butyl-N-ethyl-5-methyl-3H-1, 2,3-triazolo [4,5-d] pyrimidin-7-amine .

Part A: The product from Part E of Example 1 was treated with 1-butylamine in the same manner as summarized in Part F to give 3- [2-bromo-4- (1-methylethyl) phenyl] -N- buyl-5-methyl-3H-l, 2,3-triazolo [4,5-d]? irimidin-7-amine as a white solid (pp. 149-151 ° C). Elementary analysis for C? 8H23BrN6: Theory C: 53.60, H: 5.76, N: 20.84. Found: C: 53.46, H: 5.62, N: 20.80.

Part B: The product of Part A of Example 3 (0.34 g) was dissolved in dry DMF (10 mL) and NaH (67 g, -60% in oil) was added at room temperature under a nitrogen atmosphere. The reaction mixture was stirred for 24 hours, then EtI (0.1 mL) was added and continued for another 24 hours. The title compound was isolated in the same manner as described in Example 2 to give the colorless oil (0.21 g). Elemental analysis for C20H27BrN6: Theory C: 55.69, H: 6.32, N: 19.48. Found: C: 55.61, H: 6.19, N: 19.23.

EXAMPLE 4 N [2-bromo-4- (1-methylethyl) phenyl] -3- (cyclopropylmethyl) N -ethyl-5-methyl-3H-1, 2,3-triazole [4,5-d] pyrimidine-7 amine Part A: The product of Part E of the Example 1 was reacted with aminomethylcyclopropane in the same manner as summarized in Part F to give 3- [2-bromo-4- (1-methylethyl) phenyl] -N- (cyclopropyl-methyl) -5-methyl-3H , 1,2,3-triazolo [4, 5-d] pyrimidin-7-amine as white needles (mp 166-167 ° C). Elemental analysis for C? 8H21BrN6: Theory C: 53.87, H: 5.27, N: 20.94. Found: C: 54.11, H: 5.32, N: 21.08.

Part B: Using the procedure of Part G in Example 1, the product from Part A in Example 4 was rearranged to produce the title compound as a white crystalline solid (mp 100-101 ° C). Elemental analysis for C? 8H21BrN6: Theory C: 53.87, H: 5.27, N: 20.94. Found: C: 53.93, H: 5.28, N: 20.78.

Part C: Using the procedure for the Example 2, the product of Part B of the above was alkylated to give the title compound as a colorless oil. Elemental analysis for C20H25BrN6: Theory C: 55.95, H: 5.88, N: 19.57. Found: C: 56.11, H: 6.04, N: 19.23.

EXAMPLE 5 N- [2-bromo-4- (1-methyl) ethylphenyl] -5-methyl 1-3 - [(1-methoxymethyl) -2-methoxyethyl) -3H-1,2,3-triazole [4, 5] d] pyrimidin-7-amine.

Part A. Serinol (3.42 g) was added to a solution of trityl chloride (8.36 g) and triethylamine in 75 mL of dry DMF. After stirring at room temperature overnight, the reaction was poured into water and extracted twice with toluene. The combined organic layers were dried over potassium carbonate and concentrated to dryness. Recrystallization from boiling 1: 1 benzene / hexane (two crops) gave N-triphenylmethyl serinol (7.59 g).

Part B: Methyl iodide (2.60 mL) was added to a suspension of N-triphenyl ethyl serinol (6.34 g) and powdered sodium hydroxide (7.60 g) in 95 mL of dry DMSO. After. stirring overnight, more methyl iodide (0.35 mL) was added. After stirring for an additional 24 hours, the reaction was added to water and extracted with toluene, toluene / ether, and then ether. The combined organic layers were dried over potassium carbonate and concentrated to give 1,3-dimethoxy-2-triphenylmethylaminopropane (7.00 g) as a thick viscous oil.

Part C: To a solution of the product of Part B (1.45) in methanol (32 L) was added 1 M HCl in ether (8.4 mL). After stirring overnight, the reaction was added to hexane and extracted with methanol / water 1: 1. The methanol / water layer was washed twice with hexane and concentrated to dryness to give 1,3-dimethoxy-2-aminopropane hydrochloride (600 mg) as a solid steamed.

Part D: The product of Part C (576 mg), 3- (2-bromo-4- (1-methyl) ethylphenyl] -7-chloro-5-phenyl-3H-1,2,3-triazole [4,5-d] pyrimidine (0.733 g, from Example 1, Part E and triethylamine (0.56 L) were stirred overnight at room temperature.The reaction mixture was added to aqueous sodium phosphate and extracted three times with dichloromethane.The combined organic layers were dried over magnesium sulfate and The recrystallization from ether / hexane and then boiling methanol gave N- (1-methoxymethyl-2-methoxyethyl) -0. 3- [2-bromo-4- (1-methyl) ethylphenyl] -5-methyl-3H-1, 2,3-triazole (4,5-d] pyrimidin-7-amine (855 mg) as fusing crystals at 156.0-158.5 ° C. Calculated for C19H25N602Br: C, 50.79%; H, 5.62%; N, 18.70% Found: C, 50.48%; H, 5.65% n, 18.41%.

Part E: The product from Part D (449 mg), dry t-butanol (8 mL) and 1 M potassium t-butoxide (2 mL) was heated to reflux for 2 hours. The reaction mixture was added aqueous ammonium chloride and extracted with dichloromethane. The combined organic layers were dried over magnesium sulfate and concentrated to dryness. The residue was crystallized from partial evaporation of a dichloroethane / ether / hexane solution to give the title compound (403 mg) as an amorphous white solid which melts at 53.5-60 °. Calculated for C19H25N602Br: C, 50.79%; ?, 5.62%, N, 18.70%. Found: C, 50.92%; H, 5.62%; N, 18.77%.

EXAMPLE 6 N- [2-bromo-4- (1-methylethyl) phenyl] -3- (2-methoxyethyl) -5-methyl-3H-1, 2,3-triazolo [4,5-d] pyrimidin-7-amine .

Part A: The product of Part E of the Example 1 was reacted with 2-methoxymethylamine in the same manner as summarized in Part F to give 3- (2-bromo-4- (1-methylethyl) phenyl-N- (2-methoxyethyl) -5-methyl- 3H-1, 2, 3-triazol [4, 5-d] pyrimidin-7-amine as a white solid (mp 134-136 ° C).

Elemental analysis for C? 7H2? BrN6o: Theory C: 50.38, H: 5.22, N: 20.74. Found: C: 50.37, H: 5.32, N: . 52 Part B: Using the procedure for the Part G Example 1, the product of Part A of the Example 6 is rearranged to produce the title compound as a white crystalline solid (mp 94-95 ° C). Elemental analysis for C17H2? BrN60: Theory C: 50. 38, H: 5.22, N: 20.74. Found: C: 50.40, H: . 31, N: 20.65.

EXAMPLE 7 N- (2-bromo-4- (1-methylethyl) phenyl] -N-eti 1-3- (2-methoxyethyl) -5-methyl-3H-1, 2,3-triazole [4, 5-d] pyrimidin-7-amine Using the procedure of Example 23, the product of Part B in Example 6 was alkylated to give the title compound as a colorless oil. Elemental analysis for C? 9H25BrN60: Theory C: 52.66, H: 5.81, N: 19.39. Found: C: 52.85, H: 5.96, N: 19.02.

EXAMPLE 8 N- [2-bromo-4- (1-methylethyl) phenyl] -N-ethyl-3- (3-methoxypropyl) -5-methyl-3H-1, 2,3-triazole [4,5-d] pyrimidine -7-araina.

Part A: The product of Part E of the Example 1 was treated with * 3-methoxyethylamine in the same manner as summarized in Part F to give 3- [2-bromo-4- (1-methylethyl) phenyl] -N-ethyl-N- (3-methoxypropyl) -5-methyl-3H-1,2,8-triazolo [4,5-d] irimidin-7-amine as a white solid (mp 109-110 ° C). Elemental analysis for C18H23BrN60: Theory C: 51.56,. 5.54, N: 20.04. Found: C: 51.57, H: 5.40, N: 20.23.

Part B: The product from Part A of Example 8 was rearranged and rented in the same manner as summarized in Part B of Example 3 to give the title compound as a colorless oil. Elemental analysis for C2oH27BrN60: Theory C: 53.69, H: 6.08, N: 18.79. Found: C: 53.63, H: 5.98, N: 18.59.

EXAMPLE 9 (+ / -) -N- [2-bromo-4- (1-methylethyl) phenyl] -3- [1- (1-ethoxymethyl) propyl] -5-methyl-3H-1, 2, 3-triazole [ 4, 5-d] pyrimidin-7-amine Part. A: The product from Part E (0.72 g) of Example 1 was dissolved in a mixture of ethanol (10 L) and triethylamine (0.21 g) and added to 2-amino-1-methoxybutane (0.23 g). The reaction mixture was refluxed for 8 hours, the solvent was removed, partitioned between ethyl acetate (25 mL) and water (25 mL), the preserved organic layer was washed, dried and elemental analysis for C2? H29BrN60: Theory C: 54.66, H: 6.35, N: 18.21. Found: C: 54.76, H: 6.86, N: 17.85.

EXAMPLE 11 ' (S) -N- [2-bromo-4- (1-methylethyl) phenyl] -3- [1- (1-methoxymethyl) -2-phenylethyl] -5-methyl-3H-1, 2,3-triazole [4, 5-d] pyrimidin-7-amine.

Part A: The product from Part E of Example 1 was treated with S- (+) -2-amino-1-methoxy-3-phenylpropane hydrochloride in the same manner as summarized in Part A of Example 9 to give (S) -3- [2-Bromo-4- (1-methylethyl) phenyl] -N- [1- (1-methoxymethyl) -2-phenylethyl] -5-methyl-3H-1, 2,3-triazole [4, 5-d] pyrimidin-7-amine as a white solid (mp 67-69 ° C). Elemental analysis for C24H27BrN60: Theory C: 58.18, H: 5.49, N: 16.96. Found: C: 57.79, H: 5.39, N: 16.77.

Part B: The product from Part A of Example 11 was rearranged in the same manner as summarized in Part G of Example 1 to give the title compound as a colorless oil.

Elemental analysis for C2 H2 BrNs0: Theory C: 58.18, H: 5.49, N: 16.96. Found: C: 57.94, H: 5.49, N: 16.43.

EXAMPLE 12 (S) -meth17- [2-Bromo-4- (1-methylethyl) phenyl] -5-methyl-a- [2- (methylthio) ethyl] -3H-1,2,3-triazole [4, 5] d] pyrimidine-3-acetate.

Part A: The product of Part E of Example 1 was treated with L-methionine methyl ester hydrochloride in the same manner as summarized in Part A of Example 9 to give (S) -methyl 3- [2-bromo] 4- (1-Methylethyl) phenyl] -5-methyl-a- [2- (methylthio) ethyl] -3H-1, 2,3-triazole [4,5-d] pyrimidine-7-acetate as a white solid ( mp 135-137 ° C). Elemental analysis for C20H25BrN6O2S: Theory C: 48.68, H: 5.12, N: 17.03. Found: C: 48.73, H: 5.21, N: 16.90.

Part B: The product of Part A of Example 12 was arranged in the same manner as described in Part G of Example 1 to give the title compound as a colorless oil Elemental Analysis for C20H25BrN6O2S: Theory C: 48.68, H: 5.12, N: 17.03. Found: C: 48.55, H: 5.19, N: 16.82.

EXAMPLE 13 (+/-) -N- [2-bromo-4- (1-methylethyl) phenyl] -3- [1-ethylpentyl] -5-methyl-3H-l, 2,3-triazole [4,5-d ] pyrimidin-7-amine Part A: The product from Part E of Example 1 was reacted with 3-aminoheptane in the same manner as summarized in Part F to produce 3- [2-bromo-4- (1-methylethyl) phenyl] -N - (1-ethyl enyl] -5-methyl-3H-1,2,3-triazolo [4,5-d] pyrimidin-7-amine as a white crystalline solid (mp 137-138 ° C). Elemental analysis for C2? H29BrN6: Theory C 56.63, H: 6.56, N: 18.87. Found: C: 56.53, H 6.54, N: 18.79.

Part B: Using the procedure for Part G in Example 1, the product of the Part of Example 13 was arranged to produce the title compound as a colorless oil. Elemental analysis pair C21H29BrN6: Theory C: 56.63, H: 6.56, N: 18.87. Found: C: 56.78, H: 6.58, N: 18.79.

EXAMPLE 14 (+/-) -N- [2-bromo-4- (1-methylethyl) phenyl] -N-eti 1-3- [1-ethylpentyl] -5-methyl-3H-1, 2, 3-traizol [ 4, 5-d] pyrimidin-7-amine.

Using the procedure for Example 2, the product of Part B in Example 13 was alkylated to give the title compound as a colorless oil. Mass Spectrometry (ESI): 473.4.

EXAMPLE 15 N- [2-bromo-4- (1-methylethyl) phenyl] -3- [1-propylbutyl] -5-methyl-3H-1, 2,3-triazole [4,5-d] pyrimidin-7-amine Part A: The product of Part E of the Example 1 was reacted with 4-aminoheptane in the same manner as summarized in Part A of the Example 9 to produce 3- [2-bromo-4- (1-methylethyl) phenyl) -N- [1-propyl-butyl] -5-methyl-3H-1, 2,3-triazole- [4,5-d] pyrimidine -7-amine as a crystalline solid (mp. 162-163 ° C). Elemental analysis for C2? H29BrN6: Theory C: 56.63, H: 6.56, N: 18.87, Found: C: 5664, H: 6.56, N: 18.81.

Part B: Using the procedure for Part G in Example 1, the product of Part A in Example 15 was arranged to produce the title compound as a white crystalline solid (mp 69-70 ° C). Elemental analysis for C2j, H29BrN6: Theory C: 56.63, H: 6.56, N: 18.87. Found: C: 56.64, H: 6.56, N: 18.81.

EXAMPLE 16 N- [2-bromo-4- (1-methylethyl) phenyl] -3- [1-butylpentyl] -5-methyl-3H-1, 2,3-triazole [4, 5-d] pyrimidin-7-amine Part A: The product of Part E of the Example 1 was reacted with 5-aminononane in a manner similar to Part A of Example 9 to produce 3- [2-bromo-4- (1-methylethyl) phenyl] -N- [1.butylpentyl] -5-methyl -3H-1, 2,3-traizol [4,5-d] pyrimidin-7-amine as a white crystalline solid (p.p. 132-133 ° C). Elemental analysis for C23H33BrNs: Theory C: 58.35, H: 7.04, N: 17.75. Found: C 58.19, H: 7.00, N: 17.97.

Part B: Using the procedure for Part G in Example 1, the product from Part A in Example 16 was rearranged to produce the title compound as a colorless oil. Elemental analysis for C23H33BrNs: Theory C: 58.35, H: 7.04, N: 17.75. Found: C: 58.58, H: 7.12, N: 17.47.

EXAMPLE 17 (+/-) -N- [2-bromo-4- (1-methylethyl) phenyl] -3- [1-ethylbutyl] -5-methyl-3H-l, 2,3-triazole [4,5-d ] pyrimidin-7-amine Part A: The product from Part E of Example 1 was reacted with 3-aminohexane in a manner similar to Part A of Example 9 to produce 3- [2-bromo-4- (1-methylethyl) phenyl] -N - [1-ethylbutyl] -5-methyl-3H-1, 2,3-triazolo [4, 5-d] pyrimidin-7-amine as a white crystalline solid (mp 154-155 ° C). Elemental analysis for C20H27BrN6: Theory C: 55.69, H: 6.32, N: 19.48. Found: C: 55.57, H 6.31, N: 19.41.

Part B: Using the procedure for Part G eh Example 1, the product of Part A in Example 17 was rearranged to produce the title compound as a title compound as a white crystalline solid- (87-88 ° C. ). Elemental analysis for: C20H27BrN6: Theory C: 55.69, H: 6.32, N: 19.48. Found: C: 55.70, H: 6.36, N: 19.40.

EXAMPLE 18 (+/-) -7- [2-bromo-4- (1-methylethyl) phenyl] -5-methyl-a-propyl-3H-1, 2,3-triazolo [4,5-d] pyrimidine-3 -ethanol Part A: The product from Part E of Example 1 was treated with DL-2-amino-1-pentanol in a manner similar to Part A of Example 9 to give 3- [2-bromo-4- (1-methylethyl ) phenyl] -5-methyl-a-propyl-3H-1,2,3-triazole [4, 5-d] pyrimidine-7-ethanol as a white crystalline solid (mp 154-155 ° C). Elemental analysis for C? 9H25BrN60: Theory C: 52.66, H: 5.83, N: 19.39. Found: C: 52.54, H: 5.64, N: 19.12.

Part B: Using the procedure for Part G in Example 1, the product of Part A in Example 18 was rearranged to give the title compound with a colorless oil. Elemental analysis for: C? 9H25BrNsO: Theory C: 52.66, H: 5.-83, N: 19.39. ' Found: C: 52.46, HJ: 5.83, N: 19.18.

EXAMPLE 19 N- [2-bromo-4- (1-methylethyl) phenyl] -3- [1-ethyl-1-propyl] -5-methyl-3H-1, 2,3-triazole [4, 5-d] pyrimidine-7 -amine Part A: The product of Part E of the Example 1 was reacted with 3-aminopentane in the same manner as summarized in Part A of the Example 9 to produce 3- [2-bromo-4- (1-methylethyl) phenyl] -N- [1-ethylpropyl] -5-methyl-3H-1, 2, 3-traziol [4,5-d] pyrimidine -7-amine as a white crystalline solid (pp 171-172 ° C). Elemental analysis for C? 9H25BrN6: Theory C: 54.68, H: 6.05, N: 20.14. Found: C: 54. 54, H: 5.73, N: 20.18.

Part B: Using the procedure for the Part G in Example 1, the product from Part A of Example 19 was rearranged to produce the title compound as a white crystalline solid (mp 117-118 ° C). Elemental analysis for C2? H29BrN6: Theory C: 56.63 ', H: 6.56, N: 18.87. Found: C: 54.86, H: 5.93, N: 20.17.

EXAMPLE 20 N- [2-bromo-4- (1-methylethyl) phenyl] -N-eti 1-3- [1-ethylpropyl] -5-methyl-3H-1, 2, 3-traizol [4, 5-d] pyrimidin-7-amine.

Using the procedure for Example 2, the product from Part B of Example 19 was alkylated to give the title compound as a colorless oil. Elemental analysis for C2? H29BrN6: Theory C: 56.63, H: 6.56, N: 18.87. Found: C: 56.63, H: 6.33, N: 18.78.

EXAMPLE 21 N- (2-bromo-4,6-dimethylphenyl) -5-methyl-3- [1-propylbutyl] -3H-1, 2, 3-traizol [4, 5-d] pyrimidin-7-amine Part A: The product of Part D (9 g) from the Example was dissolved in ethanol (100 mL) and N, N-diisopropylethylamine (8 g). To this mixture was added 4-aminoheptane (7.65 g) and refluxed for 7 days. The ethanol was extracted in vacuo, the residue was partitioned between ethyl acetate (250 mL) and water (150 L). The ethyl acetate layer was washed with brine (100 mL), dried and extracted in vacuo to give a pale yellow solid. Recrystallized from 2-propanol (20 mL) to produce 5-amino-4-chloro-6- (4-heptyl) amino-2-methylpyrimidine as a white crystalline solid (12.5 g; p.p. 162-163 ° C). Elemental analysis for C? 2H2? ClN4: Theory C: 56.13, H: 8.24, N: 21.82. Found: C: 55.94, H: 8.22, N: 21.78.

Part B: Using the procedure for Part A in Example 1, the product from Part A in Example 21 was cyclized to "produce 7-chloro-5-methyl-3-fl-propylbutyl] -3H-1, 2 , 3-triazole [4,5-d] pyrimidine as a pale yellow solid (mp 92-93 ° C) Elemental analysis for C? 2H? 8ClN5: Theory C: 58.83, H: 6.79, N: 26 ^ .16 Found: C: 53.81, H: 6.60.- N: 25.98.

Part C: The product from Part B (0.27 g) of the above was combined with 4-bromo-2,6-dimethylaniline (0.2 g) and heated at 150 ° C for 4 hours. The reaction mixture was partitioned between dichloromethane (20 mL) and water (20 mL), the organic layer was washed with water, dried and extracted in vacuo to a residue. The residue was purified by flash column chromatography (MeOH + CH2C12 1: 100) for the title compound as a completely white solid (0.26 g, mp 141-142 ° C). Elemental analysis for C20H27BrN6: Theory C: 55.69, H: 6.32, N: 19.48. Found: C: 56.05, H: H.26, N: 19.71.

EXAMPLE 22 -methyl-N- [4-1-methylethyl) -2- (methylthio) phenyl] -3- [1-pripyl-butyl] -3H-1,2,3-triazole [4,5-d] pyrimidine- 7 - amine The product from Part B of Example 21 was treated with 4-isopropyl-2-methylthioaniline in a manner similar to Part C in Example 21, to produce the title compound as a pale yellow oil. Elemental analysis for C22H32N6S: Theory C: 64.04, H: 7.83, N: 20.37. Found: C: 64.12, H: 7.54, N: 20.41.

EXAMPLE 23 N- [2-bromo-4- (trifluoromethyl) phenyl)] -5-methyl-3- (1-propylbutyl) -3H-1,2,3-triazole [4,5-d] pyrimidin-7-amine The product from Part B of Example 21 was combined with 2-bromo-4-trifluoromethylaniline in a manner similar to Part C in Example 21, to yield the title compound as a white crystalline solid (mp 84-85 ° C. ). Elemental analysis for C? 9H22BrF3N6: Theory C: 48.42, H: 4.70, N: 17.83. Found: C: 48.58, H: 4.50, N: 17.78.

EXAMPLE 24 N- [2-bromo-4-6- (dimethoxy) phenyl)] - 5-methyl-3- [1-propylbutyl] -3H-1, 2,3-triazole [4,5-d] pyrimidine-7- amine The product from Part B of Example 21 was combined with 2-bromo-4, 6-dimethoxyaniline in a manner similar to Part C in Example 21, to yield the title compound as a white crystalline solid (mp 146147C). . Elemental analysis for C20H27BrN602: Theory C: 51.84, H: 5.87, Ni 18.14 Found: C: 51.95, H: 5.68, N: 18.15.

EXAMPLE 25 N- [2,6-dimethyl-4- (methylthio) phenyl)] -5-methyl-3-3- [1-propyl-butyl] -3-Hl, 2,3-triazole [4,5-d] pyrimidine-7- amine The product from Part B of Example 21 was combined with 2,6-dimethyl-4-methylthionaniline in a manner similar to Part C in Example 21 to produce the title compound as a solid or cream (mp 139-85). 140 ° C). Elemental analysis for C2? H30N6S: Theory C: 63.28, H: 7.60, N: 21.09. Found: C: 62.98, H: 7.32, N: 21.38.

EXAMPLE 26 N- (4-acetyl-2-bromo-phenyl) -3- [1-ethyl-1-propyl] -5-methyl-1-3H-1,2,3-traizol [4,5-dJ-pyrimidin-7-amine] Part A: The product of Part D of the Example 1 was treated with 3-aminopentane in a manner similar to part A of Example 21, to produce 5-amino-4-chloro-2-methyl-6- (3-pentyl) aminopyridine as a white crystalline solid (mp 155 -156 ° C). Elemental analysis for C? 0H? 7ClN4: Theory C: 52.51, H: 7.49, N: 24.50. Found: C: 52.43, H: 7.31, N: 24.59.

Part B: The product from Part A of the above was cyclized in a manner similar to Part E of Example 1 to produce 7-chloro-5-methy-3H-1,2,3-triazole [4,5-d ] pyrimidine as a white crystalline solid (mp 96-97 ° C). Elemental analysis for C? 0H? 4ClN5: Theory: 50.11, H: 5.90, N: 29.22. Found: C: 50.40, H: 5.78, N: 29.53.

Part C: The product from Part B of the above was combined with 4-acetyl-2-bromoaniline in a manner similar to Part C in Example 21, to produce the title compound as a pale yellow solid (mp 153-7). 154 ° C). Elemental analysis for C18H21BrN6OK: Theory C: 51.81, H: 5.07, N: 20.14. Found: C: 51.86, H: 5.87, N: 19.84.

EXAMPLE 27 (+/-) -N- (4-acetyl-2-bromophenyl) -3- [1- (1-methoxymethyl) propyl] -5-methyl-3H-1,2,3-triazole [4,5-d ] pyrimidin-7-amine Part A: The product from Part D of Example 1 was treated with 2-amino-1-methoxybutane in a manner similar to Part A of Example 21, to produce 5-amino-4-chloro-6- (1-methoxy) -2-butyl) amino-2-methylpyridine as a yellow-orange solid (mp 128-130 ° C).

Part B: The product of Part A of the above was cyclized in a manner similar to Part E of Example 1 to produce 7-chloro-3- [1- (1-ethoxymethyl) propyl] -5-methyl-3H- 1,2,3-triazole [4,5-d] pyrimidine as a completely white crystalline solid (mp 66-87 ° C). Elemental analysis for C? 0H? 7ClN5O: Theory C: 45.97, H: 5.53, N: 27.39. Found: C: 47.22, H: 5.43, N: 27.47.

Part C: The product of Part B of the above was combined with 4-acetyl-2-bromoaniline in a manner similar to Part C of Example 21, to produce the title compound as a pale yellow solid (mp 133-134). ° C). Elemental analysis for C? 8H21BrN602: Theory C: 49.89, H: 4.90. Found: C: 50.13, H: 4.99.

EXAMPLE 28 (+/-) -N- (4-bromo-2,6-dimethylphenyl) -3- [1- (1-methoxymethyl) propyl] -5-methyl-3H-1, 2, 3-traizol [4, 5 -d] pyrimidin-7-amine The product from Part B of Example 27 was combined with 4-bromo-2,6-dimethylaniline in a manner similar to Part C in Example 21 to afford the title compound as a white crystalline solid (mp 137-138). ° C). Elemental analysis for C? 8G23BrN605: Theory C: 51.56, H: 5.54, N: 20.04. Found: C: 51.75, H: 5.43, N: 19.99.

EXAMPLE 29 (+ / -) -N- [2,6-Dimeti 1-4- (methylthio) phenyl] -3- [1- (1-methoxymethyl) propyl] -5-methyl-3H-1, 2,3-triazole [4, 5-d] pyrimidin-7-amine The product of Part B of Example 27 was combined with 2,6-dimethyl-4-methylthioaniline in a manner similar to Part C in Example 21 to afford the title compound as a white crystalline solid (mp 128-7). 129 ° C). Elemental analysis for C? 9H26BrN6OS: Theory C: 59.04, H: 6.78. Found: C: 58.49, H: 6.48 EXAMPLE 30 (+/-) -N- (2-bromo-2, 46-dimethoxy phenyl) -3- [1- (1-methoxymethyl) propyl] -5-methyl-3H-1, 2, 3-triazole [4, 5-d] pyrimidin-7-amine The product from Part B Example 27 was treated with 2-bromoi-4,6-dimethoxyaniline in a manner similar to Part C in Example 1, to produce the title compound as a white, crystalline solid (mp 154-). 155 ° C). Elemental analysis for C18H23BrN603: Theory C: 47.90, H: 5.14, N: 18.62. Found: C: 48.28, H: 5.20, N: 18.91.

EXAMPLE 31 (+ / -) -N- (2-chloro-4,6-dimethoxyphenyl) -3- [1- (1-methoxymethyl) propyl] -5-methyl-3H-1, 2, -triazole [4, 5 d] pyrimidin-7-amine The product from Part B of Example 27 was treated with 2-chloro-4,6-dimethoxyaniline in a manner similar to Part C of Example 21, to produce the title compound, a white crystalline solid (mp 149-150). ° C). Elemental analysis for C? 8H23ClN603: Theory C: 53.14, H: 5.70 N: 20.66. Found: C: 53.36, H: 5.72, N: 20.49.

EXAMPLE 32 (+/-) - 3- [l- (1-methoxymethyl) propyl] -5-methyl-n- (2,4,6-trimethylphenyl) -3H-1, 2,3-triazole [4,5- d] pyrimidin-7-amine Part A: 4,6-Dichloro-2-methyl-5-niropyrimidine (10 g, 48 mmol) dissolved in DMSO / water (480 ml / 48 ml) followed by the addition of 2,4,6-trimethylaniline (7.43) .ml, 52.8 mmol) dropwise via syringe for 30 minutes. The reaction was stirred at room temperature for 18 hours and filtered. The solid was washed with water until the volume of the filtrate reached 600 mL. A 150 ml aliquot was removed, diluted with 1.5 liters of. Water; 100 ml of saturated brine, and extracted with 4 x 100 ml of methylene chloride. This procedure was repeated until the rest of the filtrate had been made. The combined organic extracts were dried over anhydrous magnesium sulfate. They were filtered and concentrated in vacuo. The crude solid was chromatographed on silica gel (350 g, methylene chloride / methanol 97/3) to give the desired crystalline, yellow product, 10.53 g (76%). 1 H NMR (CDC13, 300 MHz) d 12.23 (bs, 'ÍH), 10.60 (s, ÍH), 6.95 (s, 2H), 2.34 (2, 3H), 2.33 (s, 3H), 2.16 (s, 6H) ).

Part B: The product from Part A (3.1 g, 11 mmol) was suspended in phosphorus oxychloride (25 ml) and heated to just under reflux for 1 hour, to give a dark homogenous reaction. The reaction was pipetted slowly and cautiously onto 700 ml of ice / water, stirred for 30 minutes at room temperature, and diluted with 200 ml of methylene chloride and transferred to a separatory funnel. The aqueous layer was extracted and back-extracted with 3 x 50 ml of methylene chloride. The combined organic extracts were dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to constant weight to give 3.18 g (97%) of the product as a yellow solid, bright XH NMR (CDC13, 300 MHz) d 8.79 (bs , ÍH), 6.96 (s, 2H), 2.42 (s, 3H), 3.33 (s, 3H), 2.15 (s, 6H).

Part C: The product of Part B (2.73 g, 2.9 mmol) was dispersed in 60 ml of methanol, followed by the addition of acetic acid (3.4 ml), cooling to 0 ° C in an ice / acetone bath, and the addition of iodine (1.84 g). The heterogeneous reaction was stirred 5 minutes at 0 ° C, then refluxed 3 hours, cooled and filtered through celite. The celite pad was washed with 500 ml of ethyl acetate. The dark filtrate was concentrated in vacuo to pure dryness, redissolved in ethyl acetate / water and extracted. The aqueous layer was re-extracted several times with ethyl acetate. The combined organic extracts were dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. Chromatography on silica gel (300 g, ethyl acetate / hexanes 1/1) gave the product 2.18 g (88%) as a white solid. X H NMR (CDC13 / 300 MHz) d 6.93 (s, 2H), 6.25 (bs, ÍH), 3.13 (bs, 2H), 2.36 (s, (H), - 2.31 (s, 3H), 2.17 (s, 6H).

Part D: The product from Part C (1.28wg, 4.60 mmol) was dissolved in methylene chloride (20 ml), followed by the addition of 50% aqueous acetic acid (14 ml), and sodium nitrite (338 mg 4.89 mmol) in water (1 ml). The reaction was stirred for 3 hours at room temperature, transferred to a separatory funnel, diluted with 100 ml of water and 30 ml of methylene chloride and extracted. The aqueous layer was back-extracted with 3 x 30 methylene chloride. The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. Chromatography on silica gel (200 g, ethyl acetate / hexanes 2/8) gave the product 1.32 g (88%) of a completely white crystalline solid, m.p. 186-188 ° C. CI-HRMS calculated for C? 4H15N5Cl? (M + H): 288.1016. Found: 288.1008.

Part E: The product from Part D (425 mg, 1.48 mmol) was treated with triethylamine (0.247 ml, 1.78 mmol) and 2-amino-1-methoxy-butane (0.183 ml, 1.78 mmol) in ethanol (10 ml) at reflux for 2 hours. The reaction mixture was directly concentrated to dryness in vacuo. Chromatography on silica gel (150 g, hexanes / ethyl acetate 1/2) gave the purified product, 392 mg (75%) as a crystalline solid, m.p. 156-157.5 ° C. Analysis calculated for C? 9H26N60 ?: C, 64.38; H, 7.39; N, 23.71. Found: C, 64.27; H, 7.47; N, 23.62.

Part F: The product from Part E (250 mg, 0.70 mmol) was treated with sodium hydride (42 mg, 1.40 mmol, 80%) in dry dimethylformamide (5 ml). The reaction was stirred at 72 hours at room temperature, and 24 hours at 50 ° C, followed by dilution with 100 ml of water and extraction with 3 x 30 ml of ethyl acetate. The combined organic extracts were dried over anhydrous magnesium sulfate, filtered and concentrated to dryness. Chromatography on silica gel (50 g, 1/2 hexanes / ethyl acetate) gave the purified product, 239 mg (96%) as a crystalline solid, m.p. 144.5-147 ° C. Analysis calculated for C? 9H26N60 ?: C, 6.438; H, 7.39; N, 23.71 Found: C, 64.32; H, 7.33; N, 23.78. EXAMPLE 33 (+/-) -N-Ethyl-3- [1- (1-me-toxy-methyl) -propyl] -5-methyl-N- (2, 4,6-trimethylphenyl) -3H-1, 2,3 -triazol [4,5-d] plrimidin-7-amine The product of Example 32, from the Part F (125 mg, 0.35 mmol) was treated with sodium hydride (13 mg, 0.42 mmol, 80%) and ethyl iodide (42 mL, 0.42 mmol) in dry dimethylformamide (3 mL) was stirred at room temperature for 48 hours. hours. The reaction was diluted with 50 ml of water, and extracted with 4 x 30 ml of methylene chloride. The combined organic extracts were dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to dryness. Chromatography on silica gel (50 g, hexanes / ethyl acetate 3/2) gave the desired product, 111 mg (80%) as a clear, viscous oil. CI-HRMS calculated for C2? H31N60? (M + H): 383.2559. Found: 383.2567.

EXAMPLE 34 3- [1- (1-ethyl) propyl] -5-methyl-N- (2,4,6-trimethylphenyl) -3H-1,2,3-triazole [4,5-d] pyrimidin-7-amine Part A: The product of Example 32, Part D, (500 mg, 1.74 mmol) was treated with triethylamine (0.29 ml), 2.09 mol) and 3-aminopentane (0.243 ml, 2.09 mmol) in ethanol (10 ml) under reflux for 2 hours. The reaction was concentrated directly to dryness in vacuo. Chromatography on silica gel (100 g, hexanes / ethyl acetate 8/2) and the purified product, 462 mg (79%) as a crystalline solid, m.p. 184.5-186.5 ° C. Analysis calculated for d9H26N6: C, 67.43; H, 7.74; N, 24.83. Found: C, 67.11; H, 7.59; N, 24.57.

Part B: The product from Part A (300 mg, 0.89 mmol) was treated with sodium hydride (53 mg, 1.78 mmol, 80%) in dry dimethylformamide (5 ml). The reaction was stirred 72 hours at 50 ° C, followed by dilution with 125 ml of water and extraction with 3 x 40 ml with ethyl acetate. The combined organic extracts were dried over anhydrous magnesium sulfate, filtered and concentrated to dryness.

Chromatography on silica gel (75 g, hexanes / ethyl acetate 8/2) of the purified product, 239 mg (80%) as a crystalline solid, m.p. 160-162 ° C. Analysis calculated for C? 9H26N6: C, 67.43; H, 7.74; N, 24.83. Found: C, 67.07; H, 7.85; N, 24.51.

EXAMPLE 35 (+/-) - 3- [l- (1-ethyl) butyl] -5-methyl-N- (2,4,6-trimethylphenyl) -3H-1,2,3-triazole [4,5-d] pyrimidine -7-a ma Part A: The product from Example 32, Part D (525 MG, 1.82 mmol) was treated with triethylamine (0.305 mL, 3.64 mmol) and 3-aminohexane (0.219 mL, 3.364 mmol) in ethanol (8 mL) at 50 ° C. for 18 hours. The reaction was concentrated directly to dryness in vacuo. Chromatography on silica gel (190 g, hexanes / ethyl acetate 8/2) and the purified product, 450 mg (7Q%) as a crystalline solid, m.p. 170.5-172 ° C. Analysis calculated for C2oH25N6: C, 68.15; H, 8.02; N, 23.84. Found: C, 68.10; H, 7.80; N, 23.94.

Part B: The product from Part A (300 mg, 0.85 mmol) was treated with sodium hydride (64 mg, 2.13 mmol, 80%) in dry dimethylformamide (5 ml). The reaction was stirred 25 hours at room temperature and 24 hours at 50 ° C, followed by dilution with 125 ml of water and extraction with 4 x 30 ml of ethyl acetate. The combined organic extracts were dried over anhydrous magnesium sulfate, filtered and concentrated to dryness. Chromatography on silica gel (60 g, hexanes / ethyl acetate 8/2) of the purified product, 260 mg, (89%) as a crystalline solid, m.p. 156-157.5 ° C. Analysis calculated for C? 9H2SN6: C, 68.15; H, 8.01; N, 23.84. Found: C, 68.51; H, 8.10; N, 23.94.

EXAMPLE 36 (+/-) - 3- [l- (1-ethyl) pentyl) -5-methyl-N- (2,4,6-trimethylphenyl) -3H-1,2,3-triazole [4, 5 d] irimidin-7-amine Part A: The product of Example 32, Part D (500 mg, 1.74 mmol) was treated with triethylamine (0.290 ml), 4.35 mmol) and 3-aminoheptane (0.343 ml, 4.35 mmol) in ethanol (8 ml) at 50 ° C for 18 hours. The reaction was concentrated directly to dryness in vacuo. Chromatography on silica gel (125 g, hexanes / ethyl acetate 8/2) of the purified product, 465 mg (73%) as a crystalline solid, m.p. 141.5-142.5 ° C. Analysis calculated for C2? H30N6: C, 68.82; H, 8.25; N, 22.93. Found: C, 69.11; H, 8.10; N, 23.04 Part B: The product from Part A (230 mg, 0.82 mmol) was treated with sodium hydride (49 mg, 1.64 mmol, 80%) in dry dimethylformamide (5 ml). The reaction was stirred at 24 hours at 50 ° C, followed by dilution with 125 ml of water and extraction with 4 x. ml of ethyl acetate. The combined organics were dried over anhydrous magnesium sulfate, filtered and concentrated to dryness.

Chromatography on silica gel (75 g, hexanes / ethyl acetate 8/2) gave the purified product, 236 mg (79%) as a crystalline solid, m.p. 129-130.5 ° C. Analysis calculated for C2XH30N6: C, 68. 82; H, 8.25; N, 22.93. Found: C, 68.73; H, 8. 2. 3; N, 22.90.

EXAMPLE 37 -methy1-3- [1- (1-propy1) butyl] -N- (2,4,6-trimethylphenyl) -3H-1,2,3-triazolo [4,5-d] pyrimidin-4-amine Part A: The product of Example 32, Part (255 mg, 0.87 mmol) was treated with triethylamine (0.145 mL, 1.74 mmol) and 4-aminoheptane (0.120 mL, 1.74 mmol) in ethanol (5 mL) at 50 ° C for 18 hours. The reaction was concentrated directly to dryness in vacuo. Chromatography on silica gel (60 g, hexanes / ethyl acetate 8/2) gave the purified product, 33 mg (73%) as a crystalline solid, m.p. 145-146.5 ° C. Analysis calculated for C2? H30N6: C, 68.82; H, 8.25; N, 22.93. Found: C, 69.09; H, 8.21; N, 23.04.

Part B: The product of Part A (2330 mg, 0.63 mmol) was treated with sodium hydride (47 mg, 1.58 mmol, 80%) in dry dimethylformamide (5 ml). The reaction was stirred 24 hours at room temperature and 24 hours at 50 ° C, followed by dilution with 125 ml of water and extraction with 4 x 30 ml of ethyl acetate. The combined organic extractors were dried over anhydrous magnesium sulfate, filtered and concentrated to dryness. Chromatography on silica gel (60 g, hexanes / ethyl acetate 8/2) of the purified product, 211 mg, (92%) as a crystalline solid, m.p. 143-144.5 ° C. Analysis calculated for C2? H30N6: C, 68.82; H, 8-.25; N, 22.93. Found: C, 69.08; H, 8.10; N, 23.03.

EXAMPLE 38 3- (2-methoxyethyl) -5-methyl-N- (2,4,6-trimethylphenyl) -3H-1,2,3-triazole [4,5-d] pyrimidin-7-amine Part A: The product of Example 32, Part D (1.07 g, 3.70 mmol) was treated with triethylamine (0.620 mL, 4.44 mmol) and 2-methoxyethylamine (0.386 mL, 4.44 mmol) in ethanol (20 mL) at reflux for 3 hours. hours. The reaction was concentrated directly to dryness in vacuo. Chromatography on silica gel (150 g, hexanes / ethyl acetate 8/2) gave the purified product 1.18 g (97%) as a crystalline solid, m.p. 141.5-143.5 ° C. Analysis calculated for C? 7H22N6O ?: C, 62.56; H, 6.79; N, 25.75. Found: C, 62.54; H, 6.78; N, 25.70.

Part B: The product from Part A (325 mg, 1.00 mmol) was treated with sodium hydride (60 mg, 2.00 mmol, 80%) in dry dimethylformamide (5 ml). The reaction was stirred 72 hours at room temperature, and 24 hours at 50 ° C, followed by dilution with 125 ml of water and extraction with 4 x 30 ml of ethyl acetate. The combined organics were dried over anhydrous magnesium sulfate, filtered and concentrated to dryness. Chromatography on silica gel (50 g, hexanes / ethyl acetate 1/2) gave the purified product, 321 mg (99%) as a crystalline solid, m.p. 171.5- 173.5 ° C. Analysis calculated for C? 7H22N6O? : C, 62.56; H, 6.79; Found: C, 62.24; H, 6.89.

EXAMPLE 39 N-ethyl-3- (2-methoxyethyl) -5-methyl-N- (2,4,6-trimethylphenyl) -3H-1, 2,3-triazolo [4,5-d] pyrimidin-7-amma.

The product of Example 38, Part B (150 mg, 0.46 mmol) was treated with sodium hydride (17 mg, 0.55 mmol, 80%) and ethyl iodide (55 mL, 0.69 mmol) in dry dimethylformamide (3 mL) and it was stirred at room temperature for 48 hours. The reaction was diluted with 50 ml of water, extracted with 4 x 30 ml of methylene chloride. The combined organic extracts were dried over anhydrous magnesium sulfate, and filtered and concentrated in vacuo to dryness. Chromatography on silica gel (50 g, hexanes / ethyl acetate 1/1) gave the desired product, 144 mg (88%) as a clear, viscous oil. CI-HRMS calculated for Cx9H27N60? (M + H): 355.2246. Found: 355.2240.

EXAMPLE 40 N- (2-methi 1-4-bromo phenyl) -3- [1- (1-propyl) butyl] -5-methyl-3H-1, 2,3-triazole [4, 5-d] pyrimidine-7 -amine Part A: 4,6-Dichloro-2-methyl-5-nitropyrimidine (5.2 g, 25 mmol) dissolved in DMSO (480 ml) followed by the addition of 2-methyl-4-bromoaniline (4.65 g, 25 mmol) Drop by drop via syringe for 30 minutes. The reaction was stirred at RT for 18 hours, followed by the addition of 800 ml of water. The resulting precipitate was filtered and dried to constant weight giving 7.02 g (83%) of the desired pyrimidone as a yellow solid.

Part B: The product of Part B (6.95 g, 20.5 mmol) was treated with phosphorus oxychloride (12q0 ml) and refluxed for 20 minutes. The reaction was cooled, and slowly flooded in 3 ml of water / ice. The resulting precipitate was filtered and dried. Chromatography on silica gel (500 g, hexanes / ethyl acetate 8/2) gave the purified product, 5.4 g (74%), as a yellow solid.

Part C: The product from Part B (5.4 g, 15.2 mmol) was dispersed in 120 ml of methanol, followed by the addition of acetic acid (6.8 ml), cooling to 0 ° C in an ice / acetone bath, and addition of iron (4.23 g) under the same conditions described in Example 32, Part C. The resulting brown solid was used directly in the next reaction.

Part D: The product from Part C (15.2 mmol) was dissolved in methylene chloride (100 mL), followed by the addition of 50% aqueous acetic acid. (50 ml) and sodium nitrite (1.15 g, 16.70 mmol) in water (5 ml) under the same conditions as described in Example 32. Part D. Chromatography of the crude product on silica gel (40 g, ethyl acetate). ethyl / hexanes 2/8) gave the product 3.15 (62% of Part C) as a pure white crystalline solid, mp 145-147.5 ° C.

Part E: The product of Part D (600 mg, 1.78 mmol) was treated with triethylamine (300 mL, 2.14 mmol) and 4-aminoheptane (246 mL, 2.14 mmol) in ethanol (10 ml) at 50 ° C for 18 hours. The reaction was concentrated directly to dryness in vacuo. Chromatography on silica gel (125 g, hexanes / ethyl acetate 8/2) gave the purified product, 600 mg (81%) as a crystalline solid, m.p. 155-156 ° C. Analysis calculated for C? 9H25N6Br? : C, 54.68; H, 6.05; N, 20.14. Found: C, 54.36; H, 5.71; N, 20.24.

Part F: The product of Part E (350 mg, 0.84 mmol) was treated with sodium hydride (63 mg, 2.10 mmol, 80%) in dry dimethylformamide (5 ml). The reaction was stirred 24 hours at room temperature and 24 hours at 50 ° C, followed by dilution with 125 ml of water and extraction with 4 x 30 ml of ethyl acetate. The combined organics were dried over anhydrous magnesium sulfate, filtered and concentrated to dryness. Chromatography on silica gel (60 g, hexanes / ethyl acetate 8/2) gave the purified product, 333 mg (95%) as a crystalline solid, m.p. 126.5-128 ° C. Analysis calculated for C? SH25N6Br ?: C, 54.68; H, 6.05; N, 20.14. Found: C, 54.90, H, 6.04; N, 20.40.

EXAMPLE 41 (+/-) - 3- [l- (1-ethyl) butyl] -5-methyl-N- (2-methyl-4-bromo phenyl) -3H-1, 2,3-triazole [4, 5 d] pyrimidin-7-amine Part A: The product of Example 40, Part D (600 mg, 1.78 mmol) was treated with triethylamine (0.300 mL, 2.14 mmol) and 3-aminohexane (0.214 mL, 2.14 mmol) in ethanol (10 mL) at 50 ° C. for 18 hours. The reaction was concentrated directly to dryness in vacuo. Chromatography on silica gel (75 g, hexanes / ethyl acetate 8/2) "gave the purified product, 616 mg (86%) as a crystalline solid, mp 117.5-119.5 ° C. Analysis calculated for C? 8H23N6Br? : C, 53.60; H, 5.76; N, 20.84 Found: C, 53.53; H, 5.72; N, 20.95, Part B: The product from Part a (450 mg, 1.12 mmol) was treated with sodium hydride ( 84 mg, 2.80 mmol, 80%) in dry dimethylformamide (10 ml) The reaction was stirred for 72 hours at room temperature, followed by dilution with 125 ml of water and extraction with 4 x 30 ml of ethyl acetate. ethyl The combined organics were dried over anhydrous magnesium sulfate, filtered and concentrated to dryness, chromatography on silica gel (75 g hexanes / ethyl acetate 8/2) gave the purified product, 425 mg (94%). ) as a crystalline solid, mp 99-101 ° C.

EXAMPLE 42 (+/-) -N- (4-bromo-2-methylphenyl) -3- [1-thioxymethyl) propyl] -5-methyl-3H-1, 2,3-triazole [4, 5-d] pyrimidine- 7-amine Part A: The product of Example 40, Part D (800 mg, 2.37 mol) was treated with triethylamine (0.400 ml, 2.84 mmol) and 2-amino-1-methoxybutane (0.341 ml, 2.84 mmol) in ethanol (20 ml) at room temperature for 48 hours. The reaction was concentrated directly to dryness in vacuo. Chromatography on silica gel (150 g, hexanes / ethyl acetate 8/2) gave the purified product, 697 mg (72%) as a crystalline solid, m.p. 144.5-146 ° C. Analysis calculated for C17H2? NsBr ?: C, 50.38; H, 5.22; N, 20.74. Found: C, 50.35; H, 5.23; N, 20.58.

Part B: The product of Part A (550 mg, 1.36 mmol) was treated with sodium hydride (102 mg, 3.40 mmol, 80%) in dry dimethylformamide (8 ml). The reaction was stirred 72 hours at room temperature, followed by dilution with 125 ml of water and extraction with 4 x 30 ml of ethyl acetate. The combined organics were dried over anhydrous magnesium sulfate, and concentrated to dryness. Chromatography on silica gel (75 g, 8/2 hexanes / ethyl acetate) gave the purified product, 520 mg (94%) as a crystalline solid.

EXAMPLE 43 (+/-) - 3- [l- (1-ethyl) pentyl] -5-methyl-N- [(2,4,6-trimethyl) -3-pyridyl-] - 3H-1, 2,3- triazole [4,5-d] pyrimidin-7-amine Part A: A 2, 4-dichloro-2-methyl-5-nitropyrimidine (10.10 g, 48.60 mmol) in dry tetrahydrofuran (200 mol) and triethylamine (6.8 ml, 48.6 mmol) was added 3-amino-2, 4, 6-trimethylpyridine (3.30 g, 24.3 mmol) in tetrahydrofuran (30 ml) via cannulation for 10 minutes at room temperature. The reaction was stirred 72 hours, diluted with 1 L of water, and extracted with 4 x 200 mL of ethyl acetate. The combined organic extracts were dried over anhydrous magnesium sulfate, filtered and concentrated to dryness in vacuo. Chromatography on silica gel (300 g, ethyl acetate / hexanes 1/1) gave the purified product, 4.8 g (64%) as a white solid. NMR XH (300 MHz, CDC13) d 8.79 (bs, ÍH), 6.97 (s, ÍH), 2.54 (s, 3H), 2.43 (s, 3H), 2.40 (s, 3H), 2.17 (s, 3H) . -.

Part B: The product of Part A (4.8 g, 15.60 mmol) was treated with iron (4.36 g, 78.00 mmol) in methanol (110 ml) and acetic acid (6 ml) under the same reaction conditions described in Example 32, Part C. Chromatography on silica gel (250 g, methylene chloride / ethanol 9/1) gave the purified reduction product, 3.1 g, (72%) as a white solid. NMR XH (300 MHz, CDC13) d 6.94 (s, ÍH), 6.26 (bs, ÍH), 3.36 (bs, ÍH), 2.52 (s, 3H), 2.41 (s, 3H), 2.35 (s, 3H) , 2.16 (s, 3H).

Part C: The product of Part B (2.1 g, 7.56 mmol) was treated with sodium nitrite (574 mg, 8.32 mmol) in methylene chloride (44 mL) and 50% aqueous acetic acid (25 mL) under the same reaction conditions described in Example 32, Part D. Chromatography on silica gel (125 g, ethyl acetate / hexanes 1/1) gave the cyclized, purified product, 1.7 g (78%) as a crystalline solid, pf 204.5-206 ° C. Analysis calculated for C13H? 3N6Cl ?: C, 54.08; H, 4.55; N, 29.11. Found: C, 53.94; H, 4.43; N, 28.79.

Part D: The product of Part C (300 mg, 1. 04 mmol) was treated with triethylamine (175 ml, 1.25 mmol) and 3-aminoheptane (243 ml, 1.25 mmol) in ethanol (10 ml) at reflux for 2.5 hours. The reaction was directly concentrated to dryness in vacuo. Chromatography on silica gel (20 g, hexanes / ethyl acetate 1/2) gave the purified product, 356 mg, (93%) as a crystalline solid, m.p. 122-130 ° C. Analysis calculated for C20H29N7; C, 65.37; H, 7.95; N, »26.68, Found: C, 65.35; H, 7.95, N, 26.82.

Part E: The product of Part D (160 mg, 0.44 mmol) was treated with sodium hydride (27 mg, 0.88 mmol, 80%) in dimethylformamide (4 ml). The reaction was stirred 24 hours at room temperature and 100 hours at 50 ° C, followed by dilution with 100 ml of water and extraction with 3 x 30 ml of ethyl acetate. The combined organics were dried over anhydrous magnesium sulfate, filtered and concentrated to dryness. Preparative HPLC [(25-65%) acetonitrile: trifluoroacetic acid / water: trifluoroacetic acid, Dynamax C18 column] and the purified product, 60 mg (38%) as an amorphous foam. CI-HRMS calculated for C20H29N7 (M + H): 368.2545. Found: 368.2563.

EXAMPLE 44 (+/-) -N-ethyl-3- [1- (1-ethyl) pentyl] -5-methyl-N- [(2,4,6-trimethyl) -3-pyridyl-] -3H-1, 2,3-triazole [4,5-d] pyrimidin-7-amine The product of Example 43, Part E (29 mg, 0. 08 mmol) was treated with sodium hydride (3 mg, 0.1> mmol, 80%) and ethyl iodide (9.6 ml, 0.12 mmol) in dry dimethylformamide (1 ml) and stirred at room temperature for 168 hours. The reaction was diluted with 10 ml of water, and extracted with 4 x 5 ml of ethyl acetate. The combined organic extracts were dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to dryness. Chromatography on silica gel (10 g hexanes / ethyl acetate 1/1) gave the desired product, 19.7 mg (63%) as a clear viscous oil. CI-HRMS calculated for C22H33N7 (M + HK): 396.2876. Found: 396.2876.

EXAMPLE 45 (+ / -) -) - 3- [l- (1-ethyl) butyl] -5-methyl-N- [(2,4,6-trimethyl) 3-pyridyl-] -3H-1, 2,3 -triazol [4,5-d] pyrimidin-7-amine Part A: The product of Example 43, Part C (546 mg, 1.89 mmol) was treated with triethylamine (0.316 ml, 2.27 mmol) and 3-aminohexane (0.210 mg, 2.07 mmol) in ethanol (15 ml) at reflux for 2.5 hours. The reaction was concentrated directly to dryness in vacuo. Chromatography on silica gel (50 g, ethyl acetate) gave the purified product, 530 mg (79%) as a crystalline solid, m.p. 155.5-158 ° C.

Analysis calculated for C? 9H27N7: CC, 64.56; H, 7.71; N, 27.74. Found: C, 64.59; H, 7.62; N, 27.91.

Part B: The product from Part A (400 mg, 1.13 mmol) was treated with sodium hydride (94 mg, 3.11 mmol, 80%) in dry dimethylformamide (12 ml). The reaction was stirred 72 hours at 50 ° C, followed by dilution with 100 ml of water and extraction with 4 x 30 ml of ethyl acetate. The combined organics were dried over anhydrous magnesium sulfate, filtered and concentrated to dryness. Chromatography on silica gel (50 g, hexanes / ethyl acetate 1/3) of the purified product, 355 mg (89%) as a crystalline solid, m.p. 132-140.5 ° C. Analysis calculated for C? 9H27N7: C, 64.57; H, 7.71; N, 27.74. Found: C, 64.52; H, 7.58; N, 27.97.

EXAMPLE 46 N-Ethyl-3- [l- (1-ethyl) butyl] -5-methyl-N- [(2,4,6-tri-ethyl) -3-pyridyl-] -3H-1, 2,3-triazole [4,5-d] pyrimidin-7-amine The product of Example 45, Part B (250 mg, 0.71 mmol) was treated with sodium hydride (25 mg, 0.85 mmol, 80%) and ethyl iodide (0.85 mL, 1.07 mmol, in dry dimethylformamide (7 mL) The reaction was diluted with 150 ml of water, extracted with 3 x 30 of ethyl acetate, The combined organic extracts were dried over anhydrous magnesium sulfate, filtered and concentrated to dryness in vacuo. Chromatography on silica gel (20 g hexanes / ethyl acetate 1/3) and the desired product, 221 mg (81%) as a clear viscous oil.

EXAMPLE 47 3- [1- (1-propyl) butyl] -5-methyl-N- [(2, 4, y-trimethyl) -3-pyridyl-] -3H-1,2,3-triazole [4, 5] d] pyrimidin-7-amino "Part A: The product of Example 43, Part C (700 mg, 2.42 mol) was treated with triethylamine (0.405 ml, 2.91 mmol) and 4-aminoheptane ("335 mg, 291 mmol) in ethanol (20 ml) under reflux for 2.5 hours.The reaction was concentrated directly to dryness in vacuo The chromatography on silica gel (50 g, hexanes / ethyl acetate 1/3) gave the purified product, 845 mg (96%), as a crystalline solid, mp 135.5-137.5 ° C. Analysis calculated for C20H29N7 : C, 65.37; H, 7.95; N. 26.68, Found: C, 65.71; H, 7.70; N, 26.95. eleven Part B: The product of Part A (600 mg, 1.63 mmol) was treated with sodium hydride (147.5 mg, 4.89 mmol, 80%) in dry dimethylformamide (15 ml). The reaction was stirred 15 hours at 50 ° C, followed by dilution with 200 ml of water and extraction with 5 x 30 ml of ethyl acetate. The combined organics were dried over anhydrous magnesium sulfate, filtered and concentrated to dryness. Chromatography on silica gel (50 g, hexanes / ethyl acetate 1/3) of the purified product, 560 mg (93%) as a crystalline solid, m.p. 128-130 ° C. CI-HRMS calculated for C2oH29N7 (M + H): 368.2561. Found: 368.2563.

EXAMPLE 48 N-ethyl-3- [l- (1-propyl) butyl] -5-methyl-N- [(2,4,6-trimethyl) -3-pyridyl-] -3H-1,2,3-triazole [ 4,5-d] pyrimidin-7-amine The product of Example 47, Part B (400 mg, 1.09 mmol) was treated with sodium hydride (40 mg, 1.31 mmol, 80%) and ethyl iodide (0.130 mL, 1.63 mmol) in dry dimethylformamide (10 mL) and it was stirred at room temperature for 15 hours. The reaction was diluted with 150 ml of water, extracted with 3 x 30 ml of ethyl acetate. The combined organic extracts were dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to dryness. Chromatography on silica gel (20 g, hexanes / ethyl acetate 1/3) gave the purified product, 373 mg (87%) as a clear, viscous oil.

EXAMPLE 49 (+/-) - 3- [l- (1-methoxymethyl) propyl] -5-methyl-N- [(2,4,6-trimethyl) -3-pyridyl-] -3H-1, 2, 3- triazole [4,5-d] pyrimidin-7-amine Part A: The product of Example 43, Part C (700 mg, 2.42 mmol) was treated with triethylamine (0.405 mL, 2.91 mmol) and 2-aminomethoxybutane (0.350 mL, 2.91 mmol) in ethanol (20 mL) at reflux for 2.5 hours. The reaction was concentrated directly to dryness in vacuo. Chromatography on silica gel (50 g, hexanes / tetrahydrofuran 1/1) gave the purified product, 845 mg (98%) as a crystalline solid, m.p. 132-136.5 ° C. Analysis calculated for C? 8H25N70? : C, 60.82; H, 7.1; N, 27.58. Found: C, 61.13; H, 6.89; N, 27.64.

Part B: The product of Part A (600 mg, 1.68 mmol) was treated with sodium hydride (151.2 mg, 5.04 mmol, 80%) in dry dimethylformamide (15 ml). The reaction was stirred 15 hours at 50 ° C, followed by dilution with 100 ml of water and extraction with 4 x 30 ml of ethyl acetate. The combined organics were dried over anhydrous magnesium sulfate, filtered and concentrated to dryness. Chromatography on silica gel (50 g, hexanes / tetrahydrofuran 1/1) gave the purified product, 500 mg, (83%) as a crystalline solid, m.p. 141.5-144 ° C. Analysis calculated for C? 8H25N7O ?: C, 60.82; H, 7.1; N, 27.58. Found: C, 60.94; H, 6.95; N, 27.46.

EXAMPLE 50 (+/-) -N-ethyl-3- [1-methoxymethyl) propyl] -5-methyl-N- [(2,4,6-trimethyl) -3-pyridyl-] -3H-1, 2, 3-triazole [4,5-d] pyrimidin-7-amine The product of Example 49, Part B (350 mg, 0.99 mmol) was treated with sodium hydride (36 mg, 1.19 mmol, 80%) and ethyl iodide (0.119 mL, 1.49 mmol) in dry dimethylformamide (10 mL) stirred at room temperature for 15 hours. The reaction was diluted with 150 ml of water, and extracted with 3 x 30 ml of ethyl acetate. The combined organic extracts were dried over anhydrous magnesium sulfate, filtered and concentrated to dryness in vacuo. Chromatography on silica gel (20 g, hexanes / tetrahydrofuran 1/1) "gave the desired product, 338 mg (89%) as a clear viscous oil.

EXAMPLE 51 N- (2,4-dibromo-phenyl) -5-methyl-3- (1-propyl) butyl-3H-1,2,3-triazole [4,5-d] pyrimidin-7-amine Part A: 4-Aminoheptane (2.5 g) was added to a solution of 4,6-ditosyloxy-2-methylo-5-nitropyrimidine (10.5 g) and N, N-diisopropylethylamine (3.8 mL) in dichloromethane (29 mL). The reaction was stirred under nitrogen for 5 hours at room temperature and then extracted with water. The organic layer was dried over anhydrous magnesium sulfate and concentrated to yield N- (1-propyl) butyl-2-methyl-5-nitro-4-tosyloxypyrimidin-6-amine as a pale yellow solid (9.1 g). .

Part B: The product of Part A (9.0 g), anhydrous toluene (200 ml), N, N-diisopropylethylamine (3.8 ml) and 2,4-dibromoaniline (5.5 g) was heated at 65 ° C for 16 hours under nitrogen. The reaction was added to NH 4 Cl and extracted with dichloromethane (3 times). The combined organic layers were dried over anhydrous magnesium sulfate, and concentrated to yield N-4- (2,4-dibromophenyl) -N- [6- (1-propyl) butyl] -2-methyl-5-nitro- pyrimidin-4,6-diamine as a yellow solid (6.5 g).

Part C: The product of Part B (6.5 g), 1,4-dioxane (65 ml), water (65 ml), sodium dithionite (18.0 g) and 40% ammonium hydroxide (6.5 ml) were stirred for 3 hours at room temperature. The reaction mixture was added to aqueous, saturated NH 4 Cl, and extracted with ethyl acetate (3 times). The combined organic layers were dried over anhydrous magnesium sulfate and concentrated. The residue was purified by flash column chromatography on silica gel using EtOAc / hexane (2: 8) to give N- [4- (2,4-dibromophenyl)] - N - [6- (1-propyl) butyl] -2-methyl-1-5-aminopyrimidin-4,6-diamine as a pale yellow solid (5.1 g).

Part D: The product of Part C (5.0 g) was dissolved in a 2: 1: 1 mixture of dichloromethane, acetic acid and water. To this solution was added sodium nitrite (0.9 g) and the resulting solution was stirred for 2 hours at room temperature. The reaction was added to an equal volume of water and extracted with dichloromethane (3 times). The combined organic layers were washed with saturated aqueous NaHCO3, then dried over anhydrous magnesium sulfate and concentrated. The residue was purified by flash column chromatography on silica gel using ethyl acetate / hexane (2: 8) to yield N- (1-propyl) buti1-3- (2,4-dibromophenyl) -5-methyl-3H -l, 2, 3-triazole (4,5-d] pyrimidin-7-amine as a white solid (3.9 g) A small amount of the title compound, N- (2,4-dibromophenyl) -5-methyl -3- (l-propyl) 'butyl-3H-1,2,3-triazole [4,5-d] pyrimidine-7-aa (0.18 g) is also isolated from chromatography.

Part E: Sodium hydride (0.24 g) was added to a solution of the product from Part D (3.9 g) in anhydrous DMF (82 ml). The resulting solution was stirred for 16 hours under nitrogen and partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated. The resulting solid was recrystallized from boiling 2-propanol to give the title compound as a white crystalline solid. (3.6 g).

EXAMPLE 52 N- [4-acetyl-2-bromophenyl] -5-methyl-3- (1-propyl) butyl-3H-1,2,3-triazole [4,5-d] pyrimidin-7-amine Bis (triphenylphosphine) palladium-dichloride (11.9 mg), tetrakis were added (triphenylphosphine) palladium (19.6 mg) and 1-ethoxyvinyltributyltin (299 mg) to the product of Part E, of Example 51 (0.33 g) dissolved in toluene (5 ml). The reaction was heated to reflux and stirred overnight. The solvent was then removed under vacuum and the residue was partitioned between ether and saturated, aqueous NaF. The mixture was then filtered and separated. The organic layer was then washed with IN HCl, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by flash column chromatography on silica gel using ethyl acetate / hexane (2: 8) to give the title compound.

EXAMPLE 53 N- [2-bromo-4- (1-methylethyl) phenyl] -3- [1- (N, N-di etílamino-methyl) butyl] -5-methyl-3H-1, 2,3-triazole [ 4, 5-d] pyrimidin-7-amine Part A: A solution of N-CBZ-d, 1-norvaline (TCl America) in THF (0.5 M) was sequenced with 1-hydroxybenzotriazole hydrate (1.2 equivalent), dimethylamine hydrochloride (1.3 equivalent) triethylamine (1.4 equivalent), and dicyclohexylcarbodiimide (1.2 equivalent). After stirring overnight, the mixture was filtered, which was followed by aqueous work-up and chromatography, to give N, N-dimethyl-N 'CBZ-d, 1-norvalineamide, as an oil (TLC Rf = 0.10 ethyl acetate 30: 70).

Part B: A solution of the CBZ compound from Part A above was dissolved in methanol (1 M), and 5% Pd in carbon was added. The mixture was subjected to hydrogenation of a usual stirring apparatus (50 PSI overnight) The resulting mixture was filtered through celite and evaporated to give sufficiently pure product, N, N-dimethyl-d, 1-norvalineamide, as an oil (TLC base line in 30:70 ethyl acetate-hexane) Part C: The amine of Part B is made to the title compound by using the procedure outlined in Example 32 or 51. NMR 1R spectral data (300 MHz, CDC13) -: d 8.61 (1H, d, J = 8.4 Hz), 8.20 (IH, br s), 7.48 (IH, d, J = 1.8 Hz), 7.26 (IH, dd, J = 12.6, 9.7 Hz), 5.08-4.98 (HH, m), 3.27 (1H, dd, J = 12.6, 9.7 Hz), 2.91 (HH, heptet, J = 7.0 Hz), 2.68 (3H, S), 2.67 (HH, dd) , J = 12.6) Hz, 2.22 (6H, s), 2.21-2.11 (HH, m), 1.99-1.89 (1H, m), 1.27 (6H, d, J = 7.0 Hz), 1.16-1.05 (1H, m), 0.88 (3H, t, J = 7.1 Hz) MS (NH3-CI): m / e 464 (3), 463 (25), 462 (100), 461 (29), 460 (98). The compounds of Examples 54-208 can be made by the exemplified methods in Examples 1-53. Table 1 3H-1, 2,3-triazole [4,5-d] pyrimidine: Ex NO. Ar R3 R < 54 2-Br-4-i-Pr-Ph C (Me) 2CH2-OCH3 H 55 2-Br-4-i-Pr-Ph cyclopentyl H 56 2-Br-4,6- (OMe) 2-Ph CH (Bz) CH 2 -OCH 3 H 57 2-Cl-4,6- (OMe) 2-Ph CH (Bz) CH2-0CH3 H 58 4-i-Pr-2-SMe-Ph CH (Bz) CH2-OCH3 H 59 4-i-Pr-2-S02Me-Ph CH (B2) CH2-OCH3 H 60 4- (C0Me) -2-3r-Ph CH (BZ) CH2-0CH3 H 61 2-Br-4-CF3-Ph CH (Bz) CH2-OCH3 H 62 4-Br-2, 6- (Me) 2-Ph CH (Bz) CH2-OCH3 H 53 2, ß- (Me) 2-4-S02Me-Ph CH (Bz) CH2-OCH3 H 64 2,4,6- (Me) 3Ph CH (Bz) CH 2 -OCH 3 H 65 2.6- (Me) 2-4-CF3-Ph CH (Bz) CH2-OCH3 H 66 2-Br-4,6- (Me) 2-Ph CH (Bz) CH 2 -OCH 3 H 67 4-Br-2-Me-Ph CH (Bz) CH2-OCH3 H 68 4-N (Et) 2-2-Me-Ph CH (Bz) CH2-OCH3 H 69 4-I-2-Me-Ph CH (Bz) CH2-OCH3 H 70 2-1-4-i-Pr-Ph CH (Bz) CH2-OCH3 H 71 2-Br-4-SMe-Ph CH (Bz) CH2-OCH3 H 72 2-Br-4-S02Me-Ph CH (Bz) CH2-OCH3 H 73 2-Br-4-N (e) 2-6-OMe-Ph CH (Bz) CH2-OCH3 H 74 2-Br-4,6- (OMe) 2-Ph CH (Et) Bun H 75 2-Cl-4,6- (OMe) 2-Ph CH (Et) Bun H 76 4 -? - Pr-2-SMe-Ph CH (Et) BUn H 77 4-i-Pr-2-S02Me-Ph CH (Et) Bun H 78 4- (COMe) -2-Br-Ph CH (Et) Bun H 79 2-Br-4-CF3-Ph CH (Et) Bun. H 80 4-Br-2,6- (Me) 2-Ph »CH (Et) Bun H 81 2, 6- (Me) 2-4-S02Me-Ph CH (Et) Bun H 82 2, 6- (e) 2-4-S e-P CH (Et) Bun H 83 2, 6- (Me) 2"4-CF3-Ph CH (Et) Bun H 84 2- Br-4,6- (Me) 2-Ph CH (Et) Bun H 85 4- Br-2-Me-Ph CH (Et) Bun H 86 4- N (Et) 2-2-Me-Ph CH (Et) Bun H 87 4- I-2-Me-Ph CH (Et) Bun H 88 2- I-4-i-Pr-Ph CH (Et) Bun H 89 2- Br-4-S02Me-Ph CH (Ec) Bun H 90 2-: Br-4-N (Me) 2-ß-OMe-Ph CH (Et) Bup H 91 2, 4- (SMe) 2-Ph CH (Et) Bun H 92 2, 4- [S02MeJ2-Ph CH (Et) Bun H 93 2-: Br-4,6- (OMe) 2-Ph CH (Et) Prn H 94 2-? Cl-4.6- (OMe) 2-Ph CH (Et) Prn H 95 4-? -Pr-2-SMe-Ph CH (Et) Prn H 96 4-? -Pr-2-S02Me-Ph CH (Et) Prn H 97 4- (COMe) -2-Br-Ph CH (Et) Prn H 98 4-: Br-2-CF3-Ph CH (Et) Prn H 99 4-: Br-2,6- (Me) 2-Ph CH (Et) Prn H 100 2, 6- (Me) 2-4-S e-Ph CH (Et) Prn H 101 2, 6- (Me) 2-4-S02Me-Ph CH (Et) Prn H i m 2, 6- (Me) 2-4-CF3-Ph CH (Et) Prn H 1G3 2- Br-4,6- (Me) 2-Ph CH (Et) Prn H 104 4-: N (Et) 2-2-Me-Ph CH (Et) Prn H 105 2- I-4-i-Pr-Ph CH (Et) Prn H 106 2- Br-4-SMe-Ph CH (Et) Prn H 107 2- Br-4-S02Me-Ph CH (Et) Prn H 108 2- Br-4,6- (OMe) 2-Ph CH (C2H5) 2 H 108 (p.f.163 -165"O 109 2- Cl-4,6- (OMe) 2-Ph CH (C 2 H 5) 2 H 109 (p.f.166 -167 «O 110 4- i-Pr-2-SMe-Ph * CH (C2H5) 2 H 110 (p.f.89-90 ° C) 111 4- i-Pr-2-S02Me-Ph CH (C2H5) 2 H 112 4- (COMe) -2-Br-Ph CH (C2H5) H 113 2- Br-4-CF3-Ph CH (C2H5) H 114 4- Br-2,6- < Me) 2-Ph CH (C2H5) 2 H 114 (p-f .160-162"O 115 2, ß- (Me) 2-4-SMe-Ph CH (C2H5) 2 H 116 2, 6- (Me) 2-4-S02Me-Ph • CH (C2H5) 2 H 117 2, 6- (Me) 2-4-CF3-Ph CH (C2H5) 2 H 118 '2-Br-4,6- (Me) 2-Ph CH (C2H5) 2 H 119 4-N (Et) 2-2-Me-Ph CH (C2H5> 2 H 120 4-I-2-Me-Ph CH (C2H5) 2 H 121 2-I-4-i-Pr-Ph CH (C2H5) 2 H 122 2-Br-4-SMe-Ph CH (C2H5) 2 H 123 2-Br-4-S02Me-Ph CH (C2H5) 2 H 124 2-Br-4-N (Me) 2-6-OMe- Ph CH (C2H5) 2 H 125 2.4- [S (0) 2Me] 2-Ph CH (C2H5) 2 H 126 2-Cl-4,6- (OMe) 2-Ph CH (n-C3H7) 2 H 127 -. 127 - 4-i-Pr-2-S (0) 2 e-Ph CH (n-C3H7) 2 H 128 4- (COMe) -2-Br-Ph CH (n-C3H7) 2 H 129 4-Br-2-CF3-Ph CH (n-C3H7) 2 H 130 4-Br-2,6- (Me) 2-Ph CH (n-C3H7) 2 H 131 2.6- (Me) 2-4-S (0) nMe- > Ph CH (n-C3H7) 2 H 132 2.6- (Me) 2-4-CF3-Ph CH (n-C3H7) 2 H 133 2-Br-4,6- (Me) 2-Ph CH (n-C3H7) 2 H 134 4-Cl-2-Me-Ph CH (n-C3H7) 2 H 135 4-N (Et) 2-2-Me-Ph CH (n-C3H7) 2 K 136 4-I-2-Me-Ph CK (n-C3H7) 2 H 137 2-I-4-i-Pr-Ph CH (n-C3H7) 2 H 138 2-Br-4-N (Me) 2-6-OMe- -Ph CH (n-C3H7) 2 H 139 2.4- [S e] 2-Ph CH (n-C3H7) 2 H 140 2,4-tS (0) Me] 2-Ph CH (n-C3H7) 2 H 141 2.4- [S (0) 2Me] 2-Ph CH (n-C3H7) 2 H Í42 4-i-Pr-2-S (0) nMe-Ph CH (Et) CH2-OCH3 H 143 2-Br-4-CF3-Ph CH (Et) CH2-OCH3 H 144 2.6- (Me) 2-4-S (0) Me-: Ph CH (Et) CH2-OCH3 H 145 2.6- (Me) 2-4-S (0) 2Me- -Ph CH (Et) CH2-OCH3? 146 2.6- (Me) 2-4-CF3-Ph CH (Et) CH2-OCH3 H 147 2.6- (Et) 2-4-Br-Ph CH (Et) CH2-C H3 H 148 2-Br-4 (6- (Me) 2-Ph CH (Et) CH2-CCH3 H 148 (p.f.156- -157 oC) 149 4-Cl-2-Me-Ph CH (Et) CH 2 -OCH 3 H 150 4-N (Et) 2-2-Me-Ph CH (Et) CH 2 -OCH 3 H 151 4-1-2-Me-Ph CH (Et) CH2-OCH3 H 151 (p.f.122- 123 ° c) 152 2-I-4-i-Pr-Ph CH (Et) CH2-OCH3 H 153 2-Br-4-SMe-Ph CH (Et) CH 2 -OCH 3 H 154 2-Br-4-S (0) 2Me-Ph CH (Et) CH 2 -OCH 3 'H 155 2-Br-4-NMe2-Ph CH (Et) CH2-OCH3 H 156 2-Me-4-NMe2-Ph CH (Et) CH2-OCH3 H 156 (p.f.159- 162 ° C) 157 2.6- (Me) 2-4-NMe2-Ph CH (Et) CH2-OCH3 H 158 2-Br-4-OMe-Ph CH (Et) CH2-OCH3 H 159 2-N (Me) 2-4-Me-Ph CH (Et) CH2-OCH3 H 160 2-MeS-4,6 ~ (Me) 2-Ph CH (Et) CH 2 -OCH 3 H 161 2-MeS (0) -4.6- (Me) 2-Ph CH (Et) CH2-OCH3 H 162 2-MeS (0) 2-4.6- (Me) 2-Ph CH (Et) CH2-OCH3 H 163 2- (CH3CO) -4.6- (Me) 2-Ph CH (Et) CH2-OCH3 H 164 2-Br-4-NMe-Ph CH (Et) CH 2 -OCH 3 Et 165 2-Me-4-NMe2-Ph CH (Et) CH2-OCH3 Et 166 2, 6- (Me) 2-4-NMe2-Ph CH (Et) CH2-OCH Et 167 2-Br-4-OMe-Ph CH (Et) CH2-OCH3 Et 168 2-N (Me) 2-4-Me-Ph CH (Et) CH2-OCH3 In 169 2-MeS-4,6- (Me) 2-Ph CH (Et) CH 2 -OCH 3 Et 170 2-MeS (0) -4 6- (Me) 2-Ph CH (Et) CH2-CCH3 Et 171 2-MeS (0) 2-4.6- (Me) 2-Ph CH (Et) CH2-OCH3 Et 172 2- (CH3CO) -4.6- (Me) 2-Ph CH (Et) CH2-OCH3 Et 173 2-Br-4-NMe2-Ph CH (CH2-OCH3) 2 H 174 _2-Me-4-NMe2-Ph CH (CH2-OCH3) 2 H 175 2.6- (Me) 2-4-NMe2-Ph CH (CH2-OCH3) 2 H 176 2-Br-4-OMe-Ph CH (CH2 * OCH3) 2 H 177 2-N (Me) 2-4-Me-Ph CH (CH2-OCH3) 2 H 178 2-MeS-4,6- (Me) 2-Ph CH (CH 2 -OCH 3) 2 H 179 2-MeS (0) -4.6- (Me.2-Ph CH (CH2-OCH3) 2 « 180 2-MeS (0) 2-4.6- (Me) 2-Ph CH (CH2-OCH3) 2 H 181 2- (CH3CO) -4.6- (Me) 2-Ph CH (CH2-OCH3) 2 H 182 2-Br-4-NMe2-Ph CH (CH2-OCH3) 2 Et 183 2-Me-4-NMe2-Ph CH (CH2-OCH3) 2 Et 184 2.6- (Me) 2-4-NMe2-Ph CH (CH2-OCH3> 2 Et 185 2-Br-4-OMe-P CH (CH2"-OCH3) 2 Et 186 2-N (Me > 2-4 ^ Me-Ph CH (CH2-OCH3) 2 Et 187 2-MeS-4,6- (e) 2-P .CH (CH 2 -OCH 3) 2 Et 188 2-MeS (0) -4, ß- (Me) 2-Ph CH (CH2"-OCH3) 2 Et 189 2-MeS (0) 2-4, ß- (Me) 2-Ph CH (CH2 - OCH3) 2 Et 190 2- (CH3CO) -4.6- (Mer2-Ph CH (CH2-OCH3) 2 Et 191 2-Br-4-NMe2-P CHICCH2-CH2-CH3) 2 H 192 2-Me-4-NMe2-Ph CH (CH2-CH2-CH3) 2 H 193 2.6- (Me) 2-4-NMe2-P CH (CH2-CH2-CH3) 2 H 194 2-Br-4-OMe-Ph CHÍCH2 - CH2-CH3) 2 H 195 2-N (Me) 2-4-Me-P CH (CH2-CH2-CH3) 2 H 196 2-MeS-4,6- (Me) 2-P CH (CH 2 -CH 2 -CH 3) H 97 2-MeS (0) -4,6- (Me) 2-Ph CH (CH 2 -CH 2 -CH 3) 2 H 198 2-MeS (0) 2-4.6- (Me> 2-Ph CH (CH2-CH2-CH3) 2 H 199 2- (CH 3 CO) -4, d- (Me) 2-Ph CH (CH 2 -CH 2 -CH 3> 2 H 200 2-Br-4- Me2-P CH (CH2-CH2-CH3) 2 Et 201 2-Me-4-NMe2-Ph CH (CH2-CH2-CH3) 2 Et 202 2,6- (Me) 2-4-N e2-P CH (CH 2 -CH 2 -CH 3) 2 Et 203 2-Br-4-OMe-Ph CH (CH2-CH2-CH3) 2 E 204 2-N (Me) 2-4-Me-Ph CH (CH2-CH2-CH3) 2 Et 205 2-MeS-4,6- (Me) 2-P CH (CH2 -CH2-CH3)? T 206 2-MeS (0) -4.6- (Me) 2-Ph CH (CH2 -CH2-CK3) 2 Et 207 2-MeS (0) 2-4.6- (Me) 2-P CH (CH2 -CH2-CH3) 2 Et 208 2- (CH3CO) -4.6- (Me) 2-Ph CH (CH2 -CH2-CH3) 2 Et EXAMPLE 209 N- [2-bromo-4- (1-methylethyl) phenyl] -2-methyl-9- (1-propylbutyl) -9H-purin-6-amine Part A: The product from Part a (0.74 g) of Example 21 was treated with triethyl orthoformate (7.68 g) and concentrated H2SO4 (3 drops) and heated at 100 ° C for 4 hours. The excess triethyl orthoformate was removed in vacuo, and the residue was purified by flash column chromatography to yield 6-chloro-2-methyl-9- (1-propylbutyl) -9H-purine as a colorless liquid (0.32 g) .

Part B: The product of Part A of the above was combined with 2-bromo-4-isopropylaniline in a manner similar to Part C of Example 21 to give the title compound as a brown oil. Elemental analysis for C22H3oBrN5: Theory C: 59.46, H: 6.80 N: 15.76, Found: C: 59.56, H: 6.83, N: 15.67.

EXAMPLE 210 (+ / -) -N- [2-bromo-4- (1-methylethyl) phenyl) -9- (1-ethylpentyl) -2-methyl-9H-purin-6-amine Part A: The product from Part D of Example 1 was treated with 3-aminoheptane in a manner similar to Part A of Example 21, to produce 5-amino-4-chloro-6- (3-heptyl) amino-methylpyrimidine as a white crystalline solid, mp 116-117 ° C. Elemental analysis for C2? H2? ClN4: Theory C: 56.13, H: 8.24, N: 21.82 Found: C: 56.16, H: 8.26, N: 21, 82.

Part B: The product of Part A of the above was treated with triethyl orthoformate in a manner similar to Part A of Example 209 to produce 6-chloro-9- (1-ethylpentyl) -23-methyl-9H-purine as a pale yellow liquid.

Part C: The product from Part B of the above was combined with 2-bromo-4-isopropylaniline in a manner similar to Part A of Example 21 to give the title compound as a colorless oil. Elemental analysis for C22H30BrN5: Theory C: 59.46, H: 6.80 N: 15.76 Found 59.30, H 6.82 N: 15.50.

EXAMPLE 211 (+ / -) -N- [2-bromo-4- (tri-fluoromethyl) phenyl] -9- [1- (methoxymethyl) propyl] -2-methyl-9H-purin-6-amine Part A: The product from Part A of Example 27 was treated with triethyl orthoformate in a manner similar to Part A of Example 209 to produce 6-chloro-9- [1- (methoxymethyl) propyl] -2-methyl- 9H-purine as a white crystalline solid, mp 105-106 ° C). Elemental analysis for CnH? 5ClN40: Theory C: 51.87, H: 5.95 N: 22.00. Found: C: 51.85, H: 5.81, N: 21.96.

Part B: The product from Part A of the above was combined with 2-bromo-4-trifluoromethylaniline in a manner similar to Part C of Example ^ 21 to give the title compound as a completely white solid (mp 123-124). ° C). Elemental analysis for C18H? 9BrF3N50: Theory C: 47.18, H: 4.19, N: 15.28. Found: C: 47.28, H: 3.97, N: 15.50.

The compounds of Examples 212-217 can be made by the methods exemplified in Examples 209-211.

Table 2 9H-imidazo- [4, 5-d] pyrimidines Ex. NO. Ar R2 R3 R4 212 2-Br-4 -? - Pr-Ph Me CH (n-C3H7) 2 H 213 2,4,6- (Me) 3-Ph Me CH (n-C3H7) 2 H 214 4- Br-2,6- (Me) 2-Ph Me CH (n-C3H7) 2 H 215 2-Br-4-i-Pr-Ph Me CH (Et) CH20CH3 H 216 2.4.6- (M €) 3-Ph Me CH (Et) CH20CH3 K 217 4-Br-2,6- ( Me) 2-Ph Me CH (Et) CH2? CH3 H EXAMPLE 218 N- [2-bromo-4- (1-methylethyl) phenyl] -N-ethyl-5-met il- [1,2,3] thiadiazole (5,4-d) pyrimidin-7-amine Part A: The Product of Part E (1.1 g) of Example 1 was dissolved in ethanol (15 ml) and thiourea (0.27 g) was added. The reaction mixture was refluxed for 1 hourThe solvent was removed in vacuo, partitioned between CH2C12 and water, washed with brine, dried and extracted to a residue. The residue was purified by flash column chromatography (CH2C12) to give the title compound as a white crystalline solid, (1.01 g, mp 81-82 ° C). Elemental analysis for C? 4H? BrN5S: Theory C: 46.16, H: 3.87, N: 19.23, S: 8.80. Found: C: 46.15, H: 3.85, N: 19.09, S: 8.60.

Part B: Using the procedure of Example 2, the product from Part A was alkylated to give the title compound as a pale yellow acetyl. Elemental analysis for C? 6H18BrN5S: Theory C: 48.98, H: 4.62, N: 17.85. Found: C: 49.23, H: 4.71, N: 17.72.

The compounds of Examples 129 and 220 can be made by the method of Example 218.

Table 3 [1, 3, 3] -thiadiazole [5, 4-d] pyrimidines Ex. NO. Ar R 219 2-Br-4-i-Pr-Ph S n-C3H7 220 2-Br-4-i-Pr-Ph S CH2-CH = CH2 EXAMPLE 221 N- [2-bromo-4- (1-methylethyl) phenyl] -1- (1-ethylpropyl) -6-methyl-1 Hl, 2,3-triazole [4, 5, -c] pyre din 4 -amine Part A: 2,4-Dihydroxy-6-methyl-3-nitropyridine was added to phosphorus oxyelide in a manner similar to Part B of Example 1 to give 2,4-dichloro-3-nitro-6. -methylpyridine as a pale yellow solid (mp 69-70 ° C).

Part B: The product of Part A (10.35 g) of the above was dissolved in ethanol (100 ml) and then triethylamine (5.05 g) was added followed by 3-ammopentane at room temperature under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 4 days, the ethanol was removed in vacuo, the residue was partitioned between ethyl acetate (150 ml) and water (150 ml). The organic layer was washed with brine, dried, extracted to a residue and purified on flash column chromatography to give 2-chloro-6-methyl-3-nitro-4- (3-pentyl) aminopyridine as a yellow solid. pale (2.8 g, 84-85 ° C). Elemental analysis for CnH16ClN302: Theory C: 51.27, H: 6.27, N: 16.30. Found: C, 51.28, H: 6.09, N: 16.07.

Part C: The product of Part B of the above was reduced in a manner similar to Part C of Example 1 to give 3-amino-2-chloro-6-methyl-4- (3-pentyl) aminopyridine as a solid cream color (mp 165-166 ° C). Elemental analysis for CnH18ClN3: Theory C: 58.01, H: 7.98, N: 18.45. Found: C: 57.86, H: 7.83, N: 18.44.

Part D: The product of Part C of the above was cycled in a manner similar to the Part E from Example 1 to give 4-chloro-l- (1-ethylpropyl) -6-methyl-lH-1,2,3-triazole [, 5-c) pyridine as a light pink solid (mp 78-79 ° C ).

Part E: The product of Part D of the above was combined with 2-bromo-4-isopropylaniline in a manner similar to Part C of Example 21 to produce the title compound as a cream colored solid (mp 144-145 ° C). Elemental analysis for C2oH26BrN5: Theory C: 57.69, H: 6.29, N: 16.82 Found: C: 57.82, H: 6.29, N: 16.90.

EXAMPLE 222 N- (2-bromo-4, β-dimethoxyphenyl) -1- (1-ethylpropyl) -6-methyl-1H-1, 2,3-triazole- [4, 5-c] pyridin-4-amino The product from Part D of Example 221 was combined with 2-bromo-4,6-dimethoxyaniline from a part similar to Part C in Example 32, to produce the title compound as a completely white solid (mp 166-167 °). C). Elemental analysis for C? 9H24BrN502: Theory C: 52.54, H: 5.58, N; 16.12 Found: C: 52.63, H: 5.53, N: 16.16.

EXAMPLE 223 N- (2-Chloro-4 -6-dimethoxy phenyl) -1- (1-ethylpropyl) -6-methyl-1H-1, 2,3-triazole [4, 5-c] pyridin-4-amine The product from Part D of Example 221 was combined with 2-chloro-4,6-dimethoxyaniline in a manner similar to Part C in Example 21, to produce the title compound as a completely white solid (mp 168-169). ° C).

EXAMPLE 224 N- (2-bromo-4,6-dimethoxyphenyl) -6-methyl-1- (1-propylbutyl) -1H-1,2,3-triazole [4,5-c] pyridin-4-amine Part A: The product of Part A of Example 221, was trapped with 4-aminoheptane in a similar manner as summarized in Part B of Example 221 to give 2-chloro-4- (4-heptyl) amino- 6- methyl-3-nitropyridine as a yellow oil. Analysis calculated for Ci3J20C1N302: Theory C: 54.64, H: 7.05, N: 14.70. Found: C: 54.93, H: 7.03, N: 14.62.

Part B: The product of Part A of the above was reduced in a manner similar to Part C of Example 1 to give 3-amino-2-chloro-4- (4-heptyl) amino-6-methylpyridine as a solid cream color (pp. ~ 139-140 ° C).

Part C: The product from Part B of the above was cyclized in a manner similar to Part E of Example 1 to give 4-chloro-6-methyl-1- (1-propylbutyl) -1H-1, 2, 3 -triazol [4, 5-c] pyridine as a yellow-orange solid (mp 90-91 ° C).

Part D: The product from Part C of the above was combined with 2-bromo-4,6-dimethoxyaniline in a manner similar to Part C of Example 21 to produce the title compound as a red, brick solid ( mp 140-141 ° C). Elemental analysis for C2? YH28Bj: N5? 2: Theory C: 54.55, H: 6.10, N: 15.15 Found: C: 54.83, H: 5.95, N: 15.11.

EXAMPLE 225 N- (2-Chloro-4,6-dimethoxyphenyl) -6-methyl-1- (1-propylbutyl) -1 H -1,2,3-triazolo [4, 5-c] pyridin-4-amine.

The product from Part C of Example 224 was combined with 2-chloro-4,6-dimethoxyaniline in a manner similar to Part C in Example 21 to produce the title compound as a brick-red solid (mp 157-7). 158 ° C). Elemental analysis for C2? H28ClN502: Theory C: 60.35, H: 6.75, N: 16.76 Found: C: 60.43, H: 6.74, N: 16.99.

EXAMPLE 226 (+ / -) -N- [2-bromo-4- (1-methylethyl) phenyl] -1- (1-ethylpentyl) -6-methyl-lH-l, 2,3-triazole [4, 5-c] ] pyridin-4-amine Part A: The product of Part A of the Example 221, t was treated with 3-aminoheptane in the same manner as summarized in Part B of Example 221 to give 2-chloro-4- (3-heptyl) amino-6-methyl-3-nitropyridine as a yellow solid (mp 48-49 ° C). Elemental analysis for C? 3H20ClN3O2: Theory C: 54.64, H: 7.05, N: 14.70. Found: C: 54.79, H: 6.95, N: 14.68.

Part B: The product of Part A of the above was reduced in a manner similar to Part C of Example 1 to give 3-amino-2-chloro-4- (3-heptyl) amino-6-methylpyridine as a solid cream color (mp 139-140 ° C).

Part C: The product of Part B of the above was cyclized in a manner similar to Part E of Example 1 to give 4-chloro-l- (1-ethylpropyl) -6-mketyl-lH-1, 2, 3 -triazol [4, 5-c] pyridine as a colored liquid. Elemental analysis for C? 3H? 9ClN: Theory C: 58.53, H: 7.19, N: 21.00. Found: C: 58.69, H: 7.06, N: 20.76.

Part D: The product from Part C of the above was combined with 2-bromo-4-isopropylaniline in a manner similar to Part C in Example 21, to produce the title compound as a light pink solid (mp 73 -74 ° C). Elemental analysis for C2H30BrN5: Theory C: 59.46, H: 6.80, N: 15.76, Found: C: 59.56, H: 6.70, N: 15.70.

EXAMPLE 227 (+ / -) -N- (2-bromo-4,6-dimethoxy-enyl) -1- (1-ethylpentyl) 6-methyl-1H-1, 2,3-triazole [4, 5-c] pyridm- 4-amine.

The product from * Part C of Example 226 was combined with 2-bromo-4,6-dimethoxyaniline in a manner similar to Part C of Example 21, to produce the title compound as a brick-red solid (mp 127-7). 128 ° C). Elemental analysis for C2? H278BrN502: Theory C: 54.55, H: 6.10, N: 15.15. Found: C: 54.78, H: 5.84, N: 14.92.

EXAMPLE 228 (+/-) -N- (2-chloro-4,6-dimethoxy phenyl) -1- (1-ethylpentyl) 6-methyl-lH-l, 2,3-triazole [4,5-c] pyridine- 4-amine The product from Part C of Example 226 was combined with 2-bromo-4,6-dimethoxyaniline in a manner similar to Part C of Example 21, to produce the title compound as a brick-red solid (mp 155-156 ° C). Elemental analysis for C2ÍH28C1N502: Theory C: 60P.35, H: 6.5, N: 16.76. Found: C: 60.36, H: 6.65, N: 16.84.

EXAMPLE 229 N- [2-bromo-4- (1-methylethyl) phenyl] -6-methio1-1- (1-propylbutyl) -lH-1, 2,3-triazole [4,5-c] pyridin-4-amine Part A: 4-chloro-6-methyl. -3-Nitropyridone: 4-Hydroxy-6-methyl-3-nitropyridone (4.0 g, 23.52 mmol) was treated with cyclohexylamine (2.8 mL, 24.46 mmol) in MeOH (50 mL) until completely dissolved. The MeOH was removed in vacuo and the resulting salt was dried and treated with POC13 (30 ml) at 25 ° C for 30 hours. The reaction was then poured into ice / water (400 ml) and extracted with EtOAc (2 x 200 ml). The combined EtOAc extracts were washed with water (100 ml), INN NaOH (20 ml, water (100 ml) and brine, dried (MgSO 4) and extracted in vacuo.The residue was washed with 20% EtOAc / hexanes (2 x 30 ml) to give the product (2.9 g).

Part B: 6-methyl-3-nitro-4- (1-propylbutylamino) pyridone: 4-Chloro-6-methyl-3-nitropyridone (2.9 g, 15.40 mmol) was treated with 1-propyl butylamine (4 mL, 26.8 mmol) in CH3CN (30 ml) at 25 ° C for 64 hours and refluxing for 2 hours.

The reaction mixture was partitioned between EtOAc (200 ml) and water (50 ml). The EtOAc was washed with water (2 x 50 ml), brine, dried (MgSO) and extracted in vacuo. The residue was washed with 20% EtOAc / hexane (2 x 20 ml) to give the product (3.7 g).

Part C: 2-chloro-6-methyl-3-nitro-N- (1-propyl-butyl) pyridin-4-amine: 6-Methyl-3-nitro-4- (1-propylbutylamino) pyridone was treated ( 3.7 g, 13.84 mmol), with P0C13 (14 ml) at 25 ° C for 20 hours. It was then poured into ice / water (200 ml) and extracted with EtOAc (300 ml). The EtOAc was washed with water, brine, dried (MgSO 4) and extracted in vacuo. The residue was chromatographed on silica gel (20% EtOAc / hexanes, eluting solvent) to give the product (3.3 g).

Part D: N- [2-bromo-4- (1-methylethyl) phenyl] -6-methyl-3-nitro-N- (1-propylbutyl) pyridin-2,4-diamine: The 2-chloro- 6-methyl-3-nitro-N- (1-propylbutyl) pyridin-4-amine (0.5 g, 1.75 mmol) and 2-bromo-4-isopropylaniline (0.74 g, 3.5 mmol) at 140 ° C for 4.5 hours. After cooling, it was dissolved in CH2C12 and filtered through a short column of silica gel. The filtrate was concentrated and chromatographed on silica gel (5% EtOAc / hexanes, eluting solvent) to give the product (0.7 g).

Part E: N- [2-bromo-4- (1-methylethyl) phenyl) -6-methyl-N- (1-propylbuty1) pyridine-2,3,4-triamine: N- [2-bromo-4- (1-Methylethyl) phenyl] -6-methyl-3-nitro-N- (1-propyl-butyl) pyridine-2,4-diamine (0.7 g, 1.51 mmol), was dispersed between dioxane (30 ml) and water (30 ml) containing concentrated NH4OH (1.2 ml). To Na2S20 was added (2.1 g, 12.06 mmol) and the mixture was stirred at 25 ° C for 2 hours. Then an additional gram of Na2S204 was added followed by 10 ml of dioxane and 10 ml of water. After stirring for 1 hour at 25 ° C, the mixture was partitioned between EtOAc (120 ml) and water (20 ml). The EtOAc was washed with water (100 ml), brine, dried (MgSO 4) and extracted in vacuo. The residue was chromatographed on silica gel (20% EtOAc / hexanes, eluting solvent) to give the product (0.5 g).

Part F: N- [2-bromo-4- (1-methylethyl) phenyl] -6-methyl-1- (1-propylbutyl) -1H-1,2,3-triazole [4,5-c] pyridine- 4-amine: N- [2-bromo-4- (1-methyl-lethyl) phenyl] -6-methyl-N- (1-propyl-l-buty1] pyridine-2,3,4-triamine (0.5 g, 1.15 mmol), dissolved in CH2C12 (6 ml) and 50% AcOH (4 ml) was treated with NaN02 (0.0846 g, 1.22 mmol) at 25 ° C for 16 hours. The mixture was partitioned between EtOAc (100 mL) and water (20 mL). The EtOAc was washed with water (20 ml), brine, dried and extracted in vacuo. The residue was chromatographed on silica gel (20% EtOAc % / hexanes, elution solvent) to give the product (0.2 g). Elemental analysis for C22H30BrN5: C, 59.46; H, 6.80; N, 15.76; Br, 17.98. Found: C, 59.76; H, 6.83; N, 15.67; Br, 18.17.

EXAMPLE 231 N- [4- (1-Methylethyl) -2-sulfonylmethyl phenyl] -6-methyl-1- (1-propylbutyl) -1H-1,2,3-triazole [4,5-c] pyridine-4- amma N- [4- (1-Methylethyl) -2 -thiomethyl-phenyl] -6-methyl-1- (1-propylbuty1) -lH-1, 2,3-triazole [4,5-c] iridin-4- amine (0.15 g, 1 equivalent) (Example 231), synthesized under the same general conditions of Example 229, dissolved in methanol (3 ml) and water (2 ml) was added, followed by NaI0 (0.114 g, 1.5 equivalent) . The mixture was stirred at 25 ° C for 20 hours and then extracted with EtOAc (80 ml). The EtOAc was washed with water, brine, dried and extracted in vacuo. The residue was dissolved in CH2C12 and a solution of KMn0 (0.15 g, 2.5 equivalent) in water (2 ml) was added, followed by benzyltriethylamine chloride (0.15 g, 1.5 equivalent). The mixture was stirred at 25 ° C for 20 hours and then extracted with EtOAc (80 ml) and the EtOAc was washed with water, brine, dried and extracted in vacuo. The residue was chromatographed on silica gel ((10% EtOAc / hexanes, eluting solvent) -to give the product (0.2 g) Elemental analysis for C23H33BrN502S: C, 62.27: H, 7.51; N, 15.79; S, 7.24 Found: C, 62.62, H, 7.38; N, 125.58 S, 7.44.

EXAMPLE 232 N- [4- (4-acetyl-2-bromophenyl] -6-methyl-1- (1-propyl-butyl] -1H-1,2,3-triazolo [4,5-c] pyridin-4-amine Part A: Using the normal procedure for the coupling of nitropyridine (0.8 g, 2.9 mmol) and 2-bromo-4-iodoaniline (1.7 5.7 mmol) The crude material preabsorbed in 12 g of silica gel before chromatography in silica gel (5% EtOAc / hexane, eluent) to give an orange solid, 1470 g of the desired product.

Part B: To the coupled 2-bromo-4-iodoanilinonitropyridine (0.60 g, 1.1 mmol) in a dry flask, under nitrogen, was added bis (triphenylphosphine) palladium (II) chloride (18 mg, 0.026 mmol) and anhydrous toluene (5 ml). 1-Ethoxyvinyltributyltin (0.46 ml, 1.36 mmol) was added and stirred at reflux temperature for 1 1/2 hours. It was dissolved in ethyl acetate then the insoluble products were completely filtered through celite. The 2x solids were washed with ethyl acetate. The filtrates were concentrated in vacuo to pure dryness. The residue was stirred with 70 ml of 1 M hydrochloric acid for 1/2 hour. Some ethyl acetate was added and the layers were separated, the water layers were extracted with 2 x 20 ml of ethyl acetate. The combined organic products were concentrated to pure dryness. The residue was stirred in a saturated potassium fluoride (20 ml) for 1/2 hour. The layers were separated. The water layer was extracted with 2 x 20 ml of ethyl acetate, the combined extracts were washed with 10 ml of water and 20 ml of brine. The crude material was chromatographed on silica gel to give a solid, 0.37 g (73%) of the desired product.

Part C: Using the product obtained from Part B (0.70 g, 1.5 mmol), 10 ml of tetrahydrofuran, 10 ml of water, 0.70 ml of ammonium hydroxide solution (38-40%) and sodium dithionite ( 2.1 g, 12 mmol) followed by the normal procedure to reduce nitroanilinopyridine. The crude solid, 0.65 g, was obtained, which was of sufficient purity for the additional reaction.

Part D: Following normal procedures to cyclize the product obtained in Part C (0.63 g, 1.45 mmol), using 10 ml of methylene chloride, 10 ml of acetic acid / water (50%), and sodium nitrite (0.18) g, 2.59 mmoles) in 1 ml of water. Chromatograph on silica gel (10% ethyl acetate / hexane) to give a white solid, 0.31 g (48%) of the desired product, m.p. 165-166 ° C. Analysis calculated for C2? H26BrN50: C, 56.76; H, 5.91; N, 15.76; Br, 17.98. Found: C, 56.75; H, 5.76; N, .15.71; Br, 17.72. The isomer of the desired product was obtained, a white solid, 990 mg, m.p. 133-136 ° C. Calculated analysis: Found: C, 57.11, H, 5.82; N, 15.69; Br, 18.23.

The rest of the examples shown in Table 4 were prepared by following the general procedure outlined in F, j 229.

Table 4 lH-1, 2,3-triazole [4,5-c] pyridine Ex. Mp No. R3 Ar ° C 233 CH (Et) CH2-OCH3 2-Br-4-i-Pr-Ph 121-123 234 CH (Et) CH2-OCH3 4-i-Pr-2-SMe-Ph 97-100 235 CH (i-C3H7 ) 2 2-Br-4- (iC3H7) Ph 96-96 236 CH (i-C3H7) 2 4- (i-C3H7) -2-SMe- • Ph 237 CH (C2H5) 2 4- (i-C3H7) -2-SMe- • Ph 238 CH (n-C3H7) 2 2-Br-4-I-Ph 161-164 239 CH (n-C3H7) 2 2,4- (Br) 2-Ph 125-127 240 CH (Et) CH2-OCH3 2,4,6-M? 3-Ph 241 i-Pr 2-Br-4-i-Pr-Ph 242 i-Pr 4-i-Pr-2-SMe-Ph 243 c- Pr 2-Br-4-i-Pr-Ph 244 c-Pr 4-i-Pr-2-SMe-Ph 247 CH (Et) CH 2 -OCH 3 2,4- (Br) 2-P -248 CH (Et> 2 2,4- (Br) 2-Ph 249 CH (Et) CH 2 -OCH 3 2-COMe-4- Br-P 250 CH (Et) 2 4-COMe-2-Br-Ph 251 CH (Et) 2 2-Br-4-S? 2Me-Ph 252 CH (Et) 2 2,4,6-Me3-Ph 253 CH (CH 2 CN) 2 2-Br-4- (i-C 3 H 7) Ph 254 CH (Et.). CH 2 CN 2-Br-4- (i-C 3 H 7) Ph 255 CH (Et) CH 2 CON 2 Me 2-Br-4- (i ~ C3H7) P 256 CH (CH2CN) 2 2-Br-4, ß- (OMe) 2Ph 257 CH (Et) CH2CN 2-Br-4, 6- (OM?) 2Ph 25S CK (Et) CK2CON? 2 2-Br-4,6- (O e) 2Ph EXAMPLE 229 N- (2-Chloro-4,6-dimethylphenyl) -1 [1-methoxymethyl- (2-methoxyethyl] -6-methyl-lH-1, 2,3-triazole [4, 5-c] pyridine- 4- amine: * Part A: Serinol (24 g) was added to a solution of triethyl chloride (65 g) and triethylamine (51.0 g) in 600 L of dry DMF. After stirring at room temperature for 48 hours, the reaction was poured into water and extracted several times with diethyl ether. The combined organic layers were dried over anhydrous magnesium sulfate and concentrated to dryness to give N-triphenylmethyl-serinol (71.0 g).

Part B: Methyl iodide (90 ml) was added to a suspension of N-triphenylmethyl serinol (37.0 g) and powdered sodium hydroxide (45.0 g) in 400 ml of dry DMSO. After stirring at room temperature for 24-36 hours, the reaction was added to water (80O ml L and extracted with diethyl ether (3 x 500 ml) The combined organic layers were washed with water (4 x 250 ml) were dried over anhydrous magnesium sulfate and concentrated to give 1,3-dimethoxytriphenylmethylaminopropane (36.0 g) as a thick viscous oil.

Part C: To a solution to the product of Part B (36.0 g) in methanol (400 ml) was added 1 M HCl in ether (350 ml). After stirring overnight, the reaction was poured into water (800 ml) and extracted with hexane (3 x 250 ml). The methanol / water layer was concentrated to dryness to give the 1,3-dimethoxy-2-aminopropane hydrochloride (14.0 g) as a waxy solid.

Part D: 4-chloro-6-methyl-3-nitro-2-pyridone: 4-hydroxy-6-methyl-3-nitro-2-pyridone (50.0 g) was treated with cyclohexylamine (40 g) in MeOH ( 300 ml) was heated until everything dissolved. The MeOH was extracted in vacuo and the resulting salt was dried and treated with POC13 (360 ml) at 25 ° C for 48 hours. Excess POCl3 was removed under vacuum and the residue poured into ice / water (1000 ml) and extracted with EtOAc (4 x 250 ml). The combined EtOAc extracts were washed with aqueous NaHC03, brine (3 x 100 ml) dried (MgSO4) and extracted in vacuo. The residue was washed with 20% EtOAc / hexanes (2 x 100 ml) to give the product as a yellow solid (41.3 g, mp 225 ° C).

Part E: 4- [1-methoxymethyl- (2-methoxyethyl) amino-6-methyl-3-nitro-2-pyridone: 4-Chloro-6-methyl-3-nitro-2-pyridone (12.12 g; Part D) was treated with 1,3-dimethoxy-2-aminopropane hydrochloride (10.0 g of Part C) in CH3CN (200 ml) and diisopropylethylamine (20.0 g) at 25 ° C for 24 hours and refluxing for 3 hours The reaction mixture was partitioned between EtOAc (200 ml) and water (50 ml) The EtOAc was washed with water (2 x 50 ml), brine, dried (MgSO) and extracted in vacuo to give the product as a yellow solid (9.4 g, mp 172-173 ° C).

Part F: 2-chloro-N- [1-methoxymethyl- (2-methoxyethyl] -6-methyl-3-nitro-pyridin-4-amine: 4- [1-methoxymethyl- (2-methoxyethyl) amino- 6 -methyl-3-nitro-2-pyridone (9.4 g of Part E), was treated with POCl3 (55 ml) at 25 ° C for 24 hours. The excess P0C13 was removed under vacuum, and the residue was poured into ice / water (20 ml) and extracted with CH2C12 (3 x 150 ml). The combined CH2C12 extract was washed with water, dried (MgSO) and extracted in vacuo to give the product as a yellow solid (9.0 h, mp 85-87 ° C).

Part G: 2-Chloro-4- [1-methoxymethyl- (2-methoxyethyl] amino-6-methylpyridin-3-amine: The product from Part F (9.0 g) was added to acetic acid (80 ml) and methanol (400 ml) To this mixture was added iron powder (91.0 g) in portions, stirred for 5 hours at 60-65 ° C, cooled to room temperature, and filtered through celite. to a brown solid, which was extracted with ethyl acetate (2 x 150 ml), washed with NaHCO3 (100 ml), and brine (100 L) .The organic layer was dried over anhydrous magnesium sulfate, filtered and extracted to produce the product as a pale yellow solid (5.6 g, mp 100 ° C).

Part H: 4-chloro-l- [1-methoxymethyl- (2-methoxyethyl] -6-methyl-lH, 1,2,3-triazole [4,5-c] pyridine: The product of Part G (5.4 g) was dissolved in dichloromethane (100 ml) and 50% aqueous acetic acid (100 ml). To this stirred mixture was added sodium nitrite (1.7 g) in water (10 ml) dropwise at room temperature. After the completion of the addition, the reaction was stirred for an additional 15 minutes. The organic layer was separated, washed with water, dried with anhydrous magnesium sulfate and extracted to a residue The residue was purified by flash column chromatography (CH2C12) to give the product as a pale yellow solid (5.4 g).; pp. 49-50 ° C).

Part I: N- (2-chloro-4,6-dimethylphenyl) -1- [1-methoxymethyl- (2-methoxyethyl] -6-methyl-lH-1, 2,3-triazole [4, 5-c] pyridin-4-amine: The product of Part H (2.0 g) of the above was combined with 2-chloro-4,6-dimethylaniline (1.4 g) in the presence of p-toluenesulfonic acid (1.7 g) in toluene ( 25.0 ml) at 110 ° C for 4 hours The reaction mixture was partitioned between EtOAc (50 ml) and aqueous NaHCO 3 (50 ml), the organic layer was washed with brine, dried and extracted in vacuo to a residue. The residue was purified by flash column chromatography (MeOH: CH2C12 1: 100) to give the title compound as a pale yellow solid (1.7 g), mp 83-84 ° C) after crystallization from the ether / pentane . Elemental analysis for d9H24ClN502: Theory C: 58.53, H: 6.20, N: 17.96; Cl: 9.09. Found: C, 58.69, H: 6.32, N: 17.97, Cl: 9.18.

Part J: N- (2-chloro-4,6-dimethylphenyl) -1- [1-methoxymethyl- (2-methoxyethyl] -6-methyl-lH-1,2,3-triazole mesylate salt [4, 5-c] pyridin-4-amine: The product from Part I (850 mg) was dissolved in dichloromethane (5.0 ml) and then methanesulfonic acid (250 mg) was added in. The solvent was removed and the residue crystallized at room temperature. from 2-propanol (2.5 ml) to give the mesylate salt (920 mg; mp 179-180 ° C) as a white crystalline solid Elemental analysis for C2oH28ClN5? 5S: Theory C: 49.43, H: 5.82, N : 14.41, Found: C: 49.42, H: 5.79, N: 14.37.

The compounds listed in Tables 5 and 6 were prepared by the methods employed in Examples 1-53 and 526.

Table 5 3H-1, 2, 3-triazo l [4,5-d] p irimidines Ex. No. Ar R3 m.p. (° C¡ 260 2-Br-2,6- (Me) 2- • Ph CHÍE) 2 134-135 261 2-Cl-2,6- (Me) 2 - Ph CH (? Í) 2 133-134 262 4-Br-2-Cl-6-Me- • Ph CH (Et) 132-133 263 2.4- (Cl) 2-6-Me-Ph CH (Et) 2 132-133 264 2.4-. { Br) 2-6-F-Ph CH (Et) 2 186-188 265 4-Br-2-Me-Ph CH. { Et) 2 125-127 266 4-NMe2-2-Me-Ph CH (Et> 2 136-137 267 4-Cl-2-Me-P CH (Et) 2 116-118 268 4-I-2-Me-Ph CH (Et) 2 139-140 269 4-NMe2-2.6- (Me) 2-Ph CH (Et) 2 160-161 270 2-Cl-4-Me-Ph CH (Et) 2 100-101 271 2-Br-4-0Me-P CH (Et> 2 146-147 272 2-Br-4-NMe2-Ph CH (Et) 166-167 273 2-Me-4-CH2OMe-Ph CH (Et) 2 oil 274 2-CN-4-Me-Ph CH (Et) 2 221-223 275 4-CN-2-Me-Ph CH (Et) 2 216-218 276 2,4,6-Me3-Ph CH (nPr) Me 140.5-142 277 4-Br-2,6-Me2-Ph CH (nPr) Me 131-133 278 2-Cl-4,6-Me2-Ph CH (nPr) Me amorphous 279 2-Cl-4,6- (0Me) 2 - Pn CH (pPr) Me 144-145 280 2,4,5-Me3-Ph CH (nPr) Me > 110-112 281 4-Cl-2-Me-Ph CH (nPr) Me 99-101 282 4-Br-2-Me-Ph CH (nPr) Me 83-84.5 283 4-1-2-Mß-Ph CH (nPr) Me 104-105 284 2,4-Me2-Ph CH (nPr) Me 74.5-76.5 285 2-Br-4-CH (Me) 2-Ph CH (nPr) Me amorphous 286 2-Br-4-Cl-Ph CH (nPr) Me 104-108 287 2-Br-4-NMe2-Ph .CH (nPr) Me amorphous 288 4-NM? 2-2-Me-Ph CH (nPr) Me amorphous 289 2,4- (Me) 2-Ph CH (Et) n-Pr 88-89 290 4-OMe-2-Me-Ph CH (Et) n-Pr 111-112 291 2,4- (SMe) 2-Ph CH (Et) n-Pr 65- 66 292 2-Br-4-CF3-Ph CH. { Et) n-Pr '91-92 293 4-Ac-2-Br-Ph CH (Et) n-Pr 138-139 294 4-NMe2-2-Me-Ph CH (Et) n-Pr 116.5-118 295 4-Cl-2-Me-Ph CH (Et) n-Pr amorphous 296 4-I-2-Me-Ph CH (Et) n-Pr 110-111.5 297 2.6-Me2-4-I-Ph CH (Et) n-Pr 158-160 298 4-AC-2-Me-Ph CH (Et) n-Pr 107-110.5 2-NMe2-4-Me-Ph CH (Et) n-Pr 106-107 300 4-3SIMe2-2.6- (Me) 2-Ph CH (Et) n-Pr 146-148 '3C1 2,4- (SMe) 2-Ph CH (n-Pr) 2 105-106 302 -OMe -2-Me-Ph CH (n-Pr) 2 109-110 303 2-Br-4-N (Me) 2-Ph CH (n-Pr) 2 102-103 304 2.4- (Me) 2- Ph CH (n-Pr) 2 97-98 305 4-Ac-2, ß- (Me) 2-? H CH (n-Pr) 162-164 30S 4-Cl-2-Me-Ph CH (n- Pr) 2 126-127.5 307 4-NMe2-2-Me-Ph CH (n-Pr) 2 129-130.5 308 4-I-2-Me-Ph CH (n-Pr) 2 98.5-101 309 2-Me -4-CH2OMe-Ph CH (n-Pr) 2- oil 310 4-Br-2,6-Me2-Ph CH (Et) CH2OMe 140-141 311 4-Br-2,6-Me2-Ph CH (Et ) CH2OMe 139-140 312 2-Cl-4,6- (Me) 2-Ph CH (Et) CH2OMe 141-142 313 4-Br-2-Cl-6-Me-Ph CH (Et) CH2OMe 121-122 314 2.4- (Cl) 2-6-Me-Ph CH (Et) CH2OMe 109-110 315 2.4- (Br) 2-6-F-Ph CH (Et) CH2OMe 147-148 316 2-Br -3.4.6- (Me) 3-Ph CH (Et) CH2OMe 166-167 317 3-Br-2,4,6- (Me) 3-Ph CH (Et) CH2OMe 147-148 318 4-Br-2 , 6- (F) 2-Ph CH (Et) CH2OMe 148-149 319 2-Br-4-Cl-6-F-Ph CH (Et) CH2OMe 139-140 320 2-Br-4,6- (F ) 2-Ph CH (Et) CH2OMe 124-125 321 4-CN-2,6- (Cl) 2-Ph CH (Et) CH2OMe 180-181 322 2,4- (SMe) 2-Ph CH (Et) CH2OMe 75-77 323 2-Br-.4_-N (Me) 2-Ph CH (Et) CH2OMe 110-112 324 2-Cl-4-CN-6-Me-Ph-CH (Et) CH2OMe 145-146 325 2-Cl-4-CN-Ph CH (Et) CH2OMe 140 326 '2,4,5- (Me) 3-Ph CH (Et) CH2OMe 108-109 327 2.4- (Me) 2-Ph CH (Et) CH2OMe 104-105 328 4-Br-2,6- (Et) 2-Ph CH (Et) CH2OMe 151-152 329 4-Br-2,6- (Cl) 2-Ph CH (Et) CH2OMe 109-110 330 2-3r-4,6- (Cl) 2-Ph CH (Et) CH2OMe 113-114 331 2,6- < Br) 2-4-Cl-Ph CH (Et) CH2? Me 153-154 332 4-Br-2-Me-6-N02-Ph CH (Et) CH2OMe 150-151 333 4-OMe-2-Me-Ph CH (Et) CH2OMT 128-129 334 2.5-Cl2-4-NMe2-Ph CH (Et) CH2OMe 84-85 335 '2,4-Cl2-Ph CH (Et) CH2OMe 114-116 336 2-Br-4-Cl-P CH (? T) CH2OMe 133.5-135 337 4-Cl-2-Me-Ph CH (Et) CH2? Amorphous Me 338 4-1-2, 6-Me2-Ph CH (Et) CH2OMe 148.5-150 339 4-NMß2-2.6- (Me) 2-Ph CH (Et) CH2OMe 144-146 340 2-Cl-4-Me-Ph CH (Et) CHOMe 88-89 341 2-Br-4-OMe-Ph CH (Et) CH2OMe 118-120 342 2-Me-4-CH2OMe-Ph CH (Et) CH2OMe oil 343 2,4,6-Me3-P CH (Et) CH2OEt 127-130 344 2-Cl-4,6-Me2-Ph CH (Et) CH2OEt 61-62 345 4-Br-2,6-Me2-Ph CH (Et) CH2OEt 104-107 346 2,4-Mß2-Ph CH (Et) CHOOEt oil 347 2-Br-4-Me-Ph CH (Et) CH2OEt 100-102 348 2,4,6-Me3-Ph CH (Et) CH2OEt 94-96.5 349 2,4,6-Me3-Ph CH (C3H7) CH20Me 136-138 350 2-Cl-4,6-Me2-Ph CH (C3H7) CH20Me .amorfo 351 4-Br-2,6-Me2-Ph CH (C3H7) CH20Me 139-140.5 352 2,4-Me2-Ph CH (C3H7) CH20Me oil 353 2-Br-4-Me-Ph CH (C3H7) CH20Me 100.5-102 354 -. 354 -_ 2,4,5-Me3-Ph CH (C3H7) CH20Me 122-124 355 2,4,6-Me3-Ph CH (CHMe2) CH2? Me 94-96.5 356 2-Cl-4,6-Me2-Ph CH (CHMe2) CH20Me 155-156 357 4-Br-2,6-Me2-Ph CH (CHMe2) CH20Mβ 156-159 358 2,4-Me2-Ph CH (CHMe2) CH2? Me 99-103 359 2-Br-4-Me-Ph CH (CHMß2) CH20Me 93-95 360 2.4.5.-Me3-Ph CH (CHMe2) CH20Me 130-131 361 2".4,6-Me3-Ph CH (sec-Bu) CH2? Me 168-170.5 362 2-Cl-4,6-Me2-Ph CH (sec-Bu) CH20Me 136-139 363 4-Br-2,6-Me2-Ph CH (sec-Bu) CH20Me 139-142 364 2,4-Me2-Ph CH (sec-Bu) CH2OMe 85-87 365 2-Br-4-Me-Ph CH (sec-Bu) CH2OMe 78.5-80 366 2,4,5-Me3-Ph CH (sec-Bu) CH2OMe 150-153 367 2,4,6-Me3-Ph CH (ÍS? Bu) CH2? Me 126.6-129 368 2-Cl-4,6-Me2-Ph CH (isoBu) CH20Me 103-10 369 4-Br-2,6-Me2-Ph CH (isoBu) CH20Me 127.5-130 370 2,4-Me2-Ph CH (isoBu) CH20Me amorphous 371 2-Br-4-Me-Ph CH (isoBu) CH2? Me 99-100.5 372 2,4,5-Me3-Ph CH (iS? BU) CH20Me 134-138 373 2-Cl-4,6-Me2-? H CH (CH20Me) 2 98-99 374 4-Br-2,6-Me2-Ph CH (CH2? Me) 2 115-116 375 4-OMe-2-Ph-Ph CH (CH20Me) 2 55-57 376 3-Br-2,4,6-Me3-Ph CH (CH20Me) 2 151-152 377 4-Br-2,6-Et2-Ph CH (CH2OMe) 2 154-155 378 2,4,6- (Me) 3-Ph CH (CH 2? Me) 2 136-137 379 4-3r-2-Me-Ph CH (CH2OMe) 2 1C4-108 380 2-3r-4-Cl-Ph CH (CH20Me) 2 123-125 381 2,4-Cl2-Ph CH (CH2? Me) 2 87.5-90 382 4- Me2-2-Me-Ph CH (CH2OMe) 2 159-162 383 4-Cl-2-Me-Ph CH (CH20Me) 2 100-102 384 4-I-2-Me-Ph CH (CH2? Me) 2 116-117.5 385 2,6-Me2-4-I-Ph CH (CH20Me) 2 amorphous 386 2- Me2-4-Me-Ph CH (CH20Me) 2 100-102 387 2-Br-4-Me-Ph CH (CH2? Me) 2 106-108 388 2-Cl-4-Me-Ph CH (CH2? Me) 2 114-115 389 4-NMß2-2.6- (Me) 2-Ph CH (CH20Me) 2 71-73 390 2-Br-4-OMe-Ph * CH (CH2? Me) 2 127-128 391 2-Br-4-NMß2-Ph CH (CH2OMe) 2 139-141 392 2-Me-4-CH2? Me-Ph CH (CH20Mß) 2 oil 393 2,4,6-Me3-Ph CH (Et) CH2Ph amorphous 394 2,4,6-Me3-Ph 2-OMe-6-Me-Ph 202-205 395 2,4,6-Me3-Ph CH (Et) CH20H amorphous 396 2,4,6-Me3-Ph CH (Me) isoBu 126-127 397 2,4,6-Me3-Ph CH (Me) isoPr 161 -162 398 2,4,6-Me3-Ph ciel open il 174-175 399 2,4,6-Me3-Ph cycloexil 198-199 400 2,4, ß-Me3-Ph 4-methylcyclohexyl 178-180 Note: (+), (-) r (R) or (S) denotes the respective isomers Table 6 3H-1, 2, 3-triazolo [4, 5-d] pyrimidines Ex. No. Ar Ri m.p. (° C) 401 -. 401 - 2,4,6-Me3-Ph H 146-147 402 4-Br-2,6-Me2-Ph H 139-140 403 2,4,6-Me3-Ph CF3 176-177 404 4-Br-2,6-Me2-Ph CF3 183-184 405 '2-Cl-4,6-Me2-Ph CF3 174-175 406 2,4-Cl2-6-Me-Ph »CF3 160-161 407 2-Cl-4,6-Me2-Ph C2H5 111-112 408 2-Cl-4,6-Me2-Ph MeOCH2 87-88 EXAMPLE 409 6- [N- (2-chloro-4,6-dimethylphenyl)] - 9 - [(1-ethoxymethyl) propyl] -2-methyl-9H-purin-6,8-diamine: Part A: 2-Methyl-4-chloro-6- (1-methoxymethyl) propylamino-5-aminopyridine (450 mg, 1.84 mmol) was reacted with cyanogen bromide (234 mg, 2.2 mmol) in refluxing methanol 24 hours. The solvent was removed in vacuo and the resulting crude oil was taken up in ethyl acetate and washed 3 times with saturated aqueous NaHCO3. The organic layer was dried, and then extracted in vacuo and the crude product was chromatographed on silica gel (20 g, pure ethyl acetate) to afford 240 mg (48 &) of 8-amino-6-chloro-9- [(1-methoxymethyl) propyl-2-methyl-9H-purine.

Part B: The product of Part B (50 mg, 0.20 mmol) was treated with 2-chloro-4,6-dimethylaniline (30 mg, 0.20 mmol) in H »Cl 1.0 N under reflux for 24 hours. The reaction mixture was cooled, then poured into saturated aqueous NaHC03, and extracted (3 times, 50 ml) with ethyl acetate. . The organic fractions were combined, dried and extracted in vacuo. The resulting crude product was chromatographed on silica gel (20 mg, pure ethyl acetate) to give 55 mg (71%) of the title compound. Analysis calculated for C? 9H25N60cl: C, 58.76; H, 6.44; N, 21.64. Found: C, 58.50; H, 6.32; N, 21.72.

The compounds of Table 7 can be made by the methods exemplified in Examples 209-211 and 409.

Table 7 9H-imidazole, [4, 5-d] pyrimidines: Ex. No. Ar R2 R3 m.p. (° C) 410 2.4.6- (Me) 3-Ph H CH (Et) CH20CH3 212-213 411 2,4,6- (Me) 3-Ph NH2 CH (Et) CH20CH3 oil 412 2-Cl-4,6- (Me> 2-Ph NH2 CH (CH20CH3) 2 oil • 413 2.4, ß- (Me) 3-Ph NH2 CH (CH20CH3) 2 oil EXAMPLE 414 (S) - (-) - N - (2-chloro-4,6-dimethylphenyl) -6-methyl-1- (1-ethoimeti-3-methoxypropyl) -1 H-1,2,3-triazole [4 , 5-c] pyridin-4-amine.

Part A: Dispersed in L-dimethyl aspartate hydrochloride (5 g, 25.3 mmol) and triphenylmethyl chloride (7.65 g, 27.5 mmol) in dry CH3CN (50 mL at 0 ° C. To Et3N (4.5 mL, 32.3 mmol ) was added dropwise, followed by N-methylmorpholine (2.5 ml, 27.5 mmol) The mixture was stirred at 0 ° C for 1 hour and at 25 ° C for 30 minutes, then it was partitioned between EtOAc (200 ml) and Water (50 ml) and the organic extract was washed with water (50 ml), brine (50 ml), dried (MgSO 4) and extracted in vacuo.The product, diethyl N-triphenylmethyl aspartate, was> 90 % and cleaned by NMR analysis.

NMR aH (CDC13) d 7.16-7.51 (, 15H), 3.68 (s, 3H), 3.66-3.74 (m, 1H), 3.26 (s, 3H), 2.93 (d, 1H, J = 9.9 Hz), 2.63 -2.69 (dd, 1H, Ji = 25.6, J2 = 5.1 Hz), 2.48-2.55 (dd, ÍH, Jx 14.6 Hz, J2 = 7 Hz).

Part B: The (S) -diethyl-N-triphenylmethyl aspartate (approximately 25 mmol) was dissolved in dry THF (150 mL) and cooled to 0 ° C. Thereto, a 1 M solution of LiAlH in THF (50 ml, 50 mmol) was added dropwise and the reaction was stirred for 2 hours and allowed to warm to 25 ° C. Then, it was cooled and flooded with water (5 ml) and 1 N NaOH (4 ml), diluted with ether (200 ml) and the precipitated solids were completely filtered. The filtrate was precipitated in vacuo to give the product, 2-N-triphenylamino-1,4-butanediol (> 90% clean by NMR analysis). 1H-NMR (CDC13) d 7.17-7.57 (m, 15H), 3.68-3.77 (m, ÍH), 3.56-3.63 (m, ÍH), 3.19 (d, 3 ÍH, J = 8.8 Hz), 2. 76-2.86 (m, 2H), 2.2-2.7 (br, 3H), 1.54-1.63 (m, 1H), 1.36-1.54 (m, ÍH).

Part C: (S) -2-N-triphenylamino-1,4-butanediol (approximately 25 mol) dissolved in dry THF (50 ml) in a suspension of 60% NaH in oil (2.34 g, 58.5 mmol) was added. ) in dry THF (50 ml) at 0 ° C, and the mixture was stirred at 9 ° C for 30 minutes and at 25 ° C for 1 hour. Then, it was cooled in an ice bath and CH3I (3.6 m, 58.5 mmol) was added dropwise. The reaction was stirred at 0 ° C for 30 minutes and at 25 ° C for 2 hours, the excess NaH was flooded with water and the THF was extracted. The residue was partitioned between EtOAc (200 ml) and water (50 ml) and the organic extract was washed with water (50 ml), brine (50 ml), dried (MgSO 4) and extracted in vacuo. The product 2-N-triphenylamino-1,4-dimethoxybutane was > 90% clean by NMR analysis.

XH NMR (CDC13) d 7.15-7.59 (m, 15H), 3.34-3.41 (m, HH), 3.22 -3.30 (m, HH), 3.24 (s, 3H), 3.03 (s, 3H), 2. 86 (dd, ÍH, Ja = 9.5 Hz, J2 = 3.3 Hz), 2.65-2.75 (m, 1H), 2.4-2.46 (br, ÍH), 2.30-2.35 (m, ÍH), 2.57-2.8 (m, 2H).

Part D: The (S) -2-N-triphenylamino-1,4-dimethoxybutane (about 25 mmol) was dissolved in a mixture of CH2C12 (100 m) and methanol (50 ml) and 1M HCl in ether was added ( 50 ml). The reaction was stirred at 25 ° C for 16 hours, the solvent was completely extracted and the residue was washed with ether / hexane 1: 1 (3 x 50 ml). The remaining oil, 2-amino-1,4-dimethoxybutane hydrochloride, was dried under vacuum (3.87 g, 88%).

NMR XH (CDCl 3) d 8.2-8.5 (br, 3H), 3.5-3.7 (m, 5H), 3.41 (s, 3H), 3.36 (s, 3H), 2.05-2.2 (m, ÍH), 1.90-2.01 (my h) .

Part E: (S) -6-methyl-3-nitro-4- (1-methoxymethyl-3-methoxypropylamino) -pyridone: The l-methoxymethyl-3-methoxypropylamine (4.19 g, 22.3 and 4-chloro) was mixed. 6'-methyl-3-nitropyridone (3.87 g, 22.3 mmol) in CH3CN (70 ml) and diisopropyl-3-ylamine (9.4 ml, 53.6 mmol) was added in. The reaction was stirred at 25 ° C for 16 hours and refluxing for 2.5 hours The solvent was removed and the residue was dissolved in CH2C12 (150 ml) and CH2C12 was washed with water (80 ml) The water was extracted with CH2C12 (50 ml) and the combined organic extracts were dried (MgSO4) and extracted in vacuo The residue was crystallized from EtOAc and washed with 40% EtOAc / hexanes to give the product 44.8 g, 75%).

XK-NMR (dmso) d 9.13 (d, ÍH, J = 8.8 Hz), 5.9 (s, ÍH), 3.92-4.02 (m, ÍH), 3.20-3.25 (, 2H), 3.28-3.4 (, 2H), 3.25 (s, 3H), 3.18 (s, 3H), 2.09 (s, 3H), 1.65-1.90 (m, 2H).

Part F: (S) -2-chloro-6-methyl-3-nitro-N- (1-methoxymethyl-3-methoxypropy) pyridin-4-amine: 4- [3- (1, -dimethoxybutyl) was dissolved amino] -6-methyl-3-nitropyridone (4.8 g, 16.82 mmol) in P0C13 (50 mL) and stirred at 25 ° C for 40 hours; Then the reaction was poured into ice / water- (500 ml), left. The reaction was neutralized with solid NaHCO3, then EtOAc (150 ml) was added and extracted with EtOAc (2 x 300 ml). The EtOAc was dried (MgSO4) and extracted in vacuo to give the product. NMR tE (CDC13) d 7.08 (d, ÍH, J = 7.7 Hz), 6.65 (s, ÍH), 3.85-3.95 (m, ÍH), 3.30-3.50 (m, 4H), 3.38 (s, 3H), 3.33 (s, 3H), 2.43 (s, 3H), 1.80-2.02 (m, 2H).

Part G: (S) -3-amino-2-chloro-4-N- (1-methoxymethyl-3-methoxypropyl) -6-m.ethyl-pyridin-4-amine: The 2-chloro- 6-Methyl-3-nitro-N- (1-ethoxymethyl-3-methoxypropyl) pyridin-4-amine (ca. 16.82 mmol) at reflux with Fe powder (10 m) in methanol (120 ml) in the presence of acid Glacial acetic acid (10 ml) for 2 hours. Then, the iron was filtered through celite, the celite was washed with methanol (80 ml) and the filtrate was extracted in vacuo. The residue was dissolved in 10% HCl (120 ml) and EtOAc (160 ml) was added. The mixture was neutralized with solid NaHCO 3 and the aqueous layer was extracted with EtOAc (2 x 100 ml). The combined organic extracts were washed with brine (50 ml), dried (MgSO 4) and extracted in vacuo (4.1 g).

XH NMR (CDC13) 6.4 (s, ÍH), 5.2-5.35 (br s, 1H), 3.70-3.809 (m, ÍH), 3.2-3.8 (m, 6H), 3.38 (s, 3H), 3.33 (s) , 3H), 2.42 (s, 3H), 1.8-2.0 (m, 2H).

Part H: (S) -4-chloro-l- (l-methoxymethyl-3-methoxypropyl) -6-methyl-lH-l, 2,3-triazole [4,5-c] pyridine: The 3-amino- 2-chloro-6-methyl-4-N- (1-methoxymethyl-3-methoxypropyl) pyridin-4-amine (4.1 g, 14,989 mmol) was dissolved in a mixture of CH2C12 (40 ml) and 50% acetic acid (40 ml) and cooled to 0 ° C in an ice bath. To this solution was added dropwise a solution of NaN02 (1.84 g, 26.86 mmol) in water (10 ml) and the reaction was stirred at 0 ° C for 30 minutes and at 25 ° C for 1.5 hours. Then, the acetic acid was neutralized with solid NaHCO 3 and water (80 ml) was added. The mixture was extracted with EtOAc (2 x 100 ml) and the organic extracts were combined and washed with brine (50 ml), dried and extracted in vacuo. The residue was chromatographed on silica gel (40% EtOAc / hexane eluent) to give the product (4.05 g, 56% total for the eight steps).

XH NMR (CDC13) d 7.25 (s, ÍH), 5.04-5.13 (m, ÍH), 3.98 (dd, ÍH, Ji = 9.9 Hz, J2 = 8.4 Hz), 3.84 (dd, ÍH, üi = 10.2 Hz, J2 = 4.4 Hz), 3.39 (dt, ÍH, Ji 9.9 Hz, J2 = 4.8 Hz), 3.25 (s, 3H), 3.17 (s, 3H), 2.19 (dt, ÍH, Jt = 9.5 Hz, J2 = 4.0 Hz), 2.68 (s, 3H), 2.22-2.6 (m, 2H).

Part I: (S) -4-chloro-l- (l-methoxymethyl-3-methoxypropyl) -6-methyl-lH-l, 2,3-triazsl [4, 5-c] pyridine (2.0 g, 7 mmol ) and 2-chloro-4,6-dimethylaniline (1094 g, 7 mmol) were dissolved in dried THF and cooled to 0 ° C in an ice bath. Thereto, a 1 M solution of sodium hexamethyldisilazide (16 ml, 16 mmol) was added dropwise and the solution was stirred at 0 ° C for 45 minutes. Then, it was flooded with water (30 ml) and partitioned between EtOAc and water (20 ml). The organic extract was washed with brine (50 ml), dried (MgSO) and extracted in vacuo. The residue was purified by chromatography on silica gel (EtOAc al 40% / hexane eluent) and crystallized from hexane to give the product (2.4 g, 85%), m.p. 108-109 ° C, [] D25 -32.38 (c O 0.200 g / dL, CHC13) 99.6% is by chiral HPLC. This was converted to the methylsulfonate salt, m.p. 98-100 ° C, after crystallization from ether / hexanes, [] D25 29.00 (c = 0.200 g / dL, CHC13).

EXAMPLE 414A (R, S) -N- (2-chloro-4,6-dimethylphenyl) -6-methyl-1- (1-methoxymethyl-3-methoxypropyl) -1H-1,2,3-triazole [4, 5] c] pyridin-4-amine.

Part A: (R, S) -2-aminobutyrolactone hydrobromide (8.0 g, 44 mmol) and triphenylmethyl chloride (12.8 g, 46 mmol) were dispersed in dry CH3CN (80 mL) at 25 ° C. To that was added dropwise Et3N (13.6 ml, 100 mmol), the reaction mixture was stirred at 25 ° C for 4 hours and partitioned between EtOAc (120 ml) and water (50 ml). The organic layer was washed with water (50 ml), brine (50 ml), dried (MgSO) and extracted in vacuo. The residue was recrystallized from EtOAc / hexanes to give the 2-triphenylmethylamino-butyrolactone (10.5 g).

Part B: Aluminum hydride and lithium (1.4 g, -36 mmol) was dispersed in dry THF (50 ml) and cooled to 0 ° C in an ice bath. To this solution was added dropwise a solution of 2-tp-phenylmethylamino-butyrolactone (11 g, 31.9 mmol) in dry THF (70 ml), over a period of 20 minutes. After the addition, the reaction mixture was stirred at 0 ° C for 1 hour, at 25 ° C for 3 hours and was flooded by the sequential addition of water (2 ml), 1 N NaOH, (2 ml) and water (3 ml), and diluted with ether (150 ml). The precipitated solids were filtered completely and the filtrate was concentrated in vacuo to give (R, S) -2-N-triphenylamino-1,4-butanediole. This was used in the same synthesis scheme as previously described for the chiral material (Example 414, Parts C-I) to obtain the racemic material.

The compounds listed in Table 8 were prepared by the methods exemplified in Examples 221-232, 259, 414 and 414A: Table 8 lH-1, 2,3-triazole [4,5-c] pyridines Ex. No. R3 Ar m.p. (° C) 415 CH (Et) 2 '4-Br-2,6- (Me) 2-Ph 191-192 416 CH (Et) 2 2,6- (Me) 2-4-SMe-Ph 172-173 417 CH (Et) 2 2-Cl-4,6- (Me) 2-Ph 171-172 418 CH (Et) 2 2,4- (Cl) 2-6-Me-Ph 164-165 419 CH (Et) 2 2,4- (Me) 2-Ph 90-91 420 CH (Et) 2 2-Me-4-OMe-Ph 104-105 421 CH (Et) 2 2-Br-4,6- (Me) 2-Ph 178-179 422 CH (Et) 2 4-CN-2,6- (Cl) 2-Ph 189-190 423 CH (Et) 2 3-Br-2,4,6- (Me) 3-Ph 156-157 424 CH (Et) 2 4-Br-2-SMe-Ph 112-114-425 CH (Et) 2 2-CN-4,6-Me2-Ph 181-183 426 CH (Et) 2 2-Br-5-F-4-Me-Ph 132-134 427 CH (Et) 2 4-Br-5-F-2-Me-Ph 115-116 428 CH (Et) 2 2,4-Br2-Ph 164-166 429 CH (Et) 2 4-Ac-2-SMe-Ph 142-144 430 -. 430 - CH (Et) 2 4-Br-2-Cl-Ph 152-153 431 CH (Et) 2 2,4-Cl2-Ph 134-135 432 CH (Et) 2 2,4-Me2-ß-SMe-Ph 135-136 433 CH (Et) n-Pr 2,4,6- (Me) 3 ~ Ph 117-118 434 CH (Et) CH20Me 4-Br-2,6- (Me) 2-Ph 165-166 ? • a s t -r * CH (Et; CH20Me * 2-C1-4, 6- (Me) 2 ~ 126-127 436 CH (Et) CH2? Me 3-Br-2.4.6- (Me) 3-Ph 117-118 437 CH (Et) CH20Me 2.4- (Cl) 2-6-Me-Ph 131-134 438 CH (Et) CH 2? Me 2-Br-4,6- (Me) 2-Ph 127-128 439 CH (Et) CH 2? Me 4-Br-2-Cl-6-Me-Ph 136-137 440 CH (Et) CH20Me 4-Br-2,6- (Cl) 2-Ph 119-120 441 CH (Et) CH20Me 2,4- (Me) 2-Ph 76-77 442 CH (Et) CH20Me 4-MeO-2-Me-Ph 75-77 443 CH (Et) CH2OMe • 2,4,5- (Me) 3-Ph 94-95 444 CH (Et) CH20Me 2-Cl-4,6- (OMe) 2-Ph 167-168 445 'CH (Et) CH2OMe 2,4,5- (Cl) 3-Ph 151-152 446 CH (Et) CH20Me 2 * 5- (Cl) 2-4-N02-Ph 157-158 447 CH (Et) CH20Me 2-CN-4 / 5- (OMe) 2-Ph 162-163 448 CH (Et) CH20Me 2-Me-4,5- (OMe) 2-Ph 118-119 449 CH (Et) CH20Me 2.6-Cl2-4-OMe-Ph 136-137 450 CH (Et) CH2OCH3 4-Br-2-OMe-6-Me-Ph 159-162 451 CH (Et) CH2OCH3 4-Br-5-F-2-Me-Ph 111-113 452 CH (Et) CH 2 OCH 3 2-CN-4,6-Me 2-Ph 154-156 453 CH (Et) CH2OCH3 2-OMe-4,6-Me2-Ph 115-116 454 CH (Et) CH 2 OCH 3 2-Ac-4-Cl-6-Me-Ph 127-129 455 CH (Et) CH2OCH3 2-Br-4,6-F2-Ph 138-140 456 CH (Et) CH2OCH3 2,4,6-Me3-Ph 119-121 457 CH (? T) CH2OCH3 4-Br-2-SMe-Ph 70-73 458 CH (Et) CH2OCH3 2,4-Br2-Ph 119-120 459 CH (Et) CH2OCH3 2,4,6-Me3-Ph 113-115 460 CH (Et) CH2OCH3 2,4,6-Me3-Ph 113-115 461 CH (Et) CH2OCH3 2,4-Me2-6-SMe-Ph 104-106 462 CH (Et) CH2OCH3 4-Br-2-Me-Ph amorphous 463 CH (Et) CH2OCH3 4-1-2-Me-Ph 103-105 464 CH (Et) CH2OCH3 3-F-2,4,6-Me3-Ph amorphous 465 CH (Et) CH2OCH3 4-Cl-2-Me-Ph 104-105 466 CH (Et) CH2OCH3 4-Br-2,6-F2-Ph 138-140 467 CH (Et) CH 2 OCH 3 4-Cl-2-CN-6-Me-Ph 177-180 468 CH (CH20Me) 2 2,4,6- (Mß) 3-Ph 115-116 469 CH (CH 2? Me) 2 4-Br-2,6- (Me) 2-Ph 145-146 470 CH (CH20Me) 2 2.4- (Cl) 2-6-Me-Ph 111-112 471 CH (CH20Me) 2 3-Br-2,4,6- (Me) 3-Ph 105-106 472 CH (CH2? Me-2 2.4, 5- (Mß) 3-Ph 110-111 473 CH (CH 2 OMe) 2 2-Br-4-CH (Me) 2-Ph 107-108 474 CH (CH20Me) 2 2-Br-4,6- (Me) 2-Ph 83-84 475 CH (CH2? Me) 2 2,4- (Me) 2-Ph 72-73 476 CH (CH20Me) 2 4-MeO-2-Me-Ph '65-67 477 CH (CH20Me) 2 4-CH (Me) 2-Ph oil 478 CH (CH2? Me) 2 2.5-Cl2-4-N (Me) 2-Ph 110-111 479 CH (CH2? Me) 2 2-Me-4,5- (OMe) 2-Ph 111-112 480 CH (CH2? Me) 2 4-Cl-2,5- (OMe) 2-Ph 167-168 481 CH (CH20Me) 2 2-Cl-4,5- (Me) 2-Ph 169-170 482 CH (CH20Me) 2 2.6- (Cl) 2-4-OMe-Ph 145-146 483 CH (CH2? Me) 2 4-t-Bu-2,6- (Me) 2-Ph 134-135 484 CH (CH2? Me) 2 4-Cl-2-Me-5-N02-Ph 163-164 485 CH (CH 2 Me) 2 4-Br-2-Cl-5-Me-Ph 159-160 486 CH (CH2? Me) 2 2-Cl-4-OMe-6-Me-Ph 117-118 487 CH (CH2? Me) 2 4-Cl-2,5-Me2-Ph 115-116 488 CH (CH2? Me) 2 2-Cl-4-CN-6-Me-Ph 127-128 489 CH (CH20Me) 2 4-Br-2,6- (Et) 2-Ph 168-169 490 CH (CH20Me) 2 4-Br-2-Cl-6-Me-Ph 104-105 491 CH (CH2? Me) 2 2-Cl-4,6- (OMe) 2-Ph 139-140 492 CH (CH2? Me) 2 2-Br-4,6- (OMe) 2-Ph 155-156 493 CH (CH2? Me) 2 5-Cl-4-N e2-2-OMe-Ph 110-111 494 CH (CH20Me) 2 2.4- (Cl) 2-5-CF3-Ph 162-163 495 CH (CH20Me) 2 4-Cl-2-OMe-5-CF3-P 161-162 496 CH (CH2OMe) C2H4OMe 4-Cl-2-Et-6-Me-Ph 101-103 497 CH (CH2OMe) C2H4? Me 2-F-4,6-M? 2-Ph 172-174 498 CH (CH2? Me) C2HOMe 2,4-Mß2-6-SMe-Ph 147-148 499 CH (CH2OMe) C2H4OMe 2-Br-4,6-Me2-Ph 144-147 500 CH (CH2? Me) C2H4OMe 4-Cl-2,6-Me-Ph 97-100 501 CH (CH2OMe) C2H4OMe 4-Br-2-Et-6-Me-Ph 111-113 502 CH (CH2OMe) C2H OMe 2,4,6-Me3-Ph 115-116 503 CH (CH2OMe) C2H OMe 4-Br-2,6-M? 2-Ph amorphous 504 CH (CH2OMe) C2H4OMe 4-Br-2-OMe-6-Me-Ph 131-133 505 CH (CH2? Me) C2H4OMe 2-Cl-4,6-Me2-Ph 127-129 506 CH (CH2OMe) C2H OMe 2-1-4, 6-Me2-Ph 150-152 507 CH (CH2OMe) C2H4OMe 2-Cl-4-I-6-Me-Ph 119-120 508 CH (CH2OMe) C2H4OMe 3-F-2,4,6-Me3-Ph amorphous 509 CH (CH2? Me) C2H4 Me 2-Cl-4,6-Me2-Ph 127-129 510 CH (CH2OMe) C2H4OMe 2-Cl-4,6-Me2-Ph 108-109 511 CH (CH2OMe) C2H OMß 2-Br-6-F-4-Me-Ph 150-152 512 CH (CH2? Me) C2H4OMe 2-Cl-5-F-4,6-Me2-Ph 107-108 513 CH (CH2OMe) C2H4OMe 3-F-2,4,6-Me3'-Ph 117-119 514 CH (CH2OMe) C2H4OMe 3-F-2,4,6-Me3-Ph 117-119 Note: (+), (-), (R) (S) denotes the respective isomers The compounds listed in Table 9 were prepared by the methods exemplified in Examples 209-211 using the intermediate compound of Example 259, Part G.

Table 9 lH-imidazo [4, 5-c] pyridines Ex. NO. Ar R R3 m.p. (° C) 524 2-Cl-4,6- (Me) 2-Ph H CH (CH20CH3) 2 129-130 525 2-Cl-4,6- (Me) 2-Ph Me CH (CH 2? CH 3) 2 156-157 EXAMPLE 526 This example illustrates an alternative method to make the compound of Example 32.

Part A: (+) - 1-Methoxy-2-butanol methanesulfonate (1). A solution of l-methoxy-2-butane (52.08 g, 57.23 ml, 0: 5 mol) and Et3N (108.2 ml), 0.7 mol, 1.5 equivalent) in CH2C12 (500 ml) was treated , ta with methanesulfonyl chloride (68.73 g, 46.4 1.2 equivalent goal) at 0 ° C under N2 L m 1, 0.6 molr reaction mixture was heated to 25 ° C and stirred at 25 ° C for additional 4 hours before Cool rapidly with H20 (300 ml). The two layers were separated, and the aqueous layer was extracted with CH2C12 (3 x 100 ml). The combined CH2C12 extracts were washed with H2O (2 X 200 ml) and saturated aqueous NC1 (200 ml), dried (MgSO4) and concentrated in vacuo. The residue was dried enough in vacuo to give the desired mesylate 1 (85-90.0 g, 91 g theoretical, 93-98%) as a pale yellow oil, which was sufficiently pure and used directly in the next reaction without further purification. The analytically pure sample of 1 was obtained by purification of column chromatography on silica gel and 1 was obtained as a colorless oil.

Part B: (±) -l-methoxy-2-butyl azide (2). A solution of crude mesylate 1 (90. g, 0.495 mol) in DMF (500 ml) was treated with NaN3 (48.22 g, 0.74 mol, 1.5 equivalent) at 25 ° C under N2. The resulting reaction mixture was heated to 55-60 ° C for 6-8 hours with stirring before being cooled with H20 (500 mL). The pale yellow solution was then extracted with EtOAc or Et20 (4 x 200 ml). The combined EtOAc extracts (or Et20) were washed with H20 (3 x 500 ml), dried (MgSO4), and concentrated in vacuo. The residual solution was found to contain the desired azide 2 (60.3 g, 64. g theoretical, 94%), which was found to be sufficiently pure and used directly in the next reaction without further purification. The analytically pure sample of 2 obtained by purification of Si02 column chromatography as a low boiling, colorless liquid.

Part C: (±) -4-amino-5-carbamoyl-1- (1-methoxy-2-) butyl-lH-1,2,3-triazole (3). A suspension of cyanoacetamide (46.5 g, 0.553 mol, 1.2 eguivalent) in pure EtOH (200 ml) was treated with EtONa (62.73 g, 0.922 mol, 2.0 equivalent) at 25 ° C under N2, and the resulting mixture was heated to reflux for 15 minutes under N2. The cooled mixture was then treated with the solution of l-methoxy-2-butyl azide 2 (59.5 g, 0.467 mol) in Et20 and the mixture was diluted with Additional EtOH (260 ml) at 25 ° C. The resulting reaction mixture was heated to reflux and stirred for 6-8 hours at reflux before it was cooled to room temperature. The solvent was removed in vacuo, the residue was treated with H20 (300 ml) and EtOAc (300 ml). The two layers were separated, and the aqueous layer was extracted with EtOAc (5 x 100 ml). The combined EtOAc extracts were washed with saturated aqueous NaCl (50 mL), dried in vacuo and concentrated in vacuo. The residual yellow solid was recrystallized directly from MeOH (100-150 ml) to give the desired 1, 2, 3-triazole 3 (70.7 g, 98.2 g theoretical, 72%) as white crystals.

Part D: (±) -9- (l-methoxy-2-) butyl-2-methyl-8-azaadanine (4). Method A: A solution of 3 (10.65 g, 0.05 mol) in pure EtOH (50 ml) was treated with EtONa (6.8 g, 0.1 mol, 2.1 equivalent) and EtOAc (8.8 g, 10.0 ml, 0.5 mol, 10 equivalent) at 25 ° C under N2, and the resulting reaction mixture was heated to reflux with stirring for 6-8 hours before it was rapidly cooled with H20 (50 ml). The solution was then concentrated in vacuo to remove the majority of EtOH. The residue was treated with H20 (50 ml), acidified with conc. HCl (pH 6-7), and extracted with EtOAc (5 x 50 ml). The combined EtOAc extracts were washed with aqueous NaCl (20 ml), dried (MgSO), and concentrated in vacuo. The residual pale yellow solid was recrystallized directly from 80% EtOAc-hexane or EtOH to give 8-azaadanoline 4 (8.4 g, theoretical 11.85, 71%) as white crystals.

Method B: A suspension of cyanoacetamide (47.1 g, 0.561 mol, 1.2 equivalent) in pure EtOH ((200 ml) was treated with EtONa (95.3 g, 1.4 mol, 3.0 equivalent) at 25 ° C under N2, and the resulting mixture was heated to reflux for 15 minutes under N2 The cooled mixture was then treated with a solution of 1-methoxy-2-butyl azide 2 (60.3 g, 0.467 mol) in EtOAc (or Et20) in pure EtOH (170 ml) at 25 ° C, and the resulting reaction mixture was heated to reflux and stirred at 4-6 hours under reflux before being cooled to RT. EtOAc (120 ml) was added to the reaction mixture, the resulting mixture was heated to reflux for an additional 6-10 hours. The cooled reaction mixture was treated with H20 (200 ml), and the solution was concentrated in vacuo to remove the majority of EtOH. The residue was treated with H20 (100 ml) and acidified with concentrated HCl (pH 6-7), and extracted with EtOAc (6 x 150 ml). Extracts of Combined EtOAc were washed with aqueous, saturated NaCl (100 ml), dried (MgSO), and concentrated in vacuo. The residual pale yellow solid was recrystallized from 80% EtOAc-hexane) (or EtOH) to give 8-azaadenine 4 (70.8 g, 110.7 g theory, 64% for two steps) as white crystals.

Part E: (±) -4-chloro-l- (l-methoxy-2-) butyl-2-methyl-8-azzadenine (5). Method A: A solution of 4 (6.78 g, 0.17 mmol) in P0C13 (30 mL) was heated to reflux for 3 hours. The excess POCl3 was removed in vacuo, and the residue was treated with H20 (50 ml) and EtOAc (50 ml). The two layers were separated, and the aqueous layer was extracted with EtOAc (3 x 50 ml). The combined EtOAc extracts were washed with H20 (2 x 50 ml) and saturated aqueous NaCl (30 ml), dried (MgSO4) and concentrated in vacuo. Flash chromatography (Si02, 10-20% EtOAc-hexane, gradient elution) gave 5 (6.65 g, 7.30 g theoretical, 91%) as a colorless oil, which solidified on standing in vacuo.

Method B: A solution of 4 (170 mg, 0.72 mmol) was treated with P0C13 (2 ml) and N, N-diethylaniline (0.5 ml) at 25 ° C under N2, and the resulting mixture was heated to reflux for 4-6 hours. Excess P0C13 was removed in vacuo and the residue was purified directly by flash chromatography (gradient elution of 10-20% EtOAc-hexane, SiO2) to give 5 (159 mg, 184 mg theoretical, 86%) as an oil colorless, which solidified in vacuo. The product obtained by method B was identical to all aspects comparable with that obtained from Method A: Part F. (±) -1- (1-methoxy-2-) butyl-2-methyl-4- [(2,4,6-trimethyl) phenyl] amino-8-azaadenine (6).

A solution of 5 (7.0 g, 0.0274 mol) in toluene (50 ml) was treated with 2,4,6-trimethylphenylamine (8.1 g, 0.06 mol, 2.2 equivalent) at 25 ° C under N2. The resulting reaction mixture was heated to reflux for 6-8 hours under N2. The white solid (2, 4,6-trimethylaniline HCl salt) was filtered and the solid was washed with "toluene (10-20 1) .The filtrate was concentrated in vacuo.The residual pale yellow solid was recrystallized from EtOAc. 30% -hexane to give the title compound 6 (7.9 g, 9.7 g theoretical, 81%) as high crystals.

UTILITY CRF-R1 Receptor Binding Assay for the Evaluation of Biological Activity The next. is a description of the isolation of cell membranes containing the cloned human CRF-R1 receptors for use in the normal binding assay as well as a description of the assay itself. The messenger RNA was isolated from the human hippocampus. The mRNA was reverse transcribed using olive (dt) 12-18 and the coding region was amplified by PCR from the start codons to the stop codons. The representative PCR fragment was cloned into the EcoRV site of pGEMV, from where the insert was claimed using Xhol + Xbal and cloned into the Xhol + Xbal sites of the pm3ar vector (containing a CMV promoter, the nt junction "of SV40 and the oli A signals above, a viral origin of Epstein Bar replication, and a selectable marker of hydromycin.) The resulting expression vector, called phchCRFR was transfected into 293EBNA cells and the cells retaining episome were selected in the presence of hydromycin 400 μM Cells that survived 4 weeks of hygromycin selection were mixed, adapted for growth and suspension and used to generate membranes for the binding assay described below, then individual aliquots containing approximately 1 x 108 of the cells in suspension to form the sediment and were frozen.For the binding assay, a frozen sediment described above that conti In 293EBNA cells transfected with the hCRFR1 receptors, the 10 ml of ice-cold tissue buffer (HEPES 50 M buffer, pH 7.0, containing 10 mM MgCl2, 2 mM EGTA, 1 μg / ml aprotinin, 1 μg / ml leupeptin is homogenized. and 1 μg / ml pesptatin. The homogenate is centrifuged at 40,000 x g for 12 minutes and the resulting pellet is homogenized in 10 ml of tissue buffer. After another centrifugation at 40,000 x g for 12 minutes, the pellet is redispersed at a protein concentration of 360 μg / ml to be used in the assay. The binding assays are carried out in 96-well plates; each well that has a capacity of 300 μl. To each weight, 50 μl of the test drug dilutions are added (final concentration of the drugs varies from 10"10 - 10" 5), 100 μl of dd? -ovino-CRF (125? _0-CRF) (final concentration 150 pM) and 150 μl of the cell homogenate described above. The plates are then allowed to be incubated at room temperature for 2 hours before filtering the incubation on the GF / F filters (prearranged with 0.3% polyethylenimine) using an appropriate cell harvester. The filters are rinsed twice with test buffer, cooled with ice, before removing the individual filters and titrating them for radioactivity in a gamma counter. The curves of the 125I-o-CRF inhibition that bind to the cell membranes at various dilutions of the test drug are analyzed by the LIGNAD interactive curve fitting program [P. J. Munson and D. Rodbard, Anal. Biochem. 107: 220 (1980), which provides Ki values for inhibition that are then used to assess biological activity. A compound is considered to be active if it has a K ± value of less than about 1000 nM for the inhibition of CRF.

Inhibition of the Activity of the Adenilate-Cyclase Stimulated by CRF Inhibition of the activity of adenylate cyclase stimulated by CRF was performed as described by G. Battaglia et al., Synapse 1: 572 (1987). Briefly, the assays were carried out at 37 ° C for 10 minutes in 200 ml of buffer containing 100 mM Tris-HCl (pH 7.4 at 37 ° C), 10 M MgCl 2, 0.4 mM EGTA, 0.1% BSA, isobut 1 mM ilmethylxanthin (IBMX), 250 units / ml fos focreat ina kinase, 5 mM creatine phosphate, 100 mM guanosine triphosphate, 100 nM oCRF, antagonist peptides (concentration varies 10-9 to 10"6m) and 0.8 mg of the original wet weight tissue (approximately 40-60 mg of protein) .The reactions are initiated by the addition of ATP / 32P] 1 M ATP (approximately 2-4 mCi / tube) and terminated by the addition of 100 ml of 50 mM Tris-HCL, 45 M ATP and dodecyl or 2% sodium sulfate To inspect the recovery of cAMP, 1 μl of [3 H] cAMP approximately 40,000 dpm) was added to each of or before The separation of [32P] cAMP from [32P] ATP was analyzed by sequential elution on Dowex and alumina columns.The recovery was consistently greater than 80%. of the compounds of this invention were tested in this test and found to be active.

In vivo Biological Test The in vivo activity of the compositions of the present invention can be achieved using any of the biological assays available and accepted within the art. Illustrative of these tests include the Acoustic Startling Test, the Climbing Ladder Test, and the Chronic Administration Test. These and other useful models for testing the compounds of the present invention have been summarized in C.W. Berridge and A.J. Dunn Brain Research Reviews 15:71 (1990). The compounds can be tested on any species of rodent or small mammal. The description of the assays herein are not intended to limit the possibility of the invention. The compounds of this invention have utility in the treatment of equilibria associated with abnormal levels of the corticotropin releasing factor in patients suffering from depression, affective disorders, and / or anxiety. The compounds of this invention can be administered to treat these abnormalities by causing contact of the active agent with the site of action of the agent in the body of a mammal. The compounds can be administered by any conventional means available for the use of binding with pharmaceuticals either as a therapeutic agent or in combination of therapeutic agents. They can be administered alone, but will generally be administered with a pharmaceutical carrier selected on the basis of the chosen route of administration and normal pharmaceutical practice. The dose administered will vary depending on the use and known factors such as pharmacodynamic character of the particular agent, and its mode and route of administration; the age, weight, and health of the recipient; nature and degree of symptoms, kind of concurrent treatment, frequency of treatment; and desired effect. For use in the treatment of »diseases and conditions, the compounds of this invention can be administered orally on a daily basis a dose of the active ingredient from 0.002 to 200 mg / kg of body weight. Ordinarily, a dose of 0.01 to 10 mg / kg in divided doses of one to four times a day, or in a sustained release formulation will be effective in obtaining the desired pharmacological effect. Dosage forms (compositions) suitable for administration contain from about 1 mg to about 100 mg of the active ingredient per unit. In these pharmaceutical compositions, the active ingredient will ordinarily be present in an amount of about 0.5 to 95% by weight based on the total weight of the composition. The active ingredient can be administered orally in the solid dosage form, such as capsules, tablets and powder, in liquid forms such as elixirs, syrups, and / or suspensions. The compounds of this invention can also be administered from. parenterally in the formulations of liquid, sterile doses. Gelatin capsules can be used to contain the active ingredient and a suitable carrier such as, but not limited to, lactose, starch, magnesium stearate, stearic acid, or cellulose derivatives. Similar ingredients can be used to make compressed tablets. Both tablets and capsules can be manufactured as sustained release products to provide sustained release of the drug over a period of time. The compressed tablets can be sugar coated or film coated to mask any unpleasant taste, or used to protect the active ingredients from the atmosphere, or to allow selective disintegration of the tablet in the gastrointestinal tract. The liquid dosage form for oral administration may contain coloring or flavoring agents to increase patient acceptance. In general, water, pharmaceutically acceptable oils, saline, aqueous dextrose (glucose) related sugar solutions in glycols, such as, polypropylene glycol or polyethylene glycol, are suitable carriers for parenteral solutions. Solutions for parenteral administration preferably contain a water soluble salt of the active ingredient, suitable stabilizing agents, and if necessary, shortening substances. Antioxidant agents, such as sodium bisulfite, sodium sulfite, or ascorbic acid, either alone or in combination, are suitable stabilizing agents. Citric acid and its salts, and EDTA are also used. In addition, parenteral solutions may contain preservatives such as benzalkonium chloride, methyl- or propyl-paraben, and chlorobutanol. Suitable pharmaceutical carriers are described in: "Remington's Pharmaceutical Sciences", A. Osol, a standard reference in the field. The pharmaceutical dosage forms useful for the administration of the compounds of this invention can be shown as follows: Capsules A large number of capsule units are prepared by filling normal, two-piece hard gelatin capsules, each with 100 mg of the active ingredient in powder, 150 mg of lactose, 50 mg of cellulose and 6 mg of magnesium stearate.

Soft Gelatin Capsules A mixture of the active ingredient in a digestible oil such as soybean oil, cotton, or olive oil, is prepared and injected by means of a positive displacement of a positive displacement pump in a pump to form capsules of soft or soft gelatin containing 100 mg of the active ingredient. The capsules were washed and dried.

Tablets A large number of tablets are prepared by conventional procedures so that the dosage unit can be 100 mg of active ingredient, 0.2 mg of colloidal silicon dioxide, 5 mg of magnesium stearate, 275 mg of microcrystalline cellulose, 11 mg of starch , and 98.8 lactose. Appropriate coatings may be applied to increase the capacity of tasty or delayed portion. The compounds of this invention can also be used as reagents or standards in the chemical study of neurological function, dysfunction and disease.

It is noted that in relation to this date, the best method known by the applicant to carry out the present invention is that which is clear from the present description of the invention.

Having described the invention as above, the content of the following is claimed as property:

Claims (13)

1. An antagonist compound of CRF, of formula I or formula II: II or a pharmaceutically acceptable salt or prodrug form thereof, characterized in that: X is N or CR1; And it is N or CR2; Z is NR3, O, or S (O) n; G is O or S; Ar is phenyl, naphthyl, pyridyl, pyrimidinyl, triazinyl,. furanyl, quinolinyl, isoquinolinyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuranyl, benzothienyl, benzthiazolyl, isoxazolyl, or pyrazolyl, each optionally substituted with 1 to 5 groups R5, R1 is independently at each occurrence H, alkyl 1 to 4 carbon atoms, alkenyl of 2 to 4 carbon atoms, alkynyl of 2 to 4 carbon atoms, - halo, CN, haloalkyl of 1 to 4 carbon atoms, -NR9R10, NR9COR10, -OR11, SH or - S (0) nR12; R2 is H, alkyl of 1 to 4 carbon atoms, cycloalkyl of 1 to 6 carbon atoms, halo, CN, -NR6R7, NR9COR10, haloalkyl of 1 to 4 carbon atoms, -OR7, SH or -S (0) nR12; R3 is H, alkyl of 1 to 10 carbon atoms, alkenyl of 2 to 10 carbon atoms, alkynyl of 2 to 10 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, or cycloalkylalkyl of 4 to 12 carbon atoms, each optionally substituted with 1 to 3 substituents independently selected in each occurrence from alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, halo, haloalkyl of 1 to 4 carbon atoms, cyano, -OR7 , SH, -S (0) nR13, - COR7, -C02R7, -0C (0) R13, -NR8C0R7, -N (COR7) 2, - NR8 CONR6R7, -NR8 C02R1 3, -NR6COR7, - CONR6R7, aryl , heteroaryl and heterocyclyl, wherein the aryl, heteroaryl or heterocyclyl is optionally substituted with 1 to 3 substituents independently selected in each occurrence from alkyl of 1 to 6 carbon atoms, cycloalkyl of 1 to 3 carbon atoms, halo, haloalkyl of 1 to 4 carbon atoms, cyano, -OR7, SH, -S (0) nR13, -COR7, C02R7, -OC (0) R13, -NR8COR7, -N (COR7) 2 , NR8CONR6R7, -NR8C02R13, -NR6R7, and -CONR6R7; R 4 is H, alkyl of 1 to 4 carbon atoms, allyl or propargyl, where alkyl of 1 to 4 carbon atoms, allyl or propargyl is optionally substituted with cycloalkyl of 3 to 6 carbon atoms and where alkyl of 1 to 4 atoms carbon is optionally substituted with -OR7, -S (O) nR12 or -C02R7; R5 is independently in each occurrence alkyl of 1 to 10 carbon atoms, alkenyl of 2 to 10 carbon atoms, alkynyl of 2 to 10 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, cycloalkylalkyl of 4 to 12 carbon atoms , -N02, halo, -CN, haloalkyl of 1 to 4 carbon atoms, and -NR6R7, NR8COR7, NR8C02R7, -COR7 -OR7, -CONR6R7, -CO (NOR9) R7, C02R7, or -S (0) nR7 wherein alkyl of 1 to 10 carbon atoms, alkenyl of 2 to 10 carbon atoms, alkynyl of 2 to 10 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, and cycloalkylalkyl of 4 to 12 carbon atoms are optionally substituted with 1 to 3 substituents independently selected in each occurrence from alkyl of 1 to 4 carbon atoms, -N02. halo, -CN, -NR6R7, -NR6R7, NR8COR7, NR8C02R7, -COR7 -OR7. -CONR6R7, C02R7, -CO (NOR9) R7, O -S (0) nR7; R6 and R7 are independently selected at each occurrence of H, alkyl of 1 to 4 carbon atoms, haloalkyl of 1 to 4 carbon atoms, alkoxyalkyl of 2 to 8 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, cycloalkylalkyl " from 4 to 12 carbon atoms, aryl, aryl (C? -C alkyl) -; heteroaryl or heteroaryl (C? -C alkyl) -; NR6R7 is pyridine, pyrrolidine, piperazine, N-methylpiperazine, morpholine or thiomorpholine; independently in each occurrence H or alkyl of 1 to 4 carbon atoms, R9 and R10 are independently in each occurrence selected from H, alkyl of 1 to 4 carbon atoms, or cycloalkyl of 3 to 6 carbon atoms; H, alkyl of 1 to 4 carbon atoms, haloalkyl of 1 to 4 carbon atoms, or cycloalkyl of 3 to 6 carbon atoms; R 12 is alkyl of 1 to 4 carbon atoms or haloalkyl of 1 to 4 carbon atoms; R13 is alkyl of 1 to 4 carbon atoms, haloalkyl of 1 to 4 carbon atoms, alkoxyalkyl of 2 to 8 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, cycloalkylalkyl of 4 to 12 carbon atoms, aryl, aryl (C? -C alkyl) -, heteroaryl or heteroaryl (C? -C4 alkyl) -; aryl is phenyl or naphthyl, each optionally substituted with 1 to 3 substituents independently selected at each occurrence from alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, halo, haloalkyl of 1 to 4 carbon atoms , cyano, f-0R7, SH, -S (0) NR13, -COR7, C02R7, -CO (0) R13, -NR8COR7, -N (COR7) 2, -NR8CONR6R7, -NR8C02R13, -NR6R7, and - C0NR6R7; heteroaryl is pyridyl, pyrimidinyl, triazinyl, furanyl, quinolinyl, isoquinolinyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuranyl, benzothienyl, thiazolyl benz, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, or indazolyl, each optionally substituted with 1 or 3 substituents independently selected at each occurrence from alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, halo, haloalkyl of 1 to 4 carbon atoms, cyano, -OR7, SH, -S ( 0) NR13, -COR7, - C02R7, -0C (0) R13, -NR8COR7 ' "N (C0R7) 2, -NR8CONR6R7, - NR8C02R13, -NR6R7, and -C0NR6R7; heterocyclyl is saturated or partially saturated heteroaryl, optionally substituted with 1 or 3 substituents independently selected in each occurrence from alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, halo, haloalkyl of 1 to 4 carbon atoms, cyano, -OR7, SH, - S (0) nR13, -COR7, - C02R7, -0C (0) R13, -NR8C OR7, -N (COR7) 2, -NR8CONR6R7, -NR8C02R13 NR6R7. -C0NR6R7; n is independently in each occurrence 0, 1 or 2; with the proviso that R4 in formula I is not H: (a) when X is N, Y is N, Z is NR3, R1 is H, R3 is H or benzyl, and Ar is p-methylphenyl; (b) when X is N, Y is N, Z is NR3, R1 is butyl, R3 is benzyl, and Ar is phenyl; (c) when X is N, Y is CH, Z is NR3, R3 is methyl, R1 is H and Ar is phenyl or 2-fluorophenyl; (d) when X is N, Y is CH, Z is NR3, R3 is methyl, R1 is Cl and Ar is phenyl; (e) when X is N, Y is CH, Z is NR3, R1 is Cl, R3 is benzyl, and Ar is phenyl or substituted phenyl; (f) when X is N, Y is CH, Z is NR3, R3 is p-methylbenzyl, and Ar is phenyl; (g) when X is N, Y is CR2, Z is NR3, R2 is CH3, R3 is H, and Ar is phenyl or phenyl substituted with methyl, ethyl, isopropyl, fluoro or chloro; (h) when X is N, Y is N, Z is NR3, R3 is cyclopropylmethyl, R1 is H, and Ar is 2-bromo-4-isopropylphenyl, or (i) when X is N, Y is N, Z is S, R1 is H, and Ar is 2-bromo-4-isopropylphenyl.

2. A CRF antagonist compound according to claim 1 or a pharmaceutically acceptable salt or prodrug form thereof, characterized in that: X is N or CR1; Y is N or CR "Z is NR3, O, or S (O) n; G is O or S; Ar is phenyl or pyridyl, each optionally substituted with 1 to 3 groups R5, R1 is independently at each occurrence H, alkyl of 1 to 4 carbon atoms, halo, CN, haloalkyl of 1 to 4 carbon atoms, -NR9R10, -OR11, or -S (O) nR12; R2 is H, alkyl of 1 to 4 carbon atoms, cycloalkyl from 1 to 6 carbon atoms, halo, CN, -NR6R7, NR9C0R10, haloalkyl of 1 to 4 carbon atoms, -OR7, or -S (0) nR12; R3 is H, alkyl of 1 to 10 carbon atoms, alkenyl of 2 to 10 carbon atoms, alkynyl of 2 to 10 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, or cycloalkylalkyl of 4 to 12 carbon atoms, each optionally substituted with 1 to 3 substituents independently selected in each occurrence of alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, halo, haloalkyl of 1 to 4 carbon atoms, cyano, -OR7, -S (0) nR13, -C02R7, NR8COR7, -NR8CONR6R7, - NR8C02R13, -NR6C0R7, aryl and heteroaryl, wherein the aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected in each occurrence from alkyl of 1 to 4 carbon atoms, halo, cyano, -OR7, -S (0 ) nR7, -C02R7, -NR8C0R7, -NR8CONR6R7, -NR8C02R7 and -NR6R7; R 4 is H, alkyl of 1 to 4 carbon atoms, allyl or propargyl; R5 is independently in each occurrence alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, cycloalkylalkyl of 4 to 8 carbon atoms , -N02, halo, -CN, haloalkyl of 1 to 4 carbon atoms, -NR6R7, COR7, -OR7, -CONR6R7, -CO (NOR9) R7, C02R7, or -S (0) nR7, wherein alkyl of the ß carbon atoms, "alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, and cycloalkylalkyl of 4 to 12 carbon atoms are optionally substituted with 1 to 3 substituents independently selected at each occurrence from alkyl of 1 to 4 carbon atoms, -N02. halo, -CN, -NR6R7, COR7 -OR7. -CONR6R7, C02R7, -CO (NOR9) R7, or -S (0) nR7; R6 and R7 are independently at each occurrence H, alkyl of 1 to 4 carbon atoms, haloalkyl of 1 to 4 carbon atoms, alkoxyalkyl of 2 to 8 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, cycloalkylalkyl of 4 to 12 carbon atoms, aryl, aryl (C? -C4alkyl) -; heteroaryl or heteroaryl (C? -C alkyl) -; or NR6R7 is piperidine, pyrrolidine, piperazine, N-methyl-piperazine, morpholine or thiomorpholine; R8 is independently at each occurrence H or alkyl of 1 to 4 carbon atoms; R9 and R10 are independently at each occurrence selected from H, alkyl of 1 to 4 carbon atoms, or cycloalkyl of 3 to 6 carbon atoms; R11 is H, alkyl of 1 to 4 carbon atoms, haloalkyl of 1 to 4 carbon atoms, or cycloalkyl of 3 to 6 carbon atoms; R 12 is alkyl of 1 to 4 carbon atoms or haloalkyl of 1 to 4 carbon atoms; R 13 is alkyl of 1 to 4 carbon atoms, haloalkyl of 1 to 4 carbon atoms, alkoxyalkyl of 2 to 8 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, cycloalkylalkyl of 4 to 12 carbon atoms, aryl, aryl (C? -C alkyl) -, heteroaryl or heteroaryl (C? -C alkyl) -; aryl is phenyl or naphthyl, optionally substituted with 1 to 3 substituents independently selected in each occurrence from alkyl of 1 to 4 carbon atoms, halo, cyano, -OR7, -S (0) nR12, -C02R8, -NR8C0R7, NR8CONR6R7, -NR8C02R12 and -NR6R7; heteroaryl is pyridyl, pyrimidinyl, triazinyl, furanyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, or indazolyl, each optionally substituted with 1 or 3 substituents independently selected in each "occurrence from of alkyl of 1 to 4 carbon atoms, halo, cyano, -OR7, -S (0) nR12, -C02R8, -NR8COR7, NR8CONR6R7, -NR8C02R12, and -NR6R7; n is independently in each occurrence 0, 1 or 2;

3. A CRF antagonist compound according to claim 1, characterized in that it is selected from the group consisting of: N- [2-bromo-4- (1-methylethyl) phenyl] -5-met i 1-3 -propi 1-3 H-1, 2, 3-triazolo [4,5-d] pyrimidin-7-amine N- [2-bromo-4- (1-methylethyl) phenyl] -N-ethyl-5-methyl-3-propyl-3-Hl, 2,3-triazole [4, 5, -d] pyrimidin- 7 - amine N- [2-bromo-4- (1-methylethyl) phenyl] -3-butyl-N-et i 1-5-methyl-3H-l, 2,3-triazole [4, 5-d] pyrimidine-7 -amine N [2-bromo-4- (1-methylethyl) phenyl] -3- (skypropylmethyl) -N-ethyl-5-methyl-3H-1, 2,3-triazole [4,5-d] pyrimidine- 7 - amine N- [2-bromo-4- (1-methyl) ethylphenyl] "- 5-methyl-3- [(1-methoxymethyl) -2-methoxyethyl) -3H-1,2,3-triazole [4,5] -d] pyrimidin-7-amine., N- [2-bromo-4- (1-methylethyl) phenyl] -3- (2-methoxyethyl) -5-methyl-3H-l, 2,3-triazole [4,5-d] pyrimidine-7-amino . N- (2-bromo-4- (1-methylethyl) phenyl] -N-eti 1-3- (2-methoxyethyl) -5-methyl-3H-1, 2,3-triazole [4, 5-d] pir imidin- 7 -amine N- [2-bromo-4- (1-methylethyl) phenyl] -N-ethyl-3- (3-methoxypropyl) -5-methyl-3H-1, 2,3-triazole [4, 5-d] pyrimidine - 7 -amine. (+/-) -N- [2-bromo-4- (1-methylethyl) phenyl] -3- [1- (1-methoxymethyl) propyl] -5-methyl-3H-1, 2, 3-triazole [ 4, 5-d] pyrimidin-7-amino (+/-) -N- [2-bromo-4- (1-methylethyl) phenyl] -N-ethyl-3- [1- (1-methoxymethyl) propyl] -5-methyl-3H-1, 2, 3-traizol [4, 5-d] pyridin V-amine (S) -N- [2-bromo-4- (1-methylethyl) phenyl] -3- [1- (1-methoxymethyl) -2-phenylethyl] -5-methyl-3H-1, 2,3-triazole [4, 5-d] irimidin-7-amine. (S) -methi 17- [2-bromo-4- (1-methylethyl) phenyl] -5-methyl-a- [2- (methylthio) ethyl] -3H-1, 2,3-triazole [4,5 -d] pyrimidine-3-acetate. (+/-) -N- [2-Bromo-4- (1-methylethyl) phenyl] -3- [1-ethylpentyl] -5-metH1-3H-1, 2,3-triazole [4,5- d] pyrimidin-7-amino (+/-) -N- [2-bromo-4- (1-methylethyl) phenyl] -N-ethyl-3- [1-ethylpentyl] -5-methyl-3H-1, 2,3-traizol [4 , 5-d] pyrimidin-7-amino. N- [2-bromo-4- (1-methylethyl) phenyl] -3- [1-propylbutyl] -5-methyl-3H-1, 2,3-triazole [4,5-d] pyrimidin-7-amine N- [2-bromo-4- (1-methylethyl) phenyl] -3- [1-butylpentyl] -5-methyl-3H-1, 2,3-triazole [4, 5-d] pyrimidine-7-amino (+/-) -N- [2-bromo-4- (1-methylethyl) phenyl] -3- [1-ethylbutyl] -5-methyl-3H-1, 2,3-triazole [4,5-d ] pyrimidin-7-amine (+/-) -7- [2-bromo-4- (1-methylethyl) phenyl] -5-methyl-a-propyl-3H-1, 2,3-triazole [4,5-d] pyrimidine-3 -ethanol N- [2-bromo-4- (1-methylethyl) phenyl] -3- [1-ethylpropyl] -5-methyl-3H-l, 2,3-triazole [4, 5-d] pyrimidin-7-amino N- [2-bromo-4- (1-methylethyl) phenyl] -N-ethyl-3- [1-ethylpropyl] -5-metH1-3H-1, 2, 3-traizol [4, 5-d] pyrimidin-7-amine. N- (2-bromo-4,6-dimethylphenyl) -5-methyl-3- [1-propylbutyl] -3H-1, 2, 3-traizol [4, 5-d] pyrimidin-7-amine 5-methyl-N- [4-1-methylethyl) -2- (methylthio) phenyl] -3- [1-propyl-butyl] -3H-1, 2,3-triazole [4,5-d] pyrimidine-7- amine N- [2-bromo-4- (trifluoromethyl) phenyl)] -5-met i 1-3- [1-propylbutyl] -3H-1,2,3-triazole [4,5-d] pyrimidine-7- to ina N- [2-bromo-4-6- (dimethoxy) phenyl)] - 5-met il-3- [1-propylbutyl] -3H-1,2,3-triazole [4,5-d] pyrimidine- 7-amine. N- [2,6-Dimeti 1-4- (methylthio) phenyl)] -5-methyl 1-3- [1-propylbutyl] -3-Hl, 2,3-triazole [4,5-d] pyrimidine- 7-amine N- (4-acetyl-2-bromo phenyl) -3- [1-ethylpropyl] -5-methyl-1-3H-1, 2, 3-traizol [4, 5-d] pyrimidin-7-amine (+/-) -N- (4-acetyl-2-bromo phenyl) -3- [1- (1-methoxymethyl) propyl] -5-methio-3H-1, 2, 3-triazole [4, 5 d] pyrimidin-7-amine (+ / -) -N- (4-bromo-2,6-dimethylphenyl) -3- [1- (1-methoxymethyl) propyl] -5-methyl-3H-1, 2, 3-traizol [4, 5 -d] pyrimidin-7-amine (+ / -) -N- [2,6-dimethyl-4- (methylthio) phenyl] -3- [1-thioxymethyl) propyl] -5-methyl-3H-1, 2, 3-triazole [4, 5 -d] pir imidin-7 -amine (+ / -) -N- (2-bromo-2,4,6-dimethoxy phenyl) -3- [1- (1-methoxymethyl) propyl] -5-methyl-3H-I, 2,3-triazole [4, 5-d] pyrimidin-7-amino (+ / -) -N- (2-Chloro-4,6-dimethoxyphenyl) -3- [1- (1-methoxymethyl) propyl] -5-metH1-3H-1, 2, 3-triazole [4, 5-d] pyrimidin-7-amine (+ / -) -3- [1- (1-methoxyethyl) propyl] -5-methyl-n- (2,4,6-trimethylphenyl) -3H-1,2,3-triazole [4, 5-d] pi rimidin-7-amine (+/-) -N-Ethyl-3- [1- (1-methoxy-methyl) propyl] -5-methyl-N- (2,4,6-trimethylphenyl) -3H-1, 2,3 -triazol [4,5-d] pyrimidin-7-amine 3- [1- (1-ethyl) propyl] -5-met il-N- (2,4,6-trimethylphenyl) -3H-1,2,3-triazole [4,5-d] pyrimidine-7- to ina (+ / -) - 3- [l- (1-ethyl) butyl] -5-methyl-N- (2,4,6-trimethylphenyl) -3H-1,2,3-triazole [4,5-d] pyrimidine -7-amine (+ / -) - 3- [l- (1-ethyl) pentyl) -5-methyl-N- (2,4,6-trimethylphenyl) -3H-1,2,3-triazole [4,5-d ] pyrimidin-7-amine 5-methyl-3- [1- (1-propyl) butyl] -N- (2,4,6-trimethylphenyl) -3H-1,2,3-triazole [4, 5] d] pyrimidin-4-amine 3- (2-methoxyethyl) -5-methyl-N- (2,4,6-trimethylphenyl) -3H-1, 2,3-triazolo [4,5-d] pyrimidin-7-amine N-ethyl-3 - (2-methoxyethyl) -5-methyl-N- (2,4,6-trimethylphenyl) -3H-1,2,3-triazolo [4, 5-d] pyrimidin-7-aane. N- (2-methyl-4-bromo-phenyl) -3- [1- (1-propyl) butyl] -5-methyl-3H-1,2,3-triazole [4,5-d] pyrimidine- 7 -amine (+ / -) - 3- [l- (1-ethyl) butyl] -5-methyl-N- (2-methyl-4-bromo-phenyl) -3H-1,2,3-triazole [4, 5 d] pyrimidin-7-amine (+ / -) -N- (4-bromo-2-methyl phenyl) -3- [1- (1-methoxymethyl) propyl] -5-methyl-3H-1, 2, 3-triazole [4, 5 d] pyrimidin-7-amine (+ / -) - 3- [l- (1-ethyl) pentyl] -5-methyl-N- [(2,4,6- * trimethyl) -3-pyridyl-] -3H-1, 2, 3 -triazol [4, 5-d] pyrimidin-7-amine (+/-) -N-eti 1-3- [1- (1-ethyl) pentyl] -5-methyl-N- [(2,4,6-trimethyl) -3-pyridyl-] -3H-1 , 2,3-triazole [4,5-d] pyrimidine-7-amino (+ / -) -) - 3- [l- (1-ethyl) butyl] -5-methyl-N- [(2,4,6-trimethyl) 3-pyridyl-] - 3H-1, 2,3 -triazol [4,5-d] pyrimidin-7-amine N-ethyl-3- [1- (1-ethyl) butyl] -5-methyl-N- [(2,4,6-trimethyl) -3-pyridyl-] - 3H-1, 2,3-triazole [ 4,5-d] pyrimidin-7-amino 3- [1- (1-propyl) butyl] -5-methyl-N- [(2,4,6-trimethyl) -3-pyridyl-] - 3H-1, 2,3-triazole [4,5- d] pyrimidin-7-amino N-ethyl-3- [l- (1-propyl) butyl] -5-methyl-N- [(2,4,6-trimethyl) -3-pyridyl-] -3H-1, 2,3-triazole [ 4,5-d] pyrimidin-7-amino (+/-) -3- [1- (1-methoxymethyl) propyl] -5-methyl-N- [(2,4,6-trimethyl) -3-pyridyl-] - 3H-1, 2,3- triazole [4,5-d] pyrimidine-7-amino (+/-) -N-ethyl-3- [1-methoxymethyl) propyl] -5-methyl-N- [(2,4,6-trimethyl) -3-pyridyl-] -3H-1,2, 3-triazole [4,5-d] pyrimidine-7-amino N- (2,4-dibromo-phenyl) -5-methyl-3- (1-propyl) butyl-3H-1,2,3-triazolo [4, 5-d] pyrimidin-7-amino N- [4 -] acet i 1-2 -bromo phenyl] -5-methyl-3- (l-propyl) butyl-3 H -1,2,3-triazolo [4,5-d] pyrimidin-7-amine N- [2-bromo-4- (1-methylethyl) phenyl] -3- [1- (N, N-di and i-lamino-methyl) butyl] -5-methyl-3H-1, 2,3-triazole [4, 5-d] pyrimidin-7-amine N- [2-bromo-4- (1-methylethyl) phenyl] -2-methi 1-9- (1-propylbutyl) -9H-purin-6-amine (+/-) -N- [2-bromo-4- (1-methylethyl) phenyl) -9- (1-ethylpentyl) -2-methyl-9H-purin-6-amine (+ / -) -N- [2-bromo-4- (trifluoromethyl) phenyl] -9- [1- (methoxymethyl) propyl] -2-methyl-9H-purin-6-amine N- [2-bromo-4- (1-methylethyl) phenyl] -N-ethyl-5-methyl-1- [1,2,3] thiadiazole (5,4-d) pyrimidine-7-amino N- [2-bromo-4- (1-methylethyl) phenyl] -1- (1-ethylpropyl) -6-methyl-lH-1,2,3-triazole [4, 5, -c] iridin-4 -amine N- (2-bromo-4,6-dimethoxy ifenyl) -1- (1-ethylpropyl) -6-methyl-1H-1,2,3-triazole- [4,5-c] pyridin-4-amino N - (2-Chloro-4-6-dimethoxyphenyl) -1- (1-ethylpropyl) -6-methyl-lH-1,2,3-triazole [4,5-c] pyridin-4-amino N- (2-Chloro-4,6-dimethoxy-phenyl-1) -6-methyl-1- (1-propyl-butyl) -1H-1,2,3-triazole [4,5-c] pyridine-4-amino (+/-) -N- [2-bromo-4- (1-methylethyl) phenyl] -1- (1-ethylpentyl) -6-methyl-lH-l, 2,3-triazole [4, 5-c] ] pyridin-4-amine (+ / -) -N- (2-bromo-4,6-dimethoxyphenyl) -1- (1-ethylpentyl) -6-methyl-lH-1,2,3-triazole [4,5-c] pyridine- 4-amine. (+ / -) -N- (2-chloro-4,6-dimethoxy phenyl) -1- (1-ethylpentyl) -6-met i 1- HH- 1,2,3-triazole [4,5-c] ] pyridin-4-amine N- [2-bromo-4- (1-methylethyl) phenyl] -6-methiol-1- (1-propylbutyl) -1H-1,2,3-triazole [4,5-c] pyridin-4-amino N- [4- (1-methylethyl) -2-sulfonylmethylphenyl] -6-methyl-1- (1-propylbutyl) -1H-1,2,3-triazole [4,5-c] pyridin-4-amine N - [4- (4 -acet-1, 2-bromo-phenyl] -6-methyl-1- (1-propyl-butyl] -1H-1,2,3-triazole [4, 5-c] pyridine- 4 -amine N- (2-Chloro-4,6-dimethylphenyl) -1 [1-methoxymethyl- (2-methoxyethyl] -6-methyl-1Hr-1, 2,3-triazole [4, 5-c] pyridine-4 amine: N- (2-chloro-4,6-dimethylphenyl) -1 [1-methoxymethyl- (2-methoxyethyl] -6-methyl-lH-l, 2,3-tpazole mesylate salt [4, 5-c] pyridin-4-amino 6- [N- (2-Chloro-4,6-dimethylphenyl)] -9- [(1-ethoxymethyl) propyl] -2-methyl-9H-purin-6,8-di-amine: (S) - (-) -N- (2-Chloro-4,6-dimethylphenyl) -β-methyl-1- (1-me to imeti 1-3 -methoxypropyl) -1 H-1,2,3-triazole [4, 5-c] pyridin-4-amine. (R, S) -N- (2-chloro-4,6-dimethyl phenyl] -6-methyl-1- (1-methoxymethi 1-3 -methopropyl) -1H-1,2,3-triazole [4 , 5- c] pyridin-4-amine.

4. A pharmaceutical composition, characterized in that it comprises a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 1.

5. A pharmaceutical composition, characterized in that it comprises a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 2.

6. A pharmaceutical composition, characterized in that it comprises a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 3.

7. A method to treat affective disorder, anxiety, depression, irritable bowel syndrome, post-traumatic stress disorder, supranuclear impotence, immunosuppression, Alzheimer's disease, gastrointestinal disease, anorexia nervosa or other eating disorders, withdrawal symptoms of alcohol or drugs, drug addiction, inflammatory disorder, or fertility problems in a mammal, characterized in that it comprises administering to a mammal a therapeutically effective amount of a CRF antagonist compound of formula II or II: or a pharmaceutically acceptable salt or prodrug form thereof, wherein: X is N or CR1; Y is N or CR "Z is NR3, O, or S (O) n; G is O or S; Ar is phenyl, naphthyl, pyridyl, pyrimidinyl, triazinyl, furanyl, quinolinyl, isoquinolinyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuranyl, benzothienyl, benzthiazolyl, isoxazolyl, or pyrazolyl, each optionally substituted with 1 to 5 groups R5, R1 is independently in each occurrence H, alkyl of 1 to 4 carbon atoms, alkenyl of 2 to 4 carbon atoms, alkynyl of 2 to 4 carbon atoms ,, halo, CN, haloalkyl of 1 to 4 carbon atoms , -NR9R10, NR9COR10, -OR11, SH or -S (0) nR12; R2 is H, alkyl of 1 to 4 carbon atoms, cycloalkyl of 1 to 6 carbon atoms, halo, CN, -NR6R7, NR9C0R10, haloalkyl of 1 to 4 carbon atoms, -OR7, SH or -S (0) nR12; R3 is H, alkyl of 1 to 10 carbon atoms, alkenyl of 2 to 10 carbon atoms, alkynyl of 2 to 10 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, or cycloalkylalkyl of 4 to 12 carbon atoms, each optionally substituted with 1 to 3 substituents independently selected in each occurrence from alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, halo, haloalkyl of 1 to 4 carbon atoms, cyano, -OR7 , SH, -S (0) nR13, - COR7, -C02R7, -OC (0) R13, -NR8COR7, -N (COR7) 2, NR8CONR6R7, -NR8C02R13, -NR6COR7, -CONR6R7, aryl, heteroaryl and heterocyclyl, wherein the aryl, heteroaryl or heterocyclyl is optionally substituted with 1 to 3 substituents independently selected at each occurrence from alkyl of 1 to 6 carbon atoms, cycloalkyl of 1 to 3 carbon atoms, halo, haloalkyl of 1 to 4 carbon atoms carbon, cyano, -OR7, SH, -S (0) nR13, -COR7, C02R7, -OC (0) R13, -NR8COR7, -N (COR7) 2, NR8CONR6R7 , -NR8C02R13, -NR6R7, and -CONR6R7; R 4 is H, alkyl of 1 to 4 carbon atoms, allyl or propargyl, where alkyl of 1 to 4 carbon atoms, allyl or propargyl is optionally substituted with cycloalkyl of 3 to 6 carbon atoms and where alkyl of 1 to 4 atoms carbon is optionally substituted with -OR7, -S (O) "R12 or -C02R7; R5 is independently in each occurrence alkyl of 1 to 10 carbon atoms, alkenyl of 2 to 10 carbon atoms, alkynyl of 2 to 10 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, cycloalkylalkyl of 4 to 12 carbon atoms , -N02, halo, -CN, haloalkyl of 1 to 4 carbon atoms, and -NR6R7, NR8COR7, NR8C02R7, -COR7 -OR7, -CONR6R7, -CO (NOR9) R7, C02R7, or - S (0) nR7, where alkyl from 1 to 10 carbon atoms, alkenyl 2 to 10 carbon atoms, alkynyl of 2 to 10 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, and cycloalkylalkyl of 4 to 12 carbon atoms are optionally substituted with 1 to 3 substituents independently selected in each occurrence from alkyl of 1 to 4 carbon atoms, -N02. halo, -CN, -NR6R7, NR6R7, NR8COR7, NR8C02R7, -COR7 -OR7. -CONR6R7, C02R7, -CO (NOR9) R7, or -S (0) nR7; R6 and R7 are independently in each occurrence of H, alkyl of 1 to 4 carbon atoms, haloalkyl of 1 to 4 carbon atoms, alkoxyalkyl of 2 to 8 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, cycloalkylalkyl of 4 to 12 carbon atoms, aryl, aryl (C? -C4alkyl) -; heteroaryl or heteroaryl (C? -C alkyl) -; NR6R7 is pyridine, pyrrolidine, piperazine, N-methylpiperazine, morpholine or thiomorpholine; R8 is independently at each occurrence H or alkyl of 1 to 4 carbon atoms; R9 and R10 are independently in each occurrence selected from H, alkyl of 1 to 4 carbon atoms, or cycloalkyl of 3 to 6 carbon atoms; R 11 is H, alkyl of 1 to 4 carbon atoms, haloalkyl of 1 to 4 carbon atoms, or cycloalkyl of 3 to 6 carbon atoms; R is alkyl of 1 to 4 carbon atoms or haloalkyl of 1 to 4 carbon atoms; R is alkyl of 1 to 4 carbon atoms, haloalkyl of 1 to 4 carbon atoms, alkoxyalkyl of 2 to 8 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, cycloalkylalkyl of 4 to 12 carbon atoms, aryl, aryl (C? -C alkyl) -, heteroaryl or heteroaryl (C? -C alkyl) -; aryl is phenyl or naphthyl, each optionally substituted with 1 to 3 substituents independently selected in each occurrence from alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, halo, haloalkyl of 1 to 4 carbon atoms , cyano, -OR7, SH, -S (0) NR13, -COR7, * C02R7, -CO (0) R13, -NR8COR7, -N (COR7) 2, -NR8CONR6R7, -NR8C02R13, -NR6R7, and - CONR6R7; heteroaryl is pyridyl, pyrimidinyl, triazinyl, furanyl, quinolinyl, isoquinolinyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuranyl, benzothienyl, thiazolyl benz, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, or indazolyl, each optionally substituted with 1 or 3 substituents independently selected at each occurrence from alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, halo, haloalkyl of 1 to 4 carbon atoms, cyano, -OR7, SH, -S ( 0) NR13, -COR7, - C02R7, -0C (0) R13, -NR8C0R7 '-N (C0R7) 2, -NR8CONR6R7, -NR8C02R13, -NR6R7, and -C0NR6R7; heterocyclyl is saturated or partially saturated heteroaryl, optionally substituted with 1 to 3 substituents independently selected at each occurrence from alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, halo, haloalkyl of 1 to 4 carbon atoms carbon, cyano, -OR7. SH, -S (0) nR13, -COR7, -C02R7, -0C (0) R13, -NR8COR7, -N (C0R7) 2, -NR8CONR6R7, -NR8C02R13 NRSR7. -C0NR6R7; n is independently in each occurrence 0, 1 or 2; provided that R4 in formula I is not H: (a) when X is N, Y is N, Z is NR3, R3 is cyclopropylmethyl, RI is H, and Ar is 2-bromo-4-isopropylphenyl, or ( b) when X is N, Y 'is N, Z is S, R1 is H, and Ar is 2-bromo-4-isopropyl phenyl.

8. A method for treating an affective disorder, anxiety, depression, in a mammal, characterized in that it comprises administering to the mammal a therapeutically effective amount of a CRF antagonist compound of claim 2.

9. A method for treating an affective disorder, anxiety or depression in a mammal, characterized in that it comprises administering to the mammal a therapeutically effective amount of a CRF antagonist compound of claim 3.

10. A process for making a 5-amino-4-chloro-6-arylamino-2-substituted-pyrimidine of the formula VI, characterized in that it comprises reacting a 4,6-dichloro-5-nitro-2-substituted acid-pyrimidine of the formula IV with an arylamine of the formula ArNHR4 in the presence of a solvent selected from dialkylsulphoxides, dialkyl formamides and alkyl alcohols to produce a pyrimidone of the formula XIII, reacting the pyrimidone with phosphorus oxychloride to produce 4-chloro-6-arylamino-5-nitro-2-its thio-pyrimidine of the formula XII, then treating the pyrimidine of Formula XIII, with a reducing agent, as shown in the following scheme: where : Ar is phenyl, naphthyl, pyridyl, pyrimidinyl, triazinyl, furanyl, quinolinyl, isoquinolinyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuranyl, benzothienyl, benzthiazolyl, isoxazolyl, or pyrazolyl, each optionally substituted by 1 to 5. groups R5, R1 is independently in each occurrence H, alkyl of 1 to 4 carbon atoms, alkenyl of 2 to 4 carbon atoms, alkynyl of 2 to 4 carbon atoms, halo, CN, haloalkyl of 1 to 4 carbon atoms , -NR9R10, NR9C0R10, -OR11, SH or -S (0) nR12; R 4 is H, alkyl of 1 to 4 carbon atoms, allyl or propargyl, where alkyl of 1 to 4 carbon atoms, allyl or propargyl is optionally substituted with cycloalkyl of 3 to 6 carbon atoms and where alkyl of 1 to 4 atoms of carbon is optionally substituted by -OR, -S (O) nR12 or -C02R7, R5 is independently at each occurrence alkyl of 1 to 10 carbon atoms, alkenyl of 2 to 10 carbon atoms, alkynyl of 2 to 10 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, cycloalkylalkyl of 4 to 12 carbon atoms, -N02, halo, -CN, haloalkyl of 1 to 4 carbon atoms, and -NR6R7, NR8COR7, NR8C02R7, -COR7 -OR7, -C0NRSR7, -CO (NOR9) R7, C02R7, or S (0) nR7, wherein alkyl of 1 to 10 carbon atoms, alkenyl of 2 to 10 carbon atoms, alkynyl of 2 to 10 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, and cycloalkylalkyl of 4 to 12 carbon atoms are optionally substituted with 1 to 3 substituents independently selected in each occurrence from alkyl of 1 to 4 carbon atoms. carbon, -N02. halo, -CN, -NRSR7, NR6R7, NR8C0R7, NR8C02R7, -COR7 -OR7. -CONR6R7, C.02R7, -CO (NOR9) R7, or -S (0) nR7; R7 are independently selected at each occurrence of H, alkyl of 1 to 4 carbon atoms, haloalkyl of 1 to 4 carbon atoms, alkoxyalkyl of 2 to 8 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, cycloalkylalkyl of 4 to 12 carbon atoms, aryl, aryl (C? -C4alkyl) -; heteroaryl or heteroaryl (C? -C alkyl) -; NR6R7 is pyridine, pyrrolidine, piperazine, N-methylpiperazine, morpholine or -thiomorpholine; R is independently at each occurrence H or alkyl of 1 to 4 carbon atoms; R9 and R10 are independently in each occurrence selected from H, alkyl of 1 to 4 carbon atoms, or cycloalkyl of 3 to 6 carbon atoms; R 1 1 is H, alkyl of 1 to 4 carbon atoms, haloalkyl from 1 to 4 carbon atoms, or cycloalkyl of 3 to 6 carbon atoms; R 1 2 is alkyl of 1 to 4 carbon atoms or haloalkyl of 1 to 4 carbon atoms; R 1 3 is alkyl of 1 to 4 carbon atoms, haloalkyl of 1 to 4 carbon atoms, alkoxyalkyl of 2 to 8 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, cycloalkylalkyl of 4 to 12 carbon atoms, aryl , aryl (C? -C4 alkyl) -, heteroaryl or heteroaryl (C? -C4 alkyl) -; aryl is phenyl or naphthyl, each optionally substituted with 1 to 3 substituents independently selected in each occurrence from alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, halo, haloalkyl of 1 to 4 carbon atoms carbon, cyano, -OR7, SH, -S (0) nR13, -COR7, C02R7, -C0 (0) R13, -NR8COR7, -N (COR7) 2, -NR8CONR6R7, -NR8C02R13, -NR6R7, and -CONR6R7; heteroaryl is pyridyl, pyrimidinyl, triazinyl, furanyl, quinolinyl, isoquinolinyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuranyl, benzothienyl, benzyl, azolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, or indazolyl, each optionally substituted with 1 or 3 substituents independently selected at each occurrence from alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, halo, haloalkyl of 1 to 4 carbon atoms, cyano, -OR7, SH, -S ( 0) nR13, -COR7, -C02R7, -0C (0) R13, -NR8C0R7 '-N (C0R7) 2, -NR8CONR6R7, -NR8C02R13, -NR6R7, and -CONR6R7; heterocyclyl is saturated or partially saturated heteroaryl, optionally substituted with 1 or 3 substituents independently selected in each occurrence from alkyl of 1 to 6 carbon atoms ^, cycloalkyl of 3 to 6 carbon atoms, halo, haloalkyl of 1 to 4 atoms of carbon, cyano, -OR7. SH, -S (0) nR13, -COR7, -C02R7, -OC (0) R13, -NR8C0R7, -N (C0R7) 2, -NR8CONR6R7, -NR8C02R13. NR6R7. -CONR6R7;n is independently in each occurrence 0, 1

11. A pyrimidone of the formula XIII wherein Ar is phenyl, naphthyl, pyridyl, pyrimidinyl, triazinyl, furanyl, quinolinyl, isoquinolinyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuranyl, benzothienyl, benzthiazolyl, isoxazolyl, or pyrazolyl, each optionally substituted by 1 to 5 groups R5, R1 is independently at each occurrence H, alkyl of 1 to 4 carbon atoms, alkenyl of 2 to 4 carbon atoms, alkynyl of 2 to 4 carbon atoms, halo, CN, haloalkyl of 1 to 4 carbon atoms, -NR9R10, NR9COR10, -OR11, SH or -S (0) nR12; R 4 is H, alkyl of 1 to 4 carbon atoms, allyl or propargyl, where alkyl of 1 to 4 carbon atoms, allyl or propargyl is optionally substituted with cycloalkyl of 3 to 6 carbon atoms and where alkyl of 1 to 4 atoms carbon is optionally substituted with -OR7, -S (0) nR12 or -C02R7; s independently in each occurrence alkyl of 1 to 10 carbon atoms, alkenyl of 2 to 10 carbon atoms, alkynyl of 2 to 10 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, cycloalkylalkyl of 4 to 12 carbon atoms, -N02, halo, -CN, haloalkyl of 1 to 4 carbon atoms, and -NR6R7, NR8C0R7, NR8C02R7, -COR7 -OR7, -CONR6R7, -CO (NOR9) R7, C02R7, or S (0) nR7, where alkyl of 1 to 10 carbon atoms, alkenyl of 2 to 10 carbon atoms, alkynyl of 2 to 10 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, and Cycloalkylalkyl of 4 to 12 carbon atoms are optionally substituted with 1 to 3 substituents independently selected at each occurrence from alkyl of 1 to 4 carbon atoms, -N02. halo, -CN, -NR6R7, NR6R7, NR8C0R7, NR8C02R7, -COR7 -OR7. -C0NR6R7, C02R7, -CO (NOR9) R7, or -S (0) nR7; R6 and R7 are independently selected at each occurrence of H, alkyl of 1 to 4 carbon atoms, haloalkyl of 1 to 4 carbon atoms, alkoxyalkyl of 2 to 8 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, cycloalkyl-alkyl from 4 to 12 carbon atoms, aryl, aryl (C? -C4alkyl) -; heteroaryl or heteroaryl (C? -C4alkyl) -; NR6R7 is pyridine, pyrrolidine, piperazine, N-methylpiperazine, morpholine or thiomorpholine; R8 is independently at each occurrence H or alkyl of 1 to 4 carbon atoms; R9 and R10 are independently in each occurrence selected from H, alkyl of 1 to 4 carbon atoms, or cycloalkyl of 3 to 6 carbon atoms; R 11 is H, alkyl of 1 to 4 carbon atoms, haloalkyl of 1 to 4 carbon atoms, or cycloalkyl of 3 to 6 carbon atoms, R 12 is alkyl of 1 to 4 carbon atoms or haloalkyl of 1 to 4 atoms carbon; R 13 is alkyl of 1 to 4 carbon atoms, haloalkyl of 1 to 4 carbon atoms, alkoxyalkyl of 2 to 8 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, cycloalkylalkyl of 4 to 12 carbon atoms, aryl, aryl (C? -C4 alkyl) -, heteroaryl or heteroaryl (C? -C4 alkyl) -; aryl is phenyl or naphthyl, each optionally substituted with 1 to 3 substituents independently, selected in each occurrence from alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, halo, haloalkyl of 1 to 4 carbon atoms, cyano, -OR7, SH, -S (0) nR13, -COR7, C02R7, -C0 (0) ) R13, -NR8C0R7, -N (C0R7) 2, -NR8C0NR6R7, -NR8C02R13, -NR6R7, and -CONR6R7; heteroaryl is pyridyl, pyrimidinyl, triazinyl, furanyl, quinolinyl, isoquinolinyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuranyl, benzothienyl, benzthiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, or indazolyl, each optionally substituted with 1 or 3 substituents independently selected at each occurrence from alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, halo, haloalkyl of 1 to 4 carbon atoms, cyano, -OR7, SH, -S (0 ) nR13, -COR7, -C02R7, -OC (0) R13, -NR8COR7 '-N (COR7) 2, -NR8CONR6R7, -NR8C02R13, -NR6R7, and -CONR6R7; heterocyclyl is saturated or partially saturated heteroaryl, optionally substituted with 1 to 3 substituents independently selected at each occurrence from alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, halo, haloalkyl of 1 to 4 carbon atoms carbon, cyano, -OR7. SH, -S (0) nR13, -COR7, -C02R7, -OC (0) R13, -NR8COR7, -N (COR7) 2, -NR8CONR6R7, -NR8C02R13 NR6R7. -CONR6R7; n is independently in each occurrence 0, 1 or 2; with the proviso that when Ar is phenyl substituted with 2 or 3 substituents selected from alkyl of 1 to 4 carbon atoms, chlorine and bromine, or pyridyl substituted with 2 or 3 substituents selected from alkyl of 1 to 4 carbon atoms, chlorine and bromine; and R1 is methyl or ethyl; then R4 is not H or methyl.

12. A method for making a compound of the formula XVII, characterized in that a 4,6-dihydroxy-5-nitropyrimidine is reacted with a sulfonic anhydride, arylsulfonyl chloride, alkyl sulfonic anhydride, or alkyl sulfonyl chloride, to produce a compound of the formula XIV, reacting the latter compound with an amine of the formula R3NH2 to produce a compound of the formula XV, reacting this same compound with an arylamine of the formula ArNHR4 to produce the compound of the formula XVI, then treating the latter compound with a reducing agent, as shown in the following scheme: < ? I H N. .OR. »A anphmidarpidu0o O, SOa -R N NHHRFT3 N ^ N ° 2 sulfonic NA * 02 R3 H, JL J NOs k 1 - chloro-ro * j? L N O H .ÍÍSÜ ™. R R11 NN o0S02R ulfón.co so2R n1 K- -N NX "OSOaR XIV XV Ar-NHR4 wherein Ar is phenyl, naphthyl, pyridyl, pyrimidinyl, triazinyl, furanyl, quinolinyl, isoquinolinyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuranyl, benzothienyl, benzthiazolyl, isoxazolyl, or pyrazolyl, each optionally substituted with 1 to 5 groups R5, R is the residue of the hydrocarbon, of aryl or alkyl sulfuric anhydride or sulphonic chloride; R1 is independently in each occurrence H, alkyl of 1 to 4 carbon atoms, alkenyl of 2 to 4 carbon atoms, alkynyl of 2 to 4 carbon atoms, halo, CN, haloalkyl of 1 to 4 carbon atoms, -NR9R10 , NR9COR10, -OR11, SH or -S (0) nR12; R 4 is H, alkyl of 1 to 4 carbon atoms, allyl or propargyl, where alkyl of 1 to 4 carbon atoms, allyl or propargyl is optionally substituted with cycloalkyl of 3 to 6 carbon atoms and where alkyl of 1 to 4 atoms carbon is optionally substituted with -OR7, -S (O) nR12 or -C02R7; R5 is independently at each occurrence alkyl of 1 to 10 carbon atoms, alkenyl of 2 to 10 carbon atoms, alkynyl of 2 to 10 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, cycloalkylalkyl of 4 to 12 carbon atoms, -N02, halo, -CN, haloalkyl of 1 to 4 carbon atoms , and -NR6R7, NR8C0R7, NR8C02R7, -COR7 -OR7, -CONR6R7, -CO (NOR9) R7, C02R7, OS (0) nR7, wherein alkyl of 1 to 10 carbon atoms, alkenyl of 2 to 10 carbon atoms , alkynyl of 2 to 10 carbon atoms, "cycloalkyl of 3 to 6 carbon atoms, and cycloalkylalkyl., of 4 to 12 carbon atoms are optionally substituted with 1 to 3 substituents independently selected in each occurrence from alkyl of 1 to 4 carbon atoms, -N02, halo, -CN, -NR6R7, NRβR7, NR8COR7, NR8C02R7, -COR7 -OR7, -C0NR6R7, C02R7, -C0 (N0R9) R7, or -S (0) nR7; R7 are independently selected at each occurrence of H, alkyl of 1 to 4 carbon atoms, haloalkyl of 1 to 4 carbon atoms, alkoxyalkyl of 2 to 8 carbon atoms, cycloalkyl of "3 to 6 atom carbon, cycloalkylalkyl of 4 to 12 carbon atoms, aryl, aryl (C? -C alkyl) -; heteroaryl or heteroaryl (C? -C4alkyl) -; NR6R7 is pyridine, pyrrolidine, piperazine, N-methylpiperazine, morpholine or thiomorpholine; R8 is independently at each occurrence H or alkyl of 1 to 4 carbon atoms; R9 and R10 are independently in each occurrence selected from H, alkyl of 1 to 4 carbon atoms, or cycloalkyl of 3 to 6 carbon atoms; R11 is H, alkyl of 1 to 4 carbon atoms, haloalkyl of 1 to 4 carbon atoms, or cycloalkyl of 3 to 6 carbon atoms; R 12 is alkyl of 1 to 4 carbon atoms or haloalkyl of 1 to 4 carbon atoms; R 13 is alkyl of 1 to 4 carbon atoms, haloalkyl of 1 to 4 carbon atoms, alkoxyalkyl of 2 to 8 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, cycloalkylalkyl of 4 to 12 carbon atoms, aryl, aryl (C -C4 alkyl) -, heteroaryl or heteroaryl (C? -C alkyl) -; aryl is phenyl or naphthyl, each optionally substituted with l 'to 3 substituents independently selected in each occurrence from alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, halo, haloalkyl of 1 to 4 atoms of carbon, cyano, -OR7, SH, -S (0) nR13, -COR7, C02R7, -CO (0) R13, -NR8COR7, -N (COR7) 2, -NR8CONR6R7, -NR8C02R13, -NR6R7, and - C0NR6R7; heteroaryl is pyridyl, pyrimidinyl, triazinyl, furanyl, quinolinyl, isoquinolinyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuranyl, benzothienyl, benzthiazolyl, isoxazole, pyrazolyl, triazolyl, tetrazolyl, or indazolyl, each substituted optionally with 1 or 3 substituents independently selected at each occurrence from alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, halo, haloalkyl of 1 to 4 carbon atoms, cyano, -OR7, SH, -S (0) nR13, -COR7, -C02R7, -0C (0) R13, -NR8C0R7 '-N (C0R7) 2, -NR8C0NRsR7, -NR8C02R13, -NRSR7, and -CONR6R7; heterocyclyl is saturated or partially saturated heteroaryl, optionally substituted with 1 to 3 substituents independently selected at each occurrence from alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, halo, haloalkyl of 1 to 4 carbon atoms carbon, cyano, -OR7. SH, -S (0) nR13, -COR7, -C02R7, -OC (0) R13, -NR8COR7, -N (C0R7) 2, -NR8CONR6R7, -NR8C02R13. NR6R7. -CONR6R7; n is independently in each occurrence 0, 1 or 2.

13. A compound of the formula XIV or XV: characterized in that: R is the residue of the aryl hydrocarbon or alkyl sulfonic anhydride or sulphonic chloride; R1 is independently in each occurrence H, alkyl of 1 to 4 carbon atoms, alkenyl of 2 to 4 carbon atoms, alkynyl of 2 to 4 carbon atoms, halo, CN, haloalkyl of 1 to 4 carbon atoms, -NR9R10 , NR9COR10, -OR11, SH or -S (0) nR12; R3 is H, alkyl of 1 to 10 carbon atoms, alkenyl of 2 to 10 carbon atoms, alkynyl of 2 to 10 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, or cycloalkylalkyl of 4 to 12 carbon atoms, each optionally substituted with 1 to 3 substituents independently selected in each occurrence from alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, halo, haloalkyl of 1 to 4 carbon atoms, cyano, -OR7 , SH, -S (0) nR13 / -COR7, -C02R7, -0C (0) R13, -NR8COR7, -N (COR7) 2, -NR8CONR6R7, -NR8C02R13, -NR6COR7, -CONR6R7, aryl, heteroaryl and heterocyclyl , wherein the aryl, heteroaryl or heterocyclyl is optionally substituted with 1 to 3 substituents independently selected in each occurrence from alkyl of 1 to 6 carbon atoms, cycloalkyl of 1 to 3 carbon atoms, halo, haloalkyl of 1 to 4 atoms of carbon, cyano, -OR7, SH, -S (0) nR13, -COR7, C02R7, -OC (0) R13, -NR8COR7, -N (C0R7) 2, NR8CONR6R7, -N R8C02R13, -NR6R7, and -CONR6R7; R7 are independently selected at each occurrence of H, alkyl of 1 to 4 carbon atoms, haloalkyl of 1 to 4 carbon atoms, alkoxyalkyl of 2 to 8 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, cycloalkylalkyl of 4 to 12 carbon atoms, aryl, aryl (C? -C alkyl) -; heteroaryl or heteroaryl (C -C 4 alkyl) -; NR6R7 is pyridine, pyrrolidine, piperazine, N-methylpiperazine, morpholine or thiomorpholine; R is independently at each occurrence H or alkyl of 1 to 4 carbon atoms; R9 and R10 are independently in each occurrence selected from H, alkyl of 1 to 4 carbon atoms, or cycloalkyl of 3 to 6 carbon atoms; R11 is H, alkyl of 1 to 4 carbon atoms, haloalkyl of 1 to 4 carbon atoms, or cycloalkyl of 3 to 6 carbon atoms; R 12 is alkyl of 1 to 4 carbon atoms or haloalkyl of 1 to 4 carbon atoms; R 13 is alkyl of 1 to 4 carbon atoms, haloalkyl of 1 to 4 carbon atoms, alkoxyalkyl of 2 to 8 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, cycloalkylalkyl of 4 to 12 carbon atoms, aryl, aryl (C? -C alkyl) -, heteroaryl or heteroaryl (C? -C alkyl) -; it is phenyl or naphthyl, each optionally substituted with 1 to 3 substituents independently selected at each occurrence from alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, halo, haloalkyl of 1 to 4 atoms of carbon, cyano, -OR7, SH, -S (0) nR13, -COR7, C02R7, -CO (0) R13, -NR8COR7, -N (COR7) 2, -NR8CONRsR7, -NR8C02R13, -NR6R7, and - CONRsR7; heteroaryl is pyridyl, pi'rimidinyl, triazinyl, furanyl, quinolinyl, isoquinolinyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuranyl, benzothienyl, benzthiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, or indazolyl, each optionally substituted with 1 or 3 substituents independently selected at each occurrence from alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, halo, haloalkyl of 1 to 4 carbon atoms, cyano, -OR7, SH, - S (0) nR13, -COR7, -C02R7, -OC (0) R13, -NR8COR7 '"N (COR7) 2, -NR8CONR6R7, -NR8C02R13, -NR6R7, and -CONR6R7; heterocyclyl is saturated or partially saturated heteroaryl, optionally substituted with 1 or 3 substituents independently selected in each occurrence from alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, halo, haloalkyl of 1 to 4 carbon atoms, cyano, -OR7. , -S (0) nR13, -COR7, - C02R7, -OC (0) R13, -NR8 COR7, -N (COR7) 2, -NR8CONR6R7, -NR8C02R13. NR6R7. -CONR6R7; n is independently in each occurrence 0, 1 or 2;